Arylalkylheterocyclic amines,N-substituted by aryloxyalkyl group in a method for allergy treatment

A method of inhibiting Type 1 allergic responses in a living animal body with substituted heterocyclic amines is disclosed wherein the active agents are expressed generally by the formula which includes certain known and certain known compounds: ##STR1## wherein P is zero, one or two; m is one to six inclusive; A is selected from hydrogen, hydroxy or cyano; d is zero or one; Q is --CH--, CH.sub.2 -- or ##STR2## n is zero or one and when Q is --CH-- and n is one, a double bond is formed with one of the adjacent carbons but not both at the same time, and when n and d are zero at the same time, a double bond is formed between the .alpha. carbon and a carbon of the central heterocyclic amine ring; Ar, D and R are selected from phenyl, substituted phenyl, pyridinyl, thienyl, furanyl or naphthyl and in addition, R may have the values benzyl, substituted benzyl, cycloalkyl or loweralkyl and D may additionally have the values: 2H-1-benzopyran-2-one,4-oxo-4H-1-benzopyran-2-carboxylic acid loweralkyl ester, 2,3-dihydro-4H-1-benzopyran-4-one, 1,4-benzodioxanloweralkyl-2-yl or 1,1'-biphenyl-4-yl and the pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION 
1. Field of Invention 
This invention relates to a method of inhibiting Type I allergic responses 
(Gell and Coombs classification of Immune Responses) in a living animal 
body with piperidinyl, pyrrolidinyl, and homopiperidinyl derivatives 
substituted on nitrogen by aryloxyalkyl radicals and otherwise substituted 
by aryl (or diaryl)-alkanol, aryl (or diaryl)-alkyl, aryl or (diaryl)cyano 
methyl and aryl (or diaryl)alkylidine radicals. The compounds prevent 
release of histamine and synthesis of 5-lypoxygenase metabolites as well 
as antagonize end organ effects of mediators involved in the immediate 
hypertensivity response and, as such, are useful in treating allergic 
phenomena which includes asthma, rhinitis, atopic dermatitis, chronic 
hives, allergic conjunctivitis, and the like. 
2. Information Disclosure Statement 
Various systemic anti-allergy agents have long been known prior to this 
invention including, among others, aminophylline, theophylline, 
corticosteroids, the disodium salt of 
1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane, 
.alpha.-[(tertbutylamino)methyl]-3,5-dihydroxybenzylalcohol sulfate and 
oxatomide. The efficacy of some has suffered from undesirable side effects 
while others which are effective prophylactically are ineffective in acute 
manifestations of the allergic attack. By way of comparison, for example, 
the preferred compounds of the present invention are many times more 
potent than aminophylline and several times more potent than oxatomide. 
Olefinic-4-substituted piperidino derivatives useful as antihistaminic, 
antiallergy agents and bronchodilators are represented by the formula: 
##STR3## 
are disclosed in U.S. Pat. No. 3,862,173 wherein R represents hydrogen or 
forms a double bond, Y represents --CH.dbd.CH-- and Z represents thienyl, 
phenyl or phenyl substituted by halogen, alkyl, loweralkoxy, 
diloweralkylamino, pyrrolidino, piperidino, morpholino or 
N-loweralkylpiperazino. Compounds useful in the present invention differ 
in that an ether linkage is present and there is no unsaturation in the 
alkyl chain. 
Diphenylmethylenepiperidineacetic acid derivatives useful as antiallergic, 
antihistaminic, and broncholytic agents are disclosed in European Pat. No. 
48705B and have the formula: 
##STR4## 
wherein Y is OH or NR.sub.1 R.sub.2 ; compounds useful in the present 
invention have an aryl group next to the ether oxygen. 
U.S. Pat. No. 3,806,526 discloses 1-aroylalkyl-4-diphenylmethylpiperidines 
having antihistaminic, antiallergenic and bronchodilator activity. In 
contrast, the compounds useful in the present invention have an 
aryloxyalkyl radical on piperidine and pyrrolidine nitrogen rather than an 
aroylalkyl radical. 
A number of the compounds useful in the present method of treating allergy 
have been disclosed specifically and under generic formulas in U.S. Pat. 
Nos. 3,922,276 and 3,956,296 as being useful as antiinflammatory agents, 
tranquilizers and sedatives. These activities are not suggestive of use in 
treating allergy. 
The compound 4-diphenylmethylene-1-benzylpiperidine maleate is disclosed in 
Japanese Kokai No. 62,145,018 to be an antiallergy agent not liberating 
histamine. The compound is not encompassed by Formula I. 
SUMMARY OF THE INVENTION 
The heterocyclic amines useful in the antiallergy method of this invention 
are disubstituted and have the general formula: 
##STR5## 
wherein: P is zero, one or two; 
m is one to six inclusive; 
A is hydrogen, hydroxy, or cyano; 
d is zero or one; 
Q is --CH--, --CH.sub.2 -- or 
##STR6## 
n is zero or one; and when Q is --CH-- and n is 1, a double bond is formed 
with one of the adjacent carbons, but not both, and when n and d are zero 
at the same time, a double bond is formed between the .alpha.-carbon and a 
carbon of the central heterocyclic amine ring; 
Ar, D and R are selected from the group consisting of: 
##STR7## 
and in addition, R may have the values: 
##STR8## 
cycloalkyl or lower alkyl; and D may have additionally the values: 
##STR9## 
or AR(CH.sub.2).sub.1-4 --; X, Y, and Z are selected from the group 
consisting of hydrogen, loweralkyl, halogen, 
##STR10## 
R.sup.1, R.sup.2 and R.sup.3, same or different, are selected from 
hydrogen, loweralkyl, phenyl and phenylloweralkyl; R.sub.4 is selected 
from loweralkyl, phenyl and phenylloweralkyl; M is a pharmaceutically 
acceptable metal ion, and the pharmaceutically acceptable salts thereof, 
including acid addition salts, quaternary salts and hydrates and 
alcoholates thereof. 
In the further definition of symbols in the formulas hereof and where they 
appear elsewhere throughout this specification and in the claims, the 
terms have the following significance. 
The term "loweralkyl" as used herein, unless otherwise specified, includes 
straight and branched chain radicals of up to eight carbons inclusive and 
is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, 
sec-butyl, tert-butyl, amyl, isoamyl, hexyl, heptyl, and octyl radicals 
and the like. The term "loweralkoxy" has the formula --O--loweralkyl. The 
term "lowerhydroxyalkanyl" refers to loweralkyl radicals carrying a 
hydroxy radical. 
The term "cycloalkyl" as used herein includes primarily cyclic alkyl 
radicals containing 3-7 carbon atoms inclusive and includes such groups as 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 
methylcyclohexyl and the like. 
The term "halo" or "halogen" when referred to herein includes fluorine, 
chlorine, bromide and iodine unless otherwise stated. 
The term "central heterocyclic amine ring" refers to that portion of 
Formula I represented by 
##STR11## 
The term "phenylloweralkyl" includes phenyl connected by hydrocarbon chains 
exemplified by loweralkyl above and wherein phenyl may be substituted by 
nonreactive or noninterfering radicals such as halo, loweralkyl, 
loweralkoxy, and the like. 
"Pharmaceutically acceptable salts" include acid addition salts, hydrates, 
alcoholates and quaternary salts of the compounds of Formula I which are 
physiologically compatible in warm-blooded animals. The acid addition 
salts may be formed by either strong or walk acids. Representative of 
strong acids are hydrochloric, hydrobromic, sulfuric, and phosphoric 
acids. Representative of weak acids are fumaric, maleic, mandelic, 
tartaric, citric, oxalic, succinic, hexamic, and the like. Suitable 
quaternary salts include and the loweralkyl halides and loweralkyl 
sulfates. 
The primary screening method used to detect antiallergy properties of the 
compounds of Formula I is a modification of the procedure of R. R. Martel 
and J. Klicius, Intern. Arch. Allergy Appl. Immunology, vol. 54, pp. 
205-209 (1977) which measures the effect of oral administration of the 
compound on the volume of a rat paw which was previously injected with 
anti-egg albumin serum and is described in detail under Pharmacology 
Methods hereinbelow. 
A method of studying potency in preventing guinea pig anaphylaxis relative 
to known antiallergy drugs is also described hereinbelow under 
Pharmacology Methods. Generally, about 200 times more theophylline and 
5-15 times more oxatomide are required than the more active compounds used 
in the present method. 
The Gell and Coombs Classification of Immune Responses referred to 
hereinabove is well known in the art and is described in ESSENTIAL 
IMMUNOLOGY 3rd Ed (1977), (Blackwell Scientific Publications) printed by 
William Clowers & Sons, Limited, London, Beccles & Colchester. 
DETAILED DESCRIPTION OF THE INVENTION 
Antiallergy agents of Formula I above useful in the method of treating 
allergy of this invention may be prepared by methods described in U.S. 
Pat. Nos. 3,922,276 and 4,032,642. One of the general methods used in the 
detailed examples hereinbelow is outlined by equation in Chart I (Method 
A). This reaction can be carried out in alcoholic solvents, preferably 
refluxing butanol or in dimethylformamide, dimethoxyethane in the presence 
of an acid receptor as, for example, an alkali-metal carbonate, and 
preferably using potassium iodide catalyst. The reaction time may vary 
from a few hours to 24 hr, depending on reactivity of the aryloxyalkyl 
halide and temperature. Temperature can vary from about 80.degree. C. to 
145.degree. C. Products are isolated, usually by partitioning in a solvent 
such as methylene chloride, chloroform or benzene and the like and a weak 
basic aqueous solution and washing, drying and concentrating the organic 
layer to give the free base which may then be converted, if desired, to an 
acid addition salt in a conventional manner. 
Alternate Method B is shown by equation in Chart II. This reaction may be 
carried out in a suitable solvent such as tetrahydrofuran at room 
temperature for several hours. Preparation and isolation of the free base 
and a salt is typically described in Example 4. 
Alternate Method C is shown by equation in Chart III. This reaction is 
suitable only when there is no other hydroxy radical present. 
Mesylation or tosylation with such as mesyl or tosyl chloride is conducted 
in the presence of an acid receptor such as a tertiary amine; e.g., 
triethylamine, while cooling. The final reaction of the mesylate or 
tosylate with the D--OM.sup.+ is conducted in a suitable organic solvent 
and the product free base is isolated by conventional means such as 
washing, extracting with an acid solution and an organic solvent and 
evaporating the solvent. 
Alternate Method D is shown by equation in Chart IV. The method is limited 
to preparation of certain derivatives such as wherein D is 2-pyridinyl or 
2-quinolinyl. Dimethyl sulfoxide is a suitable solvent and 60.degree. C. 
is a suitable temperature for the reaction. 
##STR12## 
To prepare acid addition salts, the free base is reacted with the 
calculated amount or organic or inorganic acid in aqueous miscible solvent 
such as ethanol or 2-propanol, with isolation by concentrating and/or 
cooling, or the base is reacted with an excess of the acid in aqueous 
immiscible solvent such as diethyl ether or 2-propyl ether, with the 
desired salt separating directly. Exemplary of such organic salts are 
those formed with oxalic, maleic, fumaric, benzoic, ascorbic, pamoic, 
succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, 
malic, citraconic, itaconic, hexamic, p-aminobenzoic, glutamic and stearic 
acid and the like. Exemplary of such inorganic salts are those formed with 
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric 
acids. 
If desired, the free base may be regenerated by proportioning the acid 
addition salt between an organic solvent such as methylene chloride and a 
wealky basic aqueous solution of, for example, sodium bicarbonate and 
separating the methylene chloride layer and evaporating it. 
While, as stated above, the compounds of Formula I have generally exhibited 
positive antiallergy utility, certain compounds encompassed by Formula I 
are more potent and therefore preferred and have the formula: 
##STR13## 
wherein p is zero or one; Ar, R, m and D have the values assigned under 
Formula I, and the pharmaceutically acceptable acid salts thereof. 
Precursors (Chemical Intermediates) used in the synthesis of compounds of 
Formula I are prepared in a number of ways as illustrated by the following 
(1) to (9) sets of equations which are also applicable to pyrrolidinyl and 
homopiperidinyl derivatives. (See also U.S. Pat. Nos. 3,922,276 and 
3,956,296): 
##STR14## 
The method of preparation of certain starting materials wherein D is phenyl 
substituted by hydroxy is illustrated by the following equations: 
##STR15## 
The preparation of other hydroxyphenyl intermediates and compounds is 
illustrated by the following equation: 
##STR16## 
The preparation of certain substituted phenol starting materials is 
illustrated by the following equations:

The preparation of chemical intermediates is further illustrated in the 
following Preparations 1 to 158. Examples 1 to 188 illustrate the 
synthesis methods for preparing compounds of Formula I. The scope of the 
invention is not limited by the descriptive methods and procedures of the 
preparations and examples, however. 
PREATION 1 
4-Diphenylmethylenepiperidine 
A solution of 7.0 g of 1-acetyl-4-diphenylhydroxymethylpiperidine in 30 ml 
of absolute alcohol and 76 ml of concentrated hydrochloric acid was heated 
at reflux for seven hours, cooled and made basic with 50% sodium 
hydroxide. The oil which separated was extracted with benzene and the 
combined extracts washed with water. After drying over magnesium sulfate 
the solvent was evaporated at reduced pressure. The residual oil which 
crystallized on cooling was recrystallized twice from petroleum ether to 
give 4.0 g (73.0%) of white crystals, m.p. 85.degree.-86.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.19 N: C,86.70; H, 7.68; N, 5.62. 
Found: C,86.70;H, 7.83;N, 5.73. 
PREATION 2 
[.alpha.,.alpha.-Bis(p-fluorophenyl)]-4-piperidinemethanol hydrochloride 
hydrate [1:1:0.5] 
This compound was prepared by the method described in Preparation 1 of U.S. 
Pat. No. 4,032,642, m.p. 243.degree.-243.5.degree. C. from the Grignard 
reagent formed with p-flurobromobenzene and 
1-acetyl-4-(p-flurobenzoyl)piperidine followed by hydrolysis and 
conversion to the salt. 
PREATION 3 
1-(Phenylmethyl)-4-piperidinecarboxylic acid ethyl ester hydrochloride [1:1 
] 
1-(Phenylmethyl)-4-piperidinecarboxylic acid ethyl ester hydrochloride 
[1:1] 
A mixture of 100 g (0.637 mole) of ethyl isonipecotate, 80.64 g (0.64 mole) 
of benzyl chloride and 67.84 g (0.64 mole) of sodium carbonate in 1 liter 
of absolute ethanol was heated at reflux for 8 hours and then was stirred 
at room temperature for 10 hours. The solvent was removed in vacuo, and 
the residue was partitioned between methylene chloride and dilute sodium 
hydroxide. The methylene chloride phase was dried over magnesium sulfate 
and the solvent was removed in vacuo to give the free base of the title 
compound as a liquid. The free base was converted to the hydrochloric acid 
salt, and the salt was recrystallized from ethanol-ether to give 89.33 g 
(49.7%) of white, crystalline solid, m.p. 154.degree.-155.degree. C. 
Analysis: Calculated for C.sub.15 H.sub.22 ClNO.sub.2 : 
C,63.48;H,7.81;N,4.94. Found: C,63.07;H,7.82;N,4.91. 
PREATION 4 
.alpha.,.alpha.-Bis-(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol 
To a 6.08 g (0.25 mole) of magnesium turnings and an iodine crystal in 600 
ml of dry tetrahydrofuran and under an atmosphere of nitrogen was added, 
dropwise, a solution of p-bromofluorobenzene in 125 ml of tetrahydrofuran. 
The temperature of the reaction was kept below 10.degree. C. by cooling in 
an ice-methanol bath. The mixture was stirred at room temperature for 1.5 
hours. A solution of 24.7 g (0.10 mole) of 
1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester in 
tetrahydrofuran was added, and the mixture was stirred at room temperature 
for 17 hours. The reaction was poured into an icy, aqueous solution of 
ammonium chloride, and the resulting solution was extracted with methylene 
chloride. The methylene chloride solution was extracted with dilute sodium 
hydroxide and was dried over magnesium sulfate. The solvent was removed in 
vacuo to give an oil. This was crystallized from ether-hexane to give 
19.87 g (51%) of the title compound, m.p. 113.degree.-15.degree. C. 
Analysis: Calculated for C.sub.25 H.sub.25 F.sub.2 NO: C, 76.31;H, 
6.40;N,3.56. Found: C,76.24;H,6.38;N,3.50. 
PREATION 5 
[.alpha.,.alpha.-Bis(p-fluorophenyl)]-4-piperidinemethanol 
A solution of 31.2 g (0.079 mole) of 
.alpha.,.alpha.-bis-(4-fluorophenyl)-1-(phenylmethyl)4-piperidinemethanol 
in 400 ml of absolute ethanol was hydrogenated at 50 psi and 70.degree. C. 
over 5% palladium on carbon over the weekend. The mixture was filtered and 
the filtrate was concentrated under reduced pressure to give a gum as 
residue. Methylene chloride was added to the residue and the gum 
crystallized. The mixture was diluted with petroleum ether and the solid 
was collected by filtration, washed with petroleum ether, and dried to 
yield 22 g (92%) of white solid which was recrystallized from 2-propyl 
ether/2-propanol, m.p. 159.5.degree.-160.5.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.19 F.sub.2 NO: C,71.27;H, 
6.31;N,4.62. Found: C,70.93;H,6.71N,4.38. 
PREATION 6 
1-(phenylsulfonyl)-4-piperidinecarboxylic acid, ethyl ester. 
To a solution of 10.1 g (0.0642 mole) of ethyl isonipecotate in 300 ml of 
pyridine and cooled in an ice bath was added 13.2 g (0.075 mole) of 
benzene sulfonyl chloride. The mixture was stirred for 2 hours at room 
temperature, and the solvent was removed in vacuo. The residue was 
partitioned between methylene chloride and dilute sodium hydroxide. The 
methylene chloride solution was dried over magnesium sulfate, and the 
solvent was removed in vacuo to give a solid. This was recrystllized from 
ethanol-ether to give 4.59 g (24.1%) of crystalline solid; m.p. 
85.degree.-86.degree. C. 
Analysis: Calculated for C.sub.14 H.sub.19 NO.sub.4 S: 
C,56.55;H,6.44N,4.71. Found: C,56.53;H,6.55;N,4.67. 
In another preparation, 100 g (0.634 mole) of ethyl nipecotate and 130.4 g 
(0.74 mole) of benzene sulfonyl chloride were reacted by the above 
procedure for 4.5 hr to give the title product in 78.1% yield. 
PREATION 7 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol 
To a suspension of 33.78 g (1.39 mole) of magnesium trimmings in 1 liter of 
tetrahydrofuran (dried over molecular sieves 5A) under an atmosphere of 
nitrogen and cooled in an ice bath was added dropwise a solution of 243.25 
g (1.39 mole) of p-bromoflurobenzene in 150 of tetrahydrofuran. The 
mixture was stirred for 2 hr after the addition was completed. To this 
mixture was added 103 g (0.346 mole) of 
1-(phenylsulfonyl)-4-piperidinecarboxylic acid ethyl ester as a solid, and 
the solution was stirred at ambient temperature for 5 hr. The reaction 
mixture was poured into an icy aqueous solution of ammonium chloride. The 
phases was separated, and the solvent was removed in vacuo from the 
organic phase. The residue was partitioned between methylene chloride and 
dilute sodium hydroxide. The methylene chloride solution was dried over 
magnesium sulfate and was reduced in vacuo to .perspectiveto.1 liter 
volume. The title compound was obtained by adding hexane and cooling, 
recrystallizing and the precipitate from ethyl acetate and hexane and 
drying the solid under high vacuum at 130.degree. C. for 45 min at which 
time the product had partially melted, m.p. 142.5.degree.-144.degree. C. 
Analysis: Calculated for C.sub.24 H.sub.23 F.sub.2 NO.sub.3 S: 
C,65.00;H,5.23:N,3.16. Found: C,65.21;H,5.30;N,3.10. 
PREATION 8 
4-[Bis(4-fluorophenyl)methylene]-1-(phenylsulfonyl)piperidine 
A solution of 5.23 g (0.0118 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethano 
l in 100 ml of acetic acid and 20 ml of 2M sulfuric acid was heated at 
reflux for 2.5 hours and then poured over ice. The mixture was made basic 
with 50% sodium hydroxide and the basic mixture was extracted with 
methylene chloride. The methylene chloride solution was dried (anhydrous 
sodium sulfate), and the solvent was removed in vacuo. The residue was 
recrystallized from ether-hexane to give 3.23 g (64.4%) of white, 
crystalline, solid, m.p. 90.degree.-92.5.degree. C. 
Analysis: Calculated for C.sub.24 H.sub.21 F.sub.2 NO.sub.2 S: 
C,67.75;H,4.98;N,3.29. Found: C,67.73;H,500;N,3.21. 
PREATION 9 
4-[Bis(4-fluorophenyl)methylene]piperidine hydrobromide [1:1] 
A mixture of 164 g (0.342 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethano 
l and 80 g (80 g) of phenol in 700 ml of 48% hydrobromic acid was heated at 
reflux for 7 hr and then was stirred at room temperature for 9 hr. The 
hydrobromic acid solution was decanted from a gum in the bottom of the 
reaction flask. The gum was triturated with .about.1 liter of ether, and a 
tan solid formed. The solid was washed with several portions of ether and 
was dried under high vacuum to give 9.13 g (73%) of slightly impure title 
product, m.p. 211.degree.-215.degree. C. A small sample of this solid was 
recrystallized from methanol to give an analytically pure sample as a 
crystalline solid; m.p. 216.degree.-218.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.18 BrF.sub.2 N: 
C,59.03;H,4.95;N,3.82. Found: C,58.96;H,4.98;N,3.76. 
PREATION 10 
4-[Bis(4-fluorophenyl)methyl]piperdine fumarate hydrate [1:0.5:0.5] 
A mixture of 30.6 g (0.99 mole) of phosphorus and 15.1 g (0.059 mole) of 
iodine in 90 ml of glacial acetic acid was stirred for 20 min at room 
temperature. A mixture of 6 ml of water, 70 ml of methanesulfonic acid, 
56.19 g (0.197 mole) of 4-[bis(4-fluorophenyl)methylene]piperidine and 110 
ml of glacial acetic acid was added, and the mixture was heated at reflux 
for 7 hr. The solvent was removed in vacuo, and the resulting viscous 
liquid was poured over ice. The icy mixture was made basic with 50% sodium 
hydroxide, and the basic suspension was extracted with methylene chloride. 
The methylene chloride solution was extracted with an aqueous solution of 
sodium thiosulfate and was dried over anhydrous sodium sulfate, and the 
solution was filtered through Celite.RTM.. The solvent was removed in 
vacuo to give a gum. The gum was dissolved in 400 ml of hot methanol, and 
4.25 g of an unknown tan solid was collected from the warm solution. 
Fumaric acid (22 g, 0.190 mole) was added to the methanolic solution 
followed by the addition of ether. A white precipitate was collected to 
give 22.55 g (32.3%) of crystalline solid; m.p. 208.degree. -209.degree. 
C. 
Analysis: Calculated for C.sub.20 H.sub.21 F.sub.2 NO.sub.2.0.5H.sub.2 O: 
C,67.78;H,6.26;N,3.95. Found: C,67.78;H,6.26;N,3.95. 
PREATION 11 
4-[.alpha.-(p-Fluorophenyl)-.alpha.-phenylmethyl]piperidine hydrochloride 
[1:1] 
This compound was prepared as described in U.S. Pat. No. 4,032,642 by 
hydrogenation of .alpha.-(p-flurophenyl)benzylidinepiperidine over 
palladium charcoal catalyst, m.p. 81.degree.-82.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.21 ClFN: C,70.69;H,6.92;N,4.58. 
Found: C,70.69;H,6.93;N,4.52. 
PREATION 12 
1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone 
To a mixture of 15.15 kg (96.26 mole) of 1-bromo-3-chloropropane and 25 
liter of water heated to 86.degree. C. was added a solution of 8 kg (48.13 
mole) of acetovanillone in 3.93 kg (48.6 mole) of 50% aqueous sodium 
hydroxide and 89 liter of water over a 2.5 hr period. The mixture was 
heated at 80.degree.-85.degree. C. for 2.5 hr after addition was complete. 
The mixture was cooled and extracted twice with 49 kg portions of toluene. 
The combined extracts were washed once with 1.9 kg of 50% sodium hydroxide 
diluted to 5 gal and once with 5 gal of water. The toluene layer was dried 
over 3 lb of anhydrous sodium sulfate and concentrated under reduced 
pressure. The residue was heated to reflux in 15 gal of isopropylether, 
filtered, and the filtrate cooled. The crystallized title compound 
obtained by filtration together with additional compound obtained by 
concentrating the filtrate to 25% of its original volume amounted to 4.2 
kg (36%). Acetovanillone recovered was 3.4 kg. The product was 
recrystallized twice from cyclohexane and twice from ligroin, m.p. 
57.8.degree.-58.5.degree. C. 
analysis: Calculated for C.sub.12 H.sub.15 ClO.sub.3 : C,59.39;H,6.23. 
Found: C,59.07;H,6.22. 
PREATION 13 
1-(3-Phenoxypropyl)-4-piperidinecarboxylic acid ethyl ester oxalate [1:1] 
A mixture of ethyl isonipecotate (35.5 g 0.226 mole) 
3-phenoxy-1-bromopropane (51.6 g, 0.24 mole) and sodium carbonate (25.4 g, 
0.24 mole) in 500 ml of absolute ethanol was heated at reflux for 16 hr. 
The solvent was removed in vacuo, and the residue was partitioned between 
methylene chloride and dilute sodium hydroxide. The solution was dried 
over anhydrous sodium sulfate and the solvent was removed in vacuo to give 
a liquid. The liquid was dissolved in absolute ethanol, and a solution of 
oxalic acid (.about.0.23 mole) in absolute ethanol was added. The product 
73.43 g (87.7%) precipitated as a white, crystalline solid, m.p. 
180.degree.-181.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.27 NO.sub.7; C, 59.83;H,7.14N,3.67. 
Found: C,59.76;H,7.17;N,3.64. 
PREATION 14 
4-[Bis(4-fluorophenyl)methylene]-1-(phenylmethyl)piperidine maleate [1:1] 
A mixture of 
.alpha.-.alpha.-bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol 
(5.09 g, 0.013 mole) in 200 ml of 2M sulfuric acid was heated at reflux 
for 2 hr. The solvent was removed in vacuo, and the residue was 
partitioned between methylene chloride and dilute sodium hydroxide. The 
methylene chloride solution was dried over magnesium sulfate and the 
solvent was removed in vacuo to give the free base of the title compound 
as a solid. The free base was dissolved in methanol-ethylether and maleic 
acid (excess) was added. The product 5.24 g (82.1%) precipitated as a 
white, crystalline solid, m.p. 180.degree.-181.5.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.27 F.sub.2 NO.sub.4 : 
C,70.86;H,5.54;N,2.85. Found: C,70.80;H,5.45;N,2.79. 
PREATION 15 
.alpha.-.alpha.Bis(4-fluorophenyl)-4-pyridinemethanol 
The Grignard reagent was prepared from 4-bromofluorobenzene (66.6 g, 0.381 
mole) and magnesium (9.13 g, 0.381 mole) in tetrahydrofuran (ice bath). 
The Grignard reagent was stirred at room temperature for 1.5 hr and 
transferred (under nitrogen) to an addition funnel. This solution was 
added dropwise to a tetrahydrofuran solution of ethyl isonicotinate (25.0 
g, 0.165 mole) (ice bath cooling). The reaction mixture was stirred 3 hr 
at room temperature and poured onto ice containing ammonium chloride (28 
g, 0.5 mole). The mixture was allowed to stand overnight. The reaction 
mixture was diluted to 3 liter with water and extracted with chloroform. 
The chloroform layer was back extracted with dilute sodium hydroxide. 
Removal of chloroform gave a gummy brown solid. The brown solid was 
triturated with methanol-ethyl ether (10-120 v/v) and placed in the 
refrigerator freezer. Solid was collected by filtration and dried 
overnight in vacuo at 80.degree. C. to give 11.86 g (24%) of white, 
crystalline produce, m.p. 185.degree.-189.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.13 F.sub.2 NO: 
C,72.72;H,4.41;N,4.71 Found: C,72.76;H,4.39;N4.67. 
PREATION 16 
4-[Bis(4-Fluorophenyl)methyl]--1-(phenylmethyl)piperidine, fumarate [1:1] 
A mixture of 4.3 g (0.139 mole) of phosphorus, 44 g (0.196 mole) of a 75% 
aqueous solution of hydrogen iodide and 4.15 g (0.0106 mole) 
4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)piperidine in 60 ml of 
glacial acetic acid was heated at reflux for 1 hr. The mixture was poured 
over ice and was made with 50% sodium hydroxide. The aqueous mixture was 
extracted with methylene chloride. The methylene chloride solution was 
extracted with an aqueous solution of sodium sulfite and was dried over 
magnesium sulfate. The solvent was removed in vacuo to give 8.89 g (89%) 
of the free base of the title compound. The free base was converted to the 
fumarate salt, and the salt was recrystallized from methanol-ether to give 
3.62 g (69.3%) white solid; m.p. 201.degree.-202.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.29 F.sub.2 NO.sub.4 : 
C,70.57;H,5.92;N,2.84. Found: C,70.69;H,5.95;N,2.81. 
PREATION 17 
4-(2-Chloroethoxy)benzoic acid ethyl ester 
A mixture of 71.7 g (0.5 mole) of 1-bromo-2-chloroethane, 83.1 g (0.5 mole) 
of ethyl p-hydroxybenzoate and 69.1 g (0.5 mole) of potassium carbonate in 
200 ml of acetone was heated at reflux for 40 hr. The solids were removed 
by filtration and the filtrate was evaporated under reduced pressure to 
leave a semi-solid residue. The residue was triturated with 200 ml of 5% 
sodium hydroxide solution and filtered..sup.1 The filter cake was washed 
with water (100 ml) and dried to give 42.4 g (80%).sup.2 of a solid. A 
sample was recrystallized from benzene-petroleum ether 
(30.degree.-60.degree. C.) to give white solid, m.p. 74.degree.-76.degree. 
C. 
FNT .sup.1 The filtrate pH was adjusted to 2 with concentrated hydrochloric 
acid. The resulting solid was collected by filtration, washed with water 
(100 ml) and dried to give 44.4 g of ethyl p-hydroxybenzoate. 
FNT .sup.2 The yield is based on unrecovered starting material. 
Analysis: Calculated for C.sub.11 H.sub.13 ClO.sub.3 : C,57.78;H,5.73. 
Found: C,57.87;H,5.82 
PREATION 18 
1-[4-(2-Chloroethoxy)-3-methoxyphenyl]ethanone 
To a solution of 12.7 g (0.55 mole) of sodium metal in 750 ml of absolute 
ethanol was added 83.1 g (0.5 mole) of acetovanillone to give a slurry. 
This slurry was then added over a 3-hr period to a solution of 107.6 g 
(0.75 mole) of 1-bromo-2-chloroethane in 500 ml of absolute ethanol at 
reflux. An additional 250 ml of ethanol was used to wash the slurry into 
the reaction mixture. The mixture was heated at reflux overnight and then 
concentrated under reduced pressure to give a solid as residue. The solid 
was partitioned between 1 liter of benzene and 1 liter of water. The 
aqueous layer was extracted with 500 ml of benzene and the combined 
organic layers were washed successively with three 200 ml portions of a 5% 
sodium hydroxide solution, once with water and once with brine. The 
benzene solution was dried over anhydrous sodium sulfate and concentrated 
under reduced pressure to give an oil which gradually crystallized. The 
solid was triturated with petroleum ether, collected by filtration and 
recrystallized from 2-propanol to yield 48.5 g (42%) of off-white solid. 
An analytical sample was prepared from isopropyl ether, m.p. 
69.degree.-71.degree. C. 
Analysis: Calculated for C.sub.11 H.sub.13 ClO.sub.3: C, 57.78;H,5.73. 
Found: C,57,55;H,5.74. 
PREATION 19 
1-[4-(4-Bromobutoxy)-3-methoxyphenyl]ethanone 
to a warm solution of 12.7 g (0.55 mole) of sodium metal in 500 ml of 
absolute ethanol was added a slurry of 83.1 g (0.5 mole) of acetovanillone 
in 250 ml of absolute ethanol. All solids dissolved and then a solid 
precipitated. The mixture was stirred at ambient temperature for 1 hr and 
then added over a 3-hr period to a solution at reflux of 177 g (0.82 mole) 
of 1,4-dibromobutane in 500 ml of absolute ethanol. After addition was 
complete, the mixture was heated at reflux overnight. The mixture was 
concentrated under reduced pressure and the residue was partitioned 
between 1.5 liter of benzene and 1 liter of water. The mixture was 
filtered to remove undesirable insoluble material. The filtrate layers 
were separated and the organic layer was washed with four 300 ml portions 
of a 5% sodium hydroxide solution once with water and once with brine, 
dried over anhydrous sodium sulfate and concentrated under reduced 
pressure to give 138 g of gummy solid as residue. This solid was purified 
by column chromatography on 1 kg of silica gel, eluting with 2% 
ethylacetate in benzene to yield 69.6 g (46%) of title compound as an 
off-white solid. The solid was recrystallized from isopropyl ether, m.p. 
52.degree.-54.degree. C. 
Analysis: Calculated for C.sub.13 H.sub.17 BrO.sub.3 : C,51.84;H,5.69. 
Found: C,52.03;H,5.76. 
PREATION 20 
4-Diphenylmethyl)pyridine 
A mixture of 99 (0.379 mole) of diphenyl-4-pyridylmethanol, 50 ml of conc. 
hydrochloric acid, 200 ml of 57% hydroiodic acid and 200 ml of glacial 
acetic acid was heated at reflux for 4.5 hr and then was stirred at room 
temperature for 12 hr. The reaction mixture was poured over ice and was 
made basic with 50% hydroxide. An aqueous solution of sodium thiosulfate 
was added, and the mixture was extracted with methylene chloride. The 
methylene chloride solution was dried over magnesium sulfate and the 
solvent was removed in vacuo. The residue was recrystallized from a 
mixture of methylene chloride-ether-hexane to give two crops of 
crystalline solids: Crop I,40.87 g (44.0%),m.p. 124.degree.-126.degree. 
C.; Crop II, 25.38 g (27.3%), m.p. 123.degree.-125.degree. C. Analysis of 
the mixture of the Crops I and II was as follows: 
Analysis: Calculated for C.sub.18 H.sub.15 N: C,88.13;H,6.16;N,5.71. Found: 
C,87.67;H,6.01;N,5.56. 
1-(3-Chloropropoxy)-4-methoxybenzene 
A solution of sodium hydroxide 20.0 (0.5 mole) in 300 ml of water and 
p-methoxyphenol, 62.1 g (0.5 mole) in 300 ml of dioxane was stirred for 1 
hour at room temperature. 1-Chloro-3-bromopropane (472.35 g, 3.0 mole) in 
100 ml of dioxane was added, and the reaction mixture was stirred 
overnight at 80.degree. C. The lower layer was separated and the aqueous 
layer extracted with hexane. The lower layer and hexane layer were 
combined, dried, and solvent was removed in vacuo. The residue was 
dissolved in chloroform and extracted with 5% sodium hydroxide; removal of 
chloroform by evaporation gave a yellow oil. A 10-g sample of the oil was 
subjected to column chromatography on silica gel with an elution series 
composed of hexane-methylene chloride-methanol. This furnished 9.64 g 
(79.3% based on the aliquot taken) of pure clear oil. 
Analysis: Calculated for C.sub.10 H.sub.13 ClO.sub.2 : C,59.86;H,6.53. 
Found: C,59.39;H,6.56. 
PREATION 22 
1-[4-(3-Chloropropoxy)phenyl]ethanone 
The sodium salt of p-hydroxyacetophenone was prepared in 200 ml of 
dioxane-400 ml of water from p-hydroxyacetophenone 68.08 g (0.5 mole) and 
sodium hydroxide 20.0 g, (0.5 mole). The reaction mixture was stirred 3/4 
hr at room temperature. Next, chlorobromopropane, 472.35 g (3.0 mole) was 
added along with 200 ml of dioxane and the mixture was heated at 
80.degree.-90.degree. C. overnight with stirring. The mixture was diluted 
to 4 liters with water; the aqueous phase was extracted with hexane and 
chloroform. These were combined and back extracted with 5% sodium 
hydroxide. The solvent was removed in vacuo with heating. A 10-g sample of 
the oil was subject to column chromatography on silica gel using 
hexane-methylene chloride-methanol. Fractions with similar TLCs were 
combined and solvent removed. The oil from the column did not analyze, 
therefore a short-path bulb-bulb distillation was carried out. This 
produced 4.38 g (37.9%) of clear oil. 
Analysis: Calculated for C.sub.11 H.sub.13 ClO.sub.2 : C,62.12;H,6.16. 
Found: C,61.70;H,6.17. 
______________________________________ 
.sup.1 H NMR(CDCL.sub.3) Analysis: 
______________________________________ 
.delta.8.1 doublet aromatic portons 
2H 
.delta.6.8-7.0 
doublet aromatic portons 
2H 
.delta.4.1-4.3 
triplet CH.sub.2 2H 
.delta.3.6-3.8 
triplet CH.sub.2 2H 
.delta.2.5 singlet 
##STR18## 2H 
.delta.2-2.4 
triplet CH.sub.2 2H 
______________________________________ 
PREATION 23 
4-(Diphenylmethyl)piperidine hydrochloride [1:1] 
A mixture of 62.69 g (0.256 mole) of diphenyl-4-pyridylmethane and 6.4 g of 
10% palladium on carbon (0.0060 mole) in 300 ml of glacial acetic acid and 
under an atmosphere of hydrogen (44 psi) was shaken on a Parr apparatus at 
865.degree. for 4 days. The reaction mixture was filtered, and the solvent 
was removed in vacuo from the filtrate. The residue was partitioned 
between methylene chloride and dilute sodium hydroxide. The methylene 
chloride solution was dried over magnesium sulfate, and the solvent was 
removed in vacuo to give a solid. This was dissolved in a mixture of 
methanol-acetonitrile, and excess ethereal hydrogen chloride was added. A 
precipitate was collected to give 59.13 g (80.3%) of slightly impure title 
compound as a white, crystalline solid, m.p. 273.degree.-274.degree. C. 
Part of this was recrystallized from methanol-ether to give an 
analytically pure sample, m.p. 275.5.degree.-277.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.22 ClN: C, 75.11; H, 7.70; N, 4.87. 
Found: C, 75.03; H, 7.73; N, 4.93. 
PREATION 24 
.alpha.-(4-Fluorophenyl)-.alpha.-phenyl-4-pyridinemethanol 
To a suspension of 18.5 g (0.761 mole) of magnesium turnings and several 
crystals of iodine in 800 ml of anhydrous ether, cooled in an ice bath and 
under an atmosphere of argon was slowly added a solution of 
p-bromofluorobenzene in 200 ml of ether. The solution was stirred for 2 hr 
at 25.degree. C. and 97.02 g (0.530 mole) of 4-benzoylpyridine was added 
as a solid. An additional 1 liter of anhydrous ether was added, and the 
solution was stirred at 25.degree. C. for 3 hr. The reaction mixture was 
poured into an icy, aqueous solution of ammonium chloride. The mixture 
stood in the hood overnight and a white solid was collected. The solid was 
dissolved in a mixture of methanol-methylene chloride. The solution was 
filtered and the solvent was removed in vacuo. The residue was 
crystallized from chloroform-hexane to give 66.68 g (45%) of title 
compound as a white, crystalline solid, m.p. 189.degree.-192.degree. C. 
Part of this was recrystallized from methylene 
chloride-acetonitrile-hexane, m.p. 190.degree.-192.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.14 FNO: C, 77.40; H, 5.05; N, 5.02. 
Found: C, 77.24; H, 5.03; N, 4.90. 
PREATION 25 
.alpha.,.alpha.-Bis(4-chlorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol 
Following the procedure of Preparation 7, but substituting 
p-bromochlorobenzene for p-bromofluorobenzene, the title compound was 
prepared. 
PREATION 26 
4-[Bis(4-chlorophenyl)methylene]piperidine hydrobromide hydrate [1:1:1] 
A mixture of 69.33 g (0.146 mole) of 
.alpha.,.alpha.-bis(4-chlorophenyl)-1-(phenylsulfonyl)-4-piperidinemethano 
l and 26 g (0.277 mole) of phenol in 400 ml of 48% hydrobromic acid was 
heated at reflux for 6 hr and then was stirred at room temperature for 10 
hr. The reaction solution was decanted from a gum which had formed in the 
bottom of the reaction flask. The gum was washed with several portions of 
water and then was crystallized from ether to give a solid. The solid was 
recrystallized from a mixture of methanol-diethyl ether to give 26.52 g 
(43.6%) of white, crystalline solid, m.p. 106.degree.-109.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.20 BrCl.sub.2 N: C, 51.83; H, 4.83; 
N, 3.36. Found: C, 52.13; H, 4.62; N, 3.38. 
PREATION 27 
1-Chloro-4-(3-chloropropoxy)benzene 
A mixture of 77.2 g (0.60 mole) of p-chlorophenol, 189 g (1.2 mole) of 
1-bromo-3-chloropropane, 249 g (1.8 mole) of anhydrous potassium 
carbonate, and 600 ml of acetone was stirred vigorously and heated to 
reflux for 16 hr under a nitrogen atmosphere. The potassium carbonate was 
removed by suction filtration, and the acetone and excess 
bromochloropropane were removed by heating under reduced pressure. The 
residue was dissolved in petroleum ether, and the resulting solution was 
cooled in an ice-isopropyl alcohol bath to produce a white solid. The 
solid was collected by filtration and washed with cold petroleum ether. 
The filtrate was concentrated and cooled to yield two more crops of white 
crystals. The combined solids were dried under vacuum at ambient 
temperature to yield 107 g (87%) of white, flaky solid, m.p. 
35.degree.-36.degree. C. 
Analysis: Calculated for C.sub.9 H.sub.10 Cl.sub.2 O: C, 52.71; H, 4.92. 
Found: C, 52.99; H, 4.87. 
PREATION 28 
4-(3-Chloropropoxy)benzoic acid ethyl ester 
Ethyl, 4-hydroxybenzoate 83.1 g (0.50 mole), 107 ml (1.0 mole) of 
1-bromo-3-chloropropane, and potassium carbonate (1.5 mole, 207.3 g) were 
mechanically stirred in 600 ml of refluxing acetone under nitrogen 
overnight. The potassium carbonate was removed by filtration, and the 
filtrate was evaporated under reduced pressure to give 122 g of a liquid. 
This liquid was dissolved in 250 ml of petroleum ether and with stirring 
and cooling in an ice/2-propanol bath. A white precipitate formed and was 
collected by filtration and washed with cold petroleum ether to yield 108 
g of a solid. An additional 6 g of the product was obtained from the 
mother liquor. A small sample of the solid was dissolved in petroleum 
ether at room temperature. The solution was stirred and cooled in an ice 
bath. White crystals were collected by filtration, washed with cold 
petroleum ether and dried under vacuum at room temperature, m.p. 
24.degree.-25.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.15 ClO.sub.3 : C, 59.39; H, 6.23. 
Found: C, 59.69; H, 6.30. 
PREATION 29 
1-(3-Chloropropoxy)-4-nitrobenzene 
A mixture of 7.0 g (0.05 mole) of 4-nitrophenol, 15.7 g (0.1 mole) of 
1-bromo-3-chloropropane and 20.7 g (0.15 mole) of anhydrous potassium 
carbonate in 350 ml of acetone was heated at reflux for 17 hr. The mixture 
was cooled, filtered, and the filtrate was concentrated to give an oil 
which crystallized. The solid was collected by filtration, washed with 
petroleum ether, and dried to yield 10.1 g (94%) of the title compound. An 
analytical sample was prepared from ethyl ether-petroleum ether, m.p. 
37.degree.-39.degree. C. 
Analysis: Calculated for C.sub.9 H.sub.10 ClNO.sub.3 : C, 50.13; H, 4.67; 
N, 6.50. Found: C, 49.95; H, 4.71; N, 6.51. 
PREATION 30 
4-[Bis(4-fluorophenyl)methyl]1-1piperidinepropanol oxalate hydrate [1:1:1] 
A mixture of 10.67 g (0.0372 mole) of 
4-[bis(4-fluorophenyl)methyl]-piperidine, 5.42 g (0.039 mole) of 
3-bromo-1-propanol and 8 g (0.095 mole) of sodium bicarbonate in 400 ml of 
1-butanol was heated at reflux for 21 hr. The solvent was removed in 
vacuo, and the residue was partitioned between methylene chloride and 
dilute sodium hydroxide. The methylene chloride solution was dried over 
magnesium sulfate and the solvent was removed in vaco to give 8.88 g 
(67.3%) of oil, the free base of the title compound. A small sample of 
this oil was converted to the oxalate salt, and the salt was 
recrystallized from methanol-ether to give a white solid, m.p. 
89.degree.-94.degree. C. Overall yield was calculated to be 75.1%. 
Analysis: Calculated for C.sub.23 H.sub.29 F.sub.2 NO.sub.6 : C, 60.92; H, 
6.45; N, 3.09. Found: C, 61.49; H, 6.15; N, 3.03. 
PREATION 31 
4-(3-Chloropropoxy)-3-methoxybenzoic acid methyl ester 
A mixture of 100 g (0.549 mole) of methylvanillate, 172.8 g (1.1 mole) of 
1-bromo-3-chloropropane and 228 g (1.65 mole) of anhydrous potassium 
carbonate in 1 liter of acetone was heated at reflux for 20 hr. The 
mixture was cooled, filtered, and the filtrate concentrated to give a 
white solid as residue. The solid was triturated with petroleum ether, 
collected by filtration, and dried to yield 137.8 g (97%) of white powder 
which was recrystallized from isopropyl alcohol, m.p. 
104.degree.-105.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.15 ClO.sub.4 : C, 55.71; H, 5.84. 
Found: C, 55.87; H, 5.94. 
PREATION 32 
4-[Bis(4-methoxyphenyl)methyl]pyridine 
Anisole, 108.13 g (1.0 mole) was cooled in an ice bath. Concentrated 
sulfuric acid, 115.3 ml (2.0 mole) was added while stirring the mixture in 
an ice bath. The temperature rose to 55.degree. C. The reaction was then 
cooled in the ice bath. To this solution was added 4-pyridine 
carboxaldehyde, 53.5 g (0.5 mole). The temperature rose to 95.degree. C. 
and further cooling and stirring brought the temperature down to 
20.degree. C. The reaction mixture was heated at 70.degree. C. for 31/2 
hr. The red gel was made alkaline with 50% sodium hydroxide-ice mix. The 
alkaline phase was extracted with toluene and the toluene extracted with a 
saturated sodium chloride solution. The product crystallized from the 
toluene solution while standing at room temperature. The white solid can 
be recrystallized from hot hexane-isopropyl alcohol. 
A small 2.2 g sample of the product was recrystallized from methylene 
chloride-hexanes (1:9 v/v) and dried overnight at 80.degree. C. in vacuo. 
This furnished 1.08 g (48.6% yield based on the aliquot taken) of white 
crystalline product; m.p. 111.5.degree.-113.5.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.19 NO.sub.2 : C, 78.66; N, 6.27; N, 
4.59. Found: C, 78.14; H, 6.24; N, 4.54. 
PREATION 33 
4-[Bis(4-methoxyphenyl)methyl]piperidine hydrochloride hydrate [1:1:1] 
The precursor pyridine derivative 4-[bis-4-methoxyphenyl)methyl]pyridine 
was prepared from the reaction of anisole and 4-pyridine carboxaldehyde in 
the presence of sulfuric acid. 
To prepare the title compound, a solution of 
4-[bis-(4-methoxyphenyl)methyl]pyridine (70.8 g, 0.232 mole) in 350 ml of 
acetic acid was hydrogenated with 5% palladium on carbon (7.08 g) for five 
hours with heat. The hydrogenation was continued overnight at room 
temperature. The reaction mixture was filtered and rinsed with methanol. 
The filtrate was stripped of solvent via a rotary evaporator and the 
residue was partitioned between 5% sodium hydroxide and toluene. The 
aqueous layer was back extracted with toluene. The organic layer was dried 
over anhydrous sodium sulfate and filtered. Removal of solvent by means of 
a rotary evaporator gave 64 g (88.6%) of white solid, the free base. The 
free base was then converted to the hydrochloride salt by dissolving it in 
methanol and treating with etheral hydrogen chloride. The white solid was 
collected by filtration and dried overnight at 80.degree. C. in vacuo in 
the amount of 2.08 g (69.3%) m.p. 132.degree.-135.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.28 ClNO.sub.3 : C, 65.65; H, 7.71; 
N, 3.383. Found: C, 65.63; H, 7.53; N, 3.90. 
PREATION 34 
4-[Bis(4-methylphenyl)methyl]piperidine hydrochloride [1:1] 
The free base of the title compound was prepared by hydrogenation of 
4-[(bis-4-methylphenyl)methyl]pyridine in acetic acid using palladium on 
carbon as catalyst and converted to the hyrochloride salt in 
methanoldiethyl ether. The sale was recrystallized from methanol-ethyl 
ether and isopropanol-ethyl ether and dried overnight in vacuo at 
80.degree. C. White solid amounting to 46% yield, m.p. 232.degree. C. was 
obtained. 
Analysis: Calculated for C.sub.20 H.sub.26 ClN: C, 76.05; H, 8.30; N, 4.43. 
Found: ;C, 75.51; H, 8.33; N, 4.33. 
PREATION 35 
N-[4-(3-Chloropropoxy)phenyl]acetamide 
A mixture of 4-acetamidophenol, 182.2 g (1.2 mole), bromochloropropane, 
157.4 g (1.0 mole), and potassium carbonate, 145.0 g (1.05 mole) was 
heated at reflux overnight in 700 ml of acetone. The acetone solution was 
refrigerated overnight and white crystals formed. This white solid was 
filtered and washed with acetone. The filtrate was stripped to dryness and 
the residue was dissolved in chloroform and extracted with 5% sodium 
hydroxide. Removal of chloroform gave an oil. The white solid was also 
dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of 
chloroform gave a white solid. The white solid and oil were combined and 
placed in acetone in the refrigerator; white crystals were obtained. The 
white crystals were recrystallized twice from acetone. A 5 g-sample of the 
white crystals was recrystallized from acetone. This furnished 1.76 g 
(after drying in vacuo overnight at 80.degree. C. (23%) of white, 
crystalline product; m.p. 125.degree.-127.degree. C. 
