1,3,4-trisubstituted piperidine derivatives, the preparation and use thereof

Compounds of the formula ##STR1## where A-B-D, R.sup.1, R.sup.2 and R.sup.3 have the meanings stated in the description, and their preparation are described. The compounds are suitable for controlling diseases.

The present invention relates to 1,3,4-trisubstituted piperidine 
derivatives, to a process for their preparation and to their use as drugs. 
It is known that butyrophenone derivatives with basic substituents have 
neuroleptic and cerebroprotective effects (U.S. Pat. No. 4,605,655, EP 410 
114). It appears in this connection that the observed affinities for 
.sigma. receptors are particularly important. 
We have now found that 1,3,4-trisubstituted piperidine derivatives of the 
formula I 
##STR2## 
where R.sup.1 is hydrogen, fluorine, chlorine or bromine, 
R.sup.2 is hydroxyl, or phenyl which is unsubstituted or substituted by 
fluorine, chlorine or bromine, 
R.sup.3 is hydrogen, or 
R.sup.2 and R.sup.3 together are oxygen, and 
A-B-D is 
##STR3## 
where R.sup.4 is C.sub.1-3 -alkyl or is phenyl or thienyl which can be 
substituted by fluorine or chlorine, 
R.sup.5 is hydrogen or hydroxyl, 
R.sup.6 is hydrogen, 
R.sup.7 is hydroxyl, or 
R.sup.6 and R.sup.7 together are oxygen, and their salts with 
physiologically tolerated acids have valuable pharmacological properties. 
R.sup.1 to R.sup.7 and n in the formula I preferably have the following 
meanings: 
R.sup.1 : hydrogen, fluorine, chlorine 
R.sup.2 : hydroxyl, p-fluorophenyl 
R.sup.3 : hydrogen or together with R.sup.2 oxygen 
R.sup.4 : methyl, ethyl, phenyl, p-fluorophenyl, 2-thienyl 
R.sup.5 : hydrogen, hydroxyl 
R.sup.6 : hydrogen 
R.sup.7 : hydroxyl or with R.sup.6 oxygen. 
The following compounds are particularly preferred: 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-phenyl-(hydroxy)methyl-4-phenyl-1-p 
iperidinyl!-l-butanone, 
1-(4-fluorophenyl)-4- trans-(3-phenyl-hydroxymethyl-4-phenyl)-4-hydroxy-pi 
peridin-1-yl!-butan-1-ol, 
1-(4-fluorophenyl)-4-(3-benzoyl-4-phenyl-.DELTA..sup.4 
-dehydropiperidin-1-yl)-butan-1-one, 
1-(4-fluorophenyl)-4-(3-benzoyl-4-phenyl-.DELTA..sup.3 
-dehydropiperidin-1-yl)-butan-1-one, 
1-(bis-4-fluorophenyl)-4- trans-(3-phenyl-hydroxymethyl-4-phenyl)-4-hydrox 
y-piperidin-1-yl!-butane, 1-(4-fluorophenyl)-4- trans-(3-p- 
fluorophenyl-hydroxymethyl-4-p-fluorophenyl-4-hydroxy-piperidin-1-yl!-buta 
n-1-one, 
1-(4-fluorophenyl)-4- trans-(3-p-fluorophenyl-hydroxymethyl-4-p-fluorophen 
yl-4- hydroxypiperidin-1-yl!-butan-1-ol, 
1-(4-fluorophenyl)-4 trans-(3-acetyl-4-methyl)-4-hydroxy-piperidin-1-yl!-b 
utan-1-one, 
1-(4-fluorophenyl)-4- trans-(3-acetyl-4-methyl)-4-hydroxy-piperidin-1-yl!- 
butan-1-ol, 1-(4-fluorophenyl)-4-(3-acetyl-4-methyl-.DELTA..sup.3 
-dehydropiperidin-1yl)-butan-1-one, 
1-(4-fluorophenyl)-4-(3-acetyl-4-methyl-.DELTA..sup.3 -dehydropiperidin- 
1-yl)-butan-1-ol, 1-(bis-4-fluorophenyl)-4- 
(3-acetyl-4-methyl-.DELTA..sup.3 -dehydro-piperidin- 1-yl)-butane. 