Analysis: Calculated for C.sub.11 H.sub.14 ClNO.sub.2 : C, 58.03; H, 6.20; 
N, 6.15. Found: C, 58.21; H, 6.28; N, 6.15. 
PREATION 36 
1-(3-Chloropropoxy)-3,5-dimethoxybenzene 
A mixture of 3,5-dimethoxyphenol 100.0 g (0.6486 mole), chlorobromopropane 
148.0 g (0.96 mole) and potassium carbonate 89.6 g (0.96 mole) was heated 
overnight at gentle reflux in 600 ml of acetone. The reaction mixture was 
cooled at room temperature, filtered, and stripped to dryness via a rotary 
evaporator. The resulting oil was dissolved in chloroform and the solution 
extracted with 5% aqueous sodium hydroxide; removal of chloroform gave a 
dark brown oil. A 5-g sample of the oil was pumped in vacuo overnight at 
80.degree. C. This produced 3.23 g (53.2% yield based on the aliquot 
taken) of dark brown oil. H.sup.1 (CDCl.sub.3): .delta. 2-2.14 
(quintuplet, center methylene protons, 2H), 3.6-4.2 (m, aliphatic protons, 
4H), 3.8 (s, OCH.sub.3, 6H), 6.1 (s,aromatic protons, 3H). 
Analysis: Calculated for C.sub.11 H.sub.15 ClO.sub.3 : C, 57.27; H, 6.56. 
Found: C, 54.96; H, 6.49. 
PREATION 37 
4-(3-Chloropropoxy)benzonitrile 
A mixture of 4-cyanophenol, 125.0 g (1.05 mole), bromochloropropane, 189.0 
g (1.2 mole) and potassium carbonate, 145.0 g (1.05 mole) was heated 
overnight at reflux in 750 ml of acetone. The reaction mixture was 
filtered and stripped to dryness. The resulting residue was dissolved in 
chloroform and extracted with 5% sodium hydroxide. Removal of chloroform 
gave an oil which crystallized to a white solid. A 5-g sample was 
recrystallized from isopropyl ether. This furnished 1.22 g (24.4%) of 
white solid, m.p. 40.degree.-44.degree. C. which contained a dimer 
impurity. 
Analysis: Calculated for C.sub.10 H.sub.20 ClNO: C, 61.39; H, 5.15; N, 
7.16. Found: C, 61.57; H, 5.14; N, 7.20. 
PREATION 38 
1-[4-(3-Chloropropoxy)-3-methylphenyl]ethanone 
A mixture of 25 g (0.166 mole) of 4- hydroxy-3-methylacetophenone, 45.8 g 
(0.33 mole) of 1-bromo-3-chloropropane and 69.1 g (0.5 mole) of anhydrous 
potassium carbonate in 500 ml of acetone was heated at reflux for 20 hr. 
The mixture was cooled, filtered, and the filtrate concentrated under 
reduced pressure to give an oil as residue. The oil was crystallized in 
petroleum ether. The solid was collected by filtration, washed with 
petroleum ether and dried to yield 35.8 g (95%) of an off-white powder. An 
analytical sample, m.p. 41.5.degree.-42.5.degree. C. was prepared from 
petroluem ether. 
Analysis: Calculated for C.sub.12 H.sub.15 ClO.sub.2 : C, 63.58; H, 6.67. 
Found: C, 63.40; H, 6.64. 
PREATION 39 
4-(3-Chloropropoxy)benzamide 
A mixture of 50 g (0.365 mole) of 4-hydroxybenzamide, 114.8 g (0.729 mole) 
of 1-bromo-3-chloropropane and 151.3 g (1.1 mole) of anhydrous potassium 
carbonate in 1 liter of acetone was heated at reflux for 20 hr. The 
mixture was concentrated under reduced pressure and the residue was 
stirred with 1.2 liter of water to remove inorganic solids. The mixture 
was filtered and the filter cake was washed with water and petroleum ether 
and dried to yield 75.5 g (97%) of white solid. The solid was 
recrystallized from ethyl acetate, m.p. 142.degree.-145.degree. C. 
Analysis: Calculated for C.sub.10 H.sub.12 ClNO.sub.2 : C, 56.22; H, 5.66; 
N, 6.56. Found: C, 55.92; H, 5.61; N, 5.56. 
PREATION 40 
1-[4-(5-Chloropentoxy)-3-methoxyphenyl]ethanone 
A mixture of 59.7 g (0.36 mole) of acetovanillone, 100 g (0.539 mole) of 
1-bromo-5-chloropentane and 138 g (1 mole) of anhydrous potassium 
carbonate in 1 liter of acetone was heated at reflux for 20 hr. The 
mixture was filtered and the filtrate was concentrated under reduced 
pressure to give an oil which crystallized in petroleum ether 
(30.degree.-60.degree. C.). The solid was collected by filtration, washed 
with petroleum ether and dried to yield 81.4 g (84%) of fluffy, white 
solid. The solid was recrystallized from isopropyl ether, m.p. 
57.degree.-58.degree. C. 
Analysis: Calculated for C.sub.14 H.sub.19 ClO.sub.3 : C, 62.11; H, 7.07. 
Found: C, 62.14; H, 7.10. 
PREATION 41 
4-(3-Chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester 
A mixture of 50 g (0.238 mole) of ethyl homovanillate, 75 g (0.476 mole) of 
1-bromo-3-chloropropane and 98.7 g (0.71 mole) of anhydrous potassium 
carbonate in 1 liter of acetone was heated at reflux for 24 hr. The 
mixture was filtered and the filtrate was concentrated under reduced 
pressure to give an oil which gradually crystallized to a semi-solid. The 
solid was recrystallized from ethyl ether-petroleum ether 
(30.degree.-60.degree. C.) to yield 44.4 g (65%) of white solid, m.p. 
36.degree.-38.degree. C. 
Analysis: Calculated for C.sub.14 H.sub.19 ClO.sub.4 : C, 58.64; H, 6.68. 
Found: C, 58.74; H, 6.74. 
PREATION 42 
1-(3-Chloropropoxy)-4-(methylsulfonyl)benzene 
To a solution of 21.7 g (0.1 mole) of 
1-(3-chloropropyx)-4-(methylthio)benzene in 100 ml of chloroform was 
cautiously added a slurry of 51.8 g (0.3 mole) of m-chloroperbenzoic acid 
in 450 ml of chloroform. The mixture was stirred at ambient temperature 
for 2 days and then filtered. The filtrate was washed with four portions 
of a solution comprised of 110 ml of saturated sodium bicarbonate, 110 ml 
of water, and 30 ml of 20% sodium hydroxide, once with brine, dried 
(sodium sulfate) and concentrated under reduced pressure to give a solid 
as residue. The solid was triturated with petroleum ether, collected by 
filtration and air dried to yield 24.3 g (98%) of white solid. An 
analytical sample, m.p. 84.degree.-86.degree. C. was recrystallized from 
2-propanol. 
Analysis: Calculated for C.sub.10 H.sub.13 ClO.sub.3 S: C, 48.29; H, 5.27. 
Found: C, 48.38; H, 5.30. 
PREATION 43 
5-Oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid, methyl ester 
A solution of 158.2 g (1.0 mole) of dimethylitaconate and 107.2 g (1.0 
mole) of benzylamine in 750 ml of methanol was let stand at ambient 
temperature over the weekend. The solution was filtered and the filtrate 
was concentrated under reduced pressure to give an oil as residue. The oil 
crystallized when it was triturated with petroleum ether 
(30.degree.-60.degree. C.). The solid was collected by filtration and 
dried to yield 225.5 g (97%) of white powder. An analytical sample, m.p. 
63.degree.-65.degree. C. was prepared from isopropyl ether. 
Analysis: Calculated for C.sub.13 H.sub.15 NO.sub.3 : C, 66.94; H, 6.48; N, 
6.01. Found: C, 66.82; H, 6.48; N, 6.01. 
PREATION 44 
1-Benzyl-3-(hydroxymethyl)pyrrolidine oxalate [1:1] 
A solution of (60.0 g, 0.2553 
mole)5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester in 
dry dimethoxyethane was added to a mixture of dimethoxyethane and 47.0 g 
(1.23 mole) of lithium aluminum hydride. The reaction mixture was stirred 
2 hrs at room temperature and then heated at reflux 2 hrs. The mixture was 
then stirred overnight at room temperature, then quenched by the slow 
addition of ethyl acetate. More ethyl acetate was added and the use of 
Celite.RTM. allowed the solid material to be separated from filtrate by 
filtration. The filtrate was stripped to dryness and dissolved in 
chloroform. The chloroform layer was extracted with 10% sodium hydroxide. 
The chloroform layer was dried, filtered, and solvent removed to give an 
oil. A portion of the oil was converted to the oxalate salt. The salt was 
recrystallized from methanol-ethyl ether and dried at 80.degree. C. in 
vacuo overnight to give 2.27 g, 39.4% yield of white, crystalline solid, 
m.p. 98.degree.-102.degree. C. 
Analysis: Calculated for C.sub.14 H.sub.19 NO.sub.5 : C, 59.78; H, 6.81; N, 
4.98. Found: C, 59.43; H, 6.79; N, 4.95. 
PREATION 45 
1-[4-(6-Chlorohexyloxy)-3-methoxyphenyl]ethanone 
A mixture of 41.6 g (0.25 mole) of acetylvanillone, 76 g (0.375 mole) of 
1-bromo-6-chlorohexane and 103.7 g (0.75 mole) of anhydrous potassium 
carbonate in 750 ml of acetone was heated at reflux 20 hr. The mixture was 
cooled, filtered,and the filter cake washed with acetone. The combined 
filtrates were concentrated under vacuum pump pressure at 90.degree. C. to 
give an oil which gradually crystallized. The residue was triturated with 
petroleum ether (30.degree.-60.degree. C.), collected by filtration, and 
dried to yield 59.6 g (84%) of off-white solid. An analytical sample, m.p. 
35.degree.-38.degree. C. was prepared from isopropyl ether. 
Analysis: Calculated for C.sub.15 H.sub.21 ClO.sub.3 : C, 63.26; H, 7.43. 
Found: C, 63.50; H, 7.60. 
PREATION 46 
4-(3-Chloropropoxy)benzenesulfonamide 
A mixture of 25 g (0.144 mole) of p-hydroxybenzenesulfonamide, 45.5 g 
(0.289 mole) of 1-bromo-3-chloropropane and 59.7 g (0.432 mole) of 
anhydrous potassium carbonate in 500 ml of acetone was heated at reflux 
for 24 hr. The mixture was cooled, filtered and the filtrate concentrated 
under vacuum pump pressure at 90.degree. C. to give 32.2 g of tan gum as 
residue. The gum was purified by column chromatography on 600 g of silica 
gel. Fractions containing the title compound eluted with 8% acetone in 
benzene were combined and concentrated under reduced pressure to yield 
12.2 g (34%) of white solid, m.p. 106.degree.-107.5.degree. C. on 
recrystallization from 2-propanol. 
Analysis: Calculated for C.sub.9 H.sub.12 NO.sub.3 S: C, 43,29; H, 4.84; N, 
5.61. Found: C, 43.48; H, 4.92; N, 5.62. 
PREATION 47 
7-(3-Chloropropoxy)-2H-1-benzopyran-2-one 
A mixture of 16.8 g (0.104 mole) of 7-hydroxycoumarin, 31.6 g (0.2 mole) of 
1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium 
carbonate in 500 ml of acetone was heated at reflux for 24 hr. The mixture 
was filtered with difficulty to give a milky filtrate. The filtrate was 
treated with charcoal and filtered through Celite.RTM. to give a clear 
filtrate. The filtrate was concentrated under reduced pressure to give a 
solid residue. The solid was triturated with petroleum ether 
(30.degree.-60.degree. C.), collected by filtration; and dried to yield 
19.1 g (77%) of fluffy, white solid. An analytical sample, m.p. 
100.degree.-102.degree. C., was obtained on recrystallization from 
2-propanol. 
Analysis: Calculated for C.sub.12 H.sub.11 ClO.sub.3 : C, 60.39; H, 4.65 
Found: C, 60.35; H, 4.68. 
PREATION 48 
7-(3-Chloropropoxy)4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester 
A mixture of 23.4 g (0.1 mole) of 
7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester, 31.6 g (0.2 
mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous 
potassium carbonate in 500 ml of acetone was heated at reflux for 20 hr. 
The mixture was cooled and filtered through Celite.RTM.. The filtrate was 
concentrated under reduced pressure to give a solid residue. The solid was 
triturated with petroleum ether (30.degree.-60.degree. C.), collected by 
filtration, and recrystallized from 2-propanol to yield 22.5 g (73%) of 
white solid, m.p. 107.degree.-108.degree. C. 
Analysis: Calculated for C.sub.15 H.sub.15 ClO.sub.5 : C, 57,98; H, 4.87. 
Found: C, 58.21; H, 4.88. 
PREATION 49 
1-[4-(3-Chloropropoxy)-2-methoxyphenyl]ethanone 
A mixture of 10.6 g (0.637 mole) of 1-(4-hydroxy-2-methoxyphenyl)ethanone, 
20 g (0.127 mole) of 1-bromo-3-chloropropane and 26.4 g (0.19 mole) of 
anhydrous potassium carbonate in 250 ml of acetone was heated at reflux 
for 20 hr. The mixture was cooled, filtered and the filtrate concentrated 
under vacuum pump pressure at 90.degree. C. to give an oil which gradually 
crystallized. The solid was triturated with petroleum ether 
(30.degree.-60.degree. C.), collected by filtration and dried to yield 
14.6 g (94%) of white solid, m.p. 47.degree.-49.degree. C. on 
recrystallizing from isopropyl ether. 
Analysis: Calculated for C.sub.12 H.sub.15 ClO.sub.3 : C, 59.39; H, 6.23. 
Found: C, 59.32; H, 6.26. 
PREATION 50 
1-(3-Chloropropoxy)-4-methylsulfinylbenzene 
The title compound is prepared by treating 
1-3-(chloropropoxy)-4-methylthiobenzene with sodium perborate in glacial 
acetic acid. 
PREATION 51 
2-(3-Chloropropoxy)benzonitrile 
A mixture of 2-cyanophenol (50.0 g, 0.42 mole), 1-bromo-3-chloropropane 
(67.7 g, 0.43 mole), and potassium carbonate (58.0 g, 0.42 mole) was 
heated overnight at gentle reflux in 500 ml of acetone. The reaction 
mixture was stripped to dryness and the residue was dissolved in 
chloroform. The chloroform layer was extracted several times with 5% 
sodium hydroxide. The chloroform layer was dried (anhydrous sodium 
sulfate), filtered, and the solvent was removed, to give a brown oil 
(80.09 g). A ten gram portion of this oil was subjected to flash 
chromatography on silica gel with 10% ethyl acetate-hexanes and 20% ethyl 
acetate-hexanes used for elution. Fractions were combined and solvent 
removed in vacuo. The clear oil obtained was dried 18 hrs in vacuo at room 
temperature and 8 hrs at 80.degree. C. in vacuo. This furnished 5.24 g 
(50.0% yield--based on aliquot taken) of clear oil. .sup.1 H HMR 
(CDCl.sub.3); .delta. 2.1-2.5 (q, 2, --CH.sub.2), 3.8 (t, 2, 
--ClCH.sub.2), 4.2 (t, 2, --OCH.sub.2), 6.9 (m, 2, aromatic protons ortho 
and para to ether), 7.5 (m, 2, aromatic protons ortho and para to CN 
group). 
Analysis: Calculated for C.sub.10 H.sub.10 ClNO: C, 61.39; H, 5.15; N, 
7.16. Found: C, 61.27; H, 5.15; N, 7.14. 
PREATION 52 
1-Phenylmethyl-3-pyrrolidinemethanol methanesulfonate (ester) exalate [1:1] 
A solution of 113.80 g (0.596 mole) of 
1-benzyl-3-(hydroxymethyl)pyrrolidine and triethylamine, 66.0 g (0.66 
mole) in 600 ml of acetonitrile was prepared. This solution was cooled in 
an ice bath. A solution of tosyl chloride, 125.9 g (0.66 mole) in 300 ml 
of acetonitrile was added dropwise with stirring. The solution was allowed 
to stir overnight at room temperature. A solid precipitated and the 
solution was filtered. The solvent was removed by rotary evaporator and 
the residue was dissolved in chloroform. The chloroform layer was dried 
(anhydrous sodium sulfate), filtered, and solvent removed to given 232.9 g 
of a dark brown oil. This oil was converted to the oxalate salt and 
recrystallized from methanol-ethyl ether. After drying at 80.degree. C. in 
vacuo overnight, 181.63 g of white, crystalline solid was obtained. A five 
gram sample was recrystallized again from methanol-ethyl ether and dried 
at 80.degree. C. in vacuo overnight. A yield of 1.41 g (19.7% overall 
adjusted for the aliquot taken) of white, crystalline solid, m.p. 
147.degree.-149.degree. C. was obtained. 
Analysis: Calculated for C.sub.21 H.sub.25 NO.sub.7 S: C, 57.92; H, 5.79; 
N, 3.22. Found: C, 57.62; H, 5.82; N, 3.22 
PREATION 53 
N-[3-(3-Chloropropoxy)phenyl]urea 
A mixture of 45.6 g (0.3 mole of 1-(3-hydroxyphenyl)urea, 94.5 g (0.6 mole) 
of 1-bromo-3-chloropropane, 124.4 g (0.9 mole) of anhydrous potassium 
carbonate and 1 liter of acetone was heated at reflux with mechanical 
stirring for 20 hr. The mixture was concentrated and the residue was 
slurried with 1.5 liters of water. The mixture was filtered and the filter 
cake was recrystallized from 2-propanol to yield 57.0 g (83%) of off-white 
solid, m.p. 141.degree.-143.degree. C. 
Analysis: Calculated for C.sub.10 H.sub.13 ClN.sub.2 O.sub.2 : C, 52.52; H, 
5.73; N, 12.25. Found: C, 52.37; H, 5.79; N, 12.17. 
PREATION 54 
N-[4-(3-Chloropropoxy)phenyl]carbamic acid ethyl ester 
A mixture of 6.6 g (0.036 mole) of (4-hydroxyphenyl)carbamic acid ethyl 
ester, 11.5 g (0.072 mole) of 1-bromo-3-chloropropane, 13.8 g (0.10 mole) 
of anhydrous potassium carbonate and 150 ml of acetone was heated at 
reflux for 21 hr. The mixture was cooled and filtered. The filtrate was 
concentrated under reduced pressure to give a solid residue. The solid was 
triturated with petroleum ether (30.degree.-60.degree. C.) collected by 
filtration and recrystallized from isopropanol to yield 7.7 g (83%) of 
white solid, m.p. 91.degree.-93.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.16 ClNO.sub.3 : C, 55.93; H, 6.26; 
N, 5.43. Found: C, 55.93; H, 6.28; N, 5.46. 
PREATION 55 
.alpha.(4-Fluorophenyl)-2-pyridineacetonitrile 
A sample of sodium hydride (60%, 1.60 g, 0.04 mole) was washed with dry 
hexanes. After removal of hexanes a 100 ml portion of dimethyl sulfoxide 
was added. To this mixture was added a solution of 
4-fluorophenylacetonitrile (5.41 g, 0.04 mole). The mixture was stirred 3 
hrs at room temperature under nitrogen. 2-Bromopyridine (6.32 g, 0.04 
mole) was added to the mixture, the reaction mixture was then stirred 
overnight at 65.degree. C. The reaction mixture was poured into 1200 ml of 
water and the aqueous phase was extracted several times with chloroform 
(the chloroform layer was filtered using Celite.RTM.). The combined 
chloroform layer was extracted with water and 5% sodium hydroxide. The 
chloroform layer was dried over sodium sulfate, filtered, and solvent 
removed to give a red oil. The oil was subjected to flash chromatography 
on silica gel using 10% ethyl acetate-90% hexanes and 20% ethyl 
acetate-80% hexanes for elution. Fractions of similar purity was combined 
and solvent removed in vacuo. The oil obtained was dried in vacuo 
overnight at 80.degree. C. to give 2.43 g (28.6%) of clear oil. 
.sup.1 H (CDCl.sub.3): .delta. 8.5 (m, 1, proton adjacent to N in pyridine 
nucleus), 6.8-7.8 (m, 7, aromatics, 5.3 (s, 1, methine). 
Analysis: Calculated for C.sub.13 H.sub.9 FN.sub.2 : C, 73.57; H, 4.27; N, 
13.20. Found: C, 73.23; H, 4.23; N, 13.12 
PREATION 56 
.alpha.-(4-Fluorophenyl)-.alpha.-[1-[(4-methylphenyl)sulfonyl]-4-piperidiny 
l]-2-pyridineacetonitrile hydrate [1:0.5] 
The sodium salt of the free base of 
.alpha.-(4-fluorophenyl)-2-pyridineacetronitrile was formed in 
dimethylsulfoxide from sodium hydride (60%, 5.16 g, 0.129 mole) and the 
free base of .alpha.-4-fluorophenyl)-2-pyridineacetonitrile (27.36 g, 
0.129 mole). The salt was stirred in dimethylsulfoxide for 41/2 hr at room 
temperature. Next, 4-methylphenylsulfonic acid ester with 
1-[(4-methylbenzene) sulfonyl]-4-piperidinol (52.8 g, 0.129 mole) was 
added and the reaction mixture was stirred 2 hr at room temperature. The 
reaction mixture was stirred overnight at 80.degree. C. The solvent was 
removed in vacuo and the residue obtained was dissolved in chloroform. The 
chloroform was extracted with water and 5% sodium hydroxide. The 
chloroform layer was dried over sodium sulfate and filtered. Solvent was 
removed to give a dark brown residue. This material was triturated with 
acetone to give 36.2 g of white solid. A one gram portion was triturated 
with acetone and then recrystallized from methylene chloride-acetone. The 
solids were dried in vacuo overnight at 80.degree. C. to give 0.74 g 
(62.4% based on aliquot taken) of white crystals, m.p. 
228.degree.-229.degree. C. 
Analysis: Calc'd for C.sub.25 H.sub.24 FN.sub.3 O.sub.2 S.0.5H.sub.2 O: C, 
65.90; H, 5.49; N, 9.16. Found: C, 65.86; H, 5.27; N, 9.16. 
PREATION 57 
.alpha.-(4-Fluorophenyl)-.alpha.-(4-piperidinyl)-2-pyridineacetonitrile 
oxalate [2:3] 
A solution of 
.alpha.-(4-fluorophenyl)-.alpha.-[1-[(4-methylphenyl)sulfonyl]-4-piperidin 
yl]-2-pyridineacetonitrile (30.86 g, 0.0687 mole) and phenol (75 g, 0.8 
mole) in 200 mol of 48% hydrobromic acid was heated at reflux for 3 hrs. 
The resultant was cooled in ice and made alkaline with ice-50% sodium 
hydroxide. The aqueous layer was extracted with chloroform and the 
chloroform layer was extracted with 5% sodium hydroxide. The chloroform 
layer was dried over sodium sulfate, filtered, and solvent removed to give 
a dark brown oil. The entire oil was converted to the oxalate salt in 
methanol-ethyl ether. A one gram portion was taken and recrystallized from 
methanol-ethyl ether and dried in vacuo at 80.degree. C. overnight. This 
furnished 0.90 g (80.2% based on aliquot taken) of white, crystalline 
product, m.p. 98.degree. C. (soften, 70.degree. C.). 
Analysis: Calculated for C.sub.21 H.sub.21 FN.sub.3 O.sub.6 : C, 58.60; H, 
4.92; N, 9.76. Found: C, 58.77; H, 5.01; N, 10.04. 
PREATION 58 
4-Fluoro-.alpha.-(4-fluorophenyl)benzeneacetonitrile 
4-Fluorophenylacetonitrile (70.0 g, 62.2 ml, d=1.126, 0.518 mole) was 
heated to 120.degree. C., Bromine (83.0 g, 26.6 ml, d=3.119, 0.525 mole) 
was added dropwise over 1 hr while maintaining a temperature of 
120.degree. C. The solution was stirred for 1/2 at 120.degree. C. and then 
flushed vigorously with nitrogen for 3/4 hr (solution A). 
In a separate 2-liter flask was placed aluminum chloride (85.0 g, 0.644 
mole). Fluorobenzene (200 g, 2.08 mole, d=1.024, 195.3 ml) was added 
dropwise with stirring over 1/2 hr while flushing with nitrogen (Mixture 
B). 
Solution A was added dropwise to mixture B starting at room temperature. 
The temperature rose to 50.degree. C. The reaction mixture was stirred at 
this temperature for 1/3 hr. The temperature was raised to 70.degree. C. 
and maintained there for 1/3 hr. At this point the reaction became 
uncontrollable and part of the mixture was lost. The remainder was added 
to ice/75 ml of concentrated hydrochloric acid. The aqueous phase 
extracted several times with chloroform. The solvent layer was dried, 
filtered, and solvent removed to give a green solid. The solid was 
recrystallized from isopropanol; the solid was washed with cold 
isopropanol twice and dried in vacuo at 55.degree. C. overnight. This 
produced 29.72 g (25.1%) if light-yellow solid, m.p. 
62.degree.-63.5.degree. C. 
Analysis: Calculated for C.sub.14 H.sub.9 F.sub.2 HL C, 73.36; H, 3.96; N, 
6.11. Found: C, 73.55; H, 3.88; N, 6.10. 
PREATION 59 
1-[(4-Methylphenyl)sulfonyl]-.alpha.-.alpha.-diphenyl-3-piperidineporpaneni 
trile 
The sodium salt of diphenylacetonitrile was formed in 400 ml of 
dimethylsuloxide from sodium hydride (605, 39.0 g, 0.975 mole) and 
diphenylacetonitrile (188.90 g, 0.975 mole). The resulting solution was 
stirred under nitrogen for 1 hr at room temperature. A 90-10 mixture of 
3-(chloromethyl)-1-[(4-methylphenyl)sulfonyl]piperidine and 
4-methylbenzenesulfonic acid 1-[(4-methylphenyl)sulfonyl]piperidine-3-yl 
methyl ester (221.42 g, 0.975 mole) dissolved in 400 ml of 
dimethylsulfoxide was added. The reaction mixture was heated to 85.degree. 
C. and stirred overnight at 73.degree. C. The dimethylsulfoxide was 
removed in vacuo, and the residue obtained was dissolved in chloroform. 
The chloroform layer was extracted with 1N sulfuric acid. The chloroform 
layer was dried, filtered, and the chloroform was removed by rotary 
evaporator. A brown residue was obtained which was triturated with 
isopropyl ether to give a brown solid. A 5-g sample was recrystallized 
from ethyl acetate-isopropyl ether. This gave 4 g (56.8% based on aliquot 
taken) of white solid, m.p. 136.5.degree.-137.degree. C. 
Analysis: Calculated for C.sub.27 H.sub.28 N.sub.2 O.sub.2 S: C, 72.94; H, 
6.35; N, 6.30. Found: C, 72.82; H, 6.36; N, 6.29. 
PREATION 60 
.alpha.,.alpha.-Diphenyl-3-piperidinepropanenitrile fumarate [1:1] 
A mixture of 
1-[(4-methylphenyl)sulfonyl]-.alpha.,.alpha.-diphenyl-3-piperidinepropanen 
itrile (302.41 g, 0.68 mole), hydrogen bromide (48%, 750 ml), and phenol 
(260 g, 2.76 mole) was stirred vigorously while heating at reflux for 31/2 
hr. The reaction mixture was cooled to room temperature and made alkaline 
with 50% hydroxide-ice. The aqueous phase was extracted several times with 
chloroform, and the chloroform layer was back extracted with 5% sodium 
hydroxide. The chloroform layer was dried, filtered, and solvent removed. 
NMR showed about 80% product was obtained. The same sequence was repeated. 
The chloroform layer gave a brown oil which was converted to the oxalate 
salt. A portion of this oxalate salt was converted to the free bas by 
partitioning in chloroform and dilute aqueous sodium hydroxide and 
separating and evaporating the chloroform layer and converted to the 
fumarate salt. This salt was recrystallized from methanolethyl ether and 
dried in vacuo at 80.degree. C. overnight to give 6.53 g of white 
crystals, m.p. 181.degree.-182.degree. C. 
Analysis: Calculated for C.sub.24 H.sub.26 N.sub.2 O.sub.4 : C, 70.92; H, 
6.45; N, 6.89. Found: C, 70.46; H, 6.41; N, 6.86. 
PREATION 61 
3-(8-Quinolinyloxy)-1-propanol 
A solution of 8-hydroxyquinoline (36.0 g, 0.25 mole) and potassium 
tertbutoxide (28.0 g, 0.25 mole) in 80 ml of dimethyl sulfoxide was 
stirred for 1 hr at room temperature. 3-Chloro-1-propanol (242.0 g, 0.25 
mole) was added and the solution was heated overnight at 70.degree. C. The 
solution was poured into 500 ml of water. A brown solid/mass was obtained. 
The solid was washed with several portions of water and then triturated 
with acetone. The solid was filtered and dried in vacuo at 80.degree. C. 
overnight to give 35.67 g (70.3%) of light brown solid, m.p. 
126.degree.-127.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.13 NO.sub.2 : C, 70.92; H, 6.45; N, 
6.89. Found: C, 70.94; H, 6.49; N, 6.87. 
PREATION 62 
8-(3-Chloropropoxy)quinoline 
A solution of 3-(8-quinolinyloxy)-1-propanol (32.0 g, 0.158 mole) and 
thinoyl chloride (24.0 g, 0.203 mole) was heated at reflux for 5 hours in 
300 ml of dry benzene (dried over 4A molecular sieves). The reaction 
mixture was cooled to room temperature and then stripped to dryness. The 
residue was treated with potassium carbonate solution (30 g in 500 ml of 
water). The gummy residue was dissolved in chlorofrom and extracted with 
the potassium carbonate solution. The chloroform layer was dried over 
anhydrous sodium sulfate, filtered, and solvent removed to give a dark 
mass which crystallized. The mass was treated with 500 ml of boiling 
hexane. The hexane layer was decanted off from insoluble oil. A white 
solid crystallized on cooling, and was collected by filtration. The solid 
was dried in vacuo at room temperature overnight to give 26.69 g (76.2%) 
of white, crystalline solid, m.p. 69.degree.-71.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.12 ClNO: C, 65.02; H, 5.45; N, 
6.32. Found: C, 65.19; H, 5.51; N, 6.27. 
PREATION 63 
4-Methylphenylsulfonic acid ester with 
1-[(4-methylbenzene)sulfonyl]-4-piperidinol 
A solution of 1.63 g (0.0161 mole) of 4-hydrpxypiperidine and 13.91 g 
(0.0732 mole) of tosyl chloride i n 80 ml of pyridine was stirred at 
25.degree. C. overnight. The mixture was quenched in 200 ml of water and 
the aqueous mixture was extracted with several portions of methylene 
chloride. The methylene chloride solution was extracted with several 
portions of 1M sulfuric acid and 1M sodium hydroxide and then was dried 
over magnesium sulfate. The solvent was removed in vacuo to give a solid. 
This water recrystallized from methylene chloride-ethyl ether to give 4.82 
g (73.3%) of the product, m.p. 140.5.degree.-141.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.23 NO.sub.5 S.sub.2 : C, 55.73; H, 
5.66; N, 3.42. Found: C, 55.60; H, 5.64; N, 3.39. 
PREATION 64 
7-Hydroxy-4-oxo-4H-1benzopyran-2-carboxylic acid ethyl ester 
To a warm, stirred solution of 18.4 g (0.8 mole) of sodium metal in 250 ml 
of absolute ethanol was added dropwise a solution of 30.4 g (0.2 mole) of 
2,4-dihydroxyacetophenone and 58.5 g (0.4 mole) of diethyloxalate in 50 ml 
of absolute ethanol and 50 ml of absolute ethyl ether over a 30-min 
period. The mixture was heated at reflux for 4 hr and then poured into a 
solution of 200 ml of concentrated hydrochloric acid and 1.8 liter of 
water. The mixture was extracted with two 500-ml portions of ethyl ether 
and the combined extracts were concentrated under reduced pressure to give 
a solid residue. 
The solid was dissolved in a mixture of 250 ml of ethanol and 3 ml of 
concentrated hydrochloric acid and heated at reflux for 2 hr. The mixture 
was concentrated under reduced pressure and the solid residue was 
triturated with ethyl ether, collected by filtration, and recrystallized 
from 95% ethanol to yield 28.1 g (60%) of tan powder, m.p. 
217.degree.-221.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.10 O.sub.5 : C, 61;54; H, 4.30. 
Found: C, 61.68: H, 4.34. 
PREATION 65 
.alpha.(4-Fluorophenyl)-.alpha.-[1-(phenylsulfonyl)-4-piperidinyl]-2-pyridi 
nemethanol 
A solution of 2-bromopyridine (9.26 g, 0.059 mole) in 250 ml of 
tetrahydrofuran was prepared and cooled to -65.degree. C. in an 
acetone/dry ice bath. To this solution was added n-butyl lithium (10.5M in 
hexane, 5.60 ml, 0.05 mole) while maintaining a temperature of -45.degree. 
C. to -65.degree. C. The solution was stirred for 2 hr at -65.degree. C. A 
tetrahydrofuran solution of 
(4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone (18.2 g, 
0.0525 mole) was added dropwise while maintaining a temperature of 
-65.degree. C. The solution was stirred 72 hr while reaching room 
temperature. The solution was stripped to dryness. The residue was 
dissolved in chloroform and extracted with several portions of water. The 
chloroform layer was dried over sodium sulfate and solvent was removed in 
vacuo to give a brown oil. This oil was subjected to flash chromatography 
on silica gel using 30% ethyl acetate/hexanes and 40% ethyl 
acetate/hexanes for elution. Fractions of similar purity were combined and 
solvent removed to give a white crystalline solid. This solid was 
triturated with ethyl ether and chilled in the freezer for 12 hr. The 
solid was isolated and dried at 80.degree. C. in vacuo overnight. This 
process provided 12.12 g (54.1% yield) of white, crystalline solid m.p. 
160.degree.-163.degree. C. 
Analysis: Calculated fpr C.sub.23 H.sub.23 FN.sub.2 O.sub.3 S: C, 64.78; H, 
5.44; N, 6.57. Found: C, 64.74; H, 5.43; N, 6.49. 
PREATION 66 
2[(4-Fluorophenyl)(4-piperidinyl)methyl]pyridine hydrochloride hydrate 
[1:2:0.5] 
A mixture of 
.alpha.-(4-fluorophenyl)-.alpha.-[1-phenylsulfonyl)-4-piperidinyl]-2-pyrid 
inemethanol (62.0 g, 2.0 mole) and 500 ml of 57% hydriodic acid was heated 
at reflux for 6 hours. The reaction mixture was concentrated and then 
filtered with Celite.RTM.. The filtrate obtained was stripped to dryness. 
Ice/water was added and the mixture was made alkaline with 50% sodium 
hydroxide. The aqueous phase was extracted several times with chloroform. 
The chloroform layer was dried over sodium sulfate, filtered, and solvent 
removed to obtain an oil which crystallized on standing at room 
temperature. The oil was converted to the hydrochloride salt and 
recrystallized from methanol-ethyl ether. A white solid was obtained which 
was dried at 80.degree. C. in vacuo overnight. This furnished 15.45 g 
(71.9% yield) of yellow solid, mp 182.degree.-185.degree. C. 
Analysis: Calculated for C.sub.17 H.sub.21 FCl.sub.2 N.sub.2.0.5H.sub.2 O: 
C, 57.96; H, 6.30; N, 7.95. Found: C, 57.46; H, 6.26; N, 7.88. 
PREATION 67 
.alpha.,.alpha.-Diphenyl-1-(phenylmethyl)-4-piperidinemethanol 
A Grignard solution was prepared by the addition of 94.2 g (0.6 mole) of 
bromobenzene in 250 ml of dry (freshly distilled from lithium aluminum 
hydride) tetrahydrofuran to a mixture of 12.5 g (0.5 mole) of magnesium 
chips in 500 ml of dry tetrahydrofuran. After the addition was complete, 
the mixture was heated at reflux for 15 min to complete formation. To this 
Grignard reagent at ambient temperature, was added a solution of 44.2 g 
(0.179 mole) of the base of 1-(phenylmethyl)-4-piperidinecarboxylic acid 
ethyl ester in 250 ml of tetrahydrofuran in a stream. The solution was 
stirred overnight at ambient temperature and then poured into 2.5 liters 
of a saturated ammonium chloride solution. The layers were separated and 
the aqueous layer was extracted once with 500 ml of methylene chloride and 
twice with 250 ml of methylene chloride. The combined organic layers were 
washed successively with 500 ml of water, 750 ml of a 3% sodium hydroxide 
solution, 250 ml of water and 250 ml of brine. The organic layer was dried 
over sodium sulfate and concentrated to give a gum as residue. The gum was 
dissolved in 500 ml of ethyl ether treated with activated charcoal, 
filtered through Celite.RTM., and then concentrated to give a gum as 
residue. The gum crystallized when triturated with petroleum ether 
(30.degree.-60.degree. C.). The solid was collected by filtration and 
dried to yield 49.0 g (77%) of title compound as a white solid. An 
analytical sample, mp 89.5.degree.-90.5.degree. C., was prepared by 
recrystallization from 2-propanol. 
Analysis: Calculated for C.sub.25 H.sub.27 NO: C, 83.99; H, 7.61; N, 3.92. 
Found: C, 84,09; H, 7.63; N, 3.97. 
PREATION 68 
.alpha.,.alpha.-Diphenyl-4-piperidinemethanol 
A mixture of 35.8 g (0.1 mole) of 
.alpha.,.alpha.-diphenyl-1-(phenylmethyl)-4-piperidinemethanol and 5% 
palladium on carbon catalyst in 500 ml of absolute ethanol was 
hydrogenated at 60.degree. C. in a Parr apparatus for 3 days. The mixture 
was filtered through Celite.RTM. and the filtrate was concentrated to give 
a solid residue. The solid was triturated with petroleum ether 
(30.degree.-60.degree. C.), collected by filtration and dried to give 26.7 
g of title compound as a white solid. An analytical sample was obtained by 
recrystallization from 2-propanol-isopropyl ether, mp 
160.degree.-161.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.21 NO: C, 80.86; H, 7.92; N, 5.24. 
Found: C, 80.98; H, 7.96; N, 5.30. 
PREATION 69 
.alpha.-(4-Fluorophenyl)-.alpha.-methyl-4-piperidinemethanol 
To a solution of 49.9 g (0.2 mole) of 
1-acetyl-4-(p-fluorobenzoyl)piperidine in 500 ml of tetrahydrofuran was 
added dropwise 110 ml (0.35 mole) of a 3.2 molar solution of 
methylmagnesium bromide in ether ether* at ambient temperature. After 
addition was complete, the mixture was heated at reflux for 1 hr and then 
at ambient temperature overnight. The mixture was poured into 1.5 liters 
of a saturated ammonium chloride solution with vigorous stirring. The 
layers were separated and the aqueous layer was extracted twice with 300 
ml portions of methylene chloride. The combined organic layers were washed 
successively with 250 ml of water, 250 ml of a 40% sodium hydroxide 
solution, 250 ml of water and 250 ml of brine. The organic layer was dried 
over sodium sulfate and concentrated under reduced pressure to give 37.3 g 
(70% yield) of crude alcohol as a gum. 
FNT *Available commercially, e.g., Aldrich Chemical Co., Inc., 940 West Saint 
Paul Avenue, Milwaukee, Wis. 53233 USA. 
The gum was dissolved in 400 ml of 95% ethanol, heated with a solution of 
22.4 g (0.4 mole) potassium hydroxide in 100 ml of water, and heated at 
reflux overnight. The solution was concentrated under reduced pressure and 
the residue was triturated with water. The resulting solid was collected 
by filtration and recrystallized from 2-propanol to yield 19.8 g (44%) of 
title compound as an off-white powder, mp 184.degree.-186.degree. C. 
Analysis: Calculated for C.sub.13 H.sub.18 FNO: C, 69.93; H, 8.13; N, 6.27. 
Found: C, 70.00; H, 8.21; N, 6.27. 
PREATION 70 
.alpha.,.alpha.-Bis(4-methylphenyl)-1-(phenylmethyl)-4-piperidinemethanol 
A Grignard solution was prepared by the addition of 102.6 g (0.6 mole) of 
4-bromotoluene in 500 ml of dry tetrahydrofuran to a mixture of 12.5 g 
(0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. After the 
addition was complete, the mixture was heated at reflux for 1 hr to 
complete formation. To this Grignard reagent at ambient temperature was 
added in a stream 42.9 g (0.173 mole) of 
1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester in 250 ml of dry 
tetrahydrofuran. The solution was stirred at ambient temperature and then 
poured into 2.5 liters of a saturated ammonium chloride solution. The 
layers were separated and the aqueous layer was extracted twice with 375 
ml portions of methylene chloride. The combined organic layers were washed 
successively with 500 ml of water, 750 ml of a 3% sodium hydroxide 
solution, 250 ml of water and 250 ml of brine. The organic layer was dried 
over sodium sulfate and concentrated under pressure to give a gum as 
residue. The gum gradually cyrstallized. The solid was triturated with 
petroleum ether (30.degree.-60.degree. C.), collected by filtration and 
dried to yield 63.6 g (95%) of title compound as a white solid. An 
analytical sample was recrystallized from 2-propanol, mp 
115.degree.-117.degree. C. 
Analysis: Calculated for C.sub.27 H.sub.31 NO: C, 84.11; H, 8.10; N, 3.63. 
Found: C, 84.23; H, 8.13; N, 3.66. 
PREATION 71 
.alpha.,.alpha.-Bis(4-methylphenyl)-4-piperidinemethanol 
A solution of 38.5 g (0.1 mole) of 
.alpha.,.alpha.-bis(4-methylphenyl)-4-piperidinemethanol in 500 ml of 
absolute ethanol was hydrogenated at 50 psi and 60.degree. C. over one 5% 
palladium on carbon catalyst in Parr apparatus for 3 days. The cooled 
mixture was filtered through Celite.RTM. and the filtrate was concentrated 
under reduced pressure to give a glass as residue. The glass was 
crystallized from 2-propanol to yield 17.7 g (60%) of title compound as a 
white solid, mp 150.degree.-153.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.25 NO: C, 81.31; H, 8.53; N, 4.74. 
Found: C, 81.18; H, 8.62; N, 4.72. 
PREATION 72 
.alpha.,.alpha.-Bis(4-methoxyphenyl)-1-(phenylmethyl)-4-piperidinemethanol 
oxalate hydrate [1:1:0.5] compound with ethanol [1:0.5] 
A Grignard reagent was prepared by the addition of a solution of 112.2 g 
(0.6 mole) of 4-bromoanisole in 500 mo of dry tetrahydrofuran to a mixture 
of 12.5 g (0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. 
After the addition was complete, the mixture was heated at reflux for 0.5 
hr to complete formation. To this Grignard reagent at ambient temperature 
was added a solution of 42.8 g (0.173 mole) of the base of 
1-(phenylmethyl)-4-(piperidinecarboxylic acid ethyl ester in 250 ml of 
tetrahydrofuran in a stream. The mixture was stirred at ambient 
temperature overnight and then poured into 2.5 liters of a saturated 
ammonium chloride solution. The layers were separated and the aqueous 
layer was extracted twice with 375 ml portions of methylene chloride. The 
combined organic layers were washed successively with 500 ml of water, 750 
ml of a 3% sodium hydroxide solution, 250 ml of water and 250 ml of brine. 
The organic layer was dried over sodium sulfate and concentrated under 
reduced pressure to give a gum as residue. The gum was dissolved in 
2-propanol and converted to the oxalic acid salt. The solid was collected 
by filtration, washed with 2-propanol and ethyl ether and dried to yield 
84.8 g (97%) of title compound as a white powder. An analytical sample was 
recrystallized from absolute ethanol, mp 128.degree.-131.degree. C. (with 
decomposition) (slow heating; rapid heating gives mp .about.110.degree. 
C.). 
Analysis: Calc'd for C.sub.29 H.sub.33 NO.sub.7.0.5H.sub.2 O.C.sub.2 
H.sub.5 OH: C, 66.74; H, 6.91; N, 2.60. Found: C, 67.08; H, 6.77; N, 2.67. 
PREATION 73 
4-(3-Chloropropoxy)benzoic acid methyl ester 
A mixture of 30.4 g (0.2 mole) of methyl-4-hydroxybenzoate*, 63 g (0.4 
mole) of 1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous 
potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. 
The mixture was cooled, filtered and the filtrate concentrated to give an 
oil as residue. The oil crystallized when triturated with cold petroleum 
ether (30.degree.-60.degree. C.). The solid was collected by filtration 
and recrystallized from petroleum ether (60.degree.-110.degree. C.) to 
yield 42.9 g (94%) of title compound as a white solid, mp 
56.5.degree.-59.degree. C. 
FNT Available commercially, e.g., Aldrich Chemical Co., Inc., 940 West Saint 
Paul Avenue, Milwaukee, Wis. 53233 USA. 
Analysis: Calculated for C.sub.11 H.sub.13 ClO.sub.3 : C, 57.78; H, 5.73. 
Found: C, 57.91; H, 5.80. 
PREATION 74 
.alpha.,.alpha.-Bis(4-methoxyphenyl)-4-piperidinemethanol 
A solution of 36.7 g (0.088 mole) of 
.alpha.,.alpha.-bis(4-methoxyphenyl-1-(phenylmethyl)-4-piperidinemethanol 
in 500 ml of absolute ethanol was hydrogenated over 5% palladium on carbon 
catalyst at 60.degree. C. in a Parr apparatus for 3 days. The mixture was 
cooled, filtered through Celite.RTM., fresh catalyst added to the filtrate 
and the mixture hydrogenated. This process was repeated until no starting 
material was present by mass spectral analysis. The filtrate was 
concentrated and the residue was partitioned between methylene chloride 
and a 5% sodium hydroxide solution. The organic layer was dried over 
sodium sulfate and concentrated to give a solid residue. The solid was 
recrystallized from 2-propanol to yield 8.6 g (30%) of title compound as a 
white solid, mp 153.degree.-155.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.25 NO.sub.3 : C, 73.37; H, 7.70; N, 
4.28. Found: C, 73.42; H, 7.72; N, 4.30. 
PREATION 75 
4-(3-Chloropropoxy)-1,1'-biphenyl 
A mixture of 34 g (0.2 mole) of 4-phenylphenol, 63 g (0.4 mole) of 
1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium 
carbonate in 1 liter of acetone was heated at reflux for 17 hr. The 
mixture was cooled, filtered, and the filtrate concentrated under reduced 
pressure. The residue was triturated with petroleum ether 
(30.degree.-60.degree. C.) and a solid crystallized. The solid was 
collected by filtration and was subjected to flash chromatography on 400 g 
of silica gel on a 10-cm diameter column to remove starting phenol. The 
column was eluted with a 1:2 mixture of benzene and cyclohexane, and 
fractions containing title compound were combined and concentrated to give 
a solid residue. The solid was triturated with petroleum ether 
(30.degree.-60.degree. C.), collected by filtration, and dried to yield 
35.1 g (71%) of title compound as a white solid. An analytical sample was 
recrystallized from petroleum ether (60.degree.-110.degree. C.), mp 
65.degree.-66.degree. C. 
Analysis: Calculated for C.sub.15 H.sub.15 ClO: C, 73.02; H, 6.13. Found: 
C, 73.08; H, 6.12. 
PREATION 76 
1-[4-(3-Chloropropoxy)phenyl]-1-propanone 
A mixture of 37.6 g (0.25 mole) of 4'-hydroxypropiophenone (97%)*, 78.7 g 
(0.5 mole) of 1-bromo-3-chloropropane and 103.5 g (0.75 mole) of anhydrous 
potassium carbonate in 1 liter of acetone was heated at reflux for 18 hr. 
The mixture was cooled, filtered, and the filtrate concentrated under 
reduced pressure. The oily residue was dissolved in 500 ml of benzene and 
the solution stirred with potassium hydroxide pellets for 1.5 hr to remove 
unreacted phenol. The mixture was filtered and the filtrate was 
concentrated to give 56.1 g (99% yield) of title compound as an oil. The 
oil gradually crystallized and a portion of the solid was recrystallized 
from petroleum ether (60.degree.-110.degree. C.) to yield title compound 
as a fluffy, white solid, mp 41.degree.-43.degree. C. 
FNT Available commercially, e.g., Aldrich Chemical Co., Inc., 940 West Saint 
Paul Avenue, Milwaukee, Wis. 53233 USA. 
Analysis: Calculated for C.sub.12 H.sub.15 ClO.sub.2 : C, 63.58; H, 6.67. 
Found: C, 63.46; H, 6.82. 
PREATION 77 
4-[Bis(4-chlorophenyl)hydroxymethyl]-N,N-diethyl-1-piperidinecarboxamide 
A Grignard solution was prepared by the treatment of a slurry of 8.5 g 
(0.35 mole) of magnesium chips in 200 ml of dry tetrahydrofuran with a 
solution of 72.8 g (0.38 mole) of 1-bromo-4-chlorobenzene in 400 ml of 
tetrahydrofuran. After the addition was complete, the mixture was heated 
at reflux for 15 min to complete formation. To the Grignard solution at 
ambient temperature was added a solution of 38.4 g (0.15 mole) of 
1-[(diethylaminocarbonyl]-4-piperidine carboxylic acid ethyl ester in 200 
mo of tetrahydrofuran in a stream. The solution was stirred at ambient 
temperature overnight and poured into 2.5 liters of a saturated ammonium 
chloride solution. The layers were separated and the aqueous layer was 
extracted once with 500 ml of methylene chloride and once with 250 ml of 
methylene chloride. The combined organic layers were filtered through 
Celite.RTM. and the filtrate was washed successively with 500 ml of water, 
750 ml of a 4% sodium hydroxide solution, 250 ml of water and 250 ml of 
brine. The solution was dried over sodium sulfate and concentrated under 
reduced pressure to give a gum which gradually crystallized. The solid was 
triturated with petroleum ether (30.degree.-60.degree. C.), collected by 
filtration, and dried to yield 56.7 g (87%) of title compound as a white 
solid. An analytical sample was recrystallized from isopropanol, mp 
172.degree.-175.degree. C. 