The compounds of the formula I according to the invention can be prepared 
by reacting a compound of the formula II 
##STR4## 
where R.sup.1, R.sup.2, R.sup.3 and n have the stated meanings, and Nu is 
a nucleofugic leaving group, with a 3,4-disubstituted piperidine 
derivative of the formula III 
##STR5## 
where A, B and D have the meanings stated for formula I, and converting 
the resulting compound where appropriate into the addition salt with a 
physiologically tolerated acid. 
A suitable and preferred nucleofugic leaving group for Nu is halogen, 
especially bromine or chlorine. 
The reaction is expediently carried out in the presence of an inert base 
such as triethylamine or potassium carbonate to trap acid in an inert 
solvent such as a cyclic saturated ether, especially tetrahydrofuran or 
dioxane, or an alkylbenzene such as toluene or xylene. 
The reaction is usually carried out at from 80 to 150.degree. C. and is 
generally complete within from 1 to 10 hours. 
The products of the formula I can be converted by subsequent reactions as 
indicated in the examples. 
These reactions comprise oxidations of the 3-hydroxymethylpiperidine 
structure (R.sup.7 =OH in formula I) to the corresponding carbonyl 
derivatives with Jones reagent (chromium(VI) oxide in 25% strength 
sulfuric acid), reduction of the 2-butanone moiety (R.sup.2 +R.sup.3 
=oxygen) to the corresponding 2-butanol derivative with sodium boranate, 
elimination of H.sub.2 O from the 4-hydroxypiperidine moiety (R.sup.5 =OH) 
to give .DELTA..sup.4 -dehydropiperidine derivative with concentrated 
sulfuric acid, and the base-catalyzed double-bond shift to give the 
.DELTA..sup.3 -dehydropiperidine compound. 
The compounds of the formula I according to the invention are usually 
obtained in the form of yellowish or yellow crystals and can be purified 
by recrystallization from the conventional organic solvents, preferably 
from a lower alcohol, such as ethanol, or by column chromatography. 
The free 1,3,4-trisubstituted piperidine derivatives of the formula I can 
be converted in a conventional way into the addition salts with a 
physiologically tolerated acid, preferably by adding one equivalent of the 
appropriate acid to a solution. Examples of pharmaceutically tolerated 
acids are hydrochloric acid, phosphoric acid, sulfuric acid, 
methanesulfonic acid, sulfamic acid, maleic acid, fumaric acid, oxalic 
acid, tartaric acid and citric acid. 
The compounds according to the invention have valuable pharmacological 
properties. They can be used as neuroleptics, antidepressants, sedatives, 
hypnotics or cerebroprotectives. It is possible for a plurality of the 
said properties to be combined in one compound according to the invention. 
They are therefore suitable for the treatment of psychoses, preferably 
schizophrenia, and anxiety states, for the treatment and prevention of 
strokes or disturbances of cerebral function with an organic cause, and 
for the treatment of sleep disturbances. 
The present invention accordingly also relates to a therapeutic composition 
which contains a compound of the formula I or its physiologically 
tolerated acid addition salt as active substance in addition to 
conventional carriers and diluents, and to the use of the novel copounds 
for controlling diseases. 
The compounds according to the invention can be administered in a 
conventional way orally or parenterally, intravenously or intramuscularly. 
The dosage depends on the age, condition and weight of the patient and on 
the mode of administration. As a rule, the daily dose of active substance 
is about 1-100 mg/kg of body weight on oral administration and 0.1-2 mg/kg 
of body weight on parenteral administration. 
The novel compounds can be used in conventional solid or liquid 
pharmaceutical forms, e.g. as uncoated or (film-)coated tablets, capsules, 
powders, granules, suppositories, solutions, ointments, creams or sprays. 
These are produced in a conventional way. The active substances can for 
this purpose be processed with conventional pharmaceutical aids such as 
tablet binders, fillers, preservatives, tablet disintegrants, flow 
regulators, plasticizers, wetting agents, dispersants, emulsifiers, 
solvents, retardants, antioxidants and/or propellant gases (cf. H. Sucker 
et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The 
forms obtained in this way normally contain the active substance in an 
amount of from 0.1 to 99% by weight. 
The substances of the formula II which are required as starting materials 
for synthesizing the novel compounds are known. 