Analysis: Calculated for C.sub.23 H.sub.28 Cl.sub.2 N.sub.2 O: C, 63.54; H, 
6.48; N, 6.43. Found: C, 63.60; H, 6.64; N, 6.25. 
PREATION 78 
3-Methoxy-4-(phenylmethyloxy)benzaldehyde 
A mixture of 4-hydroxy-3-methoxybenzaldehyde (100.0 g, 0.657 mole), benzyl 
bromide (112.4 g, 0.657 mole), and potassium carbonate (90.8 g, 0.657 
mole) was heated overnight at reflux in 600 ml of dry acetonitrile (dried 
over 4A molecular sieves). The reaction mixture was stripped to dryness on 
a rotary evaporator. A white solid was obtained which was recrystallized 
form ethanol and dried in vacuo overnight at 80.degree. C., to give 147.45 
g (92.6% yield) of white crystalline product, mp 58.degree.-63.degree. C. 
Analysis: Calculated for C.sub.15 H.sub.14 O.sub.3 : C, 74.36; H, 5.83. 
Found: C, 74.36; H, 5.78. 
PREATION 79 
5-Methoxy-2-nitro-4-(phenylmethoxy)benzaldehyde 
Reference: J. Med. Chem. 1977, Vol. 20, No. 1, p. 147. 
3-Methoxy-4-(phenylmethyloxy)benzaldehyde (48.0 g, 0.198 mole) was added in 
small portions over 0.5 hour to 200 ml of concentrated nitric acid cooled 
to 0.degree. C. in an acetone-dry ice bath. The temperature was maintained 
at 0.degree.-1.degree. C. for ten minutes. The temperature was allowed 
next to reach 15.degree. C. and suddenly but briefly allowed to rise to 
45.degree. C. The temperature was cooled to 20.degree. C. and then the 
reaction mixture was poured in ice/water. A yellow solid was obtained and 
filtered and washed with ethyl ether. A two gram sample was recrystallized 
from isopropanol. The light yellow solid isolated was dried in vacuo 
overnight at 80.degree. C. to give 0.92 g (32.5% yield) of light yellow 
solid, mp 122.degree.-124.degree. C. 
Analysis: Calculated for C.sub.15 H.sub.13 NO.sub.5 : C, 62.72; H, 4.56; N, 
4.88. Found: C, 62.42; H, 4.57; N, 5.17. 
PREATION 80 
5-Methoxy-2-nitro-4-(phenylmethyloxy)benzoic acid 
A solution of 5-methoxy-2-nitro-4-(phenylmethyloxy) benzaldehyde (45.11 g, 
0.157 mole) in 600 ml of acetone was prepared. To this solution was added 
400 ml of 10% potassium permanganate solution over 1 hr. The resultant 
mixture was stirred for 1 hr at room temperature. The reaction mixture was 
cooled to room temperature and filtered with Celite.RTM., acetone was 
removed. The resulting material was made acidic with concentrated 
hydrochloric acid. A yellow solid formed and was separated from aqueous 
solution, and air dried. The yellow solid was dissolved in ethyl acetate, 
and filtered through sodium sulfate to remove traces of manganese dioxide, 
after which 25.84 g of yellow solid was obtained. A 2 g sample was 
recrystallized from isopropyl alcohol. The yellow solid isolated was dried 
in vacuo overnight at 80.degree. C., to give 1.85 g (50% yield) of yellow 
solid, mp 188.degree. C. (with decomposition). 
Analysis: Calculated for C.sub.15 H.sub.13 NO.sub.6 : C, 59.41; H, 4.32; N, 
4.62. Found: C, 59.27; H, 4.40; N, 4.46. 
PREATION 81 
4-(4-Chlorobutyoxy)benzoic acid methyl ester 
A mixture of 30.4 g (0.2 mole) of methyl-4-hydroxybenzoate, 68.6 g (0.4 
mole) of 1-bromo-4-chlorobutane and 82.9 g (0.6 mole) of anhydrous 
potassium carbonate in 1 liter of acetone was heated at reflux for 17 hr. 
The mixture was cooled, filtered, and the filtrate concentrated under 
reduced pressure to give an oil which crystallized. The solid was 
triturated with cold petroleum ether (30.degree.-60.degree. C.), collected 
by filtration, and dried to yield 44.3 g (92%) of title compound as a 
white solid. An analytical sample, mp 28.5.degree.-29.degree. C., was 
prepared from petroleum ether (30.degree.-60.degree. C.). 
Analysis: Calculated for C.sub.12 H.sub.15 ClO.sub.3 : C, 59.39; H, 6.23. 
Found: C, 59.30; H, 6.34. 
PREATION 82 
1-[4-(4-Chlorobutoxy)-3-methoxyphenyl]ethanone 
A mixture of 16.6 g (0.1 mole) of acetovanillone, 34.3 g (0.2 mole) of 
1-bromo-4-chlorobutane and 41.4 g (0.3 mole) of anhydrous potassium 
carbonate in 500 ml of acetone was heated at reflux for 18 hr. The mixture 
was cooled, filtered, and the filtrate concentrated under reduced pressure 
to give an oil which readily crystallized. The solid was triturated with 
petroleum ether (30.degree.-60.degree. C.), collected by filtration, and 
dried to yield 24.4 g (95%) of title compound as an off-white solid. An 
analytical sample, mp 68.5.degree.-70.5.degree. C., was prepared from 
isopropyl ether. 
Analysis: Calculated for C.sub.13 H.sub.17 ClO.sub.3 : C, 60.82; H, 6.67. 
Found: C, 60.83; H, 6.91. 
PREATION 83 
1-Acetyl-.alpha.-(4-fluorophenyl)-.alpha.-phenyl-4-piperidinemethanol 
A solution (667 ml, 2 mole) phenylmagnesium bromide* (3 molar in ethyl 
ether) was diluted with 2 liters of anhydrous ethyl ether, cooled to 
0.degree.-10.degree. C., and treated with a solution of 148 g (0.6 mole) 
of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 1.5 liters of anhydrous 
tetrahydrofuran dropwise over a 1.5 hr period. The mixture was stirred at 
ambient temperature overnight and then poured into a solution of 107 g (2 
mole) of ammonium chloride in 2 liters of cold water. The mixture was 
extracted thrice with 1 liter portions of benzene. The combined extracts 
were washed with water, dried over magnesium sulfate, and concentrated to 
give a semi-solid as residue. The semi-solid was triturated with isopropyl 
ether and the mass crystallized. The solid was collected by filtration and 
dried to yield 87.8 g (45%) of title compound as a white solid. An 
analytical sample was recrystallized from 2-propanol, mp 
173.degree.-175.degree. C. 
FNT *Available commercially, e.g., Morton Thiokol, Inc., Alpha Products, 152 
Andover Street, Danvers, Mass. 01923 USA. 
Analysis: Calculated for C.sub.20 H.sub.22 FNO.sub.2 : C, 73.37; H, 6.77; 
N, 4.28. Found: C, 73.20; H, 6.93; N, 4.22. 
PREATION 84 
.alpha.,.alpha.-Bis(4-chlorophenyl)-4-piperidinemethanol 
To a slurry of 8.5 g (0.225 mole) of lithium aluminum hydride in 400 ml of 
anhydrous tetrahydrofuran was added a solution of 39.2 g (0.09 mole) of 
4-[bis(4-chlorophenyl)hydroxymethyl]-N,N-diethyl-1-piperidinecarboxamide 
in 400 ml of tetrahydrofuran in a stream over a 15 min period. The mixture 
was heated at reflux for 24 hr, cooled, and treated successively with 8.5 
ml of water, 25 ml of a 3N sodium hydroxide solution and 8.5 ml of water. 
The mixture was stirred for 0.5 hr and then filtered. The filtrate was 
concentrated under reduced pressure to give a gum which crystallized. The 
solid was triturated with petroleum ether (30.degree.-60.degree. C.), 
collected by filtration and recrystallized from benzene to yield 10.5 g 
(35%) of title compound as a white solid. An analytical sample was 
recrystallized from 2-propanol, mp 184.degree.-188.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.19 Cl.sub.2 NO: C, 64.30; H, 5.70; 
N, 4.17. Found: C, 64.59; H, 5.79; N, 4.16. 
PREATION 85 
.alpha.,.alpha.-Bis(4-fluorophenyl)-4-pyridineethanol 
A solution of 27.8 g (0.30 mole) of 4-picoline in 400 ml of tetrahydrofuran 
and under an atmosphere of nitrogen was cooled to -30.degree. C. in a 
dry-ice acetone bath. A solution of 2.5 moles n-butyllithium in hexane 
(119 ml, 0.30 mole) was added over 1 hr and the mixture was stirred for an 
additional 30 min at -30.degree. C. The reaction mixture was allowed to 
warm to room temperature over 1.5 hr, and 66.7 g (0.30 mole) of 
4,4'-difluorobenzophenone in 100 ml of tetrahydrofuran was added. The 
mixture was stirred for 2 hr and then was poured into an icy solution of 
ammonium chloride. A white solid was collected. The aqueous mixture was 
extracted with several portions of methylene chloride and the methylene 
chloride then removed in vacuo to give additional solid. The solid 
fractions were combined and recrystallized from a mixture of ether-hexane 
to give 63.14 g (67.9% yield) of title compound as a white, crystalline 
solid: mp 158.degree.-159.5.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.15 F.sub.2 NO: C, 73.30; H, 4.86; 
N, 4.50 Found: C, 73.27; H, 4.79; N, 4.51 
PREATION 86 
.alpha.,.alpha.-Bis(4-fluorophenyl)-4-piperidineethanol 
A mixture of 12.25 g (0.0394 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperidineethanol and 1.3 g of 5% 
platinum on carbon catalyst in 250 ml of acetic acid was shaken under an 
atmosphere of hydrogen (53 psi) for 9 hr. The solution was filtered 
through Celite.RTM., and the solvent was removed in vacuo. The residue was 
partitioned between methylene chloride and dilute sodium hydroxide. The 
solvent was removed in vacuo to give a solid, and recrystallization from 
acetonitrile gave 10.62 g (85.0% yield of title compound as a white, 
crystalline solid: mp 169.degree.-171.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.21 F.sub.2 NO: C, 71.90; H, 6.67; 
N, 4.41 Found: C, 71.98; H, 6.75; N, 4.54 
PREATION 87 
.alpha.-(4-Fluorophenyl)-.alpha.-phenyl-4-piperidinemethanol 
A mixture of 16.3 g (0.05 mole) of 1-acetyl-.alpha.-(4-fluorophenyl) 
-.alpha.-phenyl-4-piperidinemethanol and 5.6 g (0.1 mole) of potassium 
hydroxide in 150 ml of 95% ethanol and 20 ml of water was heated at reflux 
for 18 hr. The mixture was poured into 1.5 liters of ice-water and a solid 
precipitated. The gummy solid was collected by filtration and dried. The 
solid was dissolved in ethyl ether, filtered, and the filtrate slowly 
evaporated to 50 ml. The resulting solid was collected by filtration and 
recrystallized from 2-propanolisopropyl ether to yield 3.5 g (25%) of 
title compound as a white solid, m.p. 144.5.degree.-146.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.20 FNO: C, 75.76; H, 7.06; N, 4.91. 
Found: C, 75.91; H, 7.20; N, 4.93. 
PREATION 88 
4-[2,2,Bis(4-fluorophenyl)ethyl]pyridine hydrochloride [1:1] 
A mixture of 15.05 g (0.0484 mole) of .alpha.,.alpha.-bis(4-fluorophenyl) 
ethyl]-4-pyridineethanol, 3.2 g (0.10 mole) of phosphorus and 50 ml of 
56.9% hydrogen iodide in 150 ml of glacial acetic acid was heated at 
reflux for 11 hr. The solvent was removed in vacuo, and the residue was 
partitioned between methylene chloride and dilute sodium hydroxide. The 
methylene chloride solution was dried over magnesium sulfate, and the 
solvent was removed in vacuo to give an oil. This was dissolved in a 
mixture of methanol and ether, and an excess of ethereal hydrogen chloride 
was added. The solvent was removed in vacuo, and the residue was 
recrystallized from a mixture of acetonitrile and ether to give 13.89 g 
(86.7% yield) of title compound as a white, crystalline solid, m.p. 
197.degree.-199.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.16 ClF.sub.2 N: C, 68.78; H, 4.86; 
N, 4.22. Found: C, 68.58; H, 5.17; N, 4.23. 
PREATION 89 
4-[2,2-Bis(4-fluorophenyl)ethyl]piperidine hydrochloride hydrate [1:1:0.5] 
A mixture of 10.0 g (0.30 mole) 
.alpha.,.alpha.-bis(4-fluoropheny)-4-pyridineethanol of 1.2 g of 5% 
platinum on carbon catalyst in 200 ml of acetic and was shaken under an 
atomsphere of hydrogen (49 psi)for 16 hr. The solution was filtered 
through Celite.RTM., and the solvent was removed in vacuo. The residue was 
partitioned between methylene chloride and dilute sodium hydroxide. The 
solvent was removed in vacuo to give an oil. This was dissolved in 
methanol, an excess of ethereal hydrogen chloride was added and ether was 
added. A precipitate was collected to give 7.58 g (72.4%)as a white, 
crystalline solid, m.p. 171.degree.-173.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.22 ClF.sub.2 N.0.5H.sub.2 O: C, 
65.80; H, 6.68; N, 4.04. Found: C, 65.79; H, 6.80; N, 4.05. 
PREATION 90 
4-[2,2-Bis(4-fluorophenyl)ethylene]piperidine oxalate[1:1] 
A mixture of 8.44 g (0.0266 mole) of .alpha.,.alpha.-fluorophenyl) 
-4-piperidineethanol, and 25 ml of concentrated sulfuric acid in 200 ml of 
glacial acetic acid was heated at reflux for 4 hr. The solvent was removed 
in vacuo, and the residue was made basic with 50% sodium hydroxide. The 
basic mixture was extracted with methylene chloride, and the methylene 
chloride solution was dried over magnesium sulfate. The solvent was 
removed in vacuo to give an oil. The oil was dissolved in a mixture of 
methanol/ether, and a slight excess of oxalic acid was added. Ether was 
added, and a precipitate was collected to give 9.79 g (85.0% yield) of 
title compound as a white, crystalline solid, m.p. 
225.degree.-225.5.degree. C. with decomposition. 
Analysis: Calculated for C.sub.21 H.sub.21 F.sub.2 NO.sub.4 : C, 64.78; H, 
5.44; N, 3.60. Found: C, 64.95; H, 5.56; N, 3.61. 
PREATION 91 
4-[Bis(4-chlorophenyl)methyl]piperidine oxalate hydrate [1:1:0.5] 
A mixture of 4-[bis(4-chlorophenyl)methylene]piperidine (13.05 g, 0.041 
mole), phosphorus(45.0 g,1.45 mole), glacial acetic acid (300 ml)and 57% 
hydriodic acid(230 ml) was heated at reflux for 72 hr. The mixture was 
cooled to room temperature, stirred 5 min with Celite.RTM., and filtered. 
The filtrate was made basic with ice/50% sodium hydroxide. The alkaline 
layer was extracted with chloroform. The chloroform layer was dried over 
sodium sulfate, filtered, and solvent removed to give a brown oil. A 0.65 
g portion of the oil was converted to the oxalate salt and recrystallized 
from ethanol-ethyl ether. A white solid was isolated and dried in vacuo 
overnight at 80.degree. C. This provided 0.46 g (59.1% yield) of white, 
crystalline solid, m.p. 219.degree.-220.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.21 Cl.sub.2 NO.sub.4 0.5H.sub.2 O: 
C, 57.29; H, 5.29; N, 3.34. Found: C, 57.26; H, 4.99; N, 3.36. 
PREATION 92 
Cyclohexyl[1-(phenylsulfonyl)-4-piperidinyl]methanone 
To a solution of 25.1 g (0.085 mole) of 1-(phenylsulfonyl) 
-4-piperidine-carboxylic acid, ethyl ester in 500 ml of dry 
tetrahydrofuran cooled to 0.degree. C. and under an atmosphere of 
nitrogen, was added 95 ml of a 2 molar solution(0.19 mole) of 
cyclohexylmagnesium bromide in ether. The mixture was stirred for 2 hr at 
ambient temperature and then was quenched on an icy solution of ammonium 
chloride. The mixture was extracted with methylene chloride. The methylene 
chloride solution was dried over magnesium sulfate, and the solvent was 
removed in vacuo to give a semisolid material. This was recrystallized 
from ethanol to give 8.50 g (29.8% yield) of title compound as a white, 
crystalline solid, m.p. 141.degree.-143.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.25 NO.sub.3 S: C, 64.45; H, 7.51; 
N, 4.18. Found: C, 64.39; H, 7.82; N, 4.20. 
PREATION 93 
4-[2,2-Bis(4-fluorophenyl)ethylene]pyridine 
A mixture of 1.57 g (0.0050 mole) of .alpha.,.alpha.-bis(4-fluorophenyl) 
-4-pyridineethanol, 10 ml of concentrated sulfuric acid and 80 ml of 
glacial acetic acid was heated at reflux for 2 hr. The solvent was removed 
in vacuo, and the residue was made basic with an icy solution of dilute 
sodium hydroxide. The aqueous mixture was extracted with methylene 
chloride, and the methylene chloride extract was dried over magnesium 
sulfate. The solvent was removed in vacuo to give a colorless oil. This 
was crystallized from ether-hexane to give 0.74 g (50% yield) of title 
compound as a white, crystalline solid, m.p. 111.degree.-112.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.13 F.sub.2 N: C, 77.80; H, 4.47; N, 
4.78. Found: C, 77.78; H, 4.42; N, 4.74. 
PREATION 94 
.alpha.-Cyclohexyl-.alpha.-(4-fluorophenyl)-1(phenylsulfonyl) 
-4-piperidinemethanol 
A solution of (4-fluorophenyl)[1-(phenylsulfonyl) -4- 
piperidinyl]methanone(20.8 g, 0.06 mole)in 250 ml of tetrahydrofuran 
(dried over 4A sieves) was prepared. This solution was stirred 0.5 hr 
under nitrogen atmosphere in an ice bath. Next, cyclohexylmagnesium 
chloride (35 ml of 2 molar in ethyl ether, 0.070 mole)was added dropwise 
with a syringe(under nitrogen atmosphere). The resulting solution was 
stirred for 48 hr allowing the reaction solution to cool to room 
temperature. The reaction mixture was concentrated to dryness and treated 
with aqueous ammonium chloride. The aqueous solution was extracted with 
chloroform, and the chloroform layer was washed with water. The chloroform 
layer was dried over sodium sulfate and filtered, and solvent removed to 
give a fluffy, white residue. This material was subjected to flash 
chromatography on silica gel using 20% ethyl acetate-80% hexanes, and 30% 
ethyl acetate-70% hexanes for elution. Fractions containing a single spot 
were combined, and solvent was removed in vacuo. A fluffy, white residue 
was obtained and dried in vacuo overnight at 80.degree. C. in the presence 
of phosphorus pentoxide. This procedure produced 16.72 g (74.7% yield) of 
the title compound as a white, crystalline solid, m.p. 
106.degree.-109.degree. C. 
Analysis: Calculated for C.sub.24 H.sub.30 FNO.sub.3 S: C, 66.79; H, 7.01; 
N, 3.24. Found: C, 66.78; H, 7.09; N, 3.21. 
PREATION 95 
.alpha.,.alpha.-Bis(3-fluorophenyl)-1-piperidinemethanol 
To a suspension of 7.78 g (0.33 mole) of magnesium turnings and a crystal 
of iodine in 800 ml of anhydrous ether under an atmosphere of nitrogen 
atmosphere was slowly added a solution of 3-bromofluorobenzene in 200 ml 
of ether. The mixture was stirred for 1.5 hr and 30.6 g (0.103 mole) of 
ethyl 1-benzenesulfonylisonipecotate was added as a solid. Tetrahydrofuran 
(300 ml)was added, and the mixture was stirred at room temperature for 12 
hr. The mixture was poured into an icy solution of ammonium chloride. The 
aqueous mixture was extracted with methylene chloride, and the resulting 
residue was recrystallized from ether to give 24.14 g (52.9%) of the title 
compound as a white, crystalline solid, m.p. 183.degree.-185.degree. C. 
Analysis: Calculated for C.sub.24 H.sub.23 F.sub.2 NO.sub.3 S: C, 65.00; H, 
5.23; N, 3.16. Found: C, 64.95; H, 5.38; N, 3.15. 
PREATION 96 
4-[Bis(3-fluorophenyl)methyl]piperidine hydrochloride [1:1] 
A mixture of 15.25 g (0.0344 mole) of .alpha.,.alpha.-bis(3-fluorophenyl) 
-1-phenylsulfonyl-4-piperidinemethanol, 50 mol of 57% hydrogen iodide and 
3.4 g (0.11 mole) of phosphorous in 300 ml of glacial acetic acid was 
heated at reflux for 40 hr. The reaction mixture was filtered, and the 
solvent was removed from the filtrate in vacuo. The residue was 
partitioned between methylene chloride and dilute sodium hydroxide. The 
methylene chloride solution was dried over magnesium sulfate, and the 
solvent was removed in vacuo. The residue was dissolved in methanol, 
excess ethereal hydrogen chloride was added and anhydrous ether was added. 
A white precipitate was collected to give 7.04 g (63.2% yield) of title 
compound as a white, crystalline solid, m.p. 260.degree.-262.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.20 ClF.sub.2 N: C, 66.77; H, 6.23; 
N, 4.33. Found: C, 66.45; H, 6.26; N, 4.28. 
PREATION 97 
5-Methoxy-2-nitro-4-(phenylmethoxy)benzamide 
A solution of 5-methoxy-2-nitro-4-(phenylmethoxy)benzoic acid(25.84 g, 
0.085 mole)and thionyl chloride(200 ml)was heated overnight at gentle 
reflux in 100 ml of methylene chloride. The reaction mixture was 
concentrated to dryness and dried in vacuo. To this residue was added 200 
ml of dioxane(dried over molecular sieves). Ammonia was slowly added to 
the solution with constant agitation. A brown solid was formed and the 
mixture was filtered. The brown solid was washed with dioxane, water, and 
2-propanol. The gray solid thus obtained was dried in vacuo at room 
temperature(23.2 g). A 2 g portion was triturated in refluxing ethanol and 
then cooled to room temperature. A white solid was collected by filtration 
and dried in vacuo at 80.degree. C. overnight. This furnished 1.72 g 
(77.5% yield) of white, crystalline solid, m.p. 222.degree.-223.5.degree. 
C. with decomposition. 
Analysis: Calculated for C.sub.15 H.sub.14 N.sub.2 O.sub.5 : C, 59.60; H, 
4.67; N, 9.27. Found: C, 59.48; H, 4.68; N, 9.19. 
PREATION 98 
.alpha.-Cyclohexyl-.alpha.-(4-fluorophenyl)-4-pyridinemethanol 
A solution of (4-fluorophenyl)(4-pyridinyl)methanone(23.44 g, 0.12 mole) 
was prepared in 400 ml of tetrahydrofuran. The solution was chilled in an 
ice bath and stirred under nitrogen atmosphere for 0.5 hr. A solution of 
cyclohexylmagnesium chloride (70 ml of a 2 molar solution) was added via 
syringe and a dark brown solution resulted immediately. This solution was 
stirred 0.5 hr at room temperature and then heated at reflux for 4 hr. The 
solution was cooled to room temperature and solvents were removed. The 
residue was treated with aqueous ammonium chloride and extracted with 
chloroform. The chloroform layer was dried over sodium sulfate, filtered, 
and solvent removed to give a dark brown residue. This residue was 
triturated with ethyl ether and then chilled at about 0.degree. C. and 
solvent removed to give an oil. This oil was dried in vacuo overnight at 
80.degree. C. The oil crystallized to give 2.95 g)33.8% yield) of white 
crystalline solid, m.p. 78.degree.-81.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.20 FN: C, 80.26; H, 7.48; N, 5.20. 
Found: C, 79.96; H, 7.45; N, 5.23. 
PREATION 99 
4-[(Cyclohexyl)(4-fluorophenyl)methyl]pyridine 
A mixture of the free base of .alpha.-cyclohexyl-.alpha.-(4-fluorophenyl) 
-4-pyridinemethanol (16.54 g, 0.058 mole), 57% hydrogen iodide (250 ml), 
glacial acetic acid (250 ml), and phosphorus (50.0 g) was heated overnight 
at reflux. The reaction mixture was cooled and filtered with Celite.RTM.. 
The volume of the filtrate was concentrated to 100 ml. Ice/50% sodium 
hydroxide was added and the aqueous phase was extracted with chloroform. 
The chloroform layer was dried over sodium sulfate, filtered, and solvent 
removed to give a green oil. A 4 g portion of this oil was subjected to 
flask chromatography on silica gel using 20% ethyl acetate-hexanes for 
elution. Fractions of similar purity were combined and solvent removed to 
give an oil. This oil was dried in vacuo overnight at 80.degree. C. The 
oil crystallized to give 2.95 g (33.9% yield) of white, crystalline solid, 
m.p. 78.degree.-81.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.20 FN: C, 80.26; H, 7.48; N, 5.20. 
Found: C, 79.96; H, 7.45; N, 5.23. 
PREATION 100 
4-[(Cyclohexyl)(4-fluorophenyl)methyl]piperidine 
A mixture of 4-[(cyclohexyl)(4-fluorophenyl)methyl]pyridine (10.42 g, 0.039 
mole), platinum oxide (1.5 g), and 10 drops of concentrated hydrochloric 
acid in 200 ml of glacial acetic was subjected to hydrogenation at 
80.degree. C. and 300 p.s.i. overnight, after which NMR analysis showed 
50% desired product and 50% starting material. The reaction was repeated 
using 5% platinum on carbon at 85.degree. C. and 1400 p.s.i. overnight. 
The reaction mixture was then cooled to room temperature and filtered. 
Solvent was removed by rotary evaporator. The oil obtained was dissolved 
in chloroform and extracted with 5% sodium hydroxide and water. The 
chloroform layer was dried over sodium sulfate, filtered, and solvent 
removed to give 9.94 g of brown oil. NMR analysis showed a 75%-25% mixture 
of product and starting material. The 9.94 g of oil obtained was dissolved 
in methanol and subjected to flash chromatography on silica gel using 
methanol and ammonium hydroxidemethanol for elution. Fractions of similar 
purity were combined and solvent removed. The clear oil obtained was dried 
in vacuo overnight at 80.degree. C., to give 5.86 g (59.6% yield) of title 
compound as a clear oil. 
H.sup.1 NMR (CDCl.sub.3): .delta. 6.9-7.2 (d, 7, aromatic), .delta. 0.8-3.3 
(m, 22, aliphatics). 
Analysis: Calculated for C.sub.18 H.sub.26 FN: C, 78.50; H, 9.52; N, 5.09. 
Found: C, 78.26; H, 9.41; N, 5.06. 
PREATION 101 
1-Acetyl-4-(p-fluorophenyl)piperidine 
A mixture of 93 g of (0.7 mole) of aluminum chloride in 150 ml of 
fluorobenzene was stirred while 70 g (0.37 mole) of 1-acetylisonipecotic 
acid chloride was added in small portions. After the addition was 
complete, the mixture was refluxed for 1 hr. The mixture was poured onto 
ice and the 2 resulting layers were separated. The aqueous layer was 
extracted twice with chloroform and the chloroform extracts were added to 
the fluorobenzene which was separated previously. The organic solution was 
dried over anhydrous sodium sulfate and filtered. The filtrate was 
concentrated and 73.7 g (80% yield) of 
1-acetyl-4-(p-fluorobenzoyl)piperidine was obtained as a crystalline 
residue. Recrystallization from ligroin-isopropyl ether gave a white, 
crystalline product melting at 75.degree.-78.degree. C. 
Analysis: Calculated for C.sub.14 H.sub.16 FNO.sub.2 : C, 67.45; H, 6.47; 
N, 5.62. Found: C, 67.26; H, 6.50; N, 5.54. 
PREATION 102 
(4-Fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone 
A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (53.30, 0.219 
mole) and benzenesulfonyl chloride (44 g, 0.25 mole) in 500 ml of pyridine 
was stirred at room temperature overnight. The solvent was removed in 
vacuo, and the residue was partitioned between methylene chloride and 
dilute sodium hydroxide. The methylene chloride solution was extracted 
with dilute sulfuric acid and then dried over magnesium sulfate. The 
volume was reduced to 400 ml, hexane was added and 39.20 g (50.6%) of 
title compound was collected as a white, crystalline solid, m.p. 
156.5.degree.-158.degree.. 
Analysis: Calculated for C.sub.18 H.sub.18 FNO.sub.3 S: C, 62.23; H, 5.22; 
N, 4.03. Found: C, 62.13; H, 5.20; N, 4.13. 
PREATION 103 
4-[Bis(4-fluorophenyl)methyl]-1-(3-chloropropyl)piperidine 
A solution of 4-[bis(4-fluorophenyl)methyl]-1-piperidinepropanol (40.27 g, 
0.117 mole) and thionyl chloride (17.90 g, 0.150 mole) in 350 mL of 
chloroform was stirred at room temperature for 0.5 hr. The solution was 
heated at reflux for 6 hr, cooled to room temperature, and then 
concentrated to dryness. The gum obtained was dissolved in chloroform and 
extracted with saturated sodium bicarbonate. The chloroform layer was 
dried (anhydrous sodium sulfate), filtered, and solvent removed to give a 
reddish-brown oil (42.11 g). An 8 gram sample was subjected to flash 
chromatography on silica gelusing 50-50 v/v of ethyl acetate-hexanes for 
elution. After combining fractions, removing solvent, and drying the oil 
obtained in vacuo, 6.84 g (84.6% yield) of brown oil was obtained, the 
title compound. 
H.sup.1 NMR (CDCl.sub.3): .delta.: 6.7-7.3 (m, 8, aromatics), 3.4-3.7 (m, 
3, methine adjacent to aromatics and methylenes adjacent to Cl), 1.0-3.0 
(m, 13, remaining alaphatics). 
Analysis: Calculated for C.sub.12 H.sub.24 ClF.sub.2 N: C, 69.32; H, 6.65; 
N, 3.85. Found: C, 69.09; H, 6.60; N, 3.84. 
PREATION 104 
(4-Fluorophenyl)(4-pyridinyl)methanone 
A solution of 4-cyanopyridine (20.8 g, 0.2 mole) in 300 ml of 
tetrahydrofuan was cooled in an ice bath. Next, a 100 ml solution of 
p-fluorophenyl magnesium bromide (2 moles in ethyl ether) was added with a 
syringe under nitrogen atmosphere with stirring. The resulting solution 
was stirred at room temperature for 1 hr and then heated at reflux for 6 
hr. The solution was concentrated to dryness and then transferred (via 
chloroform) to a mixture of ice and concentrated hydrochloric acid (100 
ml). The aqueous phase was made alkaline (using 5% sodium hydroxide 
solution) and the chloroform layer separated with the aid of Celite.RTM.. 
The chloroform layer was dried over sodium sulfate and filtered, and 
solvent removed to give a dark brown oil (33.1 g). The oil was subjected 
to flash chromatography on silica gel using 40% ethyl acetate-hexanes and 
50% ethyl acetate-hexanes for elution. Fractions of similar purity were 
combined and solvent removed to give a yellow solid (25.81 g). A 2 g 
portion was recrystallized from 100 ml of hexanes. A light yellow solid 
was isolated and dried in vacuo overnight at room temperature, to give 
1.88 g (77.3% yield) of light yellow solid, m.p. 85.degree.-88.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.8 FNO: C, 71.64; H, 4.01; N, 6.96. 
Found: C, 71.83; H, 3.95; N, 6.99. 
PREATION 105 
5-Oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester 
A solution of 158.2 g (1.0 mole) of dimethylitaconate and 107.2 g (1.0 
mole) of benzylamine in 750 ml of methanol was let stand at ambient 
temperature over the weekend. The solution was filtered and the filtrate 
was concentrated under reduced pressure to give an oil as residue. The oil 
crystallized when it was triturated with petroleum ether 
(30.degree.-60.degree. C.). The solid was collected by filtration and 
dried to yield 225.5 g (97%) of the title compound as a white powder. An 
analytical sample, m.p. 63.degree.-65.degree. C., was prepared from 
2-propyl ether. 
Analysis: Calculated for C.sub.13 H.sub.15 NO.sub.3 : C, 66.94; H, 6.48; N, 
6.01. Found: C, 66.82; H, 6.48; N, 6.01. 
PREATION 106 
4-[Bis(4-fluorophenyl)hydroxymethyl]-1-(phenylmethyl)-2-pyrrolidinone 
A Grignard solution was prepared by the addition of 96.3 g (0.55 mole) of 
4-bromofluorobenzene in 150 ml of dry tetrahydrofuran to a mixture of 12.2 
g (0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. After the 
reaction had subsided, the mixture was diluted with 350 ml of 
tetrahydrofuran and heated at reflux for 15 min to complete formation. 
The Grignard solution was added to a solution of 46.7 g (0.2 mole) of 
5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester in 250 ml 
of tetrahydrofuran and the mixture was stirred at ambient temperature 
overnight. The solution was poured into 2.5 liters of a cold ammonium 
chloride solution. The layers were separated and the aqueous layer was 
extracted once with 500 ml of methylene chloride and once with 250 ml of 
methylene chloride. The combined organic layers were washed once with 250 
ml of water, once with 250 ml of a 4% sodium hydroxide solution, once with 
250 ml of water and once with 250 ml of brine, dried over sodium sulfate 
and concentrated under reduced pressure to give a gum as residue. The gum 
crystallized when saturated with petroleum ether. The solid was collected 
by filtration, washed with petroleum ether and recrystallized from 
2-propanol to yield 39.4 g (50%) of the title compound as an off-white 
solid, m.p. 158.degree.-160.degree. C. 
Analysis: Calculated for C.sub.24 H.sub.21 F.sub.2 NO.sub.2 : C, 73.27; H, 
5.38; N, 3.56. Found: C, 73.09; H, 5.38; N, 3.53. 
PREATION 107 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-(phenylmethyl)-3-pyrrolidinemethanol 
To a stirred slurry of 7.6 g (0.02 mole) of lithium aluminum hydride in 150 
ml of freshly distilled tetrahydrofuran was added dropwise, over a 45 min 
period, a solution of 38.5 g (0.098 mole) of 
4-[bis(4-fluorophenyl)hydroxymethyl-1-(phenylmethyl)-2-pyrrolidinone in 
150 ml of tetrahydrofuran. After the addition was complete, the mixture 
was heated at reflux for 2 hr and then let stir at ambient temperature 
overnight. The excess lithium aluminum hydride was decomposed by the 
successive addition of 8 ml of water, 8 ml of a 15% sodium hydroxide 
solution, and 24 ml of water. The mixture was stirred for 30 min and 
filtered. The filtrate was concentrated under reduced pressure and the 
residue crystallized when triturated with petroleum ether 
(30.degree.-60.degree. C.). The solid was collected by filtration and 
recrystallized from 2-propanol to yield 30.3 g (81%) of the title compound 
as a white solid, mp 99.degree.-100.degree. C. 
Analysis: Calculated for C.sub.24 H.sub.23 F.sub.2 NO: C, 75.97; H, 6.11; 
N, 3.69. Found: C, 76.07; H, 6.06; N, 3.70. 
PREATION 108 
.alpha.,.alpha.-Bis(4-fluorophenyl)-3-pyrrolidinemethanol 
A solution of 26.6 g (0.07 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-(phenylmethyl)-3-pyrrolidinemethanol 
in 500 ml of ethanol was hydrogenated at 60 psi and 70.degree. C. over 5% 
palladium on carbon catalyst for 2 days. The mixture was cooled and 
filtered through Celite.RTM.. The filtrate was concentrated under reduced 
pressure to give a solid as residue. The solid was triturated with 
petroleum ether (30.degree.-60.degree. C.), collected by filtration and 
dried to yield 18.5 g (91%) of the title compound as a white solid, m.p. 
152.degree.-153.degree. C. (2-propanol). 
Analysis: Calculated for C.sub.17 H.sub.17 F.sub.2 NO: C, 70.57; H, 5.92; 
N, 4.84. Found: C, 70.90; H, 6.02; N, 4.83. 
PREATION 109 
4-[(3,4-Difluorophenyl)(4-fluorophenyl)methylene]piperidine oxalate [1:1] 
A mixture of 30.19 g (0.065 mole) of 
.alpha.-(3,4-difluorophenyl)-.alpha.-(4-fluorophenyl)-1-phenylsulfonyl-4-p 
iperidine methanol, 4.0 g (0.125 mole) of phosphorus and 160 ml of 47% 
hydriodic acid in 400 ml of glacial acetic acid was heated at reflux for 
52.5 hours. The solvent was removed in vacuo, and the residue was 
partitioned between methylene chloride and dilute sodium hydroxide. The 
methylene chloride solution was dried over sodium sulfate and was filtered 
through a sentered glass funnel (fine porosity), and the solvent was 
removed in vacuo. The residue was flash chromatographed (silica gel, 
elution with methanol and then with a 99/1 mixture of methanol/ammonium 
hydroxide) to give two separate products; the non-salt forms of the title 
compound and 4-[(3,4-difluorophenyl)(4-fluorophenyl)methyl]piperidine. 
Both of these were converted to the oxalate salts. The title compound was 
recrystallized from methanol ether to give 0.47 g (0.24%) of product as a 
white, crystalline solid, mp 195.degree.-198.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.18 F.sub.3 NO.sub.4 : C, 61.07; H, 
4.61; N, 3.56. Found: C, 60.88; H, 4.57; N, 3.57. 
PREATION 110 
4-[(3,4-Difluorophenyl)(4-fluorophenyl)methyl ]piperidine oxalate hydrate 
[1:1:0.5] 
A mixture of 30.19 g (0.065 mole) of 
.alpha.-(3,4-difluoropheny)-.alpha.-(4-fluorophenyl)-1-phenylsulfonyl-4-pi 
peridinemethanol, 14.0 g (0.125 mole) of phosphorus and 160 ml of 47% 
hydriodic acid in 400 ml of glacial acetic acid was heated at reflux for 
52.5 hours. The solvent was removed in vacuo, and the residue was 
partitioned between methylene chloride and dilute sodium hydroxide. The 
methylene chloride solution was dried over sodium sulfate and was filtered 
through a sentered glass funnel (fine porosity), and the solvent was 
removed in vacuo. The residue was flash chromatographed (silica gel, 
elution with methanol and then with a 99/1 mixture of methanol/ammonium 
hydroxide) to give two separate products; the non-salt forms of 
4-[(3,4-difluorophenyl)(4-fluorophenyl)methylene]piperidine and the title 
compound. The title compound was recrystallized from acetonitrile to give 
5.64 g. (21.5%) of a white solid, m.p. 78.degree.-83.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.20 F.sub.3 NO.sub.4.0.5H.sub.2 O: 
C, 59.40; H, 5.23; N, 3.46. Found: C, 59.58; H, 5.05; N, 3.48. 
PREATION 111 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolid 
ineacetonitrile 
The sodium salt of 4-fluoro-.alpha.-(4-fluorophenyl)benzeneacetonitrile was 
prepared in dimethylsulfoxide from 
4-fluoro-.alpha.-(4-fluorophenyl)benzeneacetonitrile (11.60 g, 0.0506 
mole) and sodium hydride (60%; 2.02 g, 0.0506 mole). Next, 
1-[(4-methylphenyl)sulfonyl]-3-pyrrolidino(4-methylphenyl)sulfonate ester 
(20.0 g, 0.0506 mole) in 200 ml of dimethyl sulfoxide was added. The 
solution was stirred overnight at 55.degree. C. The solvent was then 
removed. A dark brown oil was obtained and dissolved in chloroform. The 
organic layer was extracted with 1N sulfuric acid and 5% sodium hydroxide. 
The chloroform layer was dried (over sodium sulfate) and filtered; solvent 
was removed to give a dark brown oil. The oil was triturated with 
2-propanol and placed in the freezer over the weekend. A brown solid was 
separated by filtration (18.33 g). A one gram sample of the solid was 
recrystallized from 2-propanol. A light brown solid was separated and 
dried in vacuo overnight at 80.degree. C. in the presence of phosphorus 
pentoxide. This process furnished 0.57 g (45.7% based on aliquot taken) of 
light brown solid, m.p. 181.degree.-183.degree. C. 
Analysis: Calculated for C.sub.25 H.sub.22 F.sub.2 N.sub.2 O.sub.2 S: C, 
66.36; H, 4.90; N, 6.19. Found: C, 65.80; H, 4.91; N, 6.03. 
PREATION 112 
.alpha.,.alpha.-Bis(4-fluorophenyl)-3-pyrrolidineactonitrile oxalate 
hydrate [1:1:0.5] 
A mixture of 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-3-pyrroli 
dineactonitrile (16.6 g, 0.0367 mole), phenol (50 g, 0.53 mole) and 300 ml 
of 48% hydrobromic acid was heated at reflux for two hours. The reaction 
mixture was cooled to room temperature and made alkaline with ice/50% 
sodium hydroxide. The aqueous layer was extracted with chloroform. The 
chloroform layer was back extracted with 5% sodium hydroxide, dried over 
sodium sulfate, filtered, and solvent removed to produce a dark brown oil. 
The dark brown oil was dissolved in chloroform and extracted with 1N 
sulfuric acid. This acidic layer was discarded. The chloroform layer was 
extracted with base and solvent was removed to give a dark brown oil. This 
oil was converted to the oxalate salt, and the salt was recrystallized 
from methanol-ethyl ether. A white solid was isolated and dried in vacuo 
overnight at 80.degree. C., to give 7.17 g (49.2%) of the title compound 
as an off-white solid, mp 88.5.degree.-90.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.18 F.sub.2 N.sub.2 
O.sub.4.0.5H.sub.2 O: C, 60.45; H, 4.82; N, 7.05. Found: C, 60.52, H, 
4.56; N, 7.01. 
PREATION 113 
1-[(4-Methylphenyl)sulfonyl]-3-piperidinemethanol(4-methylphenyl)sulfonate 
ester 
A solution of 3-piperidinemethanol (50.0 g, 0.434 mole) in 300 ml of 
acetonitrile (dried over 4A molecular sieves) was prepared. This solution 
was cooled in an ice bath, and a solution of triethylamine (150 ml in 200 
ml of acetonitrile) was added while simultaneously adding a solution of 
p-toluenesulfonyl chloride (191 g, 1.0 mole) in 300 ml of acetonitrile. 
After the additions were complete, the resulting solution was stirred 3.5 
hours at room temperature. The mixture was filtered and solvents were 
removed by a rotary evaporator to give a dark brown oil. The oil was 
dissolved in chloroform and extracted with 5% sodium hydroxide and also 1N 
sulfuric acid. The chloroform layer was dried over sodium sulfate and 
filtered, and solvent was removed to give a dark brown oil. This oil was 
triturated with isopropyl ether to give a brownish-white solid. This light 
brown solid was separated and then triturated with hot 2-propanol. The 
mixture was chilled in the freezer and filtered. A light brown solid was 
isolated and dried in vacuo overnight at 65.degree. C. (142.29 g). A 5 
gram sample of this material was recrystallized from isopropyl alcohol, 
and the brown solid isolated was dried overnight in vacuo at 80.degree. C. 
This provided 3.55 g (55% yield based on aliquot taken) of light brown 
solid, m.p. 108.degree.-109.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.25 NO.sub.5 S.sub.2 : C, 56.72; H, 
5.95; N, 3.31. Found: C, 56.43; H, 6.00; N, 3.32. 
PREATION 114 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-3-piperidi 
nepropanenitrile 
The sodium salt of 4-fluoro-60-(4-fluorophenyl)benzeneacetonitrile was 
prepared in 350 ml of dimethyl sulfoxide (dried over 4A molecular sieves) 
from sodium hydride (60% 4.37 g, 0.109 mole) and 
4-fluoro-.alpha.-(4-fluorophenyl)benzeneacetonitrile (25.0 g, 0.109 mole). 
The resulting dark brown solution was stirred at room temperature for 1 
hour. 1-[(4-Methylphenyl)sulfonyl]piperidinemethanol 
(4-methylphenyl)sulfonate ester (46.18 g, 0.109 mole) was added and the 
resulting solution was stirred for 2 hours at room temperature. The 
solution was then stirred overnight at 60.degree. C. The dimethyl 
sulfoxide was removed by rotary evaporator. A dark brown residue was 
obtained which was dissolved in chloroform. The chloroform layer was 
extracted several times with water. The chloroform layer was dried over 
sodium sulfate, filtered, and solvent removed to give a thick brown oil. 
The oil was triturated with isopropyl ether to give a white solid (46.54 
g). A 5 g portion of this solid was recrystalizzed from 2-propanol to give 
a white solid and was isolated and dried in vacuo overnight at 80.degree. 
C. This furnished 3.96 g (70.4% yield) of the title compound as a white, 
crytalline product, m.p. 142.degree.-143.degree. C. 
Analysis: Calculated for C.sub.27 H.sub.26 F.sub.2 N.sub.2 O.sub.2 S: C, 
67.48; H, 5.45; N, 5.83. Found: C, 67.17; H, 5.46; N, 5.75. 
PREATION 115 
.alpha.,.alpha.-Bis(3,4-difluorophenyl)-1-(phenylsulfonyl)-4-piperidinemeth 
anol 
To a mechanically stirred mixture of 2.70 g (0.11 mole) of magnesium 
turnings and a crystal of iodine in 100 ml of dry tetrahydrofuran was 
slowly added a solution of 19.6 g (0.102 mole) of 
1,2-difluoro-4-bromobenzene in 50 ml of tetrahydrofuran. The three-necked 
reaction flask was fitted with a reflux condenser, and the reaction 
mixture was stirred under an atmosphere of nitrogen. The mixture was 
stirred for 1 hour, and 11.88 g (0.040 mole) of ethyl N-benzenesulfonyl 
isonipecotate was added as a solid. The solution was stirred at 23.degree. 
C. for 12 hours and was poured into an icy solution of ammonium chloride. 
The aqueous mixture was extracted with methylene chloride, and the 
methylene chloride solution was dried over magnesium sulfate. The solvent 
was removed in vacuo, and the residue was recrystallized from methylene 
chloride-hexane to give 17.43 g (90%) of the title compound as a white 
solid, m.p. 152.degree.-154.degree. C. 
Analysis: Calculated for C.sub.24 H.sub.21 F.sub.4 NO.sub.3 S: C, 60.12; H, 
4.41; N, 2.92. Found: C, 60.18; H, 4.40; N, 2.95. 
PREATION 116 
.alpha.,.alpha.-Bis(4-fluorophenyl)-3-piperidinepropanenitrile 
A mixture of 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-3-piperid 
inepropanenitrile (41.21 g, 0.0858 mole) and phenol (100 g, 1.06 mole) was 
heated at reflux for 2 hours. the reaction mixture was cooled to room 
temperature and made alkaline with ice and 50% sodium hydroxide. The 
aqueous layer was extracted with chloroform. The chloroform layer was back 
extracted with 5% sodium hydroxide. The organic layer was then dried over 
sodium sulfate and filtered and solvent was removed to give a dark brown 
oil. This oil was subjected to flash chromatography on silica gel using 
methanol for elution. Fractions of similar purity were combined and 
solvent removed. The oil obtained was dried in vacuo overnight at 
80.degree. C., to give 18.83 g (67.2% yield) of brown oil. 
H.sup.1 NMR (CDCl.sub.3): .delta. 6.9-7.6 (m, 8, aromatics) 1.1-3.1 (m, 12, 
aliphatics). 
Analysis: Calculated for C.sub.20 H.sub.20 F.sub.2 N.sub.2 : C, 73.60; H, 
6.18; N, 8.58. Found: C, 73.19; H, 6.11; N, 8.56. 
PREATION 117 
4-[Bis(3,4-difluorophenyl)methylene]piperidine oxalate [1:1] 
A mixture of 15.0 g (0.0313 mole) of 60, 
.alpha.-bis(3,4-difluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol, 
21 g (0.22 mole) of phenol, and 200 ml of 48% hydrobromic acid was heated 
at reflux for 5 hours and stirred at ambient temperature for 6 hours. The 
reaction mixture was poured over ice, and the mixture as made basic with 
50% sodium hydroxide solution. The basic mixture was extracted with 
methylene chloride, and the methylene chloride solution was dried over 
magnesium sulfate. The solvent was removed in vacuo. The residue was 
dissolved in 300 ml of methanol, 2.90 g (0.032 mole) of oxalic acid was 
added, and the volume of the solution was reduced to 200 ml. Ether was 
added until the solution became cloudy, and the solution was placed in the 
freezer. A white solid was collected to give 8.91 g (69.3%) of the title 
compound as a crystalline solid, m.p. 202.degree.-203.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.17 F.sub.4 NO.sub.4 : C, 58.40; H, 
4.17; N, 3.41. Found: C, 58.28; H, 4.11; N, 3.38. 
PREATION 118 
4-[.alpha.,.alpha.-Bis(3-fluorophenyl)hydroxymethyl]-1-phenylmethylpiperidi 
ne fumarate [1:1] 
A Grignard solution was prepared from 100 g (0.57 mole) of 
1-bromo-3-fluorobenzene and 12.2 g (0.5 mole) of magnesium chips in 750 ml 
of dry tetrahydrofuran. This solution was treated with a solution of 45.8 
g (0.185 mole) of ethyl-N-benzylisonipecotate in 250 ml of dry 
tetrahydrofuran and the mixture was stirred at ambient temperature 
overnight. The solution was poured into 2.5 liters of a saturated ammonium 
chloride solution and the layers were separated. The aqueous layer was 
extracted once with 500 ml of methylene chloride and twice with 250 ml of 
water, 250 ml of a 4% sodium hydroxide solution, 250 ml of water and 250 
ml of brine, dried over sodium sulfate and concentrated to give a glass as 
residue. The glass was dissolved in 2-propanol and converted to the 
fumaric acid salt. The solid was collected by filtration and dried to 
yield 85 g (90%) of the title compound as a white solid. An analytical 
sample was recrystallized from acetonitrile-water, m.p. 
212.degree.-214.degree. C. with decomposition. 
Analysis: Calculated for C.sub.29 H.sub.29 F.sub.2 NO.sub.5 : C, 68.36; H, 
5.74; N, 2.75. Found: C, 68.46; H, 5.74; N, 2.83. 
PREATION 119 
4-[.alpha.,.alpha.-Bis(3-fluorophenyl)hydroxymethyl]piperidine 
A solution of 39.3 g (0.1 mole) of the free base of 
4-[.alpha.,.alpha.-bis(3-fluorophenyl)hydroxymethyl]-1-phenylmethylpiperid 
ine (free base obtained in Preparation 118) in 750 ml of absolute ethanol 
was hydrogenated over 5% palladium on carbon in a Parr apparatus at 50 psi 
and 60.degree. C. for 3.5 days. The mixture was cooled and filtered 
through Celite.RTM.. The filtrate was concentrated and the residue was 
dissolved in ethyl ether and filtered through cotton to remove some 
insoluble material. The filtrate was concentrated to give a gum which 
crystallized when triturated with petroleum ether (30.degree.-60.degree. 
C.). The solid was collected by filtration and dried to yield 27.9 g (92%) 
of the title compound as a white solid. An analytical sample, m.p. 
117.degree.-118.degree. C., was recrystallized from 2-propyl ether 
2-propanol. 
Analysis: Calculated for C.sub.18 H.sub.19 F.sub.2 NO: C, 71.27; H, 6.31; 
N, 4.62. Found: C, 71.24; H, 6.27; N, 4.66. 
PREATION 120 
1-Phenylsulfonyl-4-piperidinecarboxylic acid 
In the preparation of 
.alpha.,.alpha.-bis(3,4-difluorophenyl)-1-(phenylsulfonyl)-4-piperidinemet 
hanol, the title compound was obtained as a side product. To a mixture of 
6.56 g (0.27 mole) of magnesium trimmings and a few crystals of iodine in 
500 ml of anhydrous ether under an atmosphere of nitrogen was slowly added 
a solution of 49.0 g (0.25 mole) of 4-bromo-1,2-difluorobenzene in 100 ml 
of diethyl ether. The mixture was then stirred for 45 min. Ethyl 
N-benzenesulfonylisonipecotate (32.77 g, 0.11 mole) was added as a solid, 
and a gum formed in the bottom of the reaction flask after 20 min. Dry 
tetrahydrofuran (200 ml) was added, and the reaction mixture was stirred 
for an additional hour. The reaction mixture was poured into an icy 
aqueous solution of ammonium chloride. The organic and aqueous phases were 
separated and the aqueous phase was extracted with several portions of 
ether. The organic phases were combined and drived over magnesium sulfate, 
and the solvent was removed in vacuo to give an oil. A NMR of this oil 
shows it to be a mixture of 4-(phenylthio)butanamide and ethyl 
N-benzenesulfonylisonipecotate. A solution of the reaction mixture oil in 
800 ml of 95% ethanol and 200 ml of 10% was heated at reflux for 16 hr. 
The solvent was removed in vacuo, and the residue was partitioned between 
methylene chloride and dilute sodium hydroxide solution. The methylene 
chloride solution was concentrated to give 32.89 g (62.4%) of 
.alpha.,.alpha.-bis(3,4-difluorophenyl)-1-(phenylsulfonyl)-4-piperidinemet 
hanol. The aqueous solution was made acidic with dilute sulfuric acid 
solution, and the acidic solution was extracted with methylene chloride. 
The methylene chloride solution was dried over magnesium sulfate. The 
solvent was removed in vacuo, and the residue was recrystallized from 
methylene chloride-hexane to give 5.36 g (18.1%) of the title compound as 
a crystalline solid, m.p. 156.degree.-157.5.degree. C. 
Analysis: Calculated for C.sub.12 H.sub.15 NO.sub.4 S: C, 53.52; H, 5.61; 
N, 5.20. Found: C, 53.19; H, 5.54; N, 5.16. 
PREATION 121 
4-[.alpha.,.alpha.-Bis(3,4-difluorophenyl)methyl]pyridine 
A mechanically stirred mixture of 49.0 g (0.43 mole) 1,2-difluorobenzene, 
20.6 g (0.19 mole) of 4-carboxaldehyde and 80 ml of concentrated sulfuric 
acid was heated at 70.degree. C. for 21 hr. The reaction mixture was 
poured over ice, and the icy mixture was made basic with 50% sodium 
hydroxide solution. The resulting mixture was extracted with methylene 
chloride and the methylene chloride solution was dried over sodium 
sulfate. The solvent was removed in vacuo to give 54.95 g (89.8%) of a 
solid. This was recrystallized from a mixture of methylene chloride and 
hexane to give 44.82 g (74.3%) of the title compound as a crystalline 
solid, m.p. 79.degree.-82.degree. C. Proton NMR showed that this sample 
contained .about.5% of the 2,3-difluoro isomer. 
Analysis: Calculated for C.sub.18 H.sub.11 F.sub.4 N: C, 68.14; H, 3.50; N, 
4.14. Found: C, 68.14; H, 3.36; N, 4.46. 
PREATION 122 
4-(3,4-Difluorobenzoyl)pyridine hydrochloride [1:1] 
To a mechanically stirred mixture of 3.36 g (0.14 mole) of magnesium 
turnings and a few crystals of iodine in 300 ml of tetrahydrofuran under a 
nitrogen atmosphere was added dropwise a solution 25.48 g (0.13 mole) of 
1,2-difluoro-4-bromobenzene in 50 ml of tetrahydrofuran. The mixture was 
stirred at ambient temperature for 1 hr, and 14.0 g (0.14 mole) of 
4-cyanopyridine was added as a solid. The mixture was stirred for 7 hr at 
room temperature and then was poured over ice. The icy mixture was made 
acidic with dilute sulfuric acid solution, and the aqueous acidic solution 
was allowed to stand for 40 hr. The aqueous solution was made basic with 
ammonium hydroxide, and was extracted with methylene chloride. The 
methylene chloride layer was dried over magnesium sulfate, and the solvent 
was removed in vacuo. The residue was subjected to flash column 
chromatography (silica gel, gradient elution with methylene 
chloride/methanol) to give 1.80 g of the nonsalt form of the title 
compound which was converted to the hydrochloride salt, and recrystallized 
from methanol-ether to give 1.40 g (4.2%) of the title compound as a 
white, crystalline solid, m.p. 146.degree.-148.degree. C. with 
decomposition. 
Analysis: Calculated for C.sub.12 H.sub.8 ClF.sub.2 NO: C, 56.38; H, 3.15; 
N, 5.48. Found: C, 56.41; H, 3.07; N, b 5.49. 
PREATION 123 
4-[Bis(3,4-difluorophenyl)methyl]piperidine hydrochloride [1:1] 
A mixture of 4-.alpha.,.alpha.-bis(3,4-difluorophenyl)methyl]pyridine 
(20.05 g, 0.063 mole) in glacial acetic acid (200 ml), concentrated 
hydrochloric acid (8 ml) and 5% platinum on carbon catalyst (3.0 g) was 
subjected to hydrogenation for 3 days at 60.degree. C. The reduction 
mixture was filtered through Celite.RTM., and the solvent removed in 
vacuo. The residue obtained was partitioned between methylene chloride and 
dilute sodium hydroxide. The solvent was dried over magnesium sulfate, 
filtered, and solvent removed to give an oil. The oil was pumped in vacuo 
to a weight of 19.18 g (clear oil). The oil was first dissolved in 
methanol and a white solid crystallized. Methanol was removed by a rotary 
evaporation and the white solid was dissolved in a small amount of 
methylene chloride and placed on a flash chromatography column. The column 
was eluted with methanol and 1/99 ammonium hydroxide/methanol. Fractions 
of similar purity were combined and solvent removed to give a clear oil 
(15.30 g, 67.5% yield). A 2-g portion of the oil was dissolved in 
isopropyl alcohol and treated with ethereal hydrogen chloride. A white 
solid was isolated and dried in vacuo overnight at 80.degree. C. to give 
1.35 g (41% yield) of white, crystalline solid, m.p. 
263.degree.-268.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.18 ClF.sub.4 N: C, 60.09; H, 5.04; 
N, 3.89. Found: C, 59.71; H, 5.01; N, 3.87. 
PREATION 124 
4-[.alpha.,.alpha.-Bis(2,4-difluorophenyl)methyl]pyridine hydrochloride 
[1:1] 
Sulfuric acid (40 ml) was cooled in an acetone-dry ice bath. 
1,3-Difluorobenzene (45.6 g, 0.4 mole) was added with stirring while 
maintaining a temperature of 0.degree. C. The resulting solution was 
allowed to stir until room temperature was obtained. Next, 
4-pyridinecarboxaldehyde (21.4 g, 0.2 mole) was added dropwise to the 
reaction mixture while maintaining a temperature of 0.degree. C. The 
reaction mixture was stirred until room temperature was obtained and the 
reaction mixture was then stirred overnight at 70.degree. C. The reaction 
mixture was cooled to room temperature and made alkaline with ice/50% 
sodium hydroxide solution. The aqueous layer was extracted several times 
with chloroform and the organic layer was back extracted with 5% sodium 
hydroxide solution. The chloroform layer was dried over sodium sulfate and 
filtered. The organic solvent was removed to give a clear oil (28.30 g, 
49.6% yield). A one gram portion of the clear oil was dissolved in 
2-propanol and treated with ethereal hydrogen chloride. A white 
crystalline solid formed and was separated. The solid was dried in vacuo 
overnight at 80.degree. C. This furnished 0.97 g (39%) of the title 
compound as a white crystalline solid, m.p. 218.degree.-222.degree. C. 
Analysis: Calculated for C.sub.8 H.sub.12 ClF.sub.4 N: C, 61.12; H, 3.42; 
N, 3.96. Found: C, 61.00; H, 3.32; N, 3.94. 
PREATION 125 
4-Ethyl-2-methoxyphenol 
A mixture of zinc powder, 150 ml of water and 49.9 g (0.3 mole) of 
acetovanillone was stirred and treated dropwise with 150 ml of 
concentrated hydrochloric acid. The solution was heated at reflux for 3.5 
hr, during which time, after each hour, 10 ml of additional concentrated 
hydrochloric acid was added. After 3.5 hr the solution was diluted with 
ethyl alcohol and treated with aqueous ferric chloride solution. The 
mixture was cooled and filtered and the filter cake washed with water and 
the combined filtrates saturated with sodium chloride and extracted with 
ethyl ether (3.times.150 ml). The combined extracts were dried over sodium 
sulfate and concentrated to yield 1.4 g of a pink oil. The filter cake was 
washed with 250 ml of ethyl ether. The mixture was filtered and the 
filtrate dried over sodium sulfate and concentrated to a gum residue. The 
above obtained pink oil and gum residue were combined and chromatographed 
on a 750 g column of silica gel using 1:1 benzene:ligroin as the eluting 
solvent. Appropriate fractions were combined and concentrated to give 13.2 
g (29% yield) of the title compound as an oil. 
PREATION 126 
4-.alpha.,.alpha.-[Bis(4-fluorophenyl)methyl]-1 
-piperidine-[(3-chloropropyl)propane] 
A solution of 4-[.alpha.,.alpha.-bis(4-fluorophenyl)methyl]piperidine, 
3-bromopropanol and potassium carbonate in acetonitrile is refluxed for 12 
hr to give 
4-[.alpha.,.alpha.-bis(4-fluorophenyl)methyl]-1-piperidinepropanol, which 
is then reacted neat for approximately 2 hr with thionyl chloride to give 
the hydrochloride salt of the title compound; which is reacted with sodium 
bicarbonate in chloroform to give the title compound. 
PREATION 127 
3-(3-Chloropropoxy)benzoic acid ethyl ester 
A mixture of 25 g (0.149 mole) of ethyl-3-hydroxybenzoate, 46.9 g (0.3 l 
mole) of 1-bromo-3-chloropropane and 62 g (0.45 mole) of anhydrous 
potassium carbonate in one liter of acetone was heated at reflux for 
.about.23 hr. The mixture was cooled, filtered, and the filtrate 
concentrated to give an oil as residue. The oil was dissolved in 200 ml of 
benzene, treated with potassium hydroxide pellets and stirred for 1 hr. 
The mixture was filtered through Celite.RTM. and the filtrate was 
concentrated to give 36.5 g of oil as residue. NMR analysis showed it was 
the desired product. 
PREATION 128 
1-[(Diethylamino)carbonly]-4-piperidine carboxylic acid ethyl ester 
To a solution of 72.4 g (0.46 mole) of ethylisonipecotate and 46.5 g (0.46 
mole) of triethylamine in 400 ml of methylene chloride was added dropwise 
with stirring a solution of 62.4 g (0.46 mole) of diethylcarbamyl chloride 
in 100 ml of methylene chloride. The reaction was exothermic and the 
reaction mixture began to reflux during addition of the diethylcarbamoyl 
chloride solution. The mixture was allowed to stir at ambient temperature 
for 24 hr and then treated with 50 ml of water. The layers were separated, 
and the organic layer washed with 25 ml of a 2N hydrochloric acid (twice), 
50 ml of a saturated sodium bicarbonate solution, 100 ml of a saturated 
sodium chloride solution and dried over sodium sulfate and finally 
concentrated to give a tan oil. The oil was subjected to vacuum 
distillation and appropriate fractions (0.2-0.5 mm Hg, bp 
112.degree.-118.degree. C.) collected to give 100.6 g (85% yield) of the 
desired product. 
PREATION 129 
3-(4-Ethyl-2-methoxyphenoxy)propyl chloride 
A mixture of 13.2 g (0.87 mole of 4ethyl-2-methoxyphenol, 27.3 g (0.173 
mole) of 1-bromo-3-chloropropane, 35.9 g (0.26 mole) of anhydrous 
potassium carbonate and 500 ml of acetone was heated at reflux for 20 hr. 
The reaction mixture was cooled, filtered and the filtrate concentrated to 
give 18.7 g (94% yield) of oil as a residue. The oil was chromatographed 
on a 400 g silica gel column using 2:1 benzene:ligroin as the eluting 
solvent and appropriate fractions collectred. NMR indicated approximately 
10-15% of the starting phenol compound remained. The oil was dissolved in 
250 ml of benzene and stirred with potassium hydroxide pellets for 
approximately 4 hr. The mixture was filtered thorugh Celite.RTM. and 
filtrate concentrated to give 10.3 g (52% yield) of the desired product. 
PREATION 130 
1-Chloro-3-(4-isopropylphenoxy)propane 
A mixture of 27.4 g (0.2 mole) of p-isopropylphenol, 63 g (0.4 mole) of 
1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium 
carbonate in 1 liter of acetone was heated at reflux for 24 hr. The 
reaction mixture was cooled, filtered and filtrate concentrated. The 
residue was dissolved in 200 ml of benzene and treated with potassium 
hydroxide pellets to remove excess starting phenol. The mixture was 
stirred in ambient temperature for 0.5 hr, filtered through Celite.RTM. 
and the filtrate concentrated to give 36.4 g (87% yield) of the title 
compound as an oil. 
PREATION 131 
1-Chloro-3-(4-methylphenoxy)propane 
A mixture of 27 g (0.25 mole) of p-cresol, 78.7 g (0.5 mole) of 
1-bromo-3-chloropropane and 103.7 g (0.75 mole) of anhydrous potassium 
carbonate in 1 liter of acetone was heated at reflux for 24 hr. The 
reaction mixture was cooled, filtered and concentrated in vacuo at 
90.degree. C. to give 47.1 g of an oil residue. The oil was subjected to 
vacuum distillation to give 39.3 g (85%) of clear oil, bp 
85.degree.-90.degree. C. at 0.1 mm Hg. 
PREATION 132 
3-(2-Benzyloxyphenoxy)propyl chloride 
A mixture of 50 g (0.25 mole) of 2-benzyloxyphenol, 78.7 g (0.5 mole) of 
1-bromo-3-chloropropane and 103.7 g of anhydrous potassium carbonate in 1 
liter of actone was heated at reflux for 24 hr. The reaction mixture was 
cooled, filtered and concentrated in vacuo to give 67.2 g of a tan oil as 
residue. The oil was dissolved in 300 ml of ethyl ether and washed with 
100 ml of a 5% sodium hydroxide solution. A solid precipitated, about 200 
ml of water was added and the precipitated sold redissolved. Solvent 
layers were separated and the ethyl ether layer washed twice with a 5% 
sodium hydroxide solution. The organic layer was next washed with water, 
brine, and dried over sodium sulfate and concentrated to give 58.4 g (84%) 
of oil as product. 
PREATION 133 
1-[4-(3-Chloropropoxy)-2-methoxyphenyl]ethanone 
A solution of 4-hydroxy-2-methoxyacetophenone, 1-bromo-3-chloropropane and 
potassium carbonate in acetone is heated at reflux for about 12 hr to give 
the title compound. 
PREATION 134 
1-[4-(3-Chloropropxy)-3-methoxyphenyl]ethanone 
A solution of acetovanillone, 1-bromo-3-chloropropane and potassium 
carbonate in acetone is refluxed for about 12 hr to give the title 
compound. 
PREATION 135 
4-[Bis(2,4-difluorophenyl)methyl]piperidine hydrochloride [1:1] 
A mixture of the free base of 
4-[.alpha.,.alpha.-bis(2,4-difluorophenyl)methyl]pyridine hydrochloride 
[1:1](23.84 g, 0.0752 mole) and 5% platinum on carbon (2.0 g) was 
subjected to hydrogenation for three days at 60.degree. C. in 400 ml of 
glacial acetic acid containing 3 ml of concentrated hydrochloric acid. 
Following hydrogenation, the reaction mixture was cooled to room 
temperature and filtered. Solvent was removed by rotary evaporator. The 
residue obtained was dissolved in chloroform and extracted with 5% sodium 
hydroxide. The chloroform layer was dried over sodium sulfate and 
filtered. The chloroform layer was removed by rotary evaporator to give a 
dark residue (24.40 g quantitative). A one-gram sample of this material 
was converted to the hydrochloride salt and recrystallized from 
methanol-ethyl ether. A white solid was obtained and dried in vacuo 
overnight at 80.degree. C. This provided 1.06 g (95.2%) of white, 
crystalline solid, mp 215.degree.-217.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.18 ClF.sub.4 N : C,60.09;H, 5.04;N, 
3.89. Found: C, 59.77;H, 5.02; N, 3.87. 
PREATION 136 
1-(Phenylmethyl)-4-piperidinol 4-methylbenzenesulfonate (ester) 
hydrochloride [1:1] 
A solution of 1-benzyl-4-hydroxypiperidine (95.6 g, 0.5 mole) in 500 ml of 
pyridine was cooled in an ice bath. To this solution was added dropwise a 
solution of tosyl chloride (133.5 g, 0.7 mole) in 400 ml of acetonitrile 
(dried over 4A molecular sieves). Upon the addition to the second 
solution, a color change from yellow to dark-red was observed. The 
resulting solution was stirred at room temperature for 4.5 hours. The 
reaction mixture was concentrated to dryness, and a dark-brown mass was 
obtained. This material was dissolved in chloroform and extracted with 5% 
sodium hydroxide. The chloroform layer was dried over sodium sulfate and 
filtered. The chloroform layer was removed in vacuo to give a dark brown 
mass. This material was converted to the salt, and the salt was 
recrystallized from emthanol-ethyl ether. A light brown solid was isolated 
and dried in vacuo overnight at 80.degree. C. This procedure provided 
68.17 g (35.8%) of light brown solid, mp 169.degree.-171.5.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.24 ClNO.sub.3 S:C, 59.75;H, 6.33;N, 
3.67.Found: C, 59,74;H, 6.38;N, 3.69. 
PREATION 137 
.alpha., .alpha.-Bis(3,4-difluorophenyl)-4-pyridinemethanol 
To a magnetically stirred solution of ethyl isonicotinate in dry 
tetrahydrofuran at 0.degree. C. and under an atmosphere of nitrogen is 
slowly added a solution 2.2 equivalents of 3,4-difluorophenyl magnesium 
bromide in tetrahydrofuran. The solution is stirred at ambient temperature 
of 4 hr and is poured into an icy solution of ammonium chloride. The 
mixture is extracted with methylene chloride, and the organic phase is 
dried (sodium sulfate). The solvent is removed in vacuo to give a solid. 
This solid is recrystallized from methylene chloride/hexane to give the 
title compound as a white, crystalline solid, mp 147.degree.-149.degree. 
C. 
Analysis: Calculated for C.sub.18 H.sub.11 F.sub.4 NO: C, 64.87;H, 3.33;N, 
4.20. Found: C,64.54;H, 3.22; N, 4.20. 
PREATION 138 
4-[Bis-(4-fluorophenyl)methyl]-1-(phenylsulfonyl)piperidine 
A solution of 15.18 g (0.0529 mole) of 
4-[bis(4-flurophenyl)methylene]piperidine and 10,89 g (0.0617 mole) of 
benzenesulfonyl chloride in 350 ml of pyridine was stirred at room 
temperature for 16 hr. The solvent was removed in vacuo, and the residue 
was partitioned between methylene chloride and dilute sulfuric acid. The 
methylene chloride solution was extracted with dilute sodium hydroxide, 
and the methylene chloride solution was dried over sodium sulfate. The 
solvent was removed in vacuo, and the residue was dissolved in 200 ml of 
methanol. A precipitate was collected. This was recrystallized from 
methylene chloride - methanol to give 11.14 g (49.3%) of the title 
compound as a white solid: mp 180-184.degree. C. 
Analysis: Calculated for C.sub.24 H.sub.23 F.sub.2 NO.sub.2 S: 
C,67.43;H,5.42;N,3.28. Found: C,67.17;H,5.42;N,3.27. 
PREATION 139 
.alpha.,.alpha.-Bis(3,4-difluorophenyl)-4-piperidinemethanol oxalate 
hydrate [1:0.5:0.5] 
A solution of 4.02 g (0.012 mole) of 
.alpha.,.alpha.-bis(3,4difluorophenyl)-4-pyridinemethanol in 150 ml of 
glacial acetic acid was subjected to catalytic hydrogenation with 0.70 g 
of 5% platinum on carbon (Parr hydrogenation apparatus; 53 psi of 
hydrogen) at room temperature for 70 hr. The solution was filtered through 
Celite.RTM., and the solvent was removed in vacuo. 
The residue was partitioned between methylene chloride and dilute sodium 
hydroxide, and the methylene chloride solution was dried over sodium 
sulfate. The solvent was removed in vacuo to give a white solid. This was 
dissolved in methanol, 1.0 g(0.011 mole) of oxalic acid was added, and 
anhydrous ether was added. After being cooled in the freezer, the solution 
produced 0.51 g (10.9%) of the title compound as a white crystalline 
solid. Anhydrous ether was added to the filtrate, and the solution was 
placed in the freezer. An additional 2.70 g (57.3%) of the title compound 
was collected as a white solid: mp 278.degree.-279.degree. C. (dec). 
Analysis: Calculated for C.sub.19 H.sub.18 NO.sub.3 0.5H.sub.2 O: 
C,58.02;H, 4.87;N, 3.56. Found: C,58.42;H, 4.66;N, 3.61. 
PREATION 140 
.alpha.-(4-Fluorophenyl)-.alpha.-(4-piperidinyl)-2-pyridinemethanol 
To a stirred solution of 36.3 g (0.23 mole) of 2-bromopyridine in 500 ml of 
anhydrous tetrahydrofuran (THF) at -65.degree. C. was added 88 ml (0.22 
mole) of a commercial solution of 2.5 molar n-butyllithium in hexane at 
such a rate that the temperature did not exceed -60.degree. C. The dark 
solution was stirred at -65.degree. C. for 1 hr and then treated dropwise 
with a solution of 24.9 g (0.1 mole ) of 
1-acetyl-4-(p-fluorobenzoyl)piperidine in 250 ml of THF at such a rate 
that the temperature did not exceed -60.degree. C. The mixture was stirred 
for 1 hr at -65.degree. C. and overnight at ambient temperature. The dark 
mixture was poured into 2 liters of a saturated ammonium chloride 
solution. The layers were separated and the aqueous layer was extracted 
once with a 500-ml portion of methylene chloride. The combined organic 
layers were washed successively with 500 ml of water, 500 ml of a 4% 
sodium hydroxide solution, 250 ml of water, and 250 ml of brine. 
All of the aqueous layers were combined and allowed to stand in a filter 
flask for several weeks. As the soluble organic solvents in the aqueous 
solution evaporated, a solid precipitated. The aqueous solution was 
decanted and the solid was slurried with water, collected by filtration, 
and dried. The solid was recrystallized from absolute ethanol-pyridine to 
yield 4.5 g(14%) of the title compound as an off-white solid, mp 
228.degree.-230.degree. C. (dec). 
Analysis: Calculated for C.sub.17 H.sub.19 FN .sub.2 O: 
C,71.31;H,6.69;N,9.78. Found: C,71.43;H,6.54;N,9.52. 
PREATION 141 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-(phenylmethyl)-3-piperidinemethanol 
The title compound was synthesized by the procedure described in 
Preparation 4, except that 1-phenylmethyl-3-piperidine carboxylic acid 
ethyl ester was used in place of 1-(phenylmethyl)-4-piperidinecarbhoxylic 
acid ethyl ester hydrochloride. The melting range of the white solid thus 
obtained was 104.degree.-111.5.degree. C. 
Analysis: Calculated for C.sub.25 H.sub.25 F.sub.2 NO: 
C,76.31;H,6.40;N,3.55. Found: C,76.75;H,6.46;N,3.55. 
PREATION 142 
[.alpha.,.alpha.-Bis(4-fluorophenyl)]-3-pyridineethanol 
A Grignard solution was prepared from 19.4 g (0.8 mole) of magnesium chips 
and 148.8 g (0.85 mole) of 1-bromo-3-fluorobenzene in 1.25 liters of dry 
tetrahydrofuran (THF). To this solution was added in a stream a solution 
of 41.3 g (0.25 mole) of ethyl-3-pyridylacetate (Aldrich) in 250 ml of 
THF. The mixture was stirred at ambient temperature overnight and then 
poured into 2.5 liters of saturated ammonium chloride solution. The layers 
were separated and the aqueous layer was extracted once with 500 ml of 
methylene chloride and twice with 250 ml of methylene chloride. The 
combined organic layers were washed successively with 250 ml water, 250 ml 
of a 4% sodium hydroxide solution, 250 ml of water and 250 ml of brine. 
The organic layer was dried (over sodium sulfate) and concentrated to give 
a gum which crystallized when triturated with a mixture of 100 ml of 
petroleum ether (30.degree.-60.degree. C.) and 100 ml of 2-propyl ether. 
The solid was collected by filtration, air dried and slurried with 500 ml 
of water. 
The solid was collected by filtration, washed with petroleum ether and 
dried to yield 32.5 g of tan solid. Mass spec shows m/e=312. The solid was 
slurried with 500 ml of water, collected by filtration and dried. 
The solid was next heated to reflux in .about.300 ml of 2-propanol and 
filtered to remove insolubles. The filtrate was concentrated to give a 
solid residue. The solid was recrystallized from cyclohexane-benzene to 
yield 24.3 g(31%) of off-white solid, mp 137.degree.-141.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.15 F.sub.2 NO: 
C,73.30;H,4.86;N,4.50. Found: C73.42;H,4.77;N,4.51. 
PREATION 143 
[.alpha.,.alpha.-Bis(4-fluorophenyl)]-3-piperidineethanol 
hydrochloride[1:1] 
A mixture of 23.8 g (0.076 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-3-pyridineethanol in 500 ml of 
glacial acetic acid was hydrogenated over 2.4 g of 5% platinum on carbon 
in a Parr apparatus for 24 hr. The mixture was filtered through 
Celite.RTM. and the filtrate was concentrated to give a gummy residue. The 
residue was partitioned between 300 ml of methylene chloride and 300 ml of 
a 5% sodium hydroxide solution and a solid precipitated. The solid was 
collected by filtration and partitioned between 200 ml of methylene 
chloride and 100 ml of a 5% sodium hydroxide solution. The organic layer 
was washed with brine, dried over sodium sulfate and concentrated to give 
a gum as residue. The gum was dissolved in ethyl ether and converted to 
the hydrochloride salt. The solid was collected by filtration and dried to 
yield 19.2 g (71%) of the title compound as a white solid, mp 248.degree. 
C. (dec) (absolute ethanol). 
Analysis : Calculated for C.sub.19 H.sub.22 ClF.sub.2 NO: 
C,64.50;H,6.27;N,3.96. Found: C,64.30;H,6.28;N,3.98. 
PREATION 144 
1-(Phenylmethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide [1:1] 
To a stirred mixture of 35.4 g (0.225 mole) of (.+-.) ethylnipecotate and 
31.8 g (0.3 mole) of anhydrous sodium carbonate in 300 ml of absolute 
ethanol was added dropwise 41 g (0.24 mole) of benzylbromide and the 
mixture was stirred at ambient temperature for 24 hr. The mixture was 
filtered and the filtrate was concentrated. The residue was partitioned 
between 250 ml of methylene chloride and 250 ml of a 5% sodium hydroxide 
solution. The organic layer was washed with brine, dried over sodium 
sulfate, and concentrated to give a gummy residue. The residue was 
triturated with ethyl ether, filtered, and the filtrate treated with 
hydrogen bromide gas. The solid which precipitated was collected by 
filtration and recrystallized from 2-propanol to yield 35.0 g (47%) of the 
title compound as a white solid, mp 148.degree.-152.degree. C. 
Analysis: Calculated for C.sub.15 H.sub.22 BrNO.sub.2 
:C,54.89;H,6.76;N,4.27. Found: C,54.83;H,6.83;N,4.30. 
PREATION 145 
[.alpha.,.alpha.-Bis(4-fluorophenyl)]-3-piperidinemthanol 
A solution of 26.6 g (0.0676 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-(phenylmethyl)-3-piperidinemthanol 
in 750 ml of absolute ethanol was hydrogenated at 60.degree. C. and 50 psi 
over 5% palladium on carbon in a Parr apparatus for 18 hr. The mixture was 
filtered through Celite.RTM. and the filtrate was concentrad to give a gum 
which crystallized when triturated with petroleum ester 
(30.degree.-60.degree. C.) The solid was collected by filtration and 
recrystallized from cyclohexane to yield 14.8 g (72%) of the title 
compound as a white shole, mp 114.5.degree.-115.5.degree. C. 
Analysis: Calculated for C.sub.18 H.sub.19 F.sub.2 NO: C, 71.27;H, 6.31;N, 
4.62. Found: C, 71.43;H, 6.33;N, 4.64. 
PREATION 146 
1-Chloro-3-[(2-phenylmethoxy)phenoxy]propane 
A mixture of 50g (0.25 mole) of 2-benzyloxyphenol, 78.7 g (0.5 mole) of 
1-bromo-3-chloropropane and 103.7 g (0.75 mole) of anhydrous potassium 
carbonate in one liter of acetone was heated at reflux for .about.24 hr. 
The mixture was worked up to give 67.2 g of tan oil as residue. The oil 
was dissolved in .about.300 ml of ethyl ether and washed with 100 ml of 5% 
sodium hydroxide solution and a solid precipitated. Approximately 200 ml 
of water was added and the solid dissolved. The layers were then 
separated. This process was repeated twice with 100 ml of 5% sodium 
hydroxide solution. The organic layer was washed with water and brine, 
dried over sodium carbonate, and concentrated to give 58.4 g (84%) of oil 
as residue. NMR was consistent for the title compound. 
PREATION 147 
1-Chloro-3-[2,6(dimethoxy)phenoxy]propane 
A reaction mixture consisting of the following was heated for about 18 hr 
at gentle reflux in 750 ml of acetone: 
1. 2,6-dimethoxyphenol (154.17 g, 1 mole) 
2. 1-bromo-3-chloropropane (314.8 g, 2 mole), and 
3. potassium carbonate (290.0 g, 2.1 mole). 
The reaction mixture was filtered and stripped to dryness to give a dark 
brown oil which was dissolved in chloroform and extracted with dilute (5%) 
sodium hydroxide solution. An emulsion resulted which was broken by the 
addition of saturated sodium chloride. The aqueous layer was extracted 
several times with chloroform. The chloroform layer was back extracted 
with 5% sodium hydroxide. Removal of chloroform gave a dark brown oil 
(83.55 g, 36.35 yield). NMR analysis was consistent with the desired 
product. 
PREATION 148 
1-Chloro-3-[(2-methoxy-4-methyl)phenoxy]propane 
A mixture of 50 g (0.326 mole) of 2-methoxy-4-methylphenol, 113.9 g (0.72 
mole) of 1-bromo-3-chloropropane and 150 g (1.1 mole) of anhydrous 
potassium carboxate in one liter of acetone was heated at reflux with 
stirring for .about.20 hr. The mixture was cooled, filtered, and the 
filtrate concentrated to yield 66.3 g of oil as residue. NMR showed 75% 
product and 25% phenol present. 
The oil was dissolved in 500 ml of acetone and treated with 28 g of 
1-bromo-3-chloropropane and 35 g of anhydrous potassium carbonate and the 
mixture was heated at reflux for .about.16 hr. The mixture was worked up 
as above to yield 67 g of an oil. NMR indicated it was mostly product, but 
that some replaceable proton was still present. The oil was dissolved in 
300 ml of benzene and stirred with potassium hydroxide pellets for 21 hr. 
The mixture was filtered through Celite.RTM. and the filtrate was 
concentrated to yield 54.7 g (70%) of clear oil. NMR was consistent with 
the title compound. 
PREATION 149 
1-[2-(b 3-Chloropropoxy)phenyl]ethanone 
A mixture of 40.8 g (0.3 mole) of 2-hydroxyacetophenone, 94.4 g (0.6 mole) 
of 1-bromo-3-chloropropane and 124.4 g (0.9 mole) of anhydrous potassium 
carbonate in one liter of acetone was heated at reflux for .about.18 hr. 
The mixture was cooled to room temperature, filtered and the filtrate 
concentrated under vacuum pump pressure to give .about.45 g of oil as 
residue. The oil was dissolved in 200 ml of benzene and stirred with 
potassium hydroxide pellets for .about.2 hr. The mixture was filtered 
through Celite.RTM. and the filtrate was concentrated to yield 29.6 g (46% 
of light yellow oil. NMR was consistent for desired product. Mass Spectra 
Analysis shows m/e=213. 
PREATION 150 
1-[3-(3-Chloropropoxy)phenyl]ethanone 
A mixture of 40.8 g (0.3 mole) of m-hydroxyacetophenon, 94.4 g (0.6 mole) 
of 1-bromo-3-chloropropane and 124.4 g (0.9 mole) of anhydrous potassium 
carbonate in one liter of acetone was heated at reflux for .about.20 hr. 
The mixture was worked up to yield 61.4 g (96%) of dark oil as residue. 
NMR analysis was consistent for the desired product. Mass Spectra Analysis 
showed m/e=213. 
PREATION 151 
1-Chloro-3-[(3-methoxy)phenoxy]propane 
A mixture of 37.2 g (0.3 mole) of m-methoxyphenol, 94.4 g (0.6 mole) of 
1-bromo-3-chloropropane and 124.4 g (0.9 mole) of anhydrous potassium 
carbonate in one liter of acetone was heated at reflux for .about.20 hr 
(the reaction mixture turned a dark color when the potassium carbonate was 
added). The mixture was worked up to give 57.7 g (96%) of yellow oil as 
residue. NMR Analysis was perfect for desired compound. Mass Spectra 
Analysis showed m/e=201. 
PREATION 152 
1-Chloro-3-(4-ethylphenoxy)propane 
A mixture of 36.6 g (0.3 mole) of 4-ethylphenol, 94.4 g (0.6 mole) of 
1l-bromo-3-chloropropane and 124.4 g (0.9 mole) of anhydrous potassium 
carbonate in one liter of acetone was heated at reflux for .about.24 hr. 
The mixture was worked-up to yield 48 g (81%) of pale yellow oil. NMR was 
perfect for desired product. Mass Spectra Analysis shows m/e=199. 
PREATION 153 
1-[4-(3-Chloropropoxy)benzeneacetic acid methyl ester 
A mixture of 24.3 g (0.146 mole) of methyl-4-hydroxyphenylacetate, 47.2 g 
(0.3 mole) of 1-bromo-3-chloropropane and 62.1 g (0.45 mole) of anhydrous 
potassium carbonate in 500 ml of acetone was heated at reflux for 
.about.24 hr. The mixture was cooled, filtered and the filtrate 
concentrated to give 34.8 g (98%) of oil as residue. Mass Spectra Analysis 
showed m/e=243. NMR is consistent for the desired product. 
PREATION 154 
1-Chloro-3-(2-methylphenoxy)propane 
A mixture of 32.4 g (0.3 l mole) of o-cresol, 94.4 g (0.6 mole) of 
(1-bromo-3-chloropropane and 124.4 g (0.9 mole) of anhydrous potassium 
carbonate in one liter of acetone was heated at reflux for .about.24 hr. 
The mixture was worked-up to yield 34.5 g (62%) of pale yellow oil. NMR 
looked perfect for the desired product. Mass Spectra Analysis showed 
m/e=185. 
PREATION 155 
1-Chloro-3-(2-ethoxyphenoxy)propane 
A mixture of 41.5 g (0.3 mole) of o-ethoxyphenol, 94.4 g (0.6 mole) of 
1-bromo-3-chloropropane and 124.4 g (0.9 mole) of anhydrous potassium 
carbonate in one liter of acetone was heated at reflux for .about.20 hr. 
The mixture was worked-up to give 34.3 g (53%) of clear oil as residue. 
NMR was perfect for the desired product. Mass Spectra showed m/e=215. 
PREATION 156 
1-Chloro-3-(3-methylphenoxy)propane 
A mixture of 32.4 g (0.3 mole) of m-cresol, 94.4 g (0.6 mole) of 
1-bromo-3-chloropropane and 124.4 g (0.9 mole) of anhydrous potassium 
carbonate in one liter of acetone was heated at reflux for .about.20 hr. 
The mixture was worked-up to yield 45 g (81%) of pale yellow oil as 
residue. NMR was consistent for desired product. Mass Spectra Analysis 
showed m/e=185. 
PREATION 157 
1-Chloro-3-[2-(1-methylethoxy)phenoxy]propane 
A mixture of 25 g (0.164 mole) of 2-isopropoxyphenol, 51.7 g (0.33 mole) of 
1-bromo-3-chloropropane, and 67.9 g (0.49 mole) of anhydrous potassium 
carbonate in 500 ml acetone was heated at reflux for .about.20 hr. The 
mixture was cooled and filtered and the filtrate concentrated. The residue 
was dissolved in 200 ml of benzene, treated with potassium hydroxide 
pellets and stirred overnight. The mixture was filtered through 
Celite.RTM. and the filtrate concentrated to yield 232 g (62%) of oil as 
residue. Mass Spectra Analysis showed m/e=229, NMR was perfect for desired 
compound. 
PREATION 158 
[4-(3-Chloropropoxy)phenyl]phenylmethanone 
A mixture of 49.7 g (0.20 mole) of 4-hydroxybenzophenone, 78.7 g (0.5 mole) 
of 1-bromo-3-chloropropane and 103.5 g (0.75 mole) of anhydrous potassium 
carbonate in one liter of acetone was heated reflux for 20 hr. The mixture 
was cooled to room temperature, filtered and the filtrate concentrated in 
give a dark oil as residue. Mass Spectra Analysis showed m/e=275. The oil 
was dissolved in 300 ml of benzene and stirred with potassium hydroxide 
pellets over the weekend. The mixture was filtered through Celite.RTM. and 
the filtrate was concentrated to give 67.4 g (98%) of reddish-brown oil as 
residue. NMR was perfect for the desired compound. 
EXAMPLE 1 
4-(Diphenylmethylene)-1-(3-phenoxypropyl)piperidine oxalate [1:1] 
A mixture of 3.3 g (0.013 mole) of 4-diphenylmethylenepiperidine, 3.3 g 
(0.015 mole) of (3-bromopropoxy)benzene and 5.3 g (0.05 mole) of anhydrous 
sodium carbonate in 100 ml of 1-butanol was heated at reflux for 20 hr. 
The mixture was concentrated under reduced pressure and the residue was 
partitioned between water and benzene. The benzene layer was washed with 
water and brine, dried over anhydrous sodium sulfate and concentrated 
under reduced pressure to give an oil as residue, the free base of the 
title compound. The free base was converted to the oxalic acid salt and 
the solid was recrystallized from absolute ethanol to yield 4.3 g (70%) of 
the title product as a white powder, m.p. 175.degree.-178.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.31 NO.sub.5 : C, 73.55; H, 6.60; N, 
2.96. Found: C, 73.59; H, 6.64; N, 2.83. 
EXAMPLE 2 
.alpha.,.alpha.-Bis-(4-fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethan 
ol oxalate hydrate [1:1:0.5] 
A mixture of 3.37 g (0.011 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.52 g (0.011 
mole) of (3-bromopropoxy)benzene and sodium bicarbonate (3.7 g, 0.035 
mole) in 200 ml of 1-butanol was heated overnight at reflux. The butanol 
was removed by the rotary evaporator, and the residue partitioned between 
chloroform and water. Removal of the chloroform in vacuo gave a dark brown 
oil, the free base of the title compound. The base was converted to the 
oxalate salt and recrystallized from methanol-ethyl ether to give 1.41 
(23.9%) of white solid, m.p. 163.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.31 F.sub.2 NO.sub.6.0.5H.sub.2 O: 
C, 64.92; H, 6.01; N, 2.61. Found: C, 65.27; H, 5.87; N, 2.61. 
EXAMPLE 3 
4-[Bis(4-fluorophenyl)methylene]-1-(3-phenoxypropyl)piperidine oxalate 
[1:1] 
A solution of 7.37 g (0.0168 mole) 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethan 
ol in 100 ml of methanol containing 100 ml of 6N hydrochloric acid was 
gently heated at reflux for 4 hr. The reaction mixture was cooled, made 
alkaline with ice/50% sodium hydroxide, and diluted to 1 liter with water. 
The aqueous phase was extracted with chloroform, and removal of chloroform 
gave an oil. The oil was converted to the oxalate salt and recrystallized 
from methanol-ethyl ether to give 3.45 g (40.3%) of white solid, m.p. 
190.degree.-192.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.29 F.sub.2 NO.sub.5 : C, 68.36; H, 
5.74; N, 2.75. Found: C, 68.43; H, 5.75; N, 2.69. 
EXAMPLE 4 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethano 
l oxalate [1:1] 
To a mixture of 5.10 g (0.21 mole) of magnesium turnings and a crystal of 
iodine in 800 ml of drytetrahydrofuran (distilled from lithium aluminum 
hydride) was added a solution of 36.75 g (0.21 mole) of 
p-bromofluorobenzene in 100 ml of tetrahydrofuran. The reaction flask was 
cooled in an ice bath during this addition, and the reaction mixture was 
under an atmosphere of nitrogen. The mixture was stirred at ambient 
temperature for 1 hr. A solution of 20.17 g (0.0693 mole) of ethyl 
N-(3-phenoxypropyl)isonipecotate in 100 ml of tetrahydrofuran was added 
and the solution was stirred at room temperature for 16 hr. The mixture 
was poured into an icy solution of ammonium chloride and the aqueous 
mixture was extracted with methylene chloride. The methylene chloride 
solution was extracted with dilute sodium hydroxide and was dried over 
magnesium sulfate. The solvent was removed in vacuo to give a gummy 
residue. The residue was treated with a solution of oxalic acid in 
methanol and the salt was recrystallized from methanol-ether to give 24.17 
g (66.2%) of white, crystalline solid, m.p. 153.degree.-155.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.31 F.sub.2 NO.sub.6 : C, 66.02; H, 
5.92; N, 2.66. Found: C, 65.78; H, 5.93; N, 2.63. 
EXAMPLE 5 
4-(Diphenylmethyl)-1-(4-phenoxybutyl)piperidine fumarate [1:1] 
A solution of 6.99 g (0.0278 mole) of 4-diphenylmethylpiperidine, 6.64 g 
(0.029 mole) of (4-bromobutoxy)benzene and 5 g (0.060 mole) of sodium 
bicarbonate in 400 ml of 1-butanol was heated at reflux for 11 hr. The 
solvent was removed in vacuo, an the residue was partitioned between 
methylene chloride and dilute sodium hydroxide. The methylene chloride 
solution was dried over magnesium sulfate, and the solvent was removed in 
vacuo to give an oil, the free base of the title compound. The base was 
dissolved in 500 ml of ether, and a small amount of solid was filtered 
from the solution. To the filtrate was added a solution of 3.2 g (0.0276 
mole) of fumaric acid in 60 ml of methanol. A white precipitate was 
collected to give 7.97 g (55.7%) of white, crystalline solid, m.p. 
146.degree.-147.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.37 NO.sub.5 : C, 74.54; H, 7.23; N, 
2.72. Found: C, 74.68; H, 7.24; N, 2.68. 
EXAMPLE 6 
4-(Diphenylmethyl)-1-(3-phenoxypropyl)piperidine fumarate [1:1] 
Following the procedure of Example 5, 4-(diphenylmethyl)piperidine and 
(3-bromopropoxy)benzene was reacted to give the free base of the title 
compound which was reacted with fumaric acid in methanol to give the white 
fumarate salt in 71% yield, m.p. 171.degree.-172.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.35 NO.sub.5 : C, 74.23, H, 7.03; N, 
2.79. Found: C, 74.62; H, 7.03; N, 2.73. 
EXAMPLE 7 
4-[Bis(4-fluorophenyl)methyl]-1-(3-phenoxypropyl)piperidine oxalate [1:1] 
Following the procedure of Example 
2,4-[bis(4-fluorophenyl)methyl]piperidine and (3-bromopropoxy)benzene were 
reacted to give the free base of the title compound which was reacted with 
oxalic acid, and recrystallizing from methanol-ethyl ether to give the 
white oxalate salt in 60% yield, m.p. 178.degree.-181.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.31 F.sub.2 NO.sub.5 : C, 68.09; H, 
6.11; N, 2.74. Found: C, 68.37; H, 6.13; N, 2.76. 
EXAMPLE 8 
4-(Diphenylmethyl)-1-(2-phenoxyethyl)piperidine fumarate [1:1] 
Following the procedure of Example 5,4-(diphenylmethyl)piperidine and 
(2-bromoethoxy)benzene were reacted to give the free base of the title 
compound which was reacted with fumaric acid in ether-methanol mixture to 
give the white fumarate salt in 85% yield, m.p. 189.degree.-190.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.33 NO.sub.5 : C, 
73.90;H,6.82;N,2.87. Found: C,74.07;H,6.91;N,2.85. 
EXAMPLE 9 
4-[Bis(4-fluorophenyl)methyl]-1-(2-phenoxyethyl)piperidine oxalate [1:1] 
A mixture of 5.83 g (0.02 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 
4.02 g (0.02 mole) of (2-bromoethoxy)benzene and sodium carbonate (3.18 g, 
0.03 mole) was heated overnight at gentle reflux in 300 ml of 1-butanol. 
The reaction was filtered and solvent removed in vacuo. The residue was 
dissolved in chloroform and extracted with water and 5% sodium hydroxide. 
Removal of chloroform gave an oil which was converted to the oxalate salt. 
The salt was recrystallized from ethanol-ethyl ether to give 6.0 g (60.3%) 
of white, crystalline product, m.p. 180.degree.-182.degree. C. 
Analysis: Calculated for C.sub.28 H.sub.29 F.sub.2 NO.sub.5 : 
C,67.60;H,5.88;N,2.82. Found: C,67.68;H,5.87;N,2.81. 
EXAMPLE 10 
4-[Bis(4-fluorophenyl)methyl]-1-(4-phenoxybutyl)piperidine oxalate [1:1] 
Following the procedure of Example 
2,4-[bis(4-fluorophenyl)methyl]-piperidine and (4-bromopropoxy)benzene 
were reacted to give the free base of the title compound which was reacted 
with oxalic acid to give the white oxalate salt (recrystallizing from 
ethanol-ethyl ether), in 48% yield, m.p. 206.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.33 F.sub.2 NO.sub.5 : 
C,68.56;H,6.33;N,2.67. Found: C,68.79;H,6.35;N,2.67. 
EXAMPLE 11 
4-[(4-Fluorophenyl)-phenylmethyl]-1-(3-phenoxypropyl)piperidine fumarate 
[1:1] 
A mixture of 5.4 g (0.02 mole) of 
4-[.alpha.-(p-fluorophenyl)-.alpha.-phenylmethyl]-piperidine, 4.5 g (0.021 
mole) of (3-bromopropoxy)benzene and 8.0 g (0.075 mole) of anhydrous 
sodium carbonate in 150 ml of acetonitrile was refluxed for about 20 hr 
and concentrated under reduced pressure to give a gummy residue. The 
residue was purified by column chromatography on 160 g of Florisil.RTM. 
and the product was eluted with 2% acetone in benzene to give an oil, the 
free base of the title compound. The free base was reacted with fumaric 
acid and the salt was recrystallized from isopropyl alcohol to give 4.0 g 
(38%) of white solid, m.p. 169.degree.-171.degree. C. (with 
decomposition). 
Analysis: Calculated for C.sub.31 H.sub.34 FNO.sub.5 : 
C,71.66;H,6.60;N,2.70. Found: C,71.37;H,6.55;N,2.66. 
EXAMPLE 12 
4[Bis(4-fluorophenyl)methyl]-1-[2-(2,6-dichlorophenoxy)ethyl]-piperidine. 
A mixture of 6.13 g (0.021 mole) of 
4-[bis(4-fluorophenyl)methyl]piperidine, 5.38 g (0.03 mole) of 
2-(2-bromoethoxy)-1,3-dichlorobenzene was heated overnight at gentle 
reflux in 200 ml of 1-butanol. The reaction mixture was filtered and 
stripped to dryness. The residue was dissolved in chloroform and extracted 
with water and 5% sodium hydroxide solution. The oil which was obtained 
was chromotagraphed on 300 g of silica gel using hexane-ethyl acetate 
(50/50 v/v) as eluant. The fractions containing product were combined and 
solvent removed to furnish an oil. The oil was dried overnight in vacuo at 
80.degree. C. This furnished 5.99 g (59%) of product oil. 
Analysis: Calculated for C.sub.26 H.sub.25 Cl.sub.2 F.sub.2 NO: 
C,65.55;H,5.29;N,2.94. Found: C,65.43;H,5.34;N,2.77. 
The .sup.1 H NMR spectrum of the subject compound was obtained in 
CDCl.sub.3, containing tetramethylsilane and is consistent with the 
structure indicated by the title, 
______________________________________ 
2.2-2.3 .delta. 
aliphatic protons (cyclic) 
7H 
2.8 .delta. or triplet 
CH.sub.2 next to N 
2H 
2.8-3.1 .delta. 
Hydrogen next to N 
2H 
3.5 .delta. doublet 
methine proton 1H 
4.1 .delta. triplet 
CH.sub.2 next to oxygen 
2H 
6.8-7.4 .delta. 
aromatic protons 
11H 
______________________________________ 
EXAMPLE 13 
1-[3-(4-Chlorophenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperid 
inemethanol 
A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(p-fluorophenyl)]4-piperidinemethanol, 2.0 g (0.01 
mole) of 1-chloro-4-(3-chloropropoxy)benzene, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol was heated at reflux for 20 hr to give, after working up as in 
Example 1 (recrystallizing the free base from isopropyl alcohol), 1.7 g 
(36%) of white solid, m.p. 92.degree.-93.degree. C. 
Analysis: Calculated for C.sub.27 H.sub.28 ClF.sub.2 NO.sub.2 : 
C,68.71;H,5.98;N,2.97. Found: C,68.66;H,5.99;N,2.92. 
EXAMPLE 14 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(2-fluorophenoxy)propyl]piperidine 
oxalate[1:1] 
A mixture of 5.85 g (0.02 mole) of 
4-[bis(4-fluorophenyl)methyl]-piperidine, 3.76 g (0.02 mole) 
of2-(3-chloropropoxy)-1-fluorobenzene, and sodium carbonate (4.80 g, 0.045 
mole) in 300 ml of 1-butanol containing 0.3 g of potassium iodide was 
heated overnight at gentle reflux. The reaction mixture was concentrated 
to dryness and the resulting oil partitioned between chloroform-5% sodium 
hydroxide and then between chloroform water. Removal of chloroform gave an 
oil which was converted to the oxalate salt. The salt was recrystallized 
from ethanol-ethyl ether. The salt was subsequently triturated with 
2-propanol, and was dried overnight at 80.degree. C. to give 5.82 g (55%) 
of product, m.p. 182.degree.-183.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.30 F.sub.3 NO.sub.5 : 
C,65.78;H,5.71;N,2.65. Found: C,66.05;H,5.79;N,2.59. 
EXAMPLE 15 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(3-fluorophenoxy)propyl]piperidine 
mandelate[1:1] 
Following the procedure of Example 14, 
4-[bis(4-fluorophenyl)methyl]-piperidine and 
3-(3-chloropropoxy)-1-fluorobenzene were reacted to give the free base of 
the title compound which was reacted with mandelic acid to give the white 
mandelate salt (recrystallizing from isopropyl alcohol) in 62% yield, m.p. 
145-147.5.degree. C. 
Analysis: Calculated for C.sub.35 H.sub.36 F.sub.3 NO.sub.4 : 
C,71.05;H,6.13;N,2.37. Found: C,71.10;H,6.20;N.2.36. 
EXAMPLE 16 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(4-chlorophenoxy)propyl]piperidine 
fumarate [1:1] 
Following the procedure of Example 14, 4-8 
bis(4-fluorophenyl)methyl]piperidine and 
1-[4-(3-chloropropoxy)]chlorobenzene were reacted to give the free base of 
the title compound. The free base was chromatographed on silica gel 
eluting with hexane-ethyl acetate and reacted with fumaric acid 
(recrystallizing from methanol-ethyl ether) in 9% yield, m.p. 
169.degree.-170.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.32 ClF.sub.2 NO.sub.5 : 
C,65.10;H,5.64;N,2.45. Found: C,64.85;H,5.63;N,2.46. 
EXAMPLE 17 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(4-fluorophenoxy)propyl]piperidine 
Following the combined procedures of Examples 14 and 
16,4-[bis(4-fluorophenyl)methyl]piperidine and 
4-(3-chloropropoxy)-1-fluorobenzene were reacted and worked up by 
chromatography as in Example 16, to give the free base in 53% yield as a 
yellow oil after drying in vacuo at 80.degree. C. overnight. 
Analysis: Calculated for C.sub.27 H.sub.28 F.sub.3 NO: 
C,73.78;H,6.42;N,3.19. Found: C,73.64;H,6.39;N,3.14. 
EXAMPLE 18 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(4methoxyphenoxy)propyl]piperidine 
fumarate [1:1] 
Following the procedure of Example 14, 4-[4-fluorophenyl)methyl]-piperidine 
and 1-(3-chloropropoxy)-4-methoxybenzene were reacted to give the free 
base of the title compound which was reacted with fumaric acid to give the 
white fumarate salt (recrystallizing from methanol-ethyl ether) in 64% 
yield, m.p. 172.degree.-173.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.35 F.sub.2 NO.sub.6 : 
C,67.71;H,6.22;N,2.47. Found: C,67.89;H,6.25;N,2.39. 
EXAMPLE 19 
4-[Bis(4-fluorophenyl)methyl]-1-[2-methoxyphenoxy)propyl]piperidine 
A mixture of 5.99 g (0.021 mole) of 
4-[bis(4-fluorophenyl)methyl]piperidine, 4.35 g (0.022 mole) of 
2-(3-chloroproxy)-1-methoxybenzene ether, and sodium carbonate (3.18 g, 
0.03 mole) in 1-butanol was heated overnight at gentle reflux. The 
reaction mixture was filtered and stripped to dryness. The residue was 
dissolved in chloroform and extracted with water and 5% sodium hydroxide. 
Removal of chloroform gave a dark brown oil. The oil was chromatographed 
on silica gel using acetone-ethyl acetate for elution. After combining 
fractions and removing solvent, an oil was obtained. The oil was dried in 
vacuo at 80.degree. C. overnight. This gave 3.18 g (33.5% of title 
product. 
Analysis: Calculated for C.sub.28 H.sub.31 F.sub.2 NO.sub.2 : 
C,74.48;H,6.92;N,3.12. Found: C,74.42;H,6.95;N,3.00. 
The .sup.1 H NMR spectrum of the subject compound was obtained in 
CDCl.sub.3, containing tetramethylsilane and is consistent with the 
structure indicated by the title, 
______________________________________ 
6.8 .delta. 
singlet; or protons on ring 
4H 
containing methoxy group. 
6.8-7.3 .delta. 
aromatic protons on fluoro- 
8H 
phenyl rings. 
4.0 .delta. 
triplet CH.sub.2 --O. 
2H 
3.8 .delta. 
singlet O--CH.sub.3. 
3H 
3.4 .delta. 
doublet; methine proton. 
1H 
0.8-3.1 .delta. 
multiplet. 13H 
______________________________________ 
EXAMPLE 20 
.alpha.,.alpha.-Bis(45-fluorophenyl)-1-[3-(2-methoxyphenoxy)propyl]-4-piper 
idinemethanol. 
Following the procedure of Example 1, 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol and 
1-chloro-3-(2-methoxyphenoxy)propane were reacted using in addition 
potassium iodide catalyst to give the title compound in 66% yield, 
(recrystallizing from isopropyl alcohol), m.p. 127.degree.-218.degree. C. 
Analysis: Calculated for C.sub.28 N.sub.31 F.sub.2 NO.sub.3 : 
C,71.93;H,6.68;N,3.00. Found: C,71.88;H,6.67;N,2.98. 
EXAMPLE 21 
4-[Bis(4-fluorophenyl)methylene]-1-[3-(2-methoxyphenoxy)propyl]-piperidine 
oxalate [1:1] 
Following the procedure of Example 14, 
4-[bis(4-fluorophenyl)methylene]piperidine and 
2-(3-chloropropoxy)-1-methoxybenzene were reacted using in addition 
potassium iodide catalyst to give the free base of the title compound 
which was reacted with oxalic acid give the white oxalate salt 
(recrystallizing from methanol-ethyl ether) in 73% yield, m.p. 
184.degree.-186.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.31 F.sub.2 NO.sub.6 : 
C,66.78;H,5.79;N,2.60. Found: C,66.74;H,5.79;N,2.61. 
EXAMPLE 22 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(3,4-dimethoxyphenoxy)propyl]-piperidine 
oxalate [1:1] 
A mixture of 6.02 g (0.021 mole) of 
4-[bis(4-fluorophenyl)-methyl]piperidine, 4.83 g (0.021 mole) of 
4-(3-chloropropoxy)-1,2-dimethoxybenzene, and potassium carbonate (5.52 g, 
0.04 mole) was heated at reflux overnight in 300 ml of 1-butanol 
containing potassium iodide (0.3 g). The reaction mixture was concentrated 
to dryness and partitioned between chloroform and water several times. The 
chloroform layer was dried over anhydrous sodium sulfate and then 
filtered. The chloroform was removed by rotary evaporator. The oil 
obtained was converted to the oxalate salt and then recrystallized from 
ethanol-ethyl ether and methanol isopropyl ether. This furnished 7.77 g 
(64.7%) of white solid, m.p. 188.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.35 F.sub.2 NO.sub.7 : 
C65.14;H,6.17;N,2.43. Found: C,64.78;H,6.14;N,2.44. 
EXAMPLE 23 
4-[Bis(4-methylphenyl)-methyl]-1-[3-(2,6-dimethoxyphenoxy)propyl]-piperidin 
e fumarate [1:1] 
Following the procedure of Example 22, 
4-[bis(4-methylphenyl)methyl]-piperidine and 
2-(3-chloropropoxy)-1,3-dimethoxybenzene were reacted to give the free 
base of the title compound which was reacted with fumaric acid to give the 
white fumarate salt (recrystallizing from methanol-ethyl ether) in 66% 
yield, m.p. 206-207.degree. C. 
Analysis: Calculated for C.sub.35 H.sub.43 NO.sub.7 : 
C,71.29;H,7.35;N,2.38. Found: C,71.24;H,7.38;N,2.36. 
EXAMPLE 24 
4-[Bis(4-fluorophenyl)methylene]-1-[3-(3,4-dimethoxyphenoxy)propyl]piperidi 
ne oxalate [1:1] 
Following the procedure of Example 22, 
4-[bis(4-fluorophenylmethylene]piperidine and 
4-(3-chloropropoxy)-1,2-dimethoxybenzene were reacted to give the free 
base of the title compound which was reacted with oxalic acid to give the 
cream colored oxalate salt (recrystallizing from methanol-ethyl ether) in 
51% yield, m.p. 173.degree.-176.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.33 F.sub.2 NO.sub.7 : 
C,65.37;H,5.84;N,2.46. Found: C,65.02;H,5.83;N,2.50. 
EXAMPLE 25 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(2,6-dimethoxyphenoxy)propyl]-piperidine 
oxalate hydrate [1:1:1] 
Following the procedure of Example 22, but substituting dimethoxy ethane 
for butanol, 4-[bis(4-fluorophenyl)methyl]piperidine and 
2-(3-chloropropoxy)-1,3-dimethoxybenzene were reacted to give the free 
base of the title compound which was reacted with oxalic acid to give the 
white oxalate salt (recrystallizing from methanol-ethyl ether) in 9% 
yield, m.p. 132.degree.-134.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.35 NO.sub.7 .multidot.H.sub.2 O: 
C,63.15;H,6.32;N,2.38. Found: C,62.89;H,5.98;N,2.41. 
EXAMPLE 26 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(3,5-dimethoxyphenoxy)propyl]-piperidine 
A mixture of 5.51 g (0.019 mole) of 
4-[bis(4-fluorophenyl)methyl]piperidine, 4.42 g (0.019 mole) of 
1-(3-chloropropoxy)-3,5-dimethoxybenzene and potassium carbonate (5.53 g, 
0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol 
containing potassium iodide (0.3 g). The reaction mixture was concentrated 
to dryness and the residue partitioned between chloroform-5% sodium 
hydroxide and chloroform-water. Removal of chloroform gave a brown oil. 
The oil was subjected to chromatography on a silica gel column using a 
gradient elution series of hexane-ethyl acetate and ethyl 
acetatedimethoxyethane. After combining proper fractions eluted from the 
column and removing solvent, the residue oil was dried in vacuo overnight 
at 80.degree. C. This produced 2.61 g (28.5%) of brown oil. 
Analysis: Calculated for C.sub.29 H.sub.33 F.sub.2 NO.sub.3 : 
C,72.33;H,6.91;N,2.91. Found: C,71.62;H,6.80;N,2.98. 
The .sup.1 H NMR spectrum of the subject compound was obtained in 
CDCl.sub.3 containing tetramethylsilane and is consistent with the 
structure indicated by the title: 7.0 .delta. (multiplet, aromatic protons 
on fluorophenyl ring), 6.0 (singlet, aromatic protons on methoxyphenyl 
ring, 3H), 2.8 (triplet, methylene next to ether oxygen, 2H), 3.75 
(singlet, OCH.sub.3 6H), 3.4 (doublet, methine attached to two aromatic 
rings, (1H), 0.75-2.6 (multiplet, remaining aliphatics, 13H). 
EXAMPLE 27 
4-[Bis(4-methoxyphenyl)methyl]-1-[3,4-dimethoxyphenoxy)propyl]-piperidine 
A mixture of 5.58 g (0.02 mole) of 
4-[bis(4-methoxyphenyl)methyl]-piperidine, 4.83 g (0.021 mole) of 
4-(3-chloroproxy)-1,2-dimethoxybenzene, and potassium carbonate, 5.52 g 
(0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol 
containing potassium iodide (0.3 g). The reaction mixture was concentrated 
to dryness, and the residue partitioned between chloroform-5% sodium 
hydroxide and chloroform-water. Removal of chloroform gave a dark brown 
oil. The oil was subjected to column chromatography on a silica gel column 
with elution via ethyl acetate-dimethoxyethane. This produced 4.72 g 
(46.7%) of dark brown oil. 
Analysis: Calculated for C.sub.31 H.sub.39 NO.sub.5 : 
C,73.64;H,7.77;N,2.77. Found: C,72.38;H,7.70;pN,2.72. 
The .sup.1 H NMR spectrum of the subject compound was obtained in 
CDCl.sub.3 containing tetramethylsilane and is consistent with the 
structure indicated by the title: .delta.7.1 multiplet, aromatic protons 
ortho to methine of 
##STR19## 
4H), 6.75 (multiplet, aromatic protons adjacent to methoxy groups, 5H), 
6.4(multiplet, aromatic protons adjacent to ether linkage, 2H), 3.9 
(triplet, methylene protons next to ether linkage, 2H), 3.7 (OCH.sub.3, 
6H), 3.6 (OCH.sub.3, 6H), 3.3 (doublet, methine attached to aromatic 
rings, 1H), 0.75-3.0 (multiplet, aliphatic protons, 13H). 
EXAMPLE 28 
4-[Bis(4-methoxyphenyl)methyl]-1-[3-(4-methoxyphenoxy)propyl]-piperidine 
fumarate hydrate [1:2:0.5] 
Following the procedure of Example 22, 
4-[bis(4-methoxyphenyl)methyl]piperidine and 
4-(3-chloropropoxy)-1-methoxybenzene were reacted to give the free base of 
the title compound which was separated by extracting with sodium 
hydroxide-chloroform and reacted with fumaric acid to give the title salt 
(recrystallizing from methanol-ethyl ether several times as well as 
isopropyl alcohol) in 15% yield, m.p. 163.degree.-165.degree. C. 
Analysis: Calculated for C.sub.34 H.sub.41 NO.sub.8 .multidot.0.5H.sub.2 O: 
C,67.98;H,7.05;N,2.33. Found: C,68.16;H,6.97;N,2.34. 
EXAMPLE 29 
1-[4-[3-[4-Bis(4-fluorophenyl)methylene]-1-piperidinyl]propoxy]-phenyl]etha 
none oxalate ]1:1] 
Following the procedure of Example 
2,4-[bis(4-fluorophenyl)methylene]piperidine and 
1-[4-(3-chloroproxy)phenyl]ethanone, substituting sodium carbonate for 
sodium bicarbonate, were reacted to give the free base of the title 
compound which was reacted with oxalic acid to give the oxalate salt 
(recrystallizing from ethanol-ethyl ether) in 59% yield, m.p. 
196.degree.-198.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.31 F.sub.2 NO.sub.6 : 
C,67.50;H,5.66;N,2.54. Found: C,67.18;H,5.68;N,2.43. 
EXAMPLE 30 
1-4-[3-[4-Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy phenyl]-ethanone 
oxalate [1:1] 
Following the procedure of Example 
2,4-[bis(4-fluorophenyl)methyl]-piperidine and 
1-[4-(3-chloropropoxy)phenyl]ethanone and substituting sodium carbonate 
for sodium bicarbonate were reacted to give the free base of the title 
compound which was reacted with oxalic acid to give the oxalate salt 
(recrystallizing from methanol-diethyl ether) in 75% yield, m.p. 
141.degree.-143.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.33 NO.sub.6 F.sub.2 : 
C,67.26;H,6.01;N,2.53. Found: C,66.94;H,6.01;N,2.40. 
EXAMPLE 31 
1-[4-[3-[4-Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-phenyl] 
ethanone compound with 2-propanol [1:1] 
Following the procedure of Example 1, 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol and 
1-[4-(3-chloroproxy)phenyl]ethanone were reacted using potassium iodide 
catalyst to give the free base of the title compound which when 
recrystallized from isopropyl alcohol gave the white title compound in 71% 
yield, m.p. 72.degree.-84.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.31 F.sub.2 NO.sub.3 C.sub.3 H.sub.8 
O: C,71.22;H,7.28;N,2.60. Found: C,71.26;H,7.34;N,2.56. 
EXAMPLE 32 
1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-meth 
ylphenyl]ethanone 
Following the procedure of Example 
1,.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol and 
1-[4-(3-chloroproxy)-3-methylphenyl]ethanone were reacted using potassium 
iodide catalyst to give the white title compound (recrystallizing from 
isopropyl alcohol) in 76% yield, m.p. 116.degree.-117.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.33 F.sub.2 NO.sub.3 : 
C,73.00;H,6.74;N,2.84. Found: C,72.90;H,6.80;N,2.78. 
EXAMPLE 33 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzonitri 
le 
Following the procedure of Example 1, .alpha.,60 
-bis(p-fluorophenyl)-4-piperidinemethanol and 4-(3-chloropropoxy) 
benzonitrile were reacted using potassium iodide as catalyst to give the 
white title compound (recrystallizing from isopropyl alcohol-isopropyl 
ether) in 30% yield, m.p. 107.degree.-108.degree. C. 
Analysis: Calculated for C.sub.28 H.sub.28 F.sub.2 N.sub.2 O.sub.2 : 
C,72.71;H,6.10;N,6.06. Found: C,72.82;H,6.11;N,6.05. 
EXAMPLE 34 
4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzonitrile 
fumarate [1:1] 
Following the procedure of Example 22, 
4-[bis(4-fluorophenyl)methyl]-piperidine and 
4(3-chloropropoxy)cyanobenzene were reacted using potassium iodide 
catalyst to give the free base of the title compound which was reacted 
with fumaric acid to give the fumarate salt which was recrystallized from 
ethanol-ethyl ether in 53% yield, m.p. 167.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.32 F.sub.2 N.sub.2 O.sub.5 : 
C,68.32;H,5.73;N,4.98. Found: C,68.10;H,5.70;N,4.94. 
EXAMPLE 35 
4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzoic acid 
ethyl ester hydrochloride [1:1] 
A mixture of 6.0 g(0.02 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 5.0 g (0.02 
mole) of 4-(3-chloropropoxy))benzoic acid methyl ester, 7.4 g (0.07 mole) 
of anhydrous sodium carbonate, 0.3 g of potassium iodide and 150 ml of 
dimethylformamide was heated on a steam bath for 20 hr and then poured 
into 1.5 liter of ice-water. A gum precipitated and the aqueous solution 
was decanted. The gum was dissolved in benzene and the solution was washed 
with water and dilute sodium hydroxide solution, dried over anhydrous 
sodium sulfate and concentrated under reduced pressure to give 9.2 g of 
gum as residue. The gum was purified by column chromatography on 200 g of 
Florisil.RTM. and the desired product was eluted with 20% acetone in 
benzene. The fractions containing the free base of the title compound were 
combined and concentrated under reduced pressure to give a gum, the free 
base, as residue. The free base was converted to the hydrochloric acid 
salt which was recrystallized from 2-propanol to give 5.3 g (49%) of white 
powder, m.p. 193.5-194.5.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.34 ClF.sub.2 NO.sub.4 : 
C,65.66;H,6.28;N,2.57. Found: C,66.16;H,6.32;N,2.56. 
EXAMPLE 36 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl-1-piperidinyl]propoxy -benzoic 
acid hydrochloride hydrate [1:1:0.5] 
A solution of 2.7 g (0.005 mole) of 
4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzoic 
acid ethyl ester and 1.2 g(0.022 mole) of potassium hydroxide in 50 ml of 
ethanol and 20 ml of water was heated on a steam bath for 2 hr. Acetic 
acid, 10 ml, was added and the solution was poured into 500 ml of ice 
water and the mixture was allowed to stand at ambient temperature 
overnight. Sodium chloride was added to the mixture to give a coagulated 
solid. The solid was collected by filtration and air dried. The solid was 
dissolved in 20 ml of isopropyl alcohol and the solution was poured into 
30 ml of ethereal hydrogen chloride. The salt which gradually crystallized 
was collected by filtration, washed with ethyl ether and dried to give 0.2 
g (8%) of white powder, m.p. 148.degree.-158.degree. C. with 
decomposition. 
Analysis: Calc'd for C.sub.19 H.sub.30 ClF.sub.2 NO.sub.4 
.multidot.0.5H.sub.2 O: C,63.82;H,5.93;N,2.66. Found: 
C,53.97;H,6.25;N,2.51. 
EXAMPLE 37 
4-[3-[4-[Bis(4-fluorophenyl)methylene-1-piperidinyl]propoxy]benzoic acid 
ethyl ester hydrobromide [1:1] 
A mixture of 6.09 g (0.021 mole) of 
4-[bis(4-fluorophenyl)methylene]-piperidine, 5.20 g (0.02 mole) of 
1-[4-(3-chloropropoxy)-phenyl]carbethoxybenzene and sodium carbonate 4.30 
g (0.04 mole) in 230 ml of 1-butanol containing potassium iodide (0.3 g) 
was heated overnight at gentle reflux. The reaction mixture was 
concentrated to dryness and partitioned between chloroform water and 
chloroform -5% sodium hydroxide. Removal of chloroform gave an oil. The 
oil was converted to the hydrobromide salt using hydrogen bromide in 
glacial acetic acid. The acetic acid and excess hydrogen bromide were 
removed in vacuo. The salt was recrystallized from ethanolethyl ether. The 
salt was washed with water to remove acetamide present as an impurity. The 
salt was washed with ethyl ether and dried in vacuo overnight at 
80.degree. C. A yield of 6.81 g (59.5%) of white solid, m.p. 
192.degree.-194.degree. C., was obtained. 
Analysis: Calculated for C.sub.30 H.sub.32 BrF.sub.2 NO.sub.3 : 
C,62.94;H,5.63;N,2.45. Found: C,62.83;H,5.58;N,2.45. 
EXAMPLE 38 
4-[3-[4-[Bis(4-fluorophenylmethyl]-1-piperidinyl]propoxy]benzoic acid ethyl 
ester hydrobromide [1:1] 
Following the procedure of Example 14, 4-[bis 
(4-fluorophenyl)methyl]-piperidine and 4-(3-chloropropoxy)benzoic acid 
ethyl ester were reacted using potassium iodide as catalyst to give the 
free base which was reacted with hydrogen bromide in glacial acetic acid. 
The oil was stripped to dryness and the solid obtained was recrystallized 
from isopropyl alcohol-ethyl ether to give the white salt in 20% yield, 
m.p. 142.degree.-144.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.34 BrF.sub.2 NO.sub.3 : 
C,62.72;H,5.97;N,2.44. Found: C,62.66;H,5.95;N,2.45. 
EXAMPLE 39 
4-[3-[4-[Bis(4-methoxyphenyl)methyl]-1-piperidinyl]propoxy]benzoic acid 
butyl ester 
A mixture of 6.22 g (0.02 mole) of 
4-[bis(4-methoxyphenyl)methyl]-piperidine, 4.84 g (0.02 mole) of 
4-(3-chloropropoxy)benzoic acid ethyl ester, and potassium carbonate, 5.60 
g (0.04 mole) in 350 ml of 1-butanol was refluxed overnight with potassium 
iodide. The reaction mixture was concentrated to dryness and the residue 
partitioned between chloroform-5% sodium hydroxide then chloroform-water. 
Removal of chloroform gave an oil. This oil chromatographed on a 200 g 
silica gel column packed in 50/50 v/v hexane-ethyl acetate. The material 
was eluted with hexane-ethyl acetate mixtures and finally 1% 
methanol-ethyl acetate. From the chromatography was obtained 5.09 g 
(46.6%) of an oil. 
Analysis: Calculated for C.sub.34 H.sub.43 NO.sub.5 : 
C,74.83;H,7.94;N,2.57. Found: C,74.19;H,7.91;N,2.53. 
The .sup.1 H NMR spectrum was obtained in tetramethylsilane and is 
consistent with the structure indicated by the title, .delta. 8.0 (H's 
ortho to CO.sub.2, 2H), 6.8 (m, aromatic, 10H), 4.2(m, CH.sub.2 alpha to 
O, 4H), 3.7 (S, OCH.sub.3, 6H), 0.9-3.5 (m, aliphatics, 21H). 
EXAMPLE 40 
4-[3-[4-[Bis(4-methoxyphenyl)methyl]-1-piperidinyl]propoxy]benzoic acid 
ethyl ester fumarate hydrate [1:1:0.5] 
Following the procedure of Example 22, but substituting dimethylformamide 
at 73.degree. C. for butanol, 4-[bis(40methoxyphenyl)methyl]piperidine and 
4-(3-chloropropoxy)benzoic acid ethyl ester were reacted to give the free 
base of the title compound which was reacted with fumaric acid, to give 
the white fumarate salt (recrystallizing from methanol-ethyl ether) in 27% 
yield, m.p. 147.5-148.5.degree. C. 
Analysis: Calculated for C.sub.36 H.sub.43 NO.sub.9 .multidot.0.5H.sub.2 O: 
C,67.27;H, 6.90;N,2.18. Found: C,67.26;H,6.78;N,2.19. 
EXAMPLE 41 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethoxy]-benzoic 
acid ethyl ester hydrochloride 
Following the procedure of Example 35, 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol and 
4-(2-chloroethoxy)benzoic acid ethyl ester are reacted and the 
hydrochloride salt is prepared. 
EXAMPLE 42 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxy 
benzeneacetic acid ethyl ester hydrochloride 
Following the procedure of Example 35, 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol and 
4-(3-chloroproxy)-3-methoxybenzeneacetic acid ethyl ester are reacted and 
the hydrochloride salt is prepared. 
EXAMPLE 43 
4-[Bis(4-fluorophenyl)methylene]-1-[3-[4-(1,1-dimethylethyl)phenoxy]-propyl 
]piperidine fumarate [1:1] 
Following the procedure of Example 9,4-[bis(4-fluorphenyl) 
-methylene]piperidine and 4-(3-chloroproxy)-(1,1-dimethylethyl)benzene 
were reacted using potassium iodide catalyst to give an oil which was 
dissolved in ethyl acetate and filtered through silica gel to give the 
free base of the title compound. The free base was reacted with fumaric 
acid to give the white fumarate salt (recrystallizing from isoproyl 
alcohol-ethyl ether) in 40% yield, m.p. 208.5.degree.-209.5.degree. C. 
Analysis: Calculated for C.sub.35 H.sub.39 F.sub.2 NO.sub.5 : 
C,71.05;H,6.64;N,2.37. Found: C,70.91;H,6.57;N,2.38. 
EXAMPLE 44 
4-[Bis(4-flurophenyl)methyl]-1-[3-[4-(1,1-dimethylethyl)phenoxy]-propyl]pip 
eridine fumarate hydrate [1:1:0.5] 
Following procedure of Example 9,4-[bis(4-fluorophenyl)methyl]-piperidine 
and 4-(3-chloropropoxy)-(1,1-dimethylethyl)benzene were reacted using 
potassium iodide catalyst to give the free base title compound which was 
reacted with fumaric acid to give the white fumarate salt (recrystallizing 
from methanol-ethyl ether and isopropyl alcohol-ethyl ether) in 55% yield, 
m.p. 194-196.degree. C. with decomposition. 
Analysis: Calculated for C.sub.35 H.sub.41 F.sub.2 NO.sub.5 
.multidot.0.5H.sub.2 O: C,69.75;H,7.02;N,2.32. Found: 
C,70.01;H,6.89;N,2.44. 
EXAMPLE 45 
4-[Bis(4-methoxyphenylmethyl]-1-[3-[4-(1,1dimethylethyl)phenoxy]-propyl]pip 
eridine oxalate [1:1] 
Following the procedure of Example 
22,4-[bis(4-methoxyphenyl)methyl]piperidine and 
4-(3-chloropropoxy)-(1,1-dimethylethyl)benzene were reacted using 
potassium iodide catalyst to give the free base which was reacted with 
oxalic acid to give the white oxalate salt (recrystallizing from 
methanol-ethyl ether) in 35% yield, m.p. 212.degree. C. 
Analysis: Calculated for C.sub.35 H.sub.45 NO.sub.7 : C,71.04;H,7.67;N,2.37 
Found: C,70.91;H,7.70;N,2.35. 
EXAMPLE 46 
1-[3-[4-(1,1-Dimethylethyl)phenoxy]propyl]-.alpha.,.alpha.-bis(4-fluorophen 
yl)-4-piperidinemethanol 
Following the procedure of Example 1, .alpha.,.alpha.-bis 
(p-fluorophenyl)-4-piperidinemethanol and 
4-(3-chloropropoxy)-(1,1-dimethylethyl)benzene were reacted using 
potassium iodide catalyst to give with white powder (recrystallizing from 
isopropyl alcohol) in 41% yield, m.p. 126.degree.-127.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.37 F.sub.2 NO.sub.2 : 
C,75.43;H,7.56;N,2.84. Found: C,75.21;H,7.58;N,2.82. 
EXAMPLE 47 
4-[Bis(4-fluorophenyl)methyl]-1-[3-[3-(trifluoromethyl)phenoxy]-propyl]pipe 
ridine oxalate [1:1] 
Following the procedure of Example 9,4-[bis 
(4-fluorophenyl)methyl]-piperidine and 
1-[3-chloropropoxy]-3-trifluoromethylbenzene were reacted using potassium 
iodide catalyst to give the free base of the title compound which was 
reacted with oxalic acid to give the white oxalate salt (recrystallizing 
from methanol-ethyl ether) in 39% yield, m.p. 185.degree.-186.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.30 F.sub.5 NO.sub.5 : 
C,62.17;H,5.22;N,2.42. Found: C,62.54;H,5.27;N,2.52. 
EXAMPLE 48 
N-[4-[3-[4-[Bis(4-methylphenyl)methyl]-1-piperidinyl]propoxy]phenyl]acetami 
de fumarate hydrate [1:1:0.5] 
Following the procedure of Example 22 but substituting dimethylformamide at 
73.degree. C. for refluxing butanol, 
4-[bis-(4-methylphenyl)methyl]-piperidine and 
N-[4-(3-chloropropoxy)phenyl]acetamide were reacted using potassium iodide 
catalyst to give the free base of the title compound which was reacted 
with fumaric acid to give the white fumarate hydrate (recrystallizing from 
methanol-ethyl ether), m.p. 149.degree.-152.degree. C. 
Analysis: Calculated for C.sub.35 H.sub.42 N.sub.2 O.sub.6 
.multidot.0.5H.sub.2 O: C,70.57;H,7.28;N,4.70. Found: 
C,70.80;H,7.28;N,4.65. 
EXAMPLE 49 
N-[4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]phenyl]-acetamide 
hydrobromide [1:1] 
A mixture of 25.68 g (0.089 mole) 4-[bis(4-fluorophenyl)methyl]-piperidine, 
20.3 g (0.089 mole) of N-[4-(3-chloropropoxy)phenyl]acetamide, and 
potassium carbonate, (21.4 g, 0.155 mole) was stirred overnight at 
70.degree.-80.degree. C. in 350 ml of dimethylformamide. The reaction 
mixture was concentrated to dryness and the residue was partitioned 
between chloroform and water; removal of chloroform gave a dark red oil. 
The oil was dissolved in glacial acetic acid, and the hydrobromide salt 
was formed with hydrobromic acid in glacial acetic acid. Solvent was 
removed in vacuo, and the residue was recrystallized from methanol-ethyl 
ether. A yield of 21.68 g43.5%) of pale-white solid, m.p. 
223.degree.-225.degree. C., was obtained. 
Analysis: Calculated for C.sub.29 H.sub.33 BrF.sub.2 N.sub.2 O.sub.2 : 
C,62.26;H,5.95;N,5.01. Found: C,61.99;H,5.94;N,5.01. 
EXAMPLE 50 
4-[3-4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzeneamine 
fumarate hydrate [1:1:0.5] 
A solution of 11.8 g (0.027 mole) of 
N-[4-[3-[bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]acetamide was 
heated at gentle reflux for four hours in 500 ml of methanol containing 
500 ml of 6N hydrochloric acid. The reaction was stopped and allowed to 
cool overnight. The reaction mixture was evaporated to a small volume on 
the rotary evaporator, diluted with water and made alkaline with 5% sodium 
hydroxide. The reaction mixture was then partitioned between the alkaline 
phase and chloroform. The chloroform layer was dried, filtered, and 
solvent removed to give an oil. The oil was converted to the fumarate salt 
and the salt was recrystallized from methanolethyl ether. The white solid 
obtained was dried overnight in vacuo at 80.degree. C. to give 8.49 g 
(71%) of white, crystalline product, m.p. 121.5.degree.-124.0.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.34 F.sub.2 N.sub.2 O.sub.5 
.multidot.0.5H.sub.2 O: C,66.30;H,6.28;N,4.99. Found: 
C,66.49;H,6.13;N,4.92. 
EXAMPLE 51 
N-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-phenyl 
]acetamide hydrochloride hydrate [1:1:1] 
A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)4-piperidinemethanol, 2.3 g (0.01 mole) 
of N--8 4-(3-chloropropoxy)phenyl]acetamide, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol gave a gum as residue. The gum was purified by column 
chromatography on 80 g of Florisil.RTM. and the product was eluted with 
20% acetone in benzene. The combined fractions containing product were 
concentrated under reduced pressure to give a glass as residue. The glass 
was dissolved in ethyl ether, filtered through cotton, and the filtrate 
treated with ethereal hydrogen chloride. The resulting solid was collected 
by filtration, washed with ethy7l ether and dried to yield 2.1 g (38%) of 
white solid, m.p. 135.degree.-170.degree. C. (with decomposition). 
Analysis: Calculated for C.sub.29 H.sub.33 ClF.sub.2 N.sub.2 
O.sub.3.H.sub.2 O: C,63.44;H,6.43;N,5.10. Found: C,67.05;H,5.83;N,5.74. 
EXAMPLE 53 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-benzamide 
Following the procedure of Example 1 and using potassium iodide catalyst, a 
mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p0fluorophenyl)4-piperidinemethanol, 2.1 g (0.01 mole) 
or 4-(3-chloropropoxy)benzamide and 6.9 g (0.05 mole) of anhydrous 
potassium carbonate in 100 ml of 1-butanol were reacted to give 3.0 g 
(63%) of white powder, m.p., 200.degree.-204.degree. C. The 
recrystallizing solvent used was absolute ethanol. 
Analysis: Calculated for C.sub.28 H.sub.30 F.sub.2 N.sub.2 O.sub.3 : 
C69.98;H,6.29;N,5.83. Found:C,69.61;H,6.49;N,5.70. 
EXAMPLE 54 
4-[Bis(4-fluorophenyl)methyl]-1-[2-(1-naphthalenyloxy)ethyl]piperidine 
hydrochloride [1:1] 
A mixture of 2.84 g (0.0099 mole) of 
4-[.alpha.,.alpha.-bis(p-fluorophenyl)methyl]piperidine, 3.01 g (0.012 
mole) of 1-(2-bromoethoxy)naphthalene and 5.0 g (0.060 mole) of sodium 
bicarbonate in 400 ml of 1-butanol was heated at reflux for 16 hr. The 
solvent was removed in vacuo and the residue was partitioned between 
methylene chloride and dilute sodium hydroxide. The methylene chloride 
solution was dried over magnesium sulfate, and the solvent was removed in 
vacuo to give an oil. This was dissolved in a mixture of ether and 
methanol, an excess of ethereal hydrochloride was added, and a white 
precipitate was collected to give 3.13 g (64%) of white, crystalline 
solid, m.p. 155.degree.-158.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.30 ClF.sub.2 NO: 
C,72.94;H,6.12;N,2.84.Found: C,73.20;H,6.10;N,2.78. 
EXAMPLE 55 
4-[Bis(4-fluorophenyl)methyl]-1-[2-(2-naphthalenyloxy)ethyl]piperidine 
oxalate [1:1] 
Following the procedure of Example 54 and substituting 
2-(2-bromoethoxy)naphthalene and oxalic acid for hydrogen chloride, the 
title compound was obtained in 61.9% yield as white, crystalline solid, 
m.p. 168.degree.-171.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.31 F.sub.2 NO.sub.5 : 
C,70.19;H,5.71;N,2.56. Found: C,70.25;H,5.75;N,2.63. 
EXAMPLE 56 
1-[4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphen 
yl]ethanone oxalate [1:1] 
The title compound was prepared by the method described in U.S. Pat. No. 
3,956,296 (see Example 13 of that patent) as follows: A mixture of 4.75 
g(0.0165 mole) of 4-[.alpha.,.alpha.-bis(p-fluorophenyl)methyl]piperidine, 
4.0 g (0.0165 mole) of 3-(-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 
g (0.0165 mole) of sodium bicarbonate in 60 ml of dimethylformamide was 
heated at 80.degree. C. for about 2 hours. TLC showed no product at this 
point. The temperature was raised to 100.degree. C. for 1 hr, at which 
time TLC showed the reaction to be complete. After cooling, the reaction 
mixture was filtered and the dimethylformamide was removed under reduced 
pressure. The crude product was dissolved in chloroform and filtered and 
filtrate was concentrated under reduced pressure to give 7.7 g(94%) of 
crude product. The solild was dissolved in benzene and placed on a 
Florisil.RTM. column. Upon eluting with an acetone-benzene gradient, 5.5 g 
of product was obtained. The oxalate salt was prepared and upon 
recrystallization from 2-propanolmethanol, 3.8 g of salt was obtained, 
m.p. 164.5.degree.-166.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.35 F.sub.2 NO.sub.7 : 
C,65.86;H,6.05;N,2.40 Found: C,66.11;H,6.13;N,2.39. 
1-[4-[3-4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxypheny 
l]ethanone fumarate [5:6] 
A mixture of 58.26 g (0.203 mole) of 
4-[bis(4-fluorophenyl)methyl]piperidine, 54.5 g (0.225 mole) of 
1-chloro-3-(4-acetyl-2-methoxyphenoxy) propane, 18.7 g (0.223 mole) of 
sodium bicarbonate and 1.2 g (0.0072 mole) of potassium iodide in 800 ml 
of 1-butanol was heated at reflux for 16 hr. The hot reaction mixture was 
filtered, and the solvent was removed in vacuo from the filtrate. The 
residue was partitioned between methylene chloride and dilute sodium 
hydroxide. The methylene chloride solution was dried over magnesium 
sulfate, and the solvent was removed in vacuo to give an oil. The oil was 
dissolved in 600 ml of anhydrous ether, and 4.91 g of a solid was 
collected at room temperature. The ether solution was then treated with a 
solution of 30.2 g (0.26 mole) of fumaric acid in methanol. Anhydrous 
ether was added and 99.88 g (77.7%), m.p. 160.degree.-163.degree. C., of 
title compound was isolated. This was recrystallized from 2-propanol-ethyl 
ether, (2.5 g, 0.0216 mole of additional fumaric acid was added) to give 2 
crops of title compound. [Crop I-44.15 g, m.p. 163.degree.-164.5.degree. 
C.;Crop II-38.75 g, m.p. 161.degree.-163.degree. C.]. An additional 10.00 
g (8.786%), m.p. 159.degree.-162.degree. C. of title compound collected 
from the original ether-methanol filtrate. NMR showed that the salt 
contained 1.2 equivalent of fumaric acid. 
Analysis: Calc'd for C.sub.30 H.sub.33 F.sub.2 NO.sub.3.1.2C.sub.4 H.sub.4 
O.sub.4 :C,66.05;H,6.02;N,2.21. Found: C,65.96;H,6.18;N,2.16. 
EXAMPLE 58 
1-[4-[3-[4-[Bis(4-fluorophenyl)methylene]-1-piperidinyl]propoxy]-3-methoxyp 
henyl]ethanone oxalate [1:1] 
The title compound was prepared by the method described in U.S. Pat. No. 
3,922,276 (see Example 12 of that patent) as follows: A mixture of 4.7 g 
(0.0165 mole) of 
4-[.alpha.,.alpha.-bis(p0fluorophenyl)methylene]piperidine, 4.0 g (0.0165 
mole) of 3-(-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g of sodium 
bicarbonate in 60 ml of dimethylformamide was heated at 100.degree. C. 
overnight. After cooling, the reaction mixture was filtered and the 
dimethyl formamide was removed at reduced pressure. The residual oil was 
dissolved in benzene and placed on a Florisil.RTM. column. Elution with a 
gradient of acetone-benzene gave 5.7 g (70%) of a viscous, brown oil. The 
free base was reacted with oxalic acid to give the oxalate salt, m.p. 
169.degree.-170.degree. C., after recrystallization from isopropyl alcohol 
and drying under vacuum. 
Analysis: Calculated for C.sub.32 H.sub.33 F.sub.2 NO.sub.7 : 
C,66.08;H,5.72;N,2.41. Found: C,66.01;H,5.67;N,2.40. 
EXAMPLE 59 
1-[4-[3-[4-[(4-Fluorophenyl)(phenyl)methylene]-1-piperidinyl]propoxy]3-meth 
oxyphenyl]ethanone oxalate [1:1] 
The title compound was prepared by the method described in U.S. Pat. No. 
3,922,276 (see Example 12 of that patent) as follows: A mixture of 7.1 g 
(0.027 mole) of 
4-[.alpha.-(p-fluorophenyl)-.alpha.-phenylmethylene]piperidine, 6.5 g 
(0.027 mole) of 3-(-acetyl-o-methoxyphenoxy)propyl chloride and 2.3 g 
(0.027 mole) of sodium bicarbonate in 100 ml of dimethylformamide was 
stirred and heated at 100.degree. C. for approximately 8 hours. The 
mixture was filtered and the dimethylformamide was removed under reduced 
pressure. The residual oil was dissolved in chloroform and the mixture was 
filtered. The filtrate was concentrated under vacuum to give 11.5 g of 
crude, free base (92%). The free base was reacted with oxalic acid to give 
the oxalate salt, m.p. 143.degree.-145.degree. C., after recrystallization 
from methyl isobutyl ketone. 
Analysis: Calculated for C.sub.32 H.sub.34 FNO.sub.7 : 
C,68.19;H,6.08;N,2.49. Found: C,68.14;H,6.12;N,2.54. 
EXAMPLE 60 
1-[3-Methoxy-4-[3-[4-[phenyl[3-(trifluoromethyl)phenyl]methylene]-1-piperid 
inyl]propoxy]phenyl]ethanone oxalate [1:1] 
The title compound was prepared by the method described in U.S. Pat. No. 
3,922,276 (see Example 10 of that patent) as follows; A mixture of 5.0 g 
(0.0157 mole) of 
4-[.alpha.-phenyl-.alpha.-(m-trifluoromethylphenyl)methylene]piperidine, 
3.82 g (0.0157 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 
2.52 g (0.03 mole) of sodium bicarbonate in 75 ml of 1-butanol was stirred 
and heated at reflux for 17.5 hrs. The mixture was cooled and filtered, 
and the filtrate was concentrated under reduced pressure. The glassy 
residue obtained weighed 4.25 g (52%) and was dissolved in benzene and 
placed on a Florisil.RTM. column. Using an acetone-benzene gradient 
elution, product was obtained as a glassy residue. This residue was 
dissolved in ether and the oxalate salt was obtained. The salt has a 
glassy appearance, m.p. 120.degree.-125.degree. C. 
Analysis: Calculated for C.sub.33 H.sub.34 F.sub.3 NO.sub.7 : 
C,74.59;H,5.58;N,2.28. Found: C,64.34;H,5.72;N,2.04. 
EXAMPLE 61 
1-[4-[3-[4(Cyclohexylphenylmethylene)-1-piperidinyl]propoxy]-3-methoxypheny 
l]ethanone oxalate [1:1] 
The free base of the title compound was obtained as in Example 1 of U.S. 
Pat. No. 3,922,276 by reacting 
4-[(.alpha.-cyclohexyl-.alpha.-phenyl)methylene]piperidine with 
3-(p-acetyl-o-methoxyphenoxy)propyl chloride in a mixture with sodium 
bicarbonate in dimethylformamide and converted to the oxalate salt, m.p. 
184.degree.-185.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.41 NO.sub.7 : 
C,69.67;H,7.49;N,2.54. Found: C,69.83;H,7.58;N,2.56. 
EXAMPLE 62 
1[4-[3-[4-(Cyclohexylphenylmethyl)-1-piperidinyl]propoxyl]-3-methoxyphenyl] 
ethanone oxalate hydrate[1:1:0.5] 
A mixture of 5.2 g (0.02 mole) of 
4-[(.alpha.-cyclohexyl-.alpha.-phenyl)]-piperidine, 4.9 g (0.02 mole)of 
3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.7 g (0.02 mole) of 
sodium bicarbonate in 100 ml of dimethylformamide was stirred and heated 
at 100.degree. C. for 4 hrs. The reaction mixture was cooled, filtered, 
and the dimethylformamide was removed under pressure pressure. The 
residual material was dissolved in benzene and placed on a Forisil.RTM. 
column. Elution using an acetone-benzene gradient gave 7.0 g (74.5%) of 
free base of the title compound. The oxalate salt was prepared and 
recrystallized from 2-propanol, m.p. 155.degree.-160.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.43 NO.sub.7.0.5H.sub.2 O: C, 68.31; 
H, 7.88; N, 2.49. Found: C, 6860; H, 7.78; N, 2.42. 
The free base of the title compound was obtained by reacting 
4[(.alpha.-acyclohexyl-.alpha.-phenyl)methyl]piperidine and 
3-(p-acetyl-o-methoxyphenoxy)-propyl chloride in a mixture with sodium 
bicarbonate, isolated and reacted with oxalic acid. The oxalte salt was 
recystallized from 2-propanol, m.p. 155.degree.-160.degree. C. 
EXAMPLE 63 
4-[3-[4-[Bis(4-fluorophenyl)methylene[-1-piperidinyl]propoxy]-.alpha.- 
methylbenzenemathanol oxalate [1:1]. 
A solution of 
1-[4-[3-[4-bis(4-fluorophenyl)methylene]-1-piperidinyl]-propoxy]phenyl]eth 
anone, 3.56 g (0.0077 mole) and sodium borohydride, 1.51 g(0.04 mole) was 
stirred 6 hrs at room temperature. The reaction mixture was concentrated 
to dryness and partitioned between chloroform-water and chloroform-5% 
sodium hydroxide. Removal of chloroform gave an oil which was converted to 
the oxalate salt. Recrystallization from methanol-ethyl ether gave 2.67 g 
(62.1%) of white, crystalline product, m.p. 142.degree.-145.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.33 F.sub.2 NO.sub.6 : C, 67.26; H, 
6.01; N, 2.3. Found: C, 67.17; H, 5.92; N, 2.47. 
EXAMPLE 64 
4-[3-[Bis(4-fluorophenyl)methyl)-1-piperidinyl]propoxy]-3-methoxy-.alpha.-m 
ethylbenzenemethanol. 
Sodium borohydride (3.0 g, 0.079 mole) was added to 250 ml of 95% ethanol. 
To the mixture was added 4.40 g (0.00885 mole) of 
1-[3-(p-acetyl-o-methoxyphenoxy)propyl]-4[.alpha.,.alpha.-bis(p-fluorpheny 
l)methyl]piperidine in 100 ml of 95% ethanol over 15 minutes. The resulting 
solution was stirred 2.5 at room temperature. The reaction mixture was 
concentrated to dryness and partitioned between chloroform and 5% sodium 
hydroxide. The organic layer was back extracted with 5% sodium hydroxide 
and water; removal of chloroform gave an oil. The oil formed a white solid 
in ethyl ether. The white solid was collected by filtration and 
recrystallized from methylene chloride-ethyl ether. This furnished 2.16 g 
(49.2%) of white solid, m.p. 132.degree.-135.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.35 F.sub.2 NI.sub.3 : C, 72.72; H, 
7.12; N, 2.83. Found: C, 72.28; H, 7.21; N, 2.52. 
EXAMPLE 65 
1-[4-[3[4-(Diphenylmethyl)-1-piperidinyl[propoxy]-3-methoxyphenyl]-ethanone 
oxalate [1:1]. 
A mixture of 5.0 g (0.02 mole)of 4-(.alpha.-phenylbenzyl)piperidine, 4.85 g 
(0.02 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride, and 3.4 g 
(0.04 mole) of sodium bicarbonate i 100 ml of dimethylformamide was heated 
at 100.degree. C. for about 3 hrs. The reaction mixture was cooled, 
filtered and the filtrate was concentrated under reduced pressure. The 
residual oil was dissolved in chloroform and the chloroform was filtered 
to remove insolubles. The filtrate was concentrated under reduced pressure 
to give 8.6 g of a red oil (94.5%). The oil was dissolved in a mixture of 
4:1 ether/2-propanol and treated with 2.3 g of oxalic acid dihydrate. The 
oxalate salt crystallized upon standing and trituration in ether gave 8.4 
g of salt melting at 149.degree.-155.degree. C. Recrystallization from 
isobutyl methyl ketone gave 7.0 g of the salt, m.p. 
153.degree.-155.degree. C. (See Example 11, U.S. Pat. No. 3,956,296l ). 
Analysis: Calculated for C.sub.32 H.sub.37 NO.sub.7 : C, 70.18; H, 6.81; N, 
2.56. Found: C,70.00; H, 6.76; N, 2.56. 
EXAMPLE 66 
1-[4-[3-4-[Bis-(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-meth 
oxyphenyl]ethanone. 
A mixture of 5.0 g (0.0165 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidine-methanol, 4.0 g (0.0165 
mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g (0.0165 
mole) of sodium bicarbonate in 60 ml of dimethylformanide was stirred and 
heated at 80.degree. C. for two hours. The temperature was raised to 
100.degree. C. for one hour. After cooling, the reaction mixture was 
filtered and the dimethylformamide was removed at reduced pressure. The 
residual oil which crystallized on standing in ether was dissolved in 
benzene and placed on a Florisil.RTM. column. Using a gradient elution of 
acetone-benzene, 1.8 g (21.4%) of product was obtained from the column, 
m.p. 141.5.degree.-143.degree. C. (See Example 12, U.S. Pat. No. 
3,956,296). 
Analysis: Calculated for C.sub.30 H.sub.33 F.sub.2 NO.sub.4 : C,70.71; 
H,6.53; N, 2.75. Found: C, 70.49; H,6.58; N, 2.59. 
EXAMPLE 67 
1-[4-[-4-[(4-Fluorophenyl)hydroxyphenylmethyl]-1-piperidinyl]-propoxy]-3-me 
thoxyphenyl]ethanone. 
A mixture of 6.5 g (0.023 mole) of 
.alpha.-(p-fluorophenyl)-.alpha.-phenyl-4-piperidinemethanol, 5.5 g (0.023 
mole) of 3-(p-acetyl-o-methoxyphenoxy)-propyl chloride and 1.92 g (0.023 
mole) of sodium bicarbonate in 80 ml of dimethylformamide was heated at 
110.degree.-110.degree. C. for 2 hrs. The reaction mixture was cooled and 
filtered and the dimethylformamide was removed at reduced pressure. The 
residual oil was dissolved in chloroform and filtered. The chloroform was 
removed at reduced pressure. The solid residue which remained weighed 8.6 
g (77%) and was recrystallized from ethanol to give 3.1 g of material 
melting at 147.degree.-148.degree. C. A sample was dried over refluxing 
toluene and submitted for analysis. (See Example 14, U.S. Pat. No. 
3,956,296). 
Analysis: Calculated for C.sub.30 H.sub.34 FNO.sub.4 : C,73.30; H,6.97; 
N,2.85. Found: C,73.15; H,7.05; N, 2.77. 
EXAMPLE 68 
1[4-[4-(Diphenylhydroxymethyl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethan 
one oxalate[1:1] 
A mixture of 5.2 g (0.0194 mole)of 
.alpha.,.alpha.-diphenyl-4-piperidinemethanol, 4.7 g )0.0194mole) of 
3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.6 g (0.0194 mole) of 
sodium bicarbonate in 60 ml of dimethylformamide was stirred at 
100.degree. C. for 3 hrs. After cooling, the reaction mixture was filtered 
and the dimethylformamide was removed under reduced pressure. The residual 
oil weighed 8.3 g (90%). Some of the product crystallized upon trituration 
in anhydrous ether and was collected by filtration. The filtrate was 
evaporated to dryness and the residue was dissolved in hot 
benzene-isooctane. Upon cooling, the crystalline product was obtained. A 
total yield of 6.3 g of solid product was obtained. The solid free base 
was converted to the oxalate salt. Recrystallization from isobutyl methyl 
ketone gave the off-while solid melting at 74.degree.-176.degree. C. (See 
Example 15, U.S. Pat. No. 3,956,296). 
Analysis: Calculated for C.sub.32 H.sub.37 NO.sub.8 : C,68.19; H,6.62; 
N,2.49. Found: C,68.34; H,6.75; N,2.42. 
EXAMPLE 69 
1-[4-8 
3-[4-[Hydroxyphenyl]3-(trifluoromethyl)phenyl]methyl]-1-piperidinyl]propox 
y]-3-methoxyphenyl]ethanone hydrochloride hydrate [1:1:05] 
A mixture of 7.0 g (0.021mole) of 
.alpha.-phenyl-.alpha.(m-trifluoromethylphenyl-4-piperidinemethanol, 5.1 g 
(0.21 mole) of 3-(p-acetyl-o-methoxyphenoxy)-propyl chloride and 3.0 g 
(0.036 mole) of sodium bicarbonate in 125 ml of dry dimethylformamide was 
stirred and heated at 90.degree.-95.degree. C. for 5 hours. The mixture 
was cooled and filtered. An excess of water was added to the reaction 
mixture. The mixture was extracted several times with benzene and the 
collected extracts were dried over anhydrous sodium sulfate. The mixture 
was filtered and the filtrate was concentrated under reduced pressure. The 
crude solid which was obtained was dissolved in benzene and placed on a 
Florisil.RTM. column. Elution using an acetone-benzene gradient gave a 
gummy solid. The gum was dissolved in either and the hydrochloride salt 
was prepared. The hydrochloride salt weighed 3.1 g (25%) and became a 
clear melt at 95.degree. C. (See Example U.S. Pat. No. 3,956,296). 
Analysis: Calc'd for C.sub.31 H.sub.35 ClF.sub.3 NO.sub.4.0.5H.sub.2 O; 
C,63.42; H,6.18; N2.39. Found: C,63.68; H,6.03; N,2.33. 
EXAMPLE 70 
1-[4-[3-[4(Cyclohexlhydroxyphenylmethyl)-1-piperidinyl]propoxy]-3-methoxyph 
enyl]ethanone hydrochloride [1:1]. 
A mixture of 3.9 g (0.143 mole) of 
.alpha.-cyclohexyl-.alpha.-phenyl-4-piperidinemethanol, 3.5 g (0.143 mole) 
of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 2.35 g (0.28mole) of 
sodium bicarbonate in 100 ml of dimethylformamide was heated at 
100.degree. C. for 4 hours. After cooling, the reaction mixture was 
diluted with about 600 ml of water and extracted with benzene. The 
collected benzene extracts were washed with water and dried over anhydrous 
magnesium sulfate. The mixture was filtered, and the filtrate was 
concentrated under reduced pressure. A crude solid weighing 5.1 g (74.5%) 
was obtained. The solid was dissolved in ether, and the ether solution was 
treated with an excess of ethereal hydrogen chloride. The hydrochloride 
salt obtained was recrystallized from isobutyl methyl ketone to give 4.0 g 
of the salt, m.p. 152.degree.-155.degree. C. (See Example 17, U.S. Pat. 
No. 3,956,296). 
Analysis: Calculated for C.sub.30 H.sub.42 ClNO.sub.4 : C,69.82; H,8.20; 
N,2.71. Found: C,69.50; H,8.31; N,2.62. 
EXAMPLE 71 
1-[4-[2-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethoxy]-3-metho 
xyphenyl]ethanone. 
Following the procedure of Example 1 and utilizing potassium iodide 
catalyst, a mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 
mole) of 1-[4-(2-chloroethoxy)-3-methoxyphenyl]-ethanone and sodium 
carbonate in butanol, the title compound was prepared in 22% yield, m.p. 
131.degree.-135.degree. C., after recrystallization from isopropyl 
alcohol. 
Analysis: Calculated for C.sub.29 H.sub.31 F.sub.2 NO.sub.4 ; C,70.29; 
H,6.31; N,2.83. Found: C,70.00; H,6.39; N,2.60. 
EXAMPLE 72 
1-[4-[4-[4-Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]butoxy]-3-methox 
yphenyl]ethanone. 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 35. A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 3.0 g (0.01 
mole) of 1-[4-(4-bromobutoxy)-3methoxyphenyl]ethanone, 5.3 g (0.05 mole) 
of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
dimethylformamide gave, after purification by column chromatography on 
Florisil.RTM. (acetone-benzene). 0.8 g (15%) of off-white powder m.p. 
104.degree.-105.degree. C., after recrystallization from 
2-propanol-isopropyl ether. 
Calculated for C.sub.31 H.sub.35 F.sub.2 NO: C,71.11; H,6.74; N,2.68. 
Found: C,70.84; H,6.71N,2.65. 
EXAMPLE 75 
1-[4-[5-[4-Bis(4-fluorphenyl)hydroxymethyl]-1piperindyl]pentoxy]-3-methoxyp 
henyl]ethanone. 
Following the procedure of Example 1 and utilizing potassium iodide 
catalyst, a mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.7 g (0.01 
mole) of 1-[4-(5-chloropentoxy)-3-methoxyphenyl]ethanone and 5.3 g (0.05 
mole) of anhydrous sodium carbonate in butanol, the title compound was 
prepared in 65% yield as white solid after recrystallization from 
isopropyl alcohol, m.p. 117.5.degree.-118.5.degree. C. 
Analysis: Calculated fro C.sub.32 H.sub.37 F.sub.2 NO.sub.4 ; C,71.49; 
H,6.94; N,2.61. Found: C,71.51; H,7.06; N,2.50. 
EXAMPLE 74 
1-[2-[2-4[Bis(4-fluorphenyl)methyl9 
-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone. 
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.88 g (0.017 mole), 
1-[4-(2-chloroethoxy)-3methoxyphenyl]ethanone, 3.86 g (0.017 mole), and 
potassium carbonate, 5.53 g (0.04 mole) was heated overnight at gentle 
reflux in 350 mol of 1-butanol containing potassium iodide (0.3 g). The 
reaction mixture was filtered and concentrated to dryness. The dark brown 
oil obtained was dissolved in chloroform and extracted with 1N sulfuric 
acid and 5% sodium hydroxide. The chloroform layer was dried, filtered, 
and solvent removed. This furnished a brown oil which was subjected to 
flash chromatography on silica gel using hexane-ethyl acetate for elution. 
A white solid was obtained by evaporating the fractions containing the 
product. The solid was extracted with ethyl ether and the mixture was 
placed in the freezer overnight. A white solid was obtained which was 
dried at 80.degree. C. in vacuo overnight. A yield of 2.2 g (27%) of 
white, crystalline solid, m.p. 129.degree.-131.degree. C., was obtained. 
Analysis: Calculated for C.sub.29 H.sub.31 F.sub.2 NO.sub.3 : C,72.63; 
H,6.52; N,2.92. Found: C,72.52; H,6.45; N,2.87. 
EXAMPLE 75 
1-[4-[3-[4-[Bis(4-chlorophenyl)methylene]-1-piperindyl]propoxyl]-3-methoxyp 
henyl]ethanone 
A mixture of 3.96 g (0.01305 mole) of 
4-[bis-(4-chlorophenyl)-methylene]pipridine, 3.16 g (0.013 mole) of 
1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, and 3.18 g (0.03 mole) of 
anhydrous sodium carbonate in 300 ml of 1-butanol containing 0.3 g of 
potassium iodide was heated overnight at gentle reflux. The reflux mixture 
was concentrated to dryness and partitioned between chloroform-water and 
chloroform -5% sodium hydroxide. Removal of chloroform gave an oil which 
crystallized from isopropyl alcohol. The solid was again crystallized from 
isopropyl alcohol to give 4.16 g (61%) of light yellow solid, m.p. 
143.degree.-144.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.31 Cl.sub.2 NO.sub.3 : C,68.70; 
H,5.96; N,2.67. Found: C,69.11; H,6.02; N,2.55. 
EXAMPLE 76 
1-[4-[3-[4-[(4-Fluorophenyl)phenylmethyl]-1-piperidinyl]propoxy]-3-methoxyp 
henyl]ethanone oxalate [1:1 
A solution of 4.42 g (0.0164 mole)of 
4-[-(4-fluorophenyl)phenylmethyl]-pipridine and 4.11 g (0.0170 mole) of 
1-8 4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 0.01 g of potassium 
iodide and 1-butanol was heated at reflux for 18 hr. The solvent was 
removed in vacuo, and the residue was partitioned between methylene 
chloride and dilute sodium hydroxide. The solvent was removed in vacuo to 
give an oil. A solution of the oil in methanol was treated with an 
equivalent of oxalic acid, ethyl ether was added, and 6.39 g (68.9%) of 
white crystalline solid m.p. 161.degree.-163.degree.0 C., was obtained. 
Analysis: Calculated for C.sub.32 H.sub.36 FNO.sub.7 : C,67.95; H,6.42; 
N,2.48 Found: C,67.92; H,6.42; N,2.44. 
EXAMPLE 77 
1-[4-[3-[4-Bis(4-methoxyphenyl)methyl]-1-piperidinyl]propoxyl]-3-methoxyphe 
nyl]ethanone oxalate [1:1] 
A mixture of 7.78 g (0.025 mole) of 
4-bis(4-methoxyphenyl)methyl]-piperidine, 6.05 g (0.025 mole)of 
1-[4-(3-chloropropoxy)-3-methoxyphenyl-9 -ethanone, and potassium 
carbonate (5.53 g, 0.04 mole) in 300 ml of 1-butanol containing potassium 
iodide (0.3 g) was heated at reflux overnight. The reaction mixture was 
concentrated to dryness and the residue was partitioned between chloroform 
and water; removal of chloroform in vacuo gave a dark brown oil. The oil 
was subjected to column chromatography on silica gel using a gradient 
elution composed of methanol and ethyl acetate. The corresponding 
fractions from the column were combined and reacted with oxalic acid. 
Recrystallization of the salt from methanol-ethyl ether gave 4.16 g 
(27.4%) of white solid, m.p. 163.5.degree.-165.degree. C. 
Analysis: Calculated for C.sub.34 H.sub.41 NO.sub.9 : C,67.20; H,6.80; 
N,2.31. Found: C,66.76; H,6.84; N,2.26. 
EXAMPLE 78 
1-[4-[3-[4-Bis(4-methylphenyl)methyl]-1piperidinyl]propoxy]-3methoxyphenyl] 
ethanone 
A mixture of 5.10 g (0.018 mole) 4-[bis(4-methylphenyl)methyl]-piperidine 
and 4.42 g (0.018 mole) of 1-[4-(3-chloropropoxy)-3-methylphenyl]-ethanone 
in 350 ml of 1-butanol was heated overnight at gentle reflux with 
potassium carbonate (5.53 g , 0.04 mole) and potassium iodide (0.3 g). The 
reaction mixture was stripped to dryness and the resulting residue was 
partitioned between chloroform-5% sodium hydroxide and chloroform-water. 
Removal of chloroform gave a dark brown oil. The oil was subjected to 
column chromatography on a silica gel column with a gradient elution 
series of hexane-ethyl acetate and ethyl acetate-dimethoxyethane. The 
proper fractions from the column were combined. This resulted in 2.60 g 
(29.7%) of oil (after drying in vacuo at 80.degree. C. overnight). 
Analysis: Calculated for C.sub.32 H.sub.39 NO.sub.3 ; C,79.14; H,8.09; 
N,2.88. Found: C,78.70; H,8.08; N,2.80. 
.sup.1 HNMR (CDCl.sub.3): 7.5 .delta.(multiplet, protons on ring next to 
ketone, 2H), 6.7-7.6(multiplet, aromatic proton, 9H), 4.0 (triplet, 
methylene adjacent to the ether oxygen, 2H), 3.8 singlet, OCH.sub.3 
3H,)3.3 (doublet, methine next to rings, 1H), 2.5 (singlet, methyl of 
ketone, 3H), 2.2 (singlet, methyl groups attached to aromatic rings, 6H), 
1.0-3.0 (multiplet, remaining aliphatic protons, 13H). 
EXAMPLE 79 
1-[4-[4-[4-Bis(4-fluorophenyl)methyl]-1-piperidinyl]butoxy]-b 
3-methoxyphenyl]ethanone A mixture of 6.15 g (0.02 mole) of 
4-4[-bis(4-fluorophenyl)methyl]-piperidine and 6.45 g (0.02 mole) of 
1-[4-(4-bromobutoxy)-3-methoxyphenyl]-ethanone in 350 ml of acetonitrile 
was stirred overnight at room temperature with potassium carbonate, 5.53 g 
(0.04 mole) and potassium iodide (0.3 g). The mixture was then heated five 
hours at reflux. The reaction mixture was concentrated to dryness on a 
rotary evaporator, and the residue was partitioned between chloroform -5% 
sodium hydroxide and chloroform-water. Removal of chloroform gave a dark 
brown oil. The oil was subjected to chromatography on a silica gel column 
and eluted with a hexane-ethyl acetate-dimethoxyethane series. Fractions 
from the column were combined and solvent removed by pumping in vacuo 
overnight at 80.degree. C. This provided 3.34 g (31.3%) of brown oil. 
Analysis: Calculated for C.sub.31 H.sub.35 F.sub.2 NO.sub.3 : C,73.35; 
H,6.95; N,2.76. Found: C,72.34; H,6.92; N,2.70. 
NMR analysis was obtained as follows: .sup.1 H NMR (CDCl.sub.3): 
6.8-7.6 .delta.(multiplet, aromatics, 11H), 4.1 (triplet methylene next to 
ether linkage, 2H), 3.4-3.6 (doublet, methine attached to two fluorophenyl 
rings, 1H), 3.8 (singlet, OCH.sub.3,3H), 2.5 (singlet, COCH.sub.3 3H), 
(1.1-3.0(multiplet, remaining aliphatics, 15H). 
EXAMPLE 80 
4-[3-[4-Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]3-methoxybe 
nzoic acid methyl ester 
Following the procedure of Example 1 and utilizing potassium iodide 
catalyst and substituting dimethylfrmamide for butanol, a mixture of 5.4 g 
(0.021 mole) of 4-(3-chloropropoxy)-3-methoxybenzoic acid methyl ester, 
6.0 g (0.02 mole) of [.alpha., 
.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol, 7.4 g (0.07 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 150 ml of 
dimethylformamide was reacted to give 5.7 g (53%) of white solid, m.p. 
131.degree.-132.degree. C., after recrystallization from isopropyl 
alcohol. 
Analysis: Calculated for C.sub.30 H.sub.33 F.sub.2 NO.sub.5 : C,68.56; 
H6.33; N,2.67. Found: C,68.23; H,6.35; N,2.60. 
EXAMPLE 81 
.alpha.,.alpha.-[Bis(4flurophenyl)]-1-[3-[4-(methoxylthio)phenoxy]propyl]-4 
-piperidinemethanol 
Following the procedure of Example 1, a mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.2 g (0.01 
mole) 1-chloro3-(4-methylthiophenoxy)propane, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol was reacted to give 2.3 g (48%) of white powder, m.p. 
113.degree.-115.degree. C., after recrystallization from isopropyl ether. 
Analysis: Calculated for C.sub.28 H.sub.31 F.sub.2 NO.sub.2 S: C,69.54; 
H,6.46; N,2.90. Found: C,69.57; H,6.51; N,2.85. 
EXAMPLE 82 
.alpha.,.alpha.-[Bis(4-fluorophenyl)]-1-3-[4-(methylsulfonyl)phenoxy]propyl 
]-4-piperidinemethanol fumarate [1:1]. 
Following the procedure of Example 1, a mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.5 g (0.01 
mole) of -3-chloropropxy)-4-(methylsulfonyl)benzene, pb 5.3 g (0.05 mole) 
of anhydrous sodium carbonate and 0.3 g of potassium iodide ion 100 ml of 
1-butanol was reacted to give a brown gum as residue. The gummy residue 
was reacted with fumaric acid and the fumarate salt obtained was 
recrystallized from acetonitrile to give 3.0 g (48%) of white solid, m.p. 
176.degree.-178.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.35 F.sub.2 NO.sub.8 S: C, 60.85; H, 
5.59; N, 2.22. Found: C, 60.72; H, 5.54; N, 2.20. 
EXAMPLE 83 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxy 
benzeneacetic acid ethyl ester hydrochloride 
Following the procedure of Example 45, 
.alpha.,.alpha.-bis(p-fluorophenyl-4-piperidinemethanol and 
4-(3-chloropropoxy)-3-methoxybenzeneacetic acid, ethyl ester are reacted 
and the hydrochloride salt is prepared. 
EXAMPLE 84 
4-[3-4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethoxy]benzoic acid 
ethyl ester hydrochloride 
Following the procedure of Example 45, 
.alpha.,.alpha.-bis(p-fluorophenyl-4-piperidinemethanol and 
4-(2-chloroethoxy)benzoic acid ethyl ester are reacted and the 
hydrochloride salt is prepared. 
EXAMPLE 85 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxy 
benzeneacetic acid sodium salt hydrate [1:1:0.5] 
This compound was prepared according to the procedure of Example 1. A 
mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.9 g (0.01 
mole) of 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester, 5.3 
g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide 
in 150 ml of acetonitrile gave the ester as a gum. The gum was converted 
to the hydrochloride with ethereal hydrogen chloride to give a white 
solid. The solid could not be recrystallized so it was partitioned between 
methylene chloride and a 5% sodium hydroxide solution. An emulsion 
resulted which was let stand until the layers separated. During this time 
a solid precipitated. The mixture was filtered. The filter cake was 
recrystallized from ethyl acetate to yield 0.7 g (13%) of fluffy, white 
solid, m.p. 102.degree.-112.degree. C. 
Analysis: Calc'd for C.sub.30 H.sub.32 F.sub.2 NNaO.sub.5.0.5H.sub.2 O: C, 
64,74; H, 5.98; N, 2.52. Found: C, 64.50; H, 5.97; N, 2.39. 
EXAMPLE 86 
7-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-2H-1-benz 
opyran-2-one 
This compound was prepared according to the procedure of Example 1. A 
mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.4 g (0.01 mole 
of 7-(3-chloropropoxy)2H-1-benzopyran-2-one, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol gave 3.6 g (71%) of pale yellow crystals, m.p. 
99.degree.-120.degree. C. with decomposition. 
Analysis: Calculated for C.sub.30 H.sub.29 F.sub.2 NO.sub.4 : C, 71.27; H, 
5.78; N, 2.77 Found: C, 71.02; H, 5.89; N, 2.63. 
EXAMPLE 87 
2-[3-[4-Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzoic 
acid ethyl ester fumarate [4:3] 
This compound is prepared according to the procedure of Example 1. A 
mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 
mole) of 2-(3-chloropropoxy)benzoic acid ethyl ester, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
dimethylformamide gave 5.7 g of gum as residue. The gum was purified by 
column chromatography on 100 g of silica gel. Fractions eluted with 35% 
acetone in benzene were combined and concentrated to give 3.0 g of pale 
yellow gum as residue. The gum was converted to the fumaric acid salt and 
the solid was recrystallized twice from 2-propanol to yield 2.0 g (32%) of 
white solid, m.p. 138.degree.-141.degree. C. 
Analysis: Calculated for C.sub.33 H.sub.36 F.sub.2 NO.sub.7 : C, 66.43; H, 
6.08; N, 2.35. Found: C, 66.25; H, 6.08; N, 2.27. 
EXAMPLE 88 
2-[3-4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzoic acid ethyl 
ester 
A mixture of 32.79 g (0.116 mole) of 
4-[bis(4-fluorophenyl)methyl]piperidine, 27.04 g (0.114 mole) of 
2-(3-chloropropoxy)benzoic acid ethyl ester, and potassium carbonate, 
19.40 g (0.140 mole) was heated overnight at reflux in 500 ml of 
diethoxyethane containing potassium iodide (0.4 g). The reaction was 
filtered and concentrated to dryness. The residue obtained was dissolved 
in chloroform and extracted with 5% sodium hydroxide, sodium sulfite, and 
water. The chloroform layer was dried (anhydrous sodium sulfate), 
filtered, and solvent removed to furnish a dark brown oil (56.20 g). The 
oil was subjected to flash chromatography on an 83.5 g silica gel column 
(with ethyl acetate). Fractions were combined with similar purity. One 
sample of 6.49 g (56.5%) was dried in vacuo at 80.degree. C. overnight and 
analyzed. .sup.1 H NMR (CDCl.sub.3): 7.8.delta. (m, 1, aromatic proton 
ortho to ester), 7.0.delta. (m, 11, aromatic), 4.3.delta. (q, 2, 
C--O--CH.sub.2), 4.1.delta. (t, 2, --OCH.sub.2), 3.5.delta. (d, 1, 
methine), 1.3.delta. (t, 3, CH.sub.3), 1.7-3.0.delta. (m, 13, aliphatic). 
Analysis: Calculated for C.sub.30 H.sub.33 F.sub.2 NO.sub.3 : C, 73.00; H, 
6.74; N, 2.84. Found: C, 72.98; H, 6.70; N, 2.93. 
EXAMPLE 89 
1-[4-[5-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]pentoxy]-3-methoxyphen 
yl]ethanone hydrate [1.0.5] 
A mixture of 6.03 g (0.021 mole) of 
4-[bis(4-fluorophenyl)methyl]piperidine, 5.69 g (0.021 mole) of 
1-[4-(5-chloropentoxy)-3-methoxyphenyl]ethanone, and potassium carbonate 
(5.53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 
1-butanol containing potassium iodide (0.2 g). The reaction mixture was 
cooled at room temperature, filtered, and concentrated to dryness. The 
residue obtained was dissolved in chloroform and extracted several times 
with water. The chloroform layer was dried (sodium sulfate), filtered, and 
solvent removed to give a brown oil. This oil was subjected to flash 
chromatography on silica gel using ethyl acetate and 2% methanol-ethyl 
acetate for elution. Fractions of similar purity were combined and solvent 
removed. The sample was dried in vacuo at 70.degree. C. overnight after 
being exposed to the atmosphere for 24 hours. A yield of 2.7 g (24.6%) of 
brown oil was obtained. 
.sup.1 H NMR (CDCl.sub.3): 6.8-7.6.delta. (m, 11, aromatic), 4.1.delta. (t, 
2, --OCH.sub.2), 3.9.delta. (s, 3, OCH.sub.3), 3.4-3.6.delta. (d, 1, 
methine of difluorophenyl group), 2.5.delta. (s, 3, 
##STR20## 
1-3.0.delta. (m, 18, aliphatics and 0.5 H.sub.2 O). 
Analysis: Calculated for C.sub.32 H.sub.37 NO.sub.3.0.5H.sub.2 O: C, 72.43; 
H, 7.22; N, 2.64. Found: C, 72.75; H, 7.23; N, 2.57. 
EXAMPLE 90 
4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzamide 
fumarate [2:3] 
A mixture of 6.10 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine 
and 4.53 g (0.021 mole of 4-(3-chloropropoxy)benzamide in 350 ml of 
1-butanol containing potassium carbonate (5.53 g, 0.021 mole) and 
potassium iodide (0.2 g) was heated overnight at gentle reflux. The 
reaction was filtered and stripped to dryness. The residue obtained was 
dissolved in chloroform and extracted with water. The chloroform layer was 
dried, filtered, and solvent removed to give an oil. This material was 
converted to the fumarate salt and recrystallized from methanol-ethyl 
ether. The white, crystalline solid obtained was dried in vacuo overnight 
at 65.degree. C. A yield of 5.47 g (40.3%) of white, crystalline product 
was obtained, m.p. 193.degree.-194.degree. C. 
Analysis: Calculated for C.sub.34 H.sub.36 F.sub.2 N.sub.2 O.sub.8 : C, 
63.94; H, 5.68; N, 4.39. Found: C, 64.03; H, 5.73; N, 4.37. 
EXAMPLE 91 
4-[Bis(4-fluorophenyl)methyl]-1-[3-[4-(methylsulfonyl)phenoxy]propyl]piperi 
dine oxalate [1:1] 
A mixture of 6.02 g (0.021 mole) of 4-[bis(4-fluorophenyl(methyl]piperidine 
and 5.22 g (0.021 mole) of 1-(3-chloropropoxy)-4-(methylsulfonyl)benzene 
in 350 ml of 1-butanol containing potassium carbonate (5.53 g, 0.04 mole) 
and potassium chloride (0.2 g) was heated overnight at gentle reflux. The 
reaction was filtered and concentrated to dryness. The residue obtained 
was dissolved in chloroform and extracted with water. The chloroform layer 
was dried, filtered, and solvent removed to give an oil. The dark brown 
oil was converted to the oxalate salt and recrystallized from 
methanol-ethyl ether to give a white solid. This material was dried in 
vacuo overnight at 65.degree. C. A yield of 6.21 g (50.1%) of white, 
crystalline solid, m.p. 202.degree.-204.degree. C., was obtained. 
Analysis: Calculated for C.sub.30 H.sub.33 F.sub.2 NO.sub.7 S: C, 61.11; H, 
5.64; N, 2.38. Found: C, 60.99; H, 5.64; N, 2.36. 
EXAMPLE 92 
1-[4-[6-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]hexyloxy]-3-met 
hoxyphenyl]ethanone 
Following the procedure of Example 1 and utilizing potassium iodide 
catalyst, a mixture of 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol and 
1-[4-(6-chlorohexoxy)-3-methoxyphenyl]ethanone and sodium carbonate in 
butanol, the title compound is prepared. 
EXAMPLE 93 
1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidine]propoxy]-2-metho 
xyphenyl]ethanone 
Following the procedure of Examples 1 and 66, 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol and 
3-(p-acetyl-m-methoxyphenoxy)propyl chloride are reacted to give the title 
compound. 
EXAMPLE 94 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-(2-hydroxyphenoxy)propyl]-4-piperi 
dinemethanol 
Following the procedure of Example 2 and using potassium iodide catalyst, 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol and 
2-(3-chloropropoxy)-1-benzyloxybenzene are reacted to give 
1-[3-(2-benzyloxyphenoxy)propyl]-.alpha.,.alpha.-bis(4-fluoropyhenyl)-4-pi 
peridinemethanol which is reacted with hydrogen over palladium on carbon 
catalyst to give the title compound. 
EXAMPLE 95 
.alpha.,.alpha.-[Bis(4-fluorophenyl)-1-[3-[4-(methylsulfinyl)phenoxy]propyl 
]-4-piperidine methanol fumarate 
Following the procedure of Examples 1 and 82, 
[.alpha.,.alpha.-bis-fluorophenyl)]-4-piperidinemethanol and 
1-(3-chloropropoxy)-4-(methylsulfinyl)benzene are reacted to give the free 
base of the title compound which is then reacted with fumaric acid to give 
the title compound. 
EXAMPLE 96 
4-[3-[4-(Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzenesul 
fonamide hydrochloride [1:1] 
This compound was prepared according to the procedure of Example 1. A 
mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.5 g (0.01 
mole) of 4-(3-chloropropoxy)benzenesulfonamide, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol gave a gum as residue. The gum was converted to the 
hydrochloride with ethereal hydrogen chloride and the solid was 
recrystallized from absolute ethanol to yield 3.5 g (64%) of white solid, 
m.p. 152.degree.-175.degree. C. 
Analysis: Calculated for C.sub.27 H.sub.31 ClF.sub.2 N.sub.2 O.sub.4 S: C, 
58.64; H, 5.65; N, 5.06. Found: C, 58,43; H, 5.68; N, 5.06. 
EXAMPLE 97 
N-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl] 
methanesulfonamide 
Following the procedure of Example 1, 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol and 
N-[4-(3-bromopropoxy)phenyl methanesulfonamide are reacted to give the 
title compound. 
EXAMPLE 98 
N-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl] 
-N'-methylurea 
Following the procedure of Example 1, 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol and 
N-[4-(3-bromopropoxy)phenyl]-N'-methylurea are reacted to give the title 
compound. 
EXAMPLE 99 
[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl]ca 
rbamic acid ethyl ester 
Following the procedure of Example 1, 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol and 
[4-(3-bromopropoxy)phenyl]carbamic acid ethyl ester are reacted to give 
the title compound. 
EXAMPLE 100 
N-[3-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl] 
urea 
Following the procedure of Example 1, 
[.alpha.,.alpha.-bis(fluorophenyl)]-4-piperidinemethanol and 
N-[3-(3-bromopropoxy)phenyl]urea are reacted to give the title compound. 
EXAMPLE 101 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxy 
benzoic acid sodium salt 
Following the procedures of Examples 1 and 85 but substituting 
4-(3-chloropropoxy)-2-methoxybenzoic acid for the corresponding 3-methoxy 
compound, the title compound is prepared. 
EXAMPLE 102 
1-[4-[3-[4-Bis(4-fluorophenyl)hydroxymethyl]piperidinyl]propoxy]-2-hydroxyp 
henyl]ethanone 
Following the procedure of Example 1, 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol and 
1-[4-(3-bromopropoxy)-2-hydroxyphenyl]ethanone are reacted to give the 
title compound. 
EXAMPLE 103 
7-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-4-oxo-4H- 
1-benzopyran-2-carboxylic acid ethyl ester hydrochloride [1:1] 
A ixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol, 3.1 g (0.01 
mole) of 7-(3-chloropropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl 
ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of 
potassium iodide in 150 ml of acetonitrile heated at reflux for 48 hr 
gave a gum as residue. The gum was purified by column chromatography on 
120 g of Florisil.RTM.. The desired fractions eluted with 10% acetone in 
benzene were combined and concentrated under reduced pressure to give a 
glass as residue. The glass was dissolved in ether/2-propanol and treated 
with ethereal hydrogen chloride. The solid which precipitated was 
collected by filtration and recrystallized from absolute ethanol to give 
1.9 g (31%) of white solid, m.p. 191.degree. C. with decomposition. 
Analysis: Calculated for C.sub.33 H.sub.34 ClF.sub.2 NO.sub.6 : C, 64.55; 
H, 5.58; N, 2.28. Found: C, 64.41; H, 5.51; N, 2.26. 
EXAMPLE 104 
7-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-2,3-dihyd 
ro-4H-1-benzopyran-4-one hydrochloride 
Following the procedure of Example 103, 
[.alpha.,.alpha.-bis(p-fluorophenyl]-4-piperidinemethanol and 
7-(3-bromopropoxy)-2,3-dihydro-4H-1-benzopyran-4-one are reacted to give 
the title compound. 
EXAMPLE 105 
1-[4-[3-[4-(Diphenylmethylene)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethan 
one oxalate hydrate [1:1:0.5] 
A mixture of 7.5 g (0.030 mole) of 4-diphenylmethylenepiperidine, 6.3 g 
(0.032 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl bromide, 25 g (0.18 
mole) of potassium carbonate and 150 ml of toluene was heated at reflux 
for 16 hr, cooled, filtered and the solvent evaporated at reduced 
pressure. The residual oil was dissolved in benzene, washed with water, 
dried over magnesium sulfate and then the solvent was evaporated. The free 
base was dissolved in 2-propanol and treated with 3.8 g (0.03 mole) of 
oxalic acid dihydrate in dry ether. The white salt which separated was 
recrystallized from a 2-propanol-methanol mixture. The produce weighed 8.5 
g (54%), m.p. 186.degree.-188.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.35 NO.sub.7.0.5H.sub.2 O: C, 69.29; 
H, 6.54; N, 2.53. Found: C, 69.20; H, 6.49; N, 2.71. 
EXAMPLE 106 
1-[4-[3-[4-(Cyclohexylphenylmethyl)-1,2,3,6-tetrahydropyridin-1-yl]propoxy] 
-3-methoxyphenyl]ethanone oxalate hydrate [1:1:0.5] 
The free base of the title compound was obtained by reacting 
4-(.alpha.-cyclohexylphenylmethyl)-1,2,3,6-tetrahydropyridine with 
3-(p-acetyl-o-methoxyphenoxy)propyl chloride in a mixture with sodium 
bicarbonate in dimethylformamide and isolated on a Florisil.RTM. column 
eluting with benzene. The title salt was prepared, m.p. 110.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.41 NO.sub.7.0.5H.sub.2 O: C, 68.55; 
H, 7.55; N, 2.50. Found: C, 68.79; H, 7.64; N, 2.47. 
EXAMPLE 107 
1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-2-meth 
oxyphenyl]ethanone hydrochloride [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 
mole) of 1-[4-(3-chloropropoxy)-2-methoxyphenyl]ethanone, 5.3 g (0.05 
mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 
ml of 1-butanol gave a gum as residue. The gum was purified by column 
chromatography on 80 g of Florisil.RTM. and the fractions eluted with 20% 
acetone in benzene were combined and concentrated under reduced pressure 
to give a solid as residue. The solid was converted to the hydrochloride 
and this solid was recrystallized from 2-propanol-isopropyl ether to yield 
2.2 g (40%) of white power, m.p. 196.degree.-197.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.34 ClF.sub.2 NO.sub.4 : C, 65.99; 
H, 6.28; N, 2.57. Found: C, 65.87; H, 6.31; N, 2.54. 
EXAMPLE 108 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(2,6-dichlorophenoxy)propyl]piperidine 
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (free base 6.90 g, 
0.024 mole), 1,3-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), 
and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle 
reflux in 350 m l of 1-butanol containing potassium iodide (0.2 g). The 
reaction was concentrated to dryness. The residue was partitioned several 
times between chloroform and water. The chloroform layer was dried, 
filtered, and solvent removed to give an oil. The oil was placed in the 
refrigerator overnight in 50 ml of methanol. A white solid was obtained 
and dried in vacuo overnight at 80.degree. C. A yield of 3.26 g (27.7%) of 
white, crystalline solid, m.p. 101.5.degree.-103.degree. C., was obtained. 
Analysis: Calculated for C.sub.27 H.sub.27 Cl.sub.2 F.sub.2 NO: C, 66.13; 
H, 5.55; N, 2.85. Found: C, 66.12; H, 5.56; N, 2.88. 
EXAMPLE 109 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(2,6-dichlorophenoxy)propyl]piperidine 
oxalate [1:1] 
Free base of the compound of Example 108 was converted to the oxalate salt 
and recrystallized from methanol-ethyl and dried in vacuo at 80.degree. C. 
overnight, m.p. 158.degree.-161.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.29 Cl.sub.2 F.sub.2 NO.sub.5 : C, 
60.01; H, 5.04; N, 2.44. Found: C, 60.02; H, 5.07; N, 2.46. 
EXAMPLE 110 
2-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzonitrile 
A mixture of 7.41 g (0.025 mole) of 
[4-[bis(4-fluorophenyl)methyl]piperidine, 4.90 g (0.025 mole) of 
2-(3-chloropropoxy)benzonitrile, and potassium carbonate, 5.54 g (0.04 
mole) was heated overnight at reflux in 350 ml of 1-butanol containing 
potassium iodide (0.2 g). The mixture was concentrated to dryness and the 
resulting residue was partitioned several times between water and 
chloroform. The chloroform layer was dried (anhydrous sodium sulfate), 
filtered, and solvent removed to give a brown oil. The oil was triturated 
with ethyl ether and placed in a freezer overnight. White crystals were 
obtained and dried in vacuo overnight at room temperature. A yield of 5.15 
g (46.1%) of analytically pure material, m.p. 88.5.degree.-90.degree. C., 
was obtained. 
Analysis: Calculated for C.sub.28 H.sub.28 F.sub.2 N.sub.2 O: C, 75.31; H, 
6.32; N, 6.27. Found: C, 75.16; H, 6.34; N, 6.26. 
EXAMPLE 111 
.alpha.-[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-.alpha.-(4- 
fluorophenyl)-2-pyridineacetonitrile fumarate [1:1] 
A mixture of 
.alpha.-(4-fluorophenyl)-.alpha.-(4-piperidinyl)-2-pyridineacetonitrile 
(7.18 g, 0.024 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone 
(5.89 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was 
heated overnight in 350 ml of 1-butanol containing potassium iodide (0.15 
g). The reaction mixture was concentrated to dryness and the residue 
obtained was partitioned between chloroform and water. The chloroform 
layer was extracted in 1N sulfuric acid, 5% sodium hydroxide and water. 
The chloroform layer was dried over sodium sulfate, filtered, and the 
solvent removed to give an oil. The oil was converted to the fumarate salt 
and recrystallized from methanol-ethyl ether. A white solid was obtained 
and dried in vacuo overnight at 80.degree. C. to give 9.43 g (62.7%) of 
white crystals, m.p. 166.degree.-167.degree. C. NMR indicated 0.25 H.sub.2 
O was present. 
Analysis: Calculated for C.sub.34 H.sub.36 FN.sub.3 O.sub.7.0.25H.sub.2 O: 
C, 65.64; H, 5.91; N, 6.75. Found: C, 65.57; H, 5.89; N, 6.70. 
EXAMPLE 112 
.alpha.-[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-.alpha.-(4- 
fluorophenyl)-2-pyridineacetonitrile fumarate hydrate [1:1:1] 
A portion of the compound prepared in Example 111 was exposed to the air 
for 3 days, m.p. 166.degree.-167.degree. C. 
Analysis: Calculated for C.sub.34 H.sub.36 FN.sub.3 O.sub.7.H.sub.2 O: C, 
64.24; H, 6.02; N, 6.61. Found: C, 64.07; H, 5.82; N, 6.58. 
EXAMPLE 113 
.alpha.,.alpha.-Diphenyl-1-[3-(8-quinolinyloxy)propyl]-3-piperidinepropanen 
itrile hydrate [1:0.5] 
A mixture of .alpha.,.alpha.-diphenyl-3-piperidinepropanenitrile (8.12 g, 
0.028 mole), 8-(3-chloropropoxy)quinoline (6.18 g, 0.028 mole), and 
potassium carbonate (5.53 g, 0.04 mole) was heated at reflux overnight in 
350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction 
mixture was filtered and concentrated to dryness on a rotary evaporator. 
The residue obtained was dissolved in chloroform and extracted with 5% 
sodium hydroxide and water. The chloroform layer was dried over anhydrous 
sodium sulfate, filtered, and solvent removed to give a dark red mass. 
This material was subjected to flash chromatography on a silica gel column 
using 10% methanol-ethyl acetate, 20% methanol-ethyl acetate, and 50% 
methanol-ethyl acetate for elution. Fractions of similar purity were 
combined and solvent was removed by rotary evaporator. The red blad 
residue obtained was dried in vacuo at 80.degree. C. overnight. This 
furnished 5.29 g (39%) of a dark black residue. 
.sup.1 H NMR (CDCl.sub.3): .sigma.8.9 (m, 1, proton ortho to N in ring), 
7.9-8.1 (m, 1, proton para to N in ring), 6.9-7.6 (m, 14, aromatics), 4.2 
(t, 2, methylenes adjacent to oxygen atom), 1.1-2.7 (m, 16, aliphatic 
portions and 1 H from 0.5 H.sub.2 O). 
Analysis: Calculated for C.sub.32 H.sub.32 N.sub.3 O.0.5 H.sub.2 O: C, 
79.31; H, 7.07; N, 8.67. Found: C, 79.47; H, 7.19; N, 8.69. 
EXAMPLE 114 
8-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]quinoline 
hemihydrate 
A mixture of 4-[.alpha.-(p-fluorophenyl)-p-fluorobenzyl]piperidine (8.03 g, 
0.28 mole), 8-(3-chloropropoxy) quinoline (6.18 g, 0.28 mole), and 
potassium carbonate (5.53 g, 0.04 mole) was heated overnight at gentle 
reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The 
reaction mixture was filtered through activated charcoal and solvent was 
removed by rotary evaporator. The dark red residue was dissolved in 
chloroform and then extracted with 5% sodium hydroxide and water. The 
chloroform layer was dried over anhydrous sodium filtered, and solvent 
removed to provide a dark red mass. This material was subjected to flash 
chromatography on silica gel using 10, 20 and 50% methanol in ethyl 
acetate for elution. Fractions with similar purity were combined and 
solvent removed to give dark black mass which was dried at 80.degree. C. 
in vacuo overnight. This furnished 3.74 g (28) of a dark red mass. 
.sup.1 H NMR (CDCl.sub.3 : .delta.8.9 (m, 1, proton ortho to N in ring), 
7.9-8.1 (m, 1, proton para to N in ring), 6.8-7.4 (m, 12, aromatics), 4.2 
(t, 2, CH.sub.2 attached to --O), 3.5 (d, 1, methine attached to aromatic 
rings), 1.0-3.2 (m, 14, aliphatic protons and 1H for 0.5 H.sub.2 O). 
Analysis: Calculated for C.sub.30 H.sub.31 .sub.2 N.sub.2 O.0.5H.sub.2 O: 
C, 75.53; H, 6.44; N, 5.87. Found: C, 75.66; H, 6.56; N, 5.86. 
EXAMPLE 115 
2-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]quinoline hydrate 
[1:0.5] 
The sodium salt of 4-[bis(4-fluorophenyl)methyl-1-piperidinepropanol was 
formed in 300 ml of dimethyl sulfoxide from its free base (6.90 g, 0.02 
mole) and sodium hydride (60%, 0.8 g, 0.02 mole). 2-Chloroquinoline (3.26 
g, 0.02 mole) was added and the reaction mixture was heated at 60.degree. 
C. for approximately 72 hr. The reaction mixture was concentrated to 
dryness and the residue obtained was dissolved in chloroform. This 
chloroform layer was extracted with water and 5% sodium hydroxide. The 
chloroform layer was dried over sodium sulfate, filtered, and solvent 
removed to give an oil. The oil was subjected to flash chromatography on 
silica gel using ethyl acetate for elution. Fractions of similar purity 
were combined and solvent removed. The residue was dried in vacuo 
overnight at 80.degree. C. to give 5.16 g (53.6%) of clear brown oil. 
.sup.1 H NMR (CDCl.sub.3): .delta.6.8-7.9 (m, 14, aromatics), 4.5 (t, 2, 
--OCH.sub.2), 3.4 and 3.6 (d, 1, methine attached to two aromatic rings), 
1.2-3.1 (m, 13, aliphatics remaining). 
Analysis: Calculated for C.sub.30 H.sub.30 F.sub.2 O.sub.7.0.5H.sub.2 O: C, 
74.82; H, 6.49; N, 5.82. Found: C, 74.56; H, 6.36; N, 5.69. 
EXAMPLE 116 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(2-naphthalenyloxy)propyl]-piperidine 
hydrate [1:0.5] 
The sodium salt of 2-naphthol was prepared in 300 ml of dimethyl sulfoxide 
from 2-naphthol (3.00 g, 0.0208 mole) and sodium hydride (60% 0.83 g, 
0.0208 mole). The solution was stirred 1 hr at room temperature and had a 
clear brown color. Then, 
4-[bis(4-fluorophenyl)methyl]-1-(3-chloropropyl)piperidine (free base 7.55 
g, 0.0208 mole) in 100 ml of dimethylsulfoxide was added. The resulting 
solution was stirred overnight at 60.degree. C. The solvent was removed in 
vacuo, and the residue obtained was partitioned between chloroform-water 
and chloroform-5% sodium hydroxide. The chloroform form layer was dried 
over sodium sulfate, filtered, and solvent removed to give a brown oil. An 
oxalate salt could not be obtained in pure form so the oil (free base) was 
subjected to flash chromatography on silica gel using 50-50 
ethylacetate-hexanes and 75-25 ethylacetate-hexanes for elution. Fractions 
of similar purity were combined and solvent removed to give an oil. The 
oil was dried in vacuo at 80.degree. C. overnight to give 2.97 g (32.3% 
yield) of a dark brown glass after being dried overnight at room 
temperature. 
.sup.1 H NMR (CDCl.sub.3): .delta.6.8-7.8 (m, 15, aromatics), 4-4.3 (t, 2, 
--OCH.sub.2), 3.4-3.6 (d, 1, methine attached to two fluorophenyl groups), 
1.1-3.0 (m, 13, aliphatics). 
Analysis: Calculated for C.sub.30 H.sub.30 F.sub.2 NO.0.5H.sub.2 O: C, 
77.48; H, 6.71; N, 2.91. Found: C, 77.86; H, 6.65; N, 2.04. 
EXAMPLE 117 
3-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzonitrile 
hydrate [1:0.5] 
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine, the free base of 
Preparation 10 (7.85 g, 0.027 mole), 3-(3-chloropropoxy)-1-benzonitrile 
(5.33 g, 0.027 mole), and potassium carbonate (5.84 g, 0.027 mole) was 
heated overnight at reflux in 350 ml of 1-butanol containing potassium 
iodide (0.2 g). The reaction mixture was filtered and concentrated to 
dryness. The residue obtained was dissolved in chloroform and extracted 
with water and 5% sodium hydroxide. The chloroform layer was dried over 
sodium sulfate, filtered, and solvent removed to give a brown oil. The oil 
was subjected to flash chromatography on silica gel using ethyl 
acetate-hexanes for elution. Fractions of similar purity were combined and 
solvent removed. The dark brown oil obtained was dried in vacuo overnight 
at 80.degree. C. to give 5.65 g (45.9% yield) of dark brown oil. 
H.sup.1 NMR (CDCl.sub.3): .delta.6.7-7.3 (m, 12, aromatics), 3.8-4.1 (t, 2, 
methylenes adjacent to oxygen atom), 3.4-3.6 (d, 1, methine attached to 
two phenyl rings), 1.1-3.0 (m, 13, remaining aliphatic protons). 
Analysis: Calculated for C.sub.28 H.sub.28 F.sub.2 N.sub.2 O.0.5H.sub.2 O: 
C, 73.83; H, 6.42; N, 6.15. Found: C, 74.05; H, 6.27; N, 6.09. 
EXAMPLE 118 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-(4-methoxyphenoxy)propyl]-4-piperi 
dine-methanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis (p-fluorophenyl)-4-piperidinemethanol, 2.0 g (0.01 
mole) of 1-chloro-3-(4-methoxyphenoxy) propane, 5.3 g (0.035 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol gave 2.3 g (49% yield) of title compound as a white solid, mp 
107.degree.-108.degree. C. 
Analysis: Calculated for C.sub.28 H.sub.31 F.sub.2 NO.sub.3 : 
C,71.93;H,6.68;N,3.00. Found: C,71.90;H,6.70;N,2.99. 
EXAMPLE 119 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-(4-methylphenoxy)propyl]-4-piperid 
inemethanol fumarate [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis (p-fluorophenyl)-4-piperidinemethanol, 1.8 g (0.01 
mole) of 1-chloro-3-(4-methylphenoxy) propane, 5.3 g (0.035 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol gave a gum as residue. The gum was purified by column 
chromatography on 100 g of Florisil.RTM.. Fractions eluted with 10% 
acetone in benzene were combined and concentrated to give a gum. This gum 
was converted to the fumaric acid salt and the solid was recrystallized 
from absolute ethanol to yield 3.2 g (56%) of title compound as a white 
solid, mp 193.degree.-194.degree. C. with decomposition. pe f 49495948.hsc 
Analysis: Calculated for C.sub.32 H.sub.35 F.sub.2 NO.sub.6 : 
C,67.71;H,6.22;N,2.47. Found: C,67.93;H,6.25;N,2.53. 
EXAMPLE 120 
1-[3-(4-Fluorophenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperid 
inemethanol fumarate hydrate [1:1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis (p-fluorophenyl)-4-piperidinemethanol, 1.9 g (0.01 
mole) of 1-chloro-3-(4-fluorophenoxy) propane, 5.3 g (0.035 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol gave a solid as residue. The solid was further purified by 
column chromatography on 60 g of Florisil.RTM.. Fractions eluted with 
2-10% acetone in benzene were combined and concentrated to give a solid 
residue. The solid was converted to the furmaric acid salt and this solid 
was recrystallized from isopropanol to yield 2.2 g (39%) of title compound 
as a white solid, mp 155.degree.-157.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.32 F.sub.3 NO.sub.6 
.multidot.H.sub.2 O: C,63.14; H, 5.81; N, 2.38. Found: C, 62.99; H, 5.64; 
N, 2.28. 
EXAMPLE 121 
1-[4-[3-4-[(4-Fluorophenyl)(2-pyridinyl)methyl]-1-piperidinyl]-propoxy]-3-m 
ethoxyphenyl]ethanone 
A mixture of 2-[(4-fluorophenyl)(4-piperidinyl)methyl]pyridine (6.28 g, 
0.0232 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.62 g, 
0.0232 mole), and potassium carbonate (5.53 g, 0.04 mole) was heating 
overnight at reflux in 350 ml of 1-butanol containing potassium iodide 
(0.2 g). The reaction mixture was concentrated to dryness and the residue 
obtained was dissolved in chloroform. The chloroform layer was extracted 
with 5% sodium hydroxide and water. The chloroform layer was dried over 
sodium sulfate, filtered, and solvent removed to give a brown oil. This 
oil was subjected to flash chromatography on silica gel using 10% 
methanol-ethyl acetate, 20% methanol-ethyl acetate, and 30% methanol-ethyl 
acetate for elution. Fractions of similar purity were combined and solvent 
removed to give a brown oil. This material was dried in vacuo overnight at 
80.degree. C. to give 6.89 g (62.3% yield) of dark brown oil. 
H.sup.1 NMR (CDCl.sub.3): .delta. 6.8-7.8 (m, 15, aromatics), 4-4.3 (t, 2, 
--OCH.sub.2), 3.9 (s, 3, --OCH.sub.3), 3.6-3.8 (d, 1, C--H attached to 
pyridine ring), 2.6 (s, 3, C--CH.sub.3), 1.2-3.6 (m, 9, remaining 
aliphaties). 
Analysis: Calculated for C.sub.29 H.sub.33 FN.sub.2 O.sub.3 : C, 73.09; H, 
6.98; N, 5.88. Found: C, 72.51; H, 7.10; N, 5.81. 
EXAMPLE 122 
[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl]ca 
rbamic acid ethyl ester oxalate hydrate [1:1:1.5] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanol, 2.6 (0.01 mole) 
of N-[4-(3-chloropropoxy) phenyl]carbamic acid ethyl ester, 5.3 g (0.05 
mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 
ml of dimethylformamide heated in a steambath for 24 hr gave a gum as 
residue. The gum was converted to the oxalic acid salt in ethyl acetate 
and the solid was recrystallized from 2-propanol to yield 32 g (50%) of 
title compound as a white solid, mp 70.degree.-90.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.38 F.sub.2 NO.sub.8 
.multidot.1.5H.sub.2 O: C, 59.90; H, 6.13; N, 4.37. Found: C, 59.69; H, 
5.80; N, 4.21. 
EXAMPLE 123 
1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl- 
3-pyrrolidinepropanenitrile 
A mixture of .alpha.,.alpha.-bis 
(4-fluorophenyl)-3-pyrrolidinepropanenitrile (5.00 g, 0.016 mole), 
1-[4-(3-chjloropropoxy)-3-methoxyphenyl]ethanone (3.88 g, 0.016 mole), and 
potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 
350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction 
mixture was cooled to room temperature and filtered. The butanol was 
removed by rotary evaporator to produce a dark brown oil. This oil was 
dissolved in chloroform and the organic phase was extracted several times 
with water. The chloroform layer was dried over sodium sulfate, filtered, 
and solvent removed to provide a dark brown oil. The entire oil was 
subjected to flash chromatography on silica gel using ethyl acetate, 5% 
methanol-ethyl acetate, and 10% methanol-ethyl acetate for elution. 
Fractions of similar purity were combined and solvent removed in vacuo. A 
dark brown oil was obtained and dried in vacuo overnight at 80.degree. C. 
to give 4.33 g (52.2% yield) of a glassy brown residue. 
H.sup.1 NMR(CDCl.sub.3): .delta. 6.8-7.7 (m, 11, aromatics), 4.0-4.25 (t, 
2, --CH.sub.2 --O), 3.9 (s, 3, --OCH.sub.3), 1.5-2.7 (m, 16, aliphatics). 
Analysis: Calculated for C.sub.31 H.sub.32 F.sub.2 N.sub.2 O.sub.3 : C, 
71.80; H, 6.22; N, 5.40. Found: C, 71.66; H, 6.29; N, 5.53. 
EXAMPLE 124 
2-[3-[4-[Bis(4-fluorophenyl)methylene]-1-piperidinyl]propoxy]phenol 
A mixture of 6.0 g (0.02 mole) of .alpha., 
.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 5.5 g(0.02 mole) of 
3-(2-benzyloxyphenoxy)propyl chloride, 7.4 g (0.07 mole) of anhydrous 
sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol was 
heated at reflux for 24 hr. The mixture was concentrated and the residue 
was partitioned between benzene and water. The organic layer was washed 
with water and brine, dried over sodium sulfate and concentrated to give a 
gum as residue. The gum was converted to a crystalline hydrochloride. The 
salt changed to an oil upon standing overnight. The oil was partitioned 
between methylene chloride and a saturated sodium bicarbonate solution. 
The organic layer was dried over sodium sulfate and concentrated to give a 
gum as residue. 
The gum was dissolved in 500 ml of absolute ethanol and hydrogenated in a 
Parr apparatus over 5% palladium on carbon catalyst at 70.degree. C. 
overnight. The mixture was filtered through Celite.RTM. and the filtrate 
was concentrated to give a gummy solid as residue. The solid was 
triturated with ethyl ether and the mixture was filtered. The filtrate was 
slowly evaporated and a solid precipitated. The solid was collected by 
filtration and recrystallized from isopropyl ether to yield 1.6 g (18% 
yield) of title compound as a white solid, mp 125.degree.-127.degree. C. 
Analysis: Calculated for C.sub.27 H.sub.27 F.sub.2 NO.sub.2 : C, 74.46; H, 
6.25; N, 3.22. Found: C, 74.47; H, 6.29; N, 3.12. 
EXAMPLE 125 
1-[3-(4-Ethyl-2-methoxyphenoxy)propyl]-.alpha.,.alpha.-bis 
(4-fluorophenyl)-4-piperidinemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 
mole) of 3-(4-ethyl-2-methoxyphenoxy)propyl chloride, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol gave 3.7 g (74%) of title compound as a white solid, mp 
118.degree.-120.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.35 F.sub.2 NO.sub.3 : C, 72.70; H, 
7.12; N, 2.83. Found: C, 72.72; H, 7.43; N, 2.81. 
EXAMPLE 126 
1-(3-Phenoxypropyl)-.alpha.,.alpha.-diphenyl-4-piperidinemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 4.0 g (0.015 mole) of .alpha., 
.alpha.-diphenyl-4-piperidinemethanol, 3.2 g (0.015 mole) of 
1-bromo-3-phenoxypropane, 5.3 g (0.05 mole) of anhydrous sodium carbonate 
and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.2 g (53%) of 
title compound as a white solid, mp 87.degree.-88.degree. C. 
Analysis: Calculated for C.sub.27 H.sub.31 NO.sub.2 : C, 80.76; H, 7.78; N, 
3.49. Found: C, 80.82; H, 7.79; N, 3.52. 
EXAMPLE 127 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-[4-(methylsulfinyl)phenoxy]propyl] 
-4-piperidinemethanol oxalate hydrate [1:1:1.5]compound with 2-propanol 
[1:0.5]. 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 
mole) of 1-(3-chloropropyl)-4-methylsulfinyl)benzene, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 
1-butanol gave a gum as residue. The gum was purified by column 
chromatography on 120 g of Florisil.RTM.. Fractions eluted with 15-25% 
acetone in benzene were combined and concentrated to give the purified 
base as an oil. The oil was converted to the oxalic acid salt and the 
solid was recrystallized from 2-propanol to yield 2.6 g (40% yield) of 
title compound as a white solid, mp 75.degree.-105.degree. C. 
Analysis: Calc'd for C.sub.30 H.sub.33 F.sub.2 NO.sub.7 S.multidot.1.5 
H.sub.2 O.multidot.0.5 0.5aC.sub.3 H.sub.8 O: C, 58.50; H, 6.23; N, 2.17. 
Found: C, 58.32; H, 5.99; N, 2.05. 
EXAMPLE 128 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-[4-(1-methylethyl)phenoxy]propyl]- 
1-piperidinemethanol oxalate [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 4.6 g (0.015 mole) of .alpha., 
.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 3.2 (0.015 mole) of 
1-chloro-3-(4-isopropylphenoxy)propane, 5.3 g (0.05 mole) of anhydrous 
sodium carbonate and 0.4 of potassium iodide in 100 ml of 1-butanol gave a 
solid as residue. The solid was converted to the oxalic acid salt and this 
solid was recrystallized from ethyl acetate to yield 4.6 g (54% yield) of 
title compound as a white solid, mp 105.degree.-109.degree. C. with 
decomposition. 
Analysis: Calculated for C.sub.32 H.sub.37 F.sub.2 NO.sub.6 : C, 67.47; H, 
6.55; N, 2.46. Found: C, 66.92; H, 6.61; N. 2.52. 
EXAMPLE 129 
3-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-benzoic 
acid ethyl ester fumarate [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of .alpha., 
.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.4 g (0.01 mole) of 
3-(3-chloropropoxy)benzoic acid ethyl ester, 3.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
dimethylformamide gave a gum as residue. The gum was converted to the 
fumaric acid salt and the solid was recrystallized from acetonitrile to 
yield 4.2 g (67%) of title compound as a fluffy,, white solid, mp 
123.degree.-131.degree. C. 
Analysis: Calculated for C.sub.34 H.sub.37 F.sub.2 NO.sub.8 : C, 65.27; H, 
5.96; N, 2.24. Found: C, 65.09;H, 5.95; N, 2.25. 
EXAMPLE 130 
1-[4-[3-[4-[Bis(4-methylphenyl)methylene[-1-piperidinyl]propoxy]-3-methoxyp 
henyl]ethanone 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 4.6 g (0.015 mole) of .alpha., 
.alpha.-bis(4-methylphenyl)-4-piperidinemethanol, 3.6 g (0.015 mole) of 
1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave a brown gum as residue. The gum was dissolved in ethyl 
ether and filtered to remove insolubles. The filtrate was treated with 
ethereal hydrogen chloride and a solid gradually crystallized. Attempted 
recrystallization of the solid from 2-propanol failed. The solid was 
partitioned between methylene chloride and a sodium bicarbonate solution. 
The organic layer was dried over sodium sulfate and concentrated under 
reduced pressure to give a brown gum. The gum was converted to the fumaric 
acid salt. The solid was recrystallized twice from 2-propanol but a 
satisfactory combustion analysis could not be obtained. This salt was 
partitioned between methylene chloride and a sodium bicarabonate solution 
as above to give a gum as residue. The gum crystallized after standing for 
several days. The solid was triturated with petroleum ether, collected by 
filtration, and recrystallized from 2-propanol to yield 2.2 g (46%) of 
title compound as an off-white solid, mp 92.degree.-95.degree. C. with 
decomposition. 
Analysis: Calculated for C.sub.32 H.sub.37 NO.sub.3 : C, 79.47; H, 7.71; N, 
2.90. Found: C, 79.18; H, 7.88; N, 2.88. 
EXAMPLE 131 
1-[4-[3-[4[Bis(4-methylphenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-metho 
xyphenyl]ethanone oxalate hydrate [1:1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 4.6 g (0.015 mole) of .alpha., 
.alpha.-bis(4-methylphenyl)-4-piperidinemethanol, 3.6 g (0.015 mole) of 
1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 5.3 g (0.05 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave a brown gum as residue. The gum was converted to the oxalic 
acid salt and the solid was recrystallized from absolute ethanol to yield 
5.3 g (58%) of title compound as an off-white solid, mp 
92.degree.-95.degree. C. with decomposition. 
Analysis: Calculated for C.sub.34 H.sub.41 NO.sub.8.H.sub.2 O: C, 66.97; H, 
7.11; N, 2.30. Found: C, 66.61; H, 6.79; N, 2.29. 
EXAMPLE 132 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxyl]-benzoic 
acid methyl ester fumarate [1:1] 
A mixture of 9.1 g (0.03 mole) of .alpha., 
.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 6.7 g (0.03 mole) of 
4-(3-chloropropoxy)benzoic acid methyl ester, 10.6 g (0.1 mole) of 
anhydrous sodium carbonate and 0.6 g of potassium iodide in 125 ml of 
dimethylformamide was heated in a steambath for 25 hr. The reaction 
mixture was poured into 1.5 liters of ice-water. The resulting solid was 
collected by filtration, washed with water and dried. The solid was 
converted to the fumaric acid salt to yield 12.5 g (68%) of title compound 
as a white solid, mp 140.degree.-174.degree. C. with decomposition. 
Analysis: Calculated for C.sub.33 H.sub.35 F.sub.2 NO.sub.8 : C, 64.80; H, 
5.77; N, 2.29. Found: C, 64.67; H, 5.80; N, 2.34. 
EXAMPLE 133 
1-[3-(4-Aminophenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperidi 
nemethanol oxalate [1:2] 
A solution of 2.6 g (0.0054 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-[3,(4-nitrophenoxy)propyl]-4-piperid 
inemethanol in 50 ml of tetraydrofuran was hydrogenated at ambient 
temperature over 5% palladium on carbon catalyst at 40 psi. The mixture 
was filtered and the filtrate was concentrated to give a gum as residue. 
The gum was converted to the dioxalate salt and the solid was 
recrystallized from 95% ethanol to yield 2.1 g (62%) of title compound as 
an off-white solid, mp 136.degree.-139.degree. C. with decomposition. 
Analysis: Calculated for C.sub.31 H.sub.34 F.sub.2 N.sub.2 O.sub.10 : C, 
58.86; H, 5.42; N,, 4.43. Found: C, 58.73; H, 5.48; N, 4.43. 
EXAMPLE 134 
1-[4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-2-methoxyphen 
yl]ethanone oxalate [1:1] 
A mixture of 4-[bis(4-fluorophenyl)maethyl]piperidine (5.74 g, 0.02 mole), 
1-[4-(3-chloropropoxy)-2-methoxyphenyl]ethanone (4.85 g, 0.02 mole), and 
potassium carbonate (5.54 g, 0.04 mole) was heated at reflux overnight in 
350 of 1-butanol containing potassium iodide (0.2 g). The reaction mixture 
was concentrated to dryness and the residue obtained was partitioned 
between chloroform and water. The chloroform layer was extracted with 
water, dried over sodium sulfate, filtered, and solvent removed to give a 
brown oil. The oil was converted to the oxalate salt. The oxalate salt was 
recrystallized from methanol-ethyl ether. A white solid was obtained and 
dried in vacuo overnight at 80.degree. C. to give 7.04 g (60.3% yield) of 
white, crystalline product, mp 190.5.degree.-191.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.35 F.sub.2 NO.sub.7 : C, 65.86; H, 
6.05; N, 2.40. Found: C, 65.73; H, 6.05; N, 2.45. 
EXAMPLE 135 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(4-ethyl-2-methoxyphenoxy)-propyl]piperi 
dine oxalate [1:1] 
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (5.74 g, 0.024 mole), 
1-[4-(3-chloropropoxy)-2-methoxyphenyl]ethanone (5.57 g, 0.024 mole), and 
potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle 
reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The 
reaction mixture was concentrated to dryness. The residue was partitioned 
several times between chloroform and water. The chloroform layer was back 
extracted with water and 5% sodium hydroxide. The chloroform layer was 
dried over sodium sulfate, filtered, and solvent removed to give an oil. 
The oil was converted to the oxalate salt and recrystallized from 
methanol-ethyl ether. A white solid was obtained and dried overnight in 
vacuo at 80.degree. C. to give 10.04 g (73.4% yield) of white, crystalline 
product, mp 185.degree.-186.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.37 F.sub.2 NO.sub.6 : C, 67,47; H, 
6.55; N, 2.46. Found: C, 67.41; H, 6.53; N, 2.50. 
EXAMPLE 136 
1-[3-([1,1'-Biphenyl]-4-yloxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4 
-piperidinemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of .alpha., 
.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.5 g (0.01 mole) of 
4-(3-chloropropoxy)-1,1'-biphenyl, 3.7 g (0.035 mole) of anhydrous sodium 
carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.5 g 
(69%) of title compound as a white solid, mp 108.degree.-109.degree. C. 
Analysis: Calculated for C.sub.33 H.sub.33 F.sub.2 NO.sub.2 : C, 77.17; H, 
6.48; N, 2.73. Found: C, 76.80; H, 6.83; N, 2.72. 
EXAMPLE 137 
N-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-phenyl 
]-N'-methylurea 
To a solution of 4.5 g (0.01 mole) of 
1-[3-(4-aminophenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperid 
inemethanol in 50 ml of benzene was added dropwise a solution of 0.6 g 
(0.01 mole) of methylisocyanate in 10 ml of benzene. The mixture was 
stirred for 1 hr during which time a solid precipitated. The mixture was 
diluted with 25 ml of cyclohexane, the solid was collected by filtration 
and recrystallized from 2-propanol to yield 1.6 g (31%) of title compound 
as a white solid, mp 177.degree.-178.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.33 F.sub.2 N.sub.3 O.sub.3 : C, 
68.35; H, 6.53; N, 8.25. Found: C, 68.69; H, 6.65; N, 8.29. 
EXAMPLE 138 
N-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl] 
methanesulfonamide fumarate[1:0.5]compound with 2-methoxyethanol [1:1] 
To a solution of 4.5 g (0.01 mole) of the base of 
1-[3-(4-aminophenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperid 
inemethanol and 1.5 g (0.015 mole) of triethylamine in 50 ml of benzene and 
100 mol of ethyl acetate was added dropwise a solution of 1.2 g (0.01 
mole) of methanesulfonyl chloride in 10 ml of benzene. A gum immediately 
precipitated. The mixture was stirred at ambient temperature for 2 hr and 
then treated with a saturated sodium bicarbonate solution. The mixture was 
stirred for 0.5 hr during which time all solids dissolved. The layers were 
separated and the organic layer was washed with brine, dried over sodium 
sulfate and concentrated under reduced pressure to give a gum as residue. 
The gum was converted to the fumaric acid salt and the solid was 
recrystallized from 2-methoxyethanol to yield 4.0 g (61%) of title 
compound as a tan solid, mp 153.degree.-156.degree. C. with decomposition. 
Analysis: Calc'd for C.sub.30 H.sub.34 F.sub.2 N.sub.2 O.sub.6 S.C.sub.3 
H.sub.8 O.sub.2 : C, 59.62; H, 6.37; N, 4.21. Found: C, 59.84; H, 6.59; N, 
4.17. 
EXAMPLE 139 
1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl] 
-1-propanone compound with 2-propanol [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 
mole) of 1-[4-(3-chloropropoxy)phenyl]-1-propanone, 3.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mol of 
1-butanol gave 3.7 g (76%) of title compound as a white solid, mp 
57.degree.-62.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.33 F.sub.2 NO.sub.3.C.sub.3 H.sub.8 
O: C, 71.59; H, 7.46; N, 2.53. Found: C, 71,42; H, 7.29; N, 2.63. 
EXAMPLE 140 
1-[4-[3-[4-[Bis(4-methoxyphenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-met 
hoxyphenyl]ethanone oxalate [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.2 g (0.01 mole) of 
.alpha.,.alpha.-bis(4-methoxypenyl)-4-piperidinemethanol, 2.4 g (0.01 
mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 
mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 
ml of 1-butanol gave a gum as residue. The gum was purified by columm 
chromatography on 100 g of Florisil.RTM.. Fractions eluted with 5-40% 
acetone in benzene were combined and concentrated under reduced pressure 
to give a brown glass as residue. The glass was converted to the oxalic 
acid salt. The solid was recrystallized from absolute ethanol yield 3.3 g 
(53%) of the title compound as a white solid, mp 139.degree.-142.degree. 
C. with decomposition. 
Analysis: Calculated for C.sub.34 H.sub.41 NO.sub.10 : C, 65.48; H, 6.63; 
N, 2.25. Found: C, 65.38; H, 6.70; N, 2.38. 
EXAMPLE 141 
1-[4-[6-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]hexyloxy]-3-met 
hoxyphenyl]ethanone hydrochloride [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 2.8 g (0.01 
mole) of 1-[4-(4-chlorohexyloxy)-3-methoxyphenyl]ethanone, 5.3 g (0.05 
mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 
ml of 1-butanol gave a gum as resiude. The gum was purified by column 
chromatography on 80 g of Florisil.RTM.. Fractions eluted with 2-5% 
acetone in benzene were combined and concentrated to give a glass as 
residue. The glass was dissolved in anhydrous ethyl ether, filtered and 
the filtrate treated with ethereal hydrogen chloride. A gummy solid 
precipitated. This solid was triturated with fresh ethyl ether until a 
fine, white solid resulted. The solid was collected by filtration and 
dried to yield 1.0 g (17%) of title compound as a white solid, mp 
182.degree.-186.degree. C. with decomposition. 
Analysis: Calculated for C.sub.33 H.sub.40 ClF.sub.2 NO.sub.4 : C, 67.37; 
H, 6.86; N, 2.38. Found: C, 67.17; H, 6.94; N, 2.37. 
EXAMPLE 142 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-[4-(1-hydroxyethyl)-2-methoxypheno 
xy]-4-piperidinemethanol oxalate hydrate [1:1:1.5] 
To a stirred slurry of 0.6 g (0.015 mole) of lithium aluminum hydride in 50 
ml of dry tetrahydrofuran was added a solution of 5.6 g (0.015 mole) of 
1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-met 
hoxyphenyl]ethanone in 100 ml of dry tetrahydrofuran. The mixture was 
stirred at ambient temperature for 2 hr and then cautiously treated 
successively with 1 ml of water, 1 ml of water, 1 ml of a 20% sodium 
hydroxide solution and 3 ml of water. The mixture was stirred for 0.5 hr, 
filtered and the filtrate concentrated to give a gummy solid as residue. 
The gum was converted to the oxalic acid salt. The gum was recrystallized 
from 2-propanol and then from absolute ethanol-ethyl ester to yield 3.5 g 
(39%) of title compound as a white solid, mp 81.degree.-87.degree. C. with 
decomposition. 
Analysis: Calculated for C.sub.32 H.sub.37 F.sub.2 NO.sub.8.1.5H.sub.2 O: 
C, 61.14; H, 6.41; N, 2.23. Found: C, 61.13; H, 5.97; N, 2.17. 
EXAMPLE 143 
4-[4-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]butoxy]benzoic 
acid methyl ester fumarate [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 9.1 g (0.03 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanol, 7.3 g (0.03 
mole) of 4-(4-chlorobutoxy)benzoic acid methyl ester, 10.6 g (0.1 mole) of 
anhydrous sodium carbonate and 0.5 g of potassium iodide in 125 ml of 
dimethylformamide gave a gum as residue. The gum was converted to the 
fumaric acid salt and the solid was recrystallized from 
acetonitrile-dimethylformamide to yield 12.2 g (65%) of title compound as 
a white solid, mp 186.degree.-188.degree. C. 
Analysis: Calculated for C.sub.34 H.sub.37 F.sub.2 NO.sub.8 : C, 65.27; H, 
5.96; N, 2.24. Found: C, 65.23; H, 6.00; N, 2.32. 
EXAMPLE 144 
1-[4-[3-[4-[2,2-Bis(4-fluorophenyl)-2-hydroxyethyl]-1- 
piperidinyl]propoxy]-3-methoxyphenyl]ethanone fumarate hydrate [1:1:1] 
A mixture of 4.52 g (0.0143 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperidineethanol, 3.75 g (0.0155 
mole) of 3-(4-acetyl-2-methoxyphenoxy)-1-chloropropane, 4.1 g (0.049 mole) 
of sodium bicarbonate, and 0.20 g (0.0012 mole) of potassium iodide in 300 
ml of 1-butanol was heated at reflux for 8 hr. The solvent was removed in 
vacuo, and the residue was partitioned between methylene chloride and 
dilute sodium hydroxide. The methylene chloride solution was treated with 
a small portion of activated charcoal and was dried over magnesium 
sulfate. The solvent was removed in vacuo to give the non-salt form of the 
title compound. This was converted to the fumarate salt and the salt was 
crystallized from methanol/ether to give 5.94 g (64.9%) of the title 
compound as a white, crystalline solid, mp 135.degree.-136.degree. C. 
Analysis: Calculated for C.sub.35 H.sub.41 F.sub.2 NO.sub.9 : C, 63.92; H, 
6.28; N, 2.13. Found: C, 64.03; H, 6.07; N, 2.16. 
EXAMPLE 145 
1-[4-[3-[4-[[2,2-Bis(4-fluorophenyl)ethyl]-1-piperidinyl]propoxy]-3-methoxy 
phenyl]ethanone fumarate [1:1] 
A mixture of 5.15 g (0.0148 mole) of 
4-[2,2-bis(4-fluorophenyl)ethyl]piperidine hydrochloride hydrate [1:1:1], 
3.71 (0.0153 mole) of 3-(4-acetyl-2-methoxyphenoxy)-1-chloropropane, 1.59 
g (0.015 mole) of sodium carbonate, 2.30 g (0.0274 mole) of sodium 
bicarbonate and a 0.2 g (0.0012 mole) of potassium iodide in 400 ml of 
1-butanol was heated at reflux for 12 hr. The solvent was removed in 
vacuo, and the residue was partitioned between methylene chloride and 
dilute sodium hydroxide. The methylene chloride solution was dried over 
magnesium sulfate, and the solvent was removed in vacuo to give the free 
base of the title compound as an oil. This was converted to the fumarate 
salt, and the salt was recrystallized from methanol-ether to give 5.87 g 
(63.6 g) of title compound as a white, crystalline solid, mp 
156.degree.-157.degree. C. 
Analysis: Calculated for C.sub.35 H.sub.39 F.sub.2 NO.sub.7 : C, 67.40; H, 
6.30; N, 2.25. Found: C, 67.51; H, 6.34; N, 2.29. 
EXAMPLE 146 
1-[4-[3-[4-[2,2-Bis(4-fluorophenyl)ethylene]-1-piperidinyl]propoxy]-3-metho 
xyphenyl]ethanone fumarate [1:1] 
A solution of 3.89 g (0.013 mole) of 
4-[2,2-bis(4-fluorophenyl)ethylene]piperidine, 3.20 g (0.013 mole) of 
3-(4-acetyl-2-methoxyphenoxy)-1-chloropropane and 2.02 g (0.024 mole) of 
sodium bicarbonate in 400 ml of 1-butanol was heated at reflux for 14 hr. 
The solvent was removed in vacuo, and the residue was partitioned between 
methylene chloride and dilute sodium hydroxide. The methylene chloride 
solution was dried over magnesium sulfate, and the solvent was removed in 
vacuo to give an oil. This was subjected to flash column chromatography 
(silica gel; eluted with 99/1 mixture of methylene chloride and methanol) 
to give the free base of the title compound. This was converted to the 
fumarate salt, and the salt was recrystallized from methanol/ether to give 
5.19 g (64.2%) of title compound as a white, crystalline solid, mp 
179.degree.-179.5.degree. C. 
Analysis: Calculated for C.sub.35 H.sub.37 F.sub.2 NO.sub.7 : C, 67.62; H, 
6.00; N, 2.25. Found: C, 67.59; H, 6.00; N, 2.23. 
EXAMPLE 147 
.alpha.-(4-Fluorophenyl)-.alpha.-[1-(3-phenoxypropyl)-4-piperidinyl]-2-pyri 
dineacetonitrile oxalate [1:1.5] 
A mixture of 
.alpha.-(4-fluorophenyl)-.alpha.-(4-piperidinyl)2-pyridineacetonitrile 
(11.30 g, 0.0383 mole), 3-phenoxypropyl bromide (8.20 g, 0.0383 mole), and 
potassium bicarbonate (4.0 g, 0.04 mole) was heated overnight at reflux in 
350 ml of acetonitrile (dried over 4A molecular sieves). The reaction 
mixture was cooled to room temperature and filtered, and solvent removed 
by rotary evaporation. A dark brown oil was obtained and dissolved in 
chloroform. The chloroform layer was extracted with 5% sodium hydroxide 
and water, dried over sodium sulfate and filtered, and the solvent was 
removed to give a brown oil. A 0.55 g sample of the oil was converted to 
the oxalate salt in methanol-ethyl ether. A white, crystalline solid was 
isolated and dried in vacuo overnight at 80.degree. C., to give 0.35 g 
(48.4% yield) of product, mp 121.degree.-125.degree. C. 
Analysis; Calculated for C.sub.30 H.sub.31 FN.sub.3 O.sub.7 : C, 63.82; H, 
5.53; N, 7.44. Found: C, 63.78; H, 5.56; N, 7.67. 
EXAMPLE 148 
1-[4-[3-[4-[Bis(4-chlorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphen 
yl]ethanone oxalate hydrate [1:1:0.5] 
A mixture of 4-[bis(4-chlorophenyl)methyl]piperidine (11.39 g, 0.0357 
mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (8.64 g, 0.0357 
mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at 
reflux in 300 ml of 1-butanol containing potassium iodide (0.2 g). The 
reaction mixture was concentrated to dryness, and the residue obtained was 
partitioned several times between chloroform and water. The chloroform 
layer was dried over sodium sulfate ad filtered, and the solvent was 
removed to give a dark brown oil. This oil was converted to the oxalate 
salt and the salt was recrystallized from methanol-ethyl ether. A yellow 
solid was isolated and dried in vacuo overnight at 80.degree. C. The 
yellow solid was next exposed to the atmosphere for 24 hours and submitted 
for analysis. This procedure produced 6.65 g (30% yield) of light yellow 
solid, mp 160.degree.-171.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.35 Cl.sub.2 NO.sub.7.0.5H.sub.2 O: 
C, 61.44; H, 5.80; N, 2.24. Found: C, 61.40; H, 5.71; N, 2.24. 
EXAMPLE 149 
1-[4-[3-[4-[Bis(4-chlorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-meth 
oxyphenyl]ethanone oxalate [1:1.5] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 2.5 g (0.0075 mole) of 
.alpha.,.alpha.-bis(4-chlorophenyl)-4-piperidinemethanol, 1.8 g (0.0075 
mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 
mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 
ml of 1-butanol gave a gummy solid as residue. This solid was converted to 
the oxalic acid salt and the solid was recrystallized from absolute 
ethanol to yield 1.4 g (30%) of title compound as a pale-yellow solid, mp 
89.degree.-113.degree. C. with decomposition. 
Analysis: Calculated for C.sub.33 H.sub.36 Cl.sub.2 NO.sub.10 : C, 58.50; 
H, 5.36; N, 2.07. Found: C, 58.22; H, 5.32; N, 2.07. 
EXAMPLE 150 
4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxybenzoic 
acid methyl ester 
The sodium salt of methyl vanillate was formed from methyl vanillate (11.26 
g, 0.062 mole) and sodium hydride (2.47 g, 60%, 0.062 mole) in 300 ml of 
dimethyl sulfoxide (dried over 4A molecular sieves). During the formation 
of this sodium salt, the dimethyl sulfoxide solution turned light green. 
The salt was stirred 0.5 hr at room temperature under nitrogen atmosphere. 
Next, 4-[bis(4-fluorophenyl)methyl]-3-chloropropyl)piperidine (21.32 g, 
0.062 mole) in 100 ml of dimethyl sulfoxide was added dropwise. The 
resulting solution was stirred overnight at 60.degree. C. The warm 
reaction mixture was concentrated to dryness on a rotary evaporator. The 
residue was dissolved in chloroform and extracted several time with water. 
The chloroform layer was dried over sodium sulfate, filtered, and solvent 
removed to give a dark brown oil (31.35 g). The oil was dissolved in ethyl 
acetate and placed on an 800 g silica gel column. This column was eluted 
with ethyl acetate. Fractions of similar purity were combined and dried in 
vacuo at 80.degree. C. overnight to give 22.70 g (71.9% yield) of brown 
oil. 
H.sup.1 NMR(CDCl.sub.3): .delta. 6.7-7.7 (m, 11, aromatics), 4.0-4.3 (t, 2, 
--OCH.sub.2), 3.9 (s, 6, OCH.sub.3 of ether and ester), 3.5 (d, 2, methine 
group attached to two fluorophenyl groups), 1.3-3.0 (m, 12, remaining 
aliphatics). 
Analysis: Calculated for C.sub.30 H.sub.33 F.sub.2 NO.sub.4 : C, 70.71; H, 
6.53; N, 2.75. Found: C, 70.48; H, 6.60; N, 2.71. 
EXAMPLE 151 
1-[4-[3-[4-[Bis(3-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphen 
yl]ethanone fumarate [1:1] 
A mixture of 5.32 g (0.019 mole) of 
4-[bis(3-fluorophenyl)methyl]piperidine, 4.80 g (0.020 mole) of 
3-(4-acetyl-2-methoxyphenoxy)-1-chloropropane, 2.4 g (0.029 mole) of 
sodium bicarbonate and 0.20 g (0.0012) mole of potassium iodide in 400 ml 
of 1-butanol was heated at reflux for 23 hr. The solvent was removed in 
vacuo and the residue was partitioned between methylene chloride and 
dilute sodium hydroxide. The methylene chloride solution was dried over 
magnesium sulfate and the solvent was removed in vacuo to give an oil. 
This was dissolved in methanol and the solution was treated with an excess 
of fumaric acid. Ether was added and a gum formed. The gum was triturated 
with acetonitrile to give 1.75 g (15.1%) of the title compound as a white 
crystalline solid, mp 180.degree.-181.degree. C. 
Analysis: Calculated for C.sub.34 H.sub.37 F.sub.2 NO.sub.7 : C, 66.98; H, 
6.12; N, 2.30. Found: C, 66.70; H, b 6.11; N, 2.32. 
The solvent was removed in vacuo from the filtate and the residue was 
recrystallized from a mixture of methanol-ether-acetonitrile to give 2.83 
g (24.4) of title compound, mp 181.degree.-182.degree. C. 
Analysis: Calculated for C.sub.34 H.sub.37 F.sub.2 NO.sub.7 : C, 66.98; H, 
6.12, 2.30. Found: C, 66.95; H, 6.09; N, 2.28. 
EXAMPLE 152 
4-[3-[4-[Hydroxy(diphenyl)methyl]-1-piperdinyl]propoxy]benzoic acid methyl 
ester 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 5.3 g (0.02 mole) of 
.alpha.,.alpha.-diphenyl-4-piperidinemethanol, 4.6 g (0.02 mole) of 
4-(3-chloropropoxy)benzoic acid methyl ester, 7.4 g (0.07 mole) of 
anhydrous sodium carbonate and 0.5 g of potassium iodide in 100 ml of 
dimethylformamide give 6.8 g (74%) of title compound as a fluffy, white 
solid, mp 146.degree.-147.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.33 NO.sub.4 : C, 75.59; H, 7.24; N, 
3.05. Found: C, 75.68; N, 7.22; N, 3.11. 
EXAMPLE 153 
1-[4-[6-[4-[Bis(4-fluorophenyl)methyl]-1-piperdinyl]hexyloxy]-3-methoxyphen 
yl]ethanone 
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (7.90 g, 0.0275 mole), 
1-[4-(6-chlorohexyloxy)-3-methoxyphenyl]ethanone (7.82 g, 0.025 mole), and 
potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 
400 ml of 1-butanol containing potassium iodide (0.2 g). The mixture was 
cooled to room temperature and filtered. Butanol was removed by rotary 
evaporation. The brown oil obtained was dissolved in chloroform and 
extracted several times with water. The chloroform layer was dried over 
sodium sulfate, filtered, and solvent removed to give a brown oil. This 
oil was dissolved in ethyl acetate and subjected to flask chromatography 
on silica gel using ethyl acetate and 5% methanol-ethyl acetate for 
elution. Fractions of similar purity were combined and solvent removed to 
give an oil. The oil was dried at 80.degree. C. overnight in vacuo to give 
7.28 g (54.4% yield) of title compound as a light brown oil. 
H.sup.1 NMR(CDCl.sub.3): 67 6.7-7.5 (m, 11, aromatics), 4-4.2 (m, 2, 
--OCH.sub.2), 3.9 (s, 3, --OCH.sub.3), 3.4-3.6 (d, 1, methine on carbon 
attached to two fluorophenyl groups), 2.6 (s, 3; 
##STR21## 
1.5-3.0 (m ,13, remaining aliphatics). 
Analysis: Calculated for C.sub.33 H.sub.39 F.sub.2 NO.sub.3 : C, 73.99; H, 
7.34; N, 2.61. Found: C, 73.92; H, 7.54; N, 2.62. 
EXAMPLE 154 
4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxybenzoic 
acid hydrate [1:0.5] 
A solution of 
4-[3-[4-[bis(4-fluorophenyl)methyl]-1-piperidinyl]-propoxy-3-methoxybenzoi 
c acid methyl ester (18.58 g, 0.0365 mole) in 400 ml of ethanol was heated 
for 6 hr at reflux with potassium hydroxide (16.8 g) in 50 ml of water. 
The ethanol was removed by rotary evaporation. Next, 1N sulfuric acid 
(.about.200 ml) was added. The aqueous phase was made neutral to litmus 
paper by the addition of 5% sodium hydroxide. The neutral aqueous layer 
was extracted several times with chloroform. The chloroform layer was 
dried over sodium sulfate, filtered, and solvent removed to give a white 
solid. The white solid was triturated with ethyl ether and cooled to about 
0.degree. C. The white solid was then collected by filtration and dried in 
vacuo overnight at 80.degree. C. to give 11.38 g (61.8% yield) of white, 
crystalline product, the title compound, mp 123.degree.-126.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.31 F.sub.2 NO.sub.4.0.5H.sub.2 O: 
C, 69.03; H, 6.39; N, 2.78. Found: C, 69.18; H, 6.32; N, 2.78. 
EXAMPLE 155 
4-[Bis(4-fluorophenyl)methyl]-1-[3-(3-methoxyphenoxy)propyl]piperidine 
hydrate [1:0.5] 
The sodium salt of m-methoxyphenol was prepared in dimethyl sulfoxide from 
sodium hydride (60%, 1.10 g, 0.027 mole) and m-methoxyphenol (3.36 g, 
0.027 mole). The salt was stirred for 0.75 hr at room temperature and a 
clear brown solution was obtained. Next, 
4-[bis(4-fluorophenyl)methyl]-1-(3-chloropropyl)piperidine (9.34 g, 0.027 
mole) in 100 ml of dimethyl sulfoxide was added. The resulting solution 
was stirred overnight at 55.degree. C. The solvent was removed in vacuo 
and the oil obtained was subjected to flash chromatography on silica gel 
using 50% hexanes-ethyl acetate for elution. Fractions of similar purity 
were combined and solvent removed. A brown oil was obtained and dried at 
80.degree. C. overnight in vacuo in give 3.96 g (31.8%) of brown oil. 
.sup.1 H NMR(CDCl.sub.3): .delta. 6.3-7.3 (m, 12, aromatics), 3.8-4.1 (m, 
2, --OCH.sub.2), 3.7 (S, 3, --OCH.sub.3), 3.4-3.6 (d, 1, methine attached 
to two fluorophenyl rings), 1.2-3.0 (m, 13), remaining aliphatic protons). 
Analysis: Calculated for C.sub.28 H.sub.31 F.sub.2 NO.sub.2.0.5H.sub.2 O: 
C, 73.02; H, 7.00; N, 3.04. Found: C, 72.66; H, 6.89; N, 3.06. 
EXAMPLE 156 
1-[4-[3-[4-[Cyclohexyl(4-fluorophenyl)methyl]-1-piperdinyl]propoxy]-3-metho 
xyphenyl]ethanone 
A mixture of 4-[cyclohexyl(4-fluorophenyl)methyl]piperidine (5.71 g, 0.0207 
mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.03 g, 0.207 
mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at 
reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The 
reaction mixture was cooled to room temperature and filtered. The 
1-butanol was removed by rotary evaporation to give a brown oil. This oil 
was dissolved in chloroform and the chloroform layer was extracted with 5% 
sodium hydroxide and water. The chloroform layer was dried over sodium 
sulfate, filtered, and solvent removed to give a brown oil. This oil was 
subjected to flash chromatography on silica gel. Elution was performed 
using ethyl acetate, 5% methanol-ethyl acetate, and 10% methanol-ethyl 
acetate. Separate fractions of similar purity were combined and solvent 
was removed to give a yellow oil. This oil was dried in vacuo overnight at 
80.degree. C. to give 7.36 g (73.8%) of title compound. 
.sup.1 H NMR(CDCl.sub.3): .delta. 6.7-7.4 (m, 7, aromatics), 4.0 (m, 2, 
--O--CH.sub.2), 3.9 (s, 3, --O--CH.sub.3), 2.5 (s, 3, 
##STR22## 
1.0-3.0 (m, 25, remaining aliphatics). 
Analysis: Calculated for C.sub.30 H.sub.40 FNO.sub.3 : C, 74.81; H, 8.37; 
N, 2.91. Found: C, 74.39; H, 8.36; N, 2.81. 
EXAMPLE 157 
2-[4-Fluorophenyl)[1-(3-phenoxypropyl)-4-piperidinyl]methyl]pyridine 
hydrate [1:0.5] 
A solution of 
.alpha.-(4-fluorophenyl)-.alpha.-[1-(3-phenoxypropyl)-4-piperidinyl]-2-pyr 
idineacetonitrile oxalate [1:1.5] (2.34 g, 0.00545 mole) in 75 ml of 
glacial acetic acid containing 10 drops of concentrated hydrochloric acid 
was prepared. To this solution was added 2 grams of platinum on carbon 
catalyst (1%). After reacting with hydrogen for 5 days at 80.degree. C. 
and 1000 psi, the reaction mixture was allowed to cool to room 
temperature. The mixture was filtered through Celite.RTM. and the filtrate 
washed with glacial acetic acid. The acetic acid was removed by rotary 
evaporation. The residue obtained was dissolved in chloroform, and the 
solution was extracted with 5% sodium hydroxide. The chloroform was dried 
over sodium sulfate and filtered, and the solvent removed to give a brown 
oil. This oil was subjected to flash chromatography on silica gel using 5% 
methanol-ethyl acetate for elution. Fractions of similar purity were 
combined and solvent removed to give a brown oil. The oil was dried in 
vacuo overnight at 80.degree. C. to give 0.35 (15.5% yield) of brown oil. 
.sup.1 H NMR(CDCl.sub.3): .delta.8.5 (m, 1, proton adjacent to nitrogen 
atom in pyridine ring), 6.8-7.5 (m, 12, aromatics), 4.0 (t, 2, --OCH.sub.2 
--), 3.6 (d, 1, methine proton attached to carbon bonded to fluorophenyl 
ring and also pyridine ring), 1.0-3.0 (m, 13, remaining aliphatic 
protons). 
Analysis: Calculated for C.sub.29 H.sub.29 FN.sub.2 O.0.5H.sub.2 O: C, 
75.52; H, 7.31; N, 6.77. Calculated for C.sub.29 H.sub.29 FN.sub.2 
O.0.25H.sub.2 O: C, 76.35; H, 7.27; N, 6.85. Found: C, 76.28; H, 7.14; N, 
6.85. 
EXAMPLE 158 
1-[4-[3-[4-[(3,4-Difluorophenyl)(4-fluorophenyl)methyl]-1-piperidinyl]propo 
xy]-3-methoxyphenyl]ethanone oxalate [1:1] 
A mixture of 2.68 g (0.036 mole) of 
4-[3,4-difluorophenyl)methyl]piperidine, 2.50 g (0.110 mole) of 
1-chloro-3-(4-acetyl-2-methoxyphenoxy)propane, 3.0 g (0.036 mole) of 
sodium bicarbonate, and 0.20 g (0.0012 mole) of potassium iodide in 300 ml 
of 1-butanol was heated at reflux for 30 hours. The solvent was removed in 
vacuo, and the residue was partitioned between methylene chloride and 
dilute sodium hydroxide. Methylene chloride solution was dried over sodium 
sulfate, and the solvent was removed in vacuo to give an oil. The oil was 
flash chromatographed (silica gel, elution with 95/5 methylene 
chloride-methanol) to give the nonsalt form of the title compound. This 
was converted to the oxalate salt, and the salt was recrystallized from 
methanol-ether to give 3.85 g (72.7%) of the title compound as a white, 
crystalline solid, m.p. 170.degree.-171.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.34 F.sub.3 NO.sub.4 : C, 63.89; H, 
5.70; N, 2.33. Found: C, 63.87; H, 5.71; N, 2.34. 
EXAMPLE 159 
1-[4-[3-[3-[Bis(4-fluorophenyl)hydroxymethyl]-1-pyrrolidinyl]propoxy]-3-met 
hoxyphenyl]ethanone 
A mixture of 2.9 g (0.01 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-3-pyrrolidinemethanol, 2.4 g (0.01 
mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, b 5.3 g (0.05 
mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium 
iodide in 100 ml of 1-butanol was heated at reflux for 24 hr. The mixture 
was concentrated under reduced pressure and the residue partitioned 
between 100 ml of benzene and 100 ml of water. The benzene layer was 
washed with water and brine, dried over sodium sulfate and concentrated 
under reduced pressure to give a brown gum. The gum was purified by 
columne chromatography on 80 g of Florisil.RTM. using a gradient elution 
system of 0-10% acetone in benzene. The fractions containing the desired 
product were combined and concentrated under reduced pressure to give 3.2 
g of a brown gum. This gum was further purified by high-pressure liquid 
chromatography (Waters Associates Prep LC/System 500A; PrepPak 500 silica; 
1% methanol in methylene chloride; flow rate 150 ml/min). The fractions 
containing the desired product were combined and concentrated under 
reduced pressure to yield 1.7 g (34% yield) of the title compound as a 
light-yellow, glassy solid, m.p. 44.degree.-46.degree. C. 
Analysis: Calculated for C.sub.29 H.sub.31 F.sub.2 NO.sub.4 : C, 70.29; H, 
6.31; N, 2.83. Found: C, 69.60; H, 6.26; N, 2.86. 
EXAMPLE 160 
1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl) 
-3-pyrrolidineacetonitrile 
A mixture of .alpha.,.alpha.-bis(4-fluorophenyl)-3-pyrrolidineacetonitrile 
(5.13 g, 0.0172 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone 
(4.17 g, 0.0172 mole), and potassium carbonate (5.53 g, 0.04 mole) was 
heated overnight at reflux in 350 ml of 1-butanol containing potassium 
iodide (0.2 g). The butanol was removed by rotary evaporation. The residue 
obtained was dissolved in chloroform and extracted several times with 
water. The chloroform layer was dried over sodium sulfate, filtered, and 
solvent removed in vacuo to give a dark brown oil. The oil was subjected 
to flash chromatography on silica gel using ethyl acetate and 25% 
methanol-75% ethyl acetate for elution. Fractions of similar purity were 
combined and solvents removed. A dark brown oil was obtained and dried in 
vacuo 2 days at 80.degree. C. to give 5.85 g (57.5% yield) of the title 
compound as a dark brown gum. 
.sup.1 H NMR (CDCl.sub.3): .delta.6.8-7.6 (m, 11, aromatics), 4.3 (t, 2, 
--OCH.sub.2 --), 3.9 (s, 3--OCH.sub.3), 2.6 (s, 3, --COCH.sub.3 --), 
1.3-3.8 (m, 11, aliphatics). 
Analysis: Calculated for C.sub.30 H.sub.30 F.sub.2 N.sub.2 O.sub.3 : C, 
7.41; H, 5.99; N, 5.55. Found: C, 70.94; H, 5.99; N, 5.51. 
EXAMPLE 161 
1-[(3-(4-Acetyl-2-methoxyphenoxy)propyl]-.alpha.,.alpha.-bis(3-fluorophenyl 
)-4-piperidinemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
4-[.alpha.,.alpha.-bis(4-fluorophenyl)hydroxymethyl]piperdine, 2.4 g (0.01 
mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 
mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 
ml of 1-butanol gave 3.6 g (71%) of the title compound as an off-white 
solid, m.p. 149.degree.-151.degree. C. (absolute ethanol). 
Analysis: Calculated for C.sub.30 H.sub.35 F.sub.2 NO.sub.4 : C, 70.71; H, 
6.53; N, 2.75. Found: C, 70.66; H, 6.53; N, 2.79. 
EXAMPLE 162 
1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl) 
-3-piperidinepropanetrile hydrate [1:0.5] 
A mixture of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.95 g, 
0.0184 mole), 
.alpha.,.alpha.-bis(4-fluorophenyl)-3-piperidinepropanenitrile (6.00 g, 
0.0184 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated 
overnight at reflux. The mixture was cooled to room temperature and 
concentrated to dryness on a rotary evaporator. The residue was 
partitioned between chloroform and water. The chloroform layer was 
back-extracted with water and 5% sodium hydroxide solution. The chloroform 
layer was dried over sodium sulfate, filtered, and solvent removed to give 
a dark brown oil. The oil was subjected to flash chromatography on silica 
gel using 75% ethyl acetate-25% hexanes and 100% ethyl acetate for 
elution. Fractions of similar purity were combined and solvent removed. A 
dark brown oil was obtained and dried in vacuo at 80.degree. C. to give 
5.90 g (59.2% yield) of title compound as a yellowish-brown gum. 
H.sup.1 NMR (CDCl.sub.3 : .delta.6.8-7.8 (m, 11, aromatics) 4.1 (s, 3, 
--OCH.sub.3), 4.2 (m, 2, --OCH.sub.2), 2.6 (s, 3, 
##STR23## 
1.1-2.8 (m, 15, aliphatics). 
Analysis: Calculated for C.sub.32 H.sub.34 F.sub.2 N.sub.2 
O.sub.3.0.5H.sub.2 O: C, 70.96; H, 6.51; N, 5.17. Found: C, 71.58; H, 
6.49; N, 5.12. 
EXAMPLE 163 
1-[4-[3-[4-[Bis(3,4-difluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxy 
phenyl]ethanone 
A mixture of the free base of 4-[bis(4-fluorophenyl)methyl]piperidine 
hydrochloride [1:1] (6.46 g, 0.02 mole), 
1-[4-(3-chloropropoxy-3-methoxyphenyl]ethanone (4.84 g, 0.02 mole), and 
potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 
1-butanol (350 ml (containing potassium iodide (0.2 g). The mixture was 
cooled to room temperature and then concentrated to dryness. The residue 
obtained was partitioned between chloroform and 5% sodium hydroxide 
solution. The chloroform layer was dried over sodium sulfate, filtered, 
and solvent removed in vacuo to give a yellow residue (11.17 g). The oil 
was subjected to flash chromatography on silica gel using ethyl acetate, 
5% methanol-ethyl acetate and 10% methanolethyl acetate for elution. 
Fractions of similar purity were combined and solvent removed. A thick 
viscous oil was obtained and dried in vacuo overnight at 80.degree. C. 
This procedure furnished 6.74 g (63.4%) of the title compound as a viscous 
oil. 
H.sup.1 NMR CDCl.sub.3 : .delta.6.8-7.6 (m, 9, aromatics), 4.1-4.3 (t, 2, 
--O--CH.sub.2), 3.9 (s, 3, --OCH.sub.3), 2.5 (s, 3, 
##STR24## 
1.2-3.6 (m, 14, remaining aliphatics). 
Analysis: Calculated for C.sub.30 H.sub.31 F.sub.4 NO.sub.3 : C, 68.05; H, 
5.90; N, 2.64. Found: C, 67.49; H, 6.06; N, 2.56. 
EXAMPLE 164 
[[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl]a 
mino]-oxoacetic acid ethyl ester 
To a solution of 4.5 g (0.01 mole) of the base of 
1-[3-(4-aminophenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperid 
inemethanol (free base obtained in Preparation 133), and 1.5 g (0.015 mole) 
of triethylamine in 50 ml of benzene is added dropwise a solution of 1.4 g 
(0.01 mole) of ethyloxolyl chloride in 10 ml of benzene. The mixture is 
stirred at ambient temperature for 3 hr and then treated with 50 ml of 
water. The layers are separated and the organic layer is washed with 
brine, dried over sodium sulfate, and concentrated to give the title 
compound. 
EXAMPLE 165 
[[4-[3-[4-(Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl]a 
mino]-oxoacetic acid 
A solution of 
[[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl] 
amino]oxoacetic acid ethyl ester in 50 ml of ethanol is treated with 20 ml 
of a 2N sodium bicarbonate solution and the mixture is heated at reflux 
overnight. The mixture is cooled and poured into 500 ml of water 
containing 10 ml of acetic acid. The resulting solution is collected by 
filtration and dried to give the title compound. 
EXAMPLE 166 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-[4-(dimethylamino)phenoxy]propyl]- 
4-piperidinemethanol 
A solution of 4.8 g (0.01 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-[3-(4-nitrophenoxy)propyl-4-piperidi 
nemethanol (obtained in Example 52) and 2.0 g (0.025 mole) of 37% formalin 
in 100 ml of absolute ethyl alcohol is hydrogenated at ambient temperature 
over 5% palladium on carbon catalyst overnight. The mixture is filtered 
through Celite.RTM. and the filtrate is concentrated to give the title 
compound. 
EXAMPLE 167 
1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl] 
-2,2-dimethyl-1-propanone 
A mixture of 3.0 g (0.01 mole) of 
.alpha.,.alpha.-bis(p-fluorophenyl)-4-piperidinemethanole, 2.5 g (0.01 
mole) of [4-(3-chloropropoxy)phenyl][tertiarybutyl]ketone, b 3.7 g )0.035 
mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 
ml of 1-butanol is heated at reflux overnight. The mixture is concentrated 
and the residue is partitioned between benzene and water. The organic 
layer is dried over sodium sulfate and concentrated to give the desired 
title compound. 
EXAMPLE 168 
1-[4-[3-[4-[Bis(2,4-Difluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxy 
phenyl]ethanone oxalate [1:1] 
A mixture of the free base of 4-[bis(2,4-difluorophenyl)methyl]piperidine 
hydrochloride [1:1 (7.30 g, 0.023 mole), 
1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.57 g, 0.023 mole), and 
potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 
350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction 
mixture was filtered and then concentrated to dryness. The residue was 
dissolved in chloroform, and the solution was extracted with 5% sodium 
hydroxide. The chloroform layer was dried over sodium sulfate and 
filtered. The removal of chloroform provided a dark brown oil 
(quantitative). This material was converted to the oxalate salt in 
methanol-ethyl ether. A white solid was isolated and dried in vacuo 
overnight at 80.degree. C. This procedure furnished 8.23 g (57.7%) of 
white, crystalline product, mp 151.degree.-153.degree. C. 
Analysis: Calculated for C.sub.32 H.sub.33 F.sub.4 NO.sub.7 : C, 62.03; H, 
5.37; N, 2.26. Found: C, 62.10; H, 5.37; N, 2.33. 
EXAMPLE 169 
[[4-[3-[4-Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl]am 
ino]oxoacetic acid ethyl ester fumarate [1:0.5] 
To a solution of 2.4 g (0.0054 mole) of the free base of 
1-[3-(4-aminophenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperid 
inemethanol oxalate [1:2] and 1.5 g (0.015 mole) of triethylamine in 50 ml 
of benzene was added dropwise a solution of 1.0 g (0.008 mole) of ethyl 
oxalyl chloride in 10 ml of benzene, and the mixture was stirred at 
ambient temperature overnight. The mixture was treated with 20 ml of water 
and vigorously stirred. The layers were separated, and the organic layer 
was washed with a saturated sodium bicarbonate solution, dried over sodium 
sulfate and concentrated to give a gum as residue. The gum was dissolved 
in ethyl ether and filtered to remove insolubles. The filtrate was 
concentrated, and the gummy residue was converted to the fumaric acid 
salt. The salt was recrystallized from absolute ethanol-water to yield 1.1 
g (33%) of the title compound as a white solid, mp 215.degree.-216.degree. 
C. (dec.). 
Analysis: Calculated for C.sub.33 H.sub.36 F.sub.2 N.sub.2 O.sub.7 : C, 
64.91; H, 5.94; N, 4.59. Found: C, 64.62; H, 5.90; N, 4.59. 
EXAMPLE 170 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-(2-methoxy-4-methylphenoxy)propyl] 
-4-piperidinemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 4.5 g (0.015 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 3.2 g (0.015 
mole) of 1-chloro-3-(2-methoxy-4-methylphenoxy)propane, 5.3 g (0.05 mole) 
of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave 5.4 g (75%) of the title compound as a white solid, mp 
121.degree.-122.degree. C. (2-propanol). 
Analysis: Calculated for C.sub.29 H.sub.33 F.sub.2 NO.sub.3 : C, 72.33; H, 
6.91; N, 2.91. Found: C, 72.34; H, 6.95; N, 2.90. 
EXAMPLE 171 
1-[2-[3-[4-Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl]e 
thanone 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.1 g (0.01 
mole) of 2'-(3-chloropropoxy)acetophenone, 3.7 g (0.035 mole) of anhydrous 
sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 
3.4 g (71%) of the title compound as a white solid, mp 
113.degree.-114.degree. C. Analysis: Calculated for C.sub.29 H.sub.31 
F.sub.2 NO.sub.3 : C, 72.63; H, 6.52; N, 2.92. Found: C, 72.54; H, 6.56; 
N, 2.92. 
EXAMPLE 172 
1-[3-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl] 
ethanone oxalate hydrate [1:1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.1 g )0.01 
mole) of 3'-(3-chloropropoxy)acetophenone, 13.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave a gum as residue. The gum was converted to the oxalic acid 
salt and the solid was recrystallized from 2-propanol to yield 4.4 g (75%) 
of the title compound as a tan solid, mp 95.degree.-100.degree. C. 
Analysis: Calculated for C.sub.31 H.sub.33 NO.sub.7.H.sub.2 O: C, 63.36; H, 
6.00; N, 2.38. Found: C, 62.94; H, 6.02; N, 2.20. 
EXAMPLE 173 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-(3-methoxyphenoxy)propyl]-4-piperi 
dinemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.0 g (0.01 
mole) of 1-chloro-3-(3-methoxyphenyoxy)propane, 3.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassuim iodide in 100 ml of 
1-butanol gave 3.1 g (66%) of the title compound as a white solid, mp 
107.degree.-108.degree. C. (2-propanol). 
Analysis: Calculated for C.sub.28 H.sub.31 F.sub.2 NO.sub.3 : C, 71.93; H, 
6.68; N, 3.00. Found: C, 71.90; H, 6.70; N, 3.01. 
EXAMPLE 174 
1-[3-(4-Ethylphenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperidi 
nemethanol oxalate [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.0 g (0.01 
mole) of 1-chloro-3-(4-ethylphenoxy)propane, 3.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave a solid as residue. This solid was converted to the oxalic 
acid salt and the salt was recrystallized from 2-propanol to yield 3.0 g 
(54%) of the title compound as a white solid, mp 132.degree.-135.degree. 
C. 
Analysis: Calculated for C.sub.31 H.sub.35 F.sub.2 NO.sub.6 : C, 67.01; H, 
6.35; N, 2.52. Found: C, 66.60; H, 6.32; N, 2.51. 
EXAMPLE 175 
1-[3-(4-Ethoxyphenoxy)propyl]-.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperid 
inemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.1 g (0.01 
mole) of 1-chloro-3-(2-ethoxyphenoxy)propane, 3.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave 3.6 g (75%) of the title compound as an off-white solid, mp 
89.degree.-91.degree. C. (petroleum ether, 60.degree.-110.degree. C.). 
Analysis: Calculated for C.sub.29 H.sub.33 F.sub.2 NO.sub.3 : C, 72.33; H, 
6.91; N, 2.91. Found: C, 72.39; H, 6.90; N, 2.96. 
EXAMPLE 176 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-(2-methylphenoxy)propyl]-4-piperid 
inemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 1.8 g (0.01 
mole) of 1-chloro-3-(2-methylphenoxy)prpane, 3.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave 2.5 g (56%) of the title compound as a white solid, mp 
108.5.degree.-109.degree. C. (petroleum ether, 60.degree.-110.degree. C.). 
Analysis: Calculated for C.sub.28 H.sub.31 F.sub.2 NO.sub.2 : C, 74.48; H, 
6.92; N, 3.10. Found: C, 74.57; H, 6.92; N, 3.11. 
EXAMPLE 177 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-(3-methylphenoxy)propyl]-4-piperid 
inemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4 -fluorophenyl)]-4-piperidinemethanol, 1.8 g (0.01 
mole) of 1-chloro-3-(3-methylphenoxy)propane, 3.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave 2.8 g (62%) of the title compound as a white solid, mp 
112.5.degree.-114.degree. C. (2-propanol). 
Analysis: Calculated for C.sub.28 H.sub.31 F.sub.2 NO.sub.2 : C, 74.48; H, 
6.92; N, 3.10. Found: C, 74.44; H, 6.95; N, 3.15. 
EXAMPLE 178 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-(2-phenylmethoxy)phenoxy]propyl]-4 
-piperidinemethanol fumarate [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 7.6 g (0.025 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 6.9 g (0.025 
mole) of 1-chloro-3-(2-benzyloxyphenoxy)propane, 8.5 g (0.08 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 ml of 
1-butanol gave a gum as residue. The gum was converted to the fumaric acid 
salt and the solid was recrystallized from acetonitrile to yield 10.5 g 
(64%) of the title compound as an off-white solid, mp 
172.degree.-174.degree. C. 
Analysis: Calculated for C.sub.38 H.sub.39 F.sub.2 NO.sub.7 : C, 69.18; H, 
5.96; N, 2.12. Found: C 69.15; H, 5.92; N, 2.19. 
EXAMPLE 179 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-(2-hydroxyphenoxy)propyl]-4-piperi 
dinemethanole fumarate [1:1] with ethyl acetate [1:1] 
A solution of 6.1 g (0.011 mole) of 
.alpha.,.alpha.-bis(4-fluorophenyl)-1-[3-[2-(phenylmethoxy)phenoxy]propyl] 
-4-piperidinemethanol dissolved in 200 ml of absolute ethanol was 
hydrogenated in a Parr apparatus over 5% palladium on carbon catalyst at 
60.degree. C. overnight. The cooled mixture was filtered through 
Celite.RTM. and the filtrate was concentrated to give a gum as residue. 
The dark gum was dissolved in ethyl ether and filtered to remove 
insolubles. The filtrate was concentrated to give 2.8 g of tan gum as 
residue. The gum was dissolved in ethyl acetate and mixed with an 
equivalent amount of fumaric acid dissolved in ethyl acetate. The solution 
was filtered and a solid crystallized from the filtrate. The solid was 
collected by filtration and dried to yield 2.3 g (32%) of the title 
compound as a white solid, mp 106.degree.-116.degree. C. (dec). The 
presence of 1 mole of ethyl acetate was confirmed by .sup.1 H NMR. 
Analysis: Calculated for C.sub.31 H.sub.33 F.sub.2 NO.sub.7. C.sub.4 
H.sub.8 O: C, 63.92; H, 6.28; N, 2.13. Found: C, 63.62; H, 6.08; N, 2.24. 
EXAMPLE 180 
.alpha.,.alpha.-Bis(4-fluorophenyl)-1-[3-[2-(1-methylethoxy)phenoxy)propyl] 
-4-piperidinemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.3 g (0.01 
mole) of 1-chloro-3-[2-(1-methylethoxy)phenoxy]propane, 3.7 g (0.035 mole) 
of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave 2.9 g (58%) of the title compound as a fluffy, white solid, 
mp 75.degree.-79.degree. C. (2-propyl ether). 
Analysis: Calculated for C.sub.30 H.sub.35 F.sub.2 NO.sub.3 : C, 72.70; H, 
7.12; N, 2.83. Found: C, 72.65; H, 7.47; N, 2.69,. 
EXAMPLE 181 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzeneace 
tic acid ethyl ester oxalate [1:1] with ethyl acetate [1:0.5] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 7.6 g (0.025 mole) of 
[.alpha.,.alpha.bis(4-fluorophenyl)]-4-piperidinemethanol, 6.1 g (0.025 
mole) of 4-(3-chloropropoxy)benzeneacetic acid methyl ester, 9.5 g (0.09 
mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 
ml of dimethylformamide gave a gum as residue. The gum was purified by 
column chromatography on 250 g of Florsil.RTM.. Fractions eluted with 
5-25% acetone in benzene were combined and concentrated to give a gum as 
residue. The gum was converted to the oxalic acid salt and the solid was 
recrystallized from ethyl acetate to yield 7.0 g (43%) of the title 
compound as a white compound as a white solid, mp 93.degree.-98.degree. C. 
(dec). 
Analysis: Calc'd for C.sub.32 H.sub.35 F.sub.2 NO.sub.8 0.5C.sub.4 H.sub.8 
O: C, 63.44; H, 6.10; N, 2.18. Found: C, 63.00; H, 5.99; N, 2.23. 
EXAMPLE 182 
4-[3-[4-Bis(4-fluorophenyl(hydroxymethyl]-1-piperidinyl]propoxy]N,N-dimethy 
lbenzamide fumarate[1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 
mole) of 4-(3-chloropropoxy)-N,N-dimethylbenzamide, 3.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave a gum as residue. The gum was converted to the fumaric acid 
salt and the solid was recrystallized from acetonitrile-water to yield 4.0 
g (65% of the title compound as a white solid, mp 166.degree.-168.degree. 
C. 
Analysis: Calculated for C.sub.34 H.sub.38 F.sub.2 N.sub.2 O.sub.7 : C, 
65.37; H, 6.13; N, 4.48. Found: C, 65.21; H, 6.12; N, 4.45. 
EXAMPLE 183 
1-3-(2,6-Dimethoxyphenoxy)propyl].alpha.,.alpha.-bis(4-fluorophenyl)-4-pipe 
ridinemethanol 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl-4-piperidinemethanol, 2.3 g (0.01 
mole) of 1-(3-chloropropoxy)-2,6-dimethoxybenzene, 3.7 g (0.035 mole) of 
anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 
1-butanol gave 2.0 g (40%) of the title compound as a white solid, mp 
136.degree.-137.degree. C. (2-propyl ether/2-propanol). 
Analysis: Calculated for C.sub.29 H.sub.33 F.sub.2 NO.sub.4 : C, 70.00; H, 
6.68; N, 2.81. Found: C, 70.15; H, 6.78; N, 2.85. 
EXAMPLE 184 
[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl]ph 
enylmethanone fumarate [1:1]. 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha..alpha.-bis(4-fluorophenyl)]-4-piperidinemethanol, 3.7 g (0.035 
mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 
ml of 1-butanol gave a gum as residue. The gum was converted to the 
fumaric acid salt and the solid was recrystallized from absolute ethanol 
to yield 4.3 g (65%) of the title compound as a tan solid, mp 
200.degree.-201.degree. C. (dec). 
Analysis: Calculated for C.sub.38 H.sub.37 F.sub.2 NO.sub.7 : C, 69.39; H, 
5.67; N, 2.13. Found: C, 69.36; H, 5.63; N, 2.17. 
EXAMPLE 185 
1-[4-[3-[4-[Bis(3,4-difluorophenyl)hydroxymethyl]1-piperidinyl]-propoxy]-3- 
methoxyphenyl]ethanone 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 1.4 g (0.004 mole) of 
.alpha.,.alpha.-bis(3,4-difluorophenyl)-4-piperidinemethanol, 1.0 g (0.004 
mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 1.6 g (0.015 
mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 
ml of 1-butanol gave 1.1 g (48%) of the title compound as an off-white 
solid, mp 143.degree.-146.degree. C. (2-propanol). 
Analysis: Calculated for C.sub.30 H.sub.31 F.sub.4 NO.sub.4 : C, 66.05; H, 
5.73; N, 2.57. Found: C, 66.03; H, 5.89; N, 2.50. 
EXAMPLE 186 
4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzeneace 
tic acid hydrate [1:0.5] 
A mixture of 3.7 g (0.0073 mole) of the free base of 
4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzeneac 
etic acid ethyl ester oxalate [1:1], 0.8 g (0.0145 mole) of potassium 
hydroxide, 10 ml of water and 50 ml of 95% ethanol was heated at reflux 
under a nitrogen atmosphere for 1.5 hr. The solution was poured into a 
mixture of 1.3 g (0.022 mole) of glacial acetic acid in 500 ml of ice 
water and let stand at ambient temperature overnight. The solid which had 
precipitated was collected by filtration, washed with water, air dried, 
and recrystallized from 2-propanol to yield 2.9 g (78%) of the title 
compound as a white solid, mp 113.degree.-121.degree. C. (dec). 
Analysis: Calculated for C.sub.29 H.sub.31 F.sub.2 NO.sub.4.0.5H.sub.2 O: 
C, 69.03; H, 6.39; N, 2.78. Found: C, 69.35; H, 6.43; N, 2.74. 
EXAMPLE 187 
1-[4-[3-[3-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-meth 
oxyphenyl]ethanone 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 
[.alpha.,.alpha.-bis(4-fluorophenyl)]-3-piperidinemethanol, 2.4 g (0.01 
mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 
mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 
ml of 1-butanol gave 4.0 g (78%) of the title compound as an off-white 
solid, mp 100.degree.-105.degree. C. (2-propanol). 
Analysis: Calculated for C.sub.30 H.sub.33 F.sub.2 NO.sub.4 : C, 70.71; H, 
6.53; N, 2.75. Found: C, 70.62; H, 6.61; N, 2.77. 
EXAMPLE 188 
1-[4-[3-[3-[2,2-Bis(4-fluorophenyl)-2-hydroxyethyl]-1-piperidinyl]propoxy]- 
3-methoxyphenyl ethanone fumarate [1:1] 
This compound was prepared according to the procedure used to synthesize 
the compound of Example 1. A mixture of 3.7 g (0.012 mole) of the base of 
[.alpha.,.alpha.-bis(4-fluoropheny]-3-piperidineethanol hydrochloride 
[1:1], 2.8 g free (0.012 mole) of 
1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 4.3 g (0.04 mole) of 
anhydrous sodium carbonate and 0.5 g of potassium iodide in 100 ml of 
1-butanol gave a gum as residue. The gum was purified by column 
chromatography on 120 g of Florisil.RTM.. Fractions eluted with 20-60% 
acetone in benzene were combined and concentrated to give a gum. This gum 
was converted to the fumaric acid salt and the solid was recrystallized 
from ethyl acetate-acetonitrile to yield 2.6 g (35%) of the title compound 
as a white solid, mp 133.degree.-136.degree. C. 
Analysis: Calculated for C.sub.35 H.sub.39 F.sub.2 NO.sub.8 : C, 65.72; H, 
6.15; N, 2.19. Found: C, 65.41; H, 6.15; N, 2.18. 
3 TABLE 1 
##STR25## 
Ex. Ring No. P Ar R (A)d (Q)n Position m D Salt 
1 1 C.sub.6 H.sub.5 C.sub.6 H.sub.5 -- -- 4 3 C.sub.6 H.sub.5 oxalate 2 
1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 C.sub.6 H.sub.5 
oxalate 0.5 H.sub.2 O 3 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 -- -- 4 
3 C.sub.6 H.sub.5 oxalate 4 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH 
-- 4 3 C.sub.6 H.sub.5 oxalate 5 1 C.sub. 6 H.sub.5 C.sub.6 H.sub.5 H -- 
4 4 C.sub.6 H.sub.5 fumarate 6 1 C.sub.6 H.sub.5 C.sub.6 H.sub.5 H -- 4 
4 C.sub.6 H.sub.5 fumarate 7 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H 
-- 4 3 C.sub.6 H.sub.5 oxalate 8 1 C.sub.6 H.sub.5 C.sub.6 H.sub.5 H -- 
4 2 C.sub.6 H.sub.5 fumarate 9 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H 
-- 4 2 C.sub.6 H.sub.5 oxalate 10 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 4 C.sub.6 H.sub.5 oxalate 11 1 4-FC.sub.6 H.sub.4 C.sub.6 
H.sub.5 H -- 4 3 C.sub.6 H.sub.5 fumarate 12 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 H -- 4 2 2,6-Cl.sub.2C.sub.6 
H.sub.3 -- 13 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 
4-ClC.sub.6 H.sub.4 -- 14 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 
3 2-FC.sub.6 H.sub.4 oxalate 15 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 
H -- 4 3 3-FC.sub.6 H.sub.4 mandelate 16 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 4-ClC.sub.6 H.sub.4 fumarate 17 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 H -- 4 3 4-FC.sub.6 H.sub.4 -- 18 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 4-OCH.sub.3C.sub.6 H.sub.4 fumarate 
19 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 2-OCH.sub.3C.sub.6 
H.sub.4 -- 20 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 2-OCH.sub. 3C.sub.6 H.sub.4 -- 21 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 -- -- 4 3 2-OCH.sub.3C.sub.6 H.sub.4 oxalate 
22 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 C 
H.sub.4 H -- 4 3 3,4-(OCH.sub.3).sub.2.sub.6 H.sub.3 oxalate 23 1 
4-CH.sub.3C.sub.6 H.sub.4 4-CH.sub.3C.sub.6 
H.sub.4 H -- 4 3 2,6-(OCH.sub.3).sub.2C.sub.6 H.sub.3 fumarate 24 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 -- -- 4 3 3,4-(OCH.sub.3).sub.2C.sub.6 
H.sub.3 -- 25 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 3 2,6-(OCH.sub.3).sub.2C.sub.6 H.sub.3 oxalate, H.sub.2 
O 26 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 3 3,5-(OCH.sub.3).sub.2C.sub.6 
H.sub.3 -- 27 1 4-OCH.sub.3C.sub.6 H.sub.4 4-OCH.sub.3C.sub. 6 H.sub.4 
H -- 4 3 3,4-(OCH.sub.3).sub.2C.sub.6 H.sub.3 -- 28 1 4-OCH.sub.3C.sub.6 
H.sub.4 4-OCH.sub.3C.sub.6 H.sub.4 H -- 4 3 4-OCH.sub.3C.sub.6 H.sub.4 
fumarate, 0.5 H.sub.2 O 29 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 -- -- 
4 3 4-C(O)CH.sub.3C.sub.6 H.sub.4 oxalate 30 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 H -- 4 3 4-C(O)CH.sub.3C.sub.6 H.sub.4 oxalate 31 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-C(O)CH.sub.3C.sub.6 
H.sub.4 2-propanolate 32 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 
3 2-CH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 33 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH -- 4 3 4-CNC.sub.6 H.sub.4 -- 34 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 4-CNC.sub.6 H.sub.4 fumarate 35 1 C 
4-F.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-C(O)OC.sub.2 
H.sub.5C.sub.6 H.sub.4 HCl 36 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 
OH -- 4 3 4-C(O)OHC.sub.6 H.sub.4 HCl, 0.5 H.sub.2 O 37 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 -- -- 4 3 4-C(O)OC.sub.2 H.sub.5C.sub.6 
H.sub.4 HBr 38 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 3 4-C(O)OC.sub.2 H.sub.5C.sub.6 H.sub.4 HBr 39 1 
4-OCH.sub.3C.sub.6 H.sub.4 4-OCH.sub.3C.sub.6 
H.sub.4 H -- 4 3 4-C(O)OC.sub.4 H.sub.9C.sub.6 
H.sub.4 -- 40 1 4-OCH.sub.3C.sub.6 H.sub.4 4-OCH.sub.3C.sub.6 H.sub.4 H 
-- 4 3 4-C(O)OC.sub.2 H.sub.5C.sub.6 H.sub.4 fumarate, 0.5 H.sub.2 O 41 
1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 2 4-C(O)OC.sub.2 
H.sub.5C.sub.6 H.sub.4 HCl 42 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH 
-- 4 3 2-OCH.sub.34-CH.sub.2C(O)OC.sub.2 H.sub.5C.sub.6 H.sub.4 HCl 43 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 -- -- 4 3 4-t-butyl-C.sub.6 
H.sub.4 fumarate 44 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 
4-t-butyl-C.sub.6 H.sub.4 fumarate, 0.5 H.sub.2 
O 45 1 4-OCH.sub.3C.sub.6 H.sub.4 4-OCH.sub.3C.sub.6 H.sub.4 H -- 4 3 
4-t-butyl-C.sub.6 H.sub.4 oxalate 46 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 4-t-butyl-C.sub.6 H.sub.4 -- 47 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 H -- 4 3 3-CF.sub.3C.sub.6 H.sub.4 oxalate 48 1 
4-CH.sub.3C.sub.6 H.sub.4 4-CH.sub.3C.sub.6 
H.sub.4 H -- 4 3 4-NHC(O)CH.sub.3C.sub.6 H.sub.4 fumarate, 0.5 H.sub.2 
O 49 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 3 4-NHC(O)CH.sub.3C.sub.6 H.sub.4 HBr 50 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 4-NH.sub.2C.sub.6 H.sub.4 fumarate, 
0.5 H.sub.2 O 51 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 
4-NHC(O)CH.sub.3C.sub.6 H.sub.4 HCl, H.sub.2 O 52 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH -- 4 3 4-NO.sub.2C.sub.6 
H.sub.4 -- 53 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 
4-C(O)NH.sub.2C.sub.6 H.sub.4 -- 54 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 2 1-C.sub.10 H.sub.7 HCl 55 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 H -- 4 2 1-C.sub.10 H.sub.7 oxalate 56 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 2-OCH.sub.34C(O)CH.sub.3C.sub.6 
H.sub.3 oxalate 57 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 
2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 1.2 fumarate 58 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 
H.sub.4 -- -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6.sub.H.sub.3 oxalate 
59 1 4-FC.sub.6 H.sub.4 C.sub.6 
H.sub.5 -- -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate 60 1 
3-CF.sub.3C.sub.6 H.sub.4 C.sub.6 
H.sub.5 -- -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate 61 1 
C.sub.6 H.sub.5 C.sub.6 
H.sub.11 -- -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate 62 
1 C.sub.6 H.sub.5 C.sub.6 
H.sub.11 H -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate, 0.5 
H.sub.2 O 63 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 -- -- 4 3 4-CHOHCH.sub.3C.sub.6 H.sub.4 oxalate 64 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 2-OCH.sub.34-CHOHCH.sub.3-C.sub.6 
H.sub.3 -- 65 1 C.sub.6 H.sub.5 C.sub.6 
H.sub.5 H -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate 66 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 C 
H.sub.4 OH -- 4 3 2-OCH.sub.34-C(O)CH.sub.3.sub.6 H.sub.3 -- 67 1 
4-FC.sub.6 H.sub.4 C.sub.6 
H.sub.5 OH -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 68 1 
C.sub.6 H.sub.5 C.sub.6 
H.sub.5 OH -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub. 6 H.sub.3 oxalate 69 
1 3-CF.sub.3C.sub.6 H.sub.4 C.sub.6 
H.sub.5 OH -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 HCl, 0.5 
H.sub.2 O 70 1 C.sub.6 H.sub.5 C.sub.6 
H.sub.11 OH -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 HCl 71 1 C 
4-F.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 2 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 72 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 C 
H.sub.4 OH -- 4 4 2-OCH.sub.34-C(O)CH.sub.3.sub.6 H.sub.3 -- 73 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 C 
H.sub.4 OH -- 4 5 2-OCH.sub.34-C(O)CH.sub.3.sub.6 H.sub.3 -- 74 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 2 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 75 1 
4-ClC.sub.6 H.sub.4 4-ClC.sub.6 
H.sub.4 -- -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 76 1 
4-FC.sub.6 H.sub.4 C.sub.6 
H.sub.5 H -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate 77 1 
4-OCH.sub.3C.sub.6 H.sub.4 4-OCH.sub.3C.sub.6 
H.sub.4 H -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate 78 1 
4-CH.sub.3C.sub.6 H.sub.4 4-CH.sub.3C.sub.6 
H.sub.4 H -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 79 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 4 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 80 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 2-OCH.sub.34-C(O)OCH.sub.3C.sub.6 H.sub.3 -- 81 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-SCH.sub.3C.sub.6 
H.sub.4 -- 82 1 4-F C.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 
4-S(O).sub.2 CH.sub.3C.sub.6 H.sub.4 fumarate 83 1 4-FC.sub.6 H.sub.4 C 
4-F.sub.6 H.sub.4 OH -- 4 3 2-OCH.sub.34-CH.sub.2C(O)OC.sub.2 
H.sub.5C.sub.6 H.sub.3 HCl 84 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 
OH -- 4 2 4-C(O)OC.sub.2 H.sub.5C.sub.6 H.sub.4 HCl 85 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 2-OCH.sub.34-CH.sub.2 
C(O)ONaC.sub.6 H.sub.3 0.5 H.sub.2 O 86 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 
##STR26## 
87 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 2-C(O)OC.sub.2 
H.sub.5C.sub.6 H.sub.4 0.75 fumarate 88 1 4-FC.sub.6 H.sub.4 4-F C.sub.6 
H.sub.4 H -- 4 3 2-C(O)OC.sub.2 H.sub.5C.sub.6 
H.sub.4 -- 89 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 5 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 0.5 H.sub.2 O 
90 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 3 4-C(O)NH.sub.2C.sub.6 H.sub.4 1.5 fumarate 91 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 4-S(O).sub.2 
CH.sub.3C.sub.6 H.sub.4 oxalate 92 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 6 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 93 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 C 
H.sub.4 OH -- 4 3 3-OCH.sub.34-C(O)CH.sub.3.sub.6 H.sub.3 -- 94 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 2-OHC.sub.6 H.sub.4 -- 
95 1 4-F C.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 4-S(O)CH.sub.3C.sub.6 
H.sub.4 fumarate 96 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 
4-S(O).sub.2 NH.sub.2C.sub.6 H.sub.4 HCl 97 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH -- 4 3 4-NHS(O).sub.2 CH.sub.3 -- 98 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-NHC(O)NHCH.sub.3C.sub.6 H.sub.4 
-- 99 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-NHC(O)OC.sub.2 
H.sub.5C.sub.6 H.sub.4 -- 100 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH 
-- 4 3 3-NHC(O)NH.sub.2C.sub.6 H.sub.4 -- 101 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH -- 4 3 2-OCH.sub.34-C(O)OHC.sub.6 H.sub.3 sodium 
102 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 C 
H.sub.4 OH -- 4 3 3-OH4-C(O)CH.sub.3.sub.6 H.sub.4 -- 103 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 
##STR27## 
HCl 104 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 
##STR28## 
HCl 105 1 C.sub.6 H.sub.5 C.sub.6 
H.sub.5 -- -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate, 0.5 
H.sub.2 O 106 1 C.sub.6 H.sub.5 C.sub.6 H.sub.11 H -- 
4* 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate, 0.5 H.sub.2 O 
107 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 3-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 HCl 108 1 C 
4-F.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 2,6-Cl.sub.2C.sub.6 
H.sub.3 -- 109 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 3 2,6-Cl.sub.2C.sub.6 H.sub.3 oxalate 110 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 2-CNC.sub.6 H.sub.4 -- 111 1 
4-FC.sub.6 
H.sub.4 2-pyridinyl CN -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 
fumarate 112 1 4-FC.sub.6 
H.sub.4 2-pyridinyl CN -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 
fumarate, H.sub.2 O 113 1 C.sub.6 H.sub.5 C.sub.6 H.sub.5 CN CH.sub.2 3 
3 quinolin-8-yl 0.5 H.sub.2 O 114 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 3 quinolin-8-yl 0.5 H.sub.2 O 115 1 4-FC.sub.6 H.sub.4 C 
4-F.sub.6 H.sub.4 H -- 4 3 quinolin-2-yl 0.5 H.sub.2 O 116 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 napthal-2-yl 0.5 H.sub.2 O 117 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 3-CNC.sub.6 H.sub.4 0.5 
H.sub.2 O 118 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 4-OCH.sub.3C.sub.6 H.sub.4 -- 119 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-CH.sub.3C.sub.6 H.sub.4 fumarate 
120 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-FC.sub.6 H.sub.4 
fumarate, H.sub.2 O 121 1 4-FC.sub.6 H.sub.4 2-pyridinyl H -- 4 3 
2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 122 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH -- 4 3 4-NHC(O)OC.sub.2 H.sub.5C.sub.6 H.sub.4 
oxalate, 1.5 H.sub.2 O 123 0 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 CN 
CH.sub.2 3 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 
H.sub.3 -- 124 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 -- -- 4 3 
2-OHC.sub.6 H.sub.4 -- 125 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 
4 3 2-OCH.sub.34-C.sub.2 H.sub.5C.sub.6 H.sub.3 -- 126 1 C.sub.6 H.sub.5 
C.sub.6 H.sub.5 OH -- 4 3 C.sub.6 H.sub.5 -- 127 1 4-FC.sub.6 H.sub.4 C 
4-F.sub.6 H.sub.4 OH -- 4 3 4-S(O)CH.sub.3C.sub.6 H.sub.4 oxalate, 1.5 
H.sub.2 O, 0.5 2-propanolate 128 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 
OH -- 4 3 4-CH(CH.sub.3).sub.2C.sub.6 H.sub.4 oxalate 129 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 3-C(O)OC.sub. 2 H.sub.5C.sub.6 
H.sub.4 fumarate 130 1 4-CH.sub.3C.sub.6 H.sub.4 4-CH.sub.3C.sub.6 
H.sub.4 -- -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 131 1 
4-CH.sub.3C.sub.6 H.sub.4 4-CH.sub.3C.sub.6 4 
H.sub.4 OH -- 4 3 2-OCH.sub.3-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate, 
H.sub.2 O 132 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 4-C(O)OCH.sub.3C.sub.6 H.sub.4 fumarate 133 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-NH.sub.2C.sub.6H.sub.4 
2.0 oxalate 134 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 
3-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate 135 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 2-OCH.sub.34-C.sub.2 H.sub.5C.sub.6 
H.sub.3 oxalate 136 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 
##STR29## 
-- 137 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 4-NHC(O)NHCH.sub.3C.sub.6 H.sub.4 -- 138 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-NHS(O).sub.2 CH.sub.3C.sub.6 
H.sub.4 0.5 fumarate, 2-methoxy-ethanolate 139 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH -- 4 3 4-C(O)C.sub.2 H.sub.5C.sub.6 H.sub.4 
2-propanolate 140 1 4-OCH.sub.3C.sub.6 H.sub.4 4-OCH.sub.3C.sub.6 
H.sub.4 OH -- 4 3 2-OCH.sub.34-C(O)CH.sub.3 C.sub.6 H.sub.3 oxalate 141 
1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 6 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 HCl 142 1 C 
4-F.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 2-OCH.sub.34-CH(OH)(CH.sub.3)C.sub. 6 H.sub.3 
oxalate, 1.5 H.sub.2 O 143 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 
4 4 4-C(O)OCH.sub.3C.sub.6 H.sub.4 fumarate 144 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH CH.sub.2 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 
H.sub.3 fumarate, H.sub.2 O 145 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 
H CH.sub.2 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 fumarate 146 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 C 
H.sub.4 -- CH 4 3 2-OCH.sub.34-C(O)CH.sub.3.sub.6 H.sub.3 fumarate 147 
1 4-FC.sub.6 H.sub.4 2-pyridinyl CN -- 4 3 C.sub.6 H.sub.5 1.5 oxalate 
148 1 4-ClC.sub.6 H.sub.4 4-ClC.sub.6 
H.sub.4 H -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate, 0.5 
H.sub.2 O 149 1 4-ClC.sub.6 H.sub.4 4-ClC.sub.6 H.sub.4 OH -- 4 3 
2-OCH.sub. 34-C(O)CH.sub.3C.sub.6 H.sub.3 1.5 oxalate 150 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 2-OCH.sub.34-C(O)OCH.sub.3C.sub.6 
H.sub.3 -- 151 1 3-FC.sub.6 H.sub.4 3-FC.sub.6 
H.sub.4 H -- 4 3 2-OCH.sub.34-C(O)OCH.sub.3C.sub.6 H.sub.3 fumarate 152 
1 C.sub.6 H.sub.5 C.sub.6 H.sub.5 OH -- 4 3 4-C(O)OCH.sub.3C.sub.6 
H.sub.4 -- 153 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 6 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 154 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 H -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 0.5 H.sub.2 O 
155 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 H -- 4 3 3-OCH.sub.3C.sub.6 
H.sub.4 0.5 H.sub.2 O 156 1 4-FC.sub.6 H.sub.4 C.sub.6 H.sub.11 H -- 4 3 
2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 157 1 4-FC.sub.6 H.sub.4 
2-pyridinyl H -- 4 3 C.sub.6 H.sub.5 0.5 H.sub.2 
O 158 1 3,4 F.sub.2C.sub.6 H.sub.3 4-FC.sub.6 
H.sub.4 H -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate 159 0 
4-FC.sub.6 H.sub.4 4-FC.sub.6 C 
H.sub.4 OH -- 3 3 2-OCH.sub.34-C(O)CH.sub.3.sub.6 H.sub.3 -- 160 0 
4-FC.sub.6 H.sub.4 4-FC.sub.6 C 
H.sub.4 CN -- 3 3 2-OCH.sub.34-C(O)CH.sub.3.sub.6 H.sub.3 -- 161 1 
3-FC.sub.6 H.sub.4 3-FC.sub.6 C 
H.sub.4 OH -- 3 3 2-OCH.sub.34-C(O)CH.sub.3.sub.6 H.sub.3 -- 162 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 CN CH.sub.2 3 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 0.5 
H.sub.2 O 163 1 3,4-F.sub.2C.sub.6 H.sub.3 3,4-F.sub.2C.sub.6 H.sub.3 H 
-- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 -- 164 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-[NH[C(O)C(O)OC.sub.2 
H.sub.5]]C.sub.6 H.sub.4 -- 165 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 
OH -- 4 3 4-[NH[C(O)C(O)OH]]C.sub.6 H.sub.4 -- 166 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH -- 4 3 4-N(CH.sub.3).sub.2C.sub.6 H.sub.4 -- 167 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-[C(O)C(CH.sub.3).sub.3 
]C.sub.6 H.sub.4 -- 168 1 2,4-F.sub.2C.sub.6 H.sub.3 2,4-F.sub.2C.sub.6 
H.sub.3 -- -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 H.sub.3 oxalate 169 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-NH[C(O)C(O)OC.sub.2 
H.sub.5]C.sub.6 H.sub.4 0.5 fumarate 170 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 4-CH.sub.32-OCH.sub.3C.sub.6 
H.sub.3 -- 171 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 
2-C(O)CH.sub.3C.sub.6 H.sub.4 -- 172 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 3-C(O)CH.sub.3C.sub.6 H.sub.4 oxalate, H.sub.2 O 173 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 3-CH.sub.3 OC.sub.6 
H.sub.4 -- 174 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 
4-C.sub.2 H.sub.5C.sub.6 H.sub.4 oxalate 175 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH -- 4 3 2-C.sub.2 H.sub.5OC.sub.6 H.sub.4 -- 176 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 2-CH.sub.3C.sub.6 
H.sub.4 -- 177 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 
3-CH.sub.3C.sub.6 H.sub.4 -- 178 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 
OH -- 4 3 2-(C.sub.6 H.sub.5CH.sub.2O)C.sub.6 H.sub.4 fumarate 179 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 2-OHC.sub.6 H.sub.4 
fumarate, with ethyl acetate 180 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 
OH -- 4 3 2-[(CH.sub.3).sub.2 CHO]C.sub.6 H.sub.4 -- 181 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4-[CH.sub.3OC(O)CH.sub.2]C.sub.6 
H.sub.4 oxalate, with 0.5 ethyl acetate 182 1 4-FC.sub.6 H.sub.4 
4-FC.sub.6 H.sub.4 OH -- 4 3 4-[(CH.sub.3).sub.2 NC(O)]C.sub.6 H.sub.4 
fumarate 183 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 
H.sub.4 OH -- 4 3 2,6-(OCH.sub.3).sub.2C.sub.6 H.sub.3 -- 184 1 
4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 4[C.sub.6 
H.sub.5C(O)]C.sub.6 H.sub.4 fumarate 185 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 
H.sub.3 -- 186 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 
4-[CH.sub.2C(O)CH.sub.3 ]C.sub.6 H.sub.4 0.5 H.sub.2 O 187 1 4-FC.sub.6 
H.sub.4 4-FC.sub.6 H.sub.4 OH -- 4 3 2-OCH.sub.34-C(O)CH.sub.3C.sub.6 
H.sub.3 -- 188 1 4-FC.sub.6 H.sub.4 4-FC.sub.6 H.sub.4 OH CH.sub.2 4 3 
2-OCH.sub.34-C(O)CH.sub.3C.sub.6 
*1,2,3,6-tetrahydropyridine. 
PHARMACOLOGY METHODS 
Antiallergy Screening Method--Rats 
As stated above, the primary screening method used to demonstrate 
antiallergy properties of the compounds of Formula I is a modification of 
the procedure of R. R. Martel and J. Klicius, International Archives 
Allergy Appl. Immunology, Vol. 54, pp. 205-209 (1977) which measures the 
effect of oral administration of a compound on the volume of a rat paw 
which was previously injected with anti-egg albumin serum following egg 
albumin challenge. The procedure is as follows: Fed rats are injected in 
the right hind paw with 0.2 ml of rat anti-egg albumin serum at a dilution 
previously shown to produce significant edema upon antigen challenge. The 
animals are then fasted, but allowed water ad libitum. The next day the 
rats are randomized into groups of 6 by means of tables generated by the 
IBM scrambler. Random number tables are used to determine the groups 
receiving the control, reference and test articles. On the test day, the 
right foot volume of each rat is determined plethysmographically using the 
hairline as the reference point. Volume of this foot is measured with a 
mercury filled tube that is connected to a P23 A Statham.RTM. pressure 
transducer that in turn is connected to a linear Cole Parmer.RTM. recorder 
(Model No. 255). The instrument is adjusted so that a pen deflection of 50 
mm is equivalent to 1 ml volume. Separately, the reference and test 
compounds and control articles are dissolved or suspended in 0.5% Tween 80 
in distilled water. Sonification is used to facilitate dissolution or 
reduce particle size. The animals are dosed orally (10 ml/kg) at 1 hr 
prior to the intravenous injection of the antigen, 2 mg of egg albumin in 
0.2 ml of sterile saline. Thirty minutes later the right foot volume is 
measured again and edema is determined by difference. Results are 
expressed as the average foot edema (ml).+-.S.D. A significant decrease 
(p&lt;0.05) in the edema of the treated group from that of the control group 
is considered as indicative of antiallergic activity. The results are 
acceptable only if the group receiving the reference article shows a 
significant decrease in foot edema. The foot volume for each animal is 
measured twice, once prior to dosing and again 30 min following the 
intravenous administration of antigen. Data are analyzed with the 
Dunnett's t-test that compares several treated groups with a control 
group. Differences between groups are determined by the studentized Range 
Test. Regression analysis may be used to determine relative potency. 
Guinea Pig Anaphylaxis Method 
The method used to test antiallergy effectiveness of the compounds in 
guinea pigs as compared to other drugs is as follows: 
Guinea pigs are first sensitized to egg albumin (EA, Sigma Chemical Co., 
St. Louis, Mo.), at least 20 days prior to aerosol challenge by receiving 
0.5 ml of EA-AlOH.sub.3 conjugate (33 .mu.g EA/ml) intramuscularly in each 
hind leg. 
On the test day, fasted, sensitized guinea pigs are divided into a control 
group (8 animals per group) and test groups of four animals per group by 
using random number tables generated by an IBM scrambler. The reference; 
e.g., theophylline or test drug (Formula I compound) dissolved or 
suspended in 0.5% Tween 80 in distilled water or the control article (0.5% 
Tween 80 in distilled water) are administered orally in a volume of liquid 
at 10 ml/kg. Either 1, 5, or 24 hours following the oral administration of 
the test drug, reference drug, or control article, each animal is placed 
in an aerosolization chamber. EA (10 mg/ml) aerosolized at a rate of 10 
liters of air/min is delivered into the chamber for a maximum of 5 
minutes. The anaphylactic response consists of coughing, dyspena, reeling, 
collapse and death. Upon collapsing, the animals are removed from the 
chamber. Animals are considered protected if they do not collapse within 5 
min of exposure to the aerosolized antigen. The number of animals that 
collapse in each group is recorded. ED.sub.50 for collapse is calculated 
by the method of Litchfield and Wilcoxon (1949), J. PHARMACOL. EXP. 
THERAP. 95, 99-113 for evaluation of dose-effect experiments. 
Comparisons of ED.sub.50 S from different experimental trials and 
determinations of relative potency are determined by the Litchfield and 
Wilcoxon method, ibid. The following conditions must be met before an 
experiment is acceptable: 
(1) Control groups shows collapse in 7/8 or 8/8 animals, and 
(2) Theophylline reference group shows protection in 3/4 or 4/4 animals 
treated 1 hr to 5 hr prior to antigen exposure. 
Pharmaceutical Compositions and Administration 
Compositions for administration to living animals are comprised of at least 
one of the compounds of Formula I according to the antiallergy method of 
the invention in association with a pharmaceutical carrier or excipient. 
Effective quantities of the compounds may be administered in any one of 
various ways, for example, orally as in elixirs, capsules, tablets or 
coated tablets, parenterally in the form of sterile solutions, 
suspensions, and in some cases intravenously in the form of sterile 
solutions, intranasally and to the throat or bronchial region in the form 
of drops, gargles, sprays, aerosols and powders, etc. or cutaneously as 
topical ointments, solutions, powders, etc. Suitable tableting excipients 
include lactose, potato and maize starches, talc, gelatin, stearic and 
silica acids, magnesium stearate and polyvinyl pyrrolidone. 
For parenteral administration, the carrier or excipient can be comprised of 
a sterile parenterally acceptable liquid; e.g., water or arachis oil 
contained in ampoules. 
Advantageously, the compositions are formulated as dosage units, each unit 
being adapted to supply a fixed dose of active ingredients. Tablets, 
coated tablets, capsules, ampoules, sprays and suppositories are examples 
of preferred dosage forms. It is only necessary that the active ingredient 
constitute an effective amount such that a suitable effective dosage will 
be consistent with the dosage form employed, in multiples if necessary. 
The exact individual dosages, as well as daily dosages, will of course be 
determined according to standard medical principles under the direction of 
a physician or veterinarian. Generally, the pharmacology tests on guinea 
pigs in comparison to certain other antiallergy drugs suggest an effective 
dose for an adult will be in the range of 0.5 to 10 mg for the more active 
compounds with a daily dosage amounting to about 2 to 40 mg/day. 
Based on the animal data, unit dosages containing an amount of compound 
equivalent to about 0.01 to 0.1 mg of active drug per kilogram of body 
weight are contemplated. Daily dosages of about 0.05 to 0.5 mg/kg of body 
weight are contemplated for humans and obviously several small dosage 
forms may be administered at one time. However, the amount of the active 
compounds administered need not be limited by these contemplations due to 
uncertainty in transposing animal data to human treatment. 
Various modifications and equivalents will be apparent to one skilled in 
the art and may be made in the compounds, methods of treatment and 
compositions of the present invention without departing from the spirit or 
scope thereof, and it is therefore to be understood that the invention is 
to be limited only by the scope of the appended claims.