The substances of the formula III have not previously been described (but 
see DE 41 12 352). They are prepared, for example, by reacting 2 mole 
equivalents of an .alpha.,.beta.-unsaturated ketone of the formula IV 
EQU CH.sub.2 =CH--CO--R.sup.4 IV 
or a .beta.-halo ketone of the formula V 
EQU Hal--CH.sub.2 --CH.sub.2 --CO--R.sup.4 V, 
where R.sup.4 has the abovementioned meanings, with an amine H.sub.2 
N--R.sup.8 where R.sup.8 is benzyl which is unsubstituted or substituted 
by halogen, methoxy or nitro, or is allyl, in the presence of 1 mole 
equivalent of sodium hydroxide solution in methanol at 50.degree. C. This 
reaction is usually diastereoselective to give the compound VI with 
diequatorial trans configuration with respect to R.sup.4 
##STR6## 
which can be converted by elimination of R.sup.8 and, where appropriate, 
subsequent elimination of water and possible rearrangement and reduction 
as described above for the final products into the compounds of the 
formula III.

The following examples illustrate the invention: 
EXAMPLE 1 
a) Preparation of the starting material 
4-hydroxytrans-3-phenyl(hydroxy)methyl-4-phenylpiperidine 
600 g (1.62 mol) of trans-3-benzoyl-4-phenyl-4-hydroxy-1-benzylpiperidine 
in 1.4 1 of ethyl acetate mixed with 1.4 1 of methanol were catalytically 
hydrogenated with the addition of 20 g of palladium (10%) on carbon at 
70.degree. C. under a hydrogen pressure of 100 bar for 12 h. The mixture 
was filtered at 50.degree. C. to remove catalyst, evaporated to dryness, 
taken up in 0.6 l of acetone and stirred while cooling. The precipitated 
product was filtered off with suction, the filtrate was concentrated, the 
residue was stirred in 300 ml of acetone again while cooling, and a second 
product fraction was filtered off with suction. 
Yield: 345 g (75%) of the pure diastereomer of the product, melting point 
167.degree.-169.degree. C. 
b) Preparation of the final product 
1-(4-fluorophenyl)-4- 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-p 
iperidinyl!-1-butanone 
20.0 g (70.7 mmol) of 
4-hydroxy-trans-3-phenyl-(hydroxy)methyl-4-phenylpiperidine in 210 ml Of 
xylene were mixed with 26.7 ml (162 mmol) of 
.omega.-chloro-4-fluorobutyrophenone and with 18.8 g (136 mmol) of finely 
powdered potassium carbonate in addition to 1.0 g of potassium iodide and 
refluxed while stirring vigorously for 16 h. After cooling, 200 ml of 
toluene were added and the mixture was stirred vigorously while the pale 
solid precipitated. The crude product was filtered off with suction, 
washed with toluene and dried at 50.degree. C. under reduced pressure. The 
solid was then digested in 11 of water at 50.degree. C. and finally the 
product was filtered off with suction (melting point 
182.degree.-183.degree. C.), yield: 22.6 g (72%). 
The following can be prepared in a similar way: 
2. 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-p 
iperidinyl!butane Alkylating reagent: 1-(p-fluorophenyl)-4-chlorobutane 
3. 
1-Phenyl-4- 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl 
!-1-butanone, Melting point 173.degree.-175.degree. C. 
4. 
1-Phenyl-4- 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl 
!butane 
5.1-(4-Bromophenyl)-4- 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-p 
iperidinyl!-1-butanone, Melting point 186.degree.-187.degree. C. 
EXAMPLE 6 
a) Preparation of the starting material 
4-Hydroxy-trans-3-p-fluorophenyl(hydroxy)methyl-4-p-fluorophenylpiperidine 
30.0 g (67.6 mmol) of 
4-hydroxy-1-benzyl-trans-3-p-fluorobenzoyl-4-p-fluorophenylpiperidine 
hydrochloride in 1 l of methanol were catalytically hydrogenated with the 
addition of 4.0 g of palladium (10%) on carbon at 50.degree. C. for 8 h. 
After filtration and washing with methanol, the filtrate was evaporated to 
dryness. The residue was taken up in a mixture of 140 ml of methanol and 
500 ml of water at 70.degree. C., concentrated ammonia was added until the 
mixture was alkaline, and the precipitated product was filtered off with 
suction and washed thoroughly with water. Drying at 60.degree. C. under 
reduced pressure resulted in 20.2 g (94%) of product of melting point 
215.degree.-217.degree. C. 
b) Preparation of the final product 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-p-fluoro-phenyl(hydroxy)methyl-4-p- 
fluorophenyl-1piperidinyl!-1-butanone 
20.0 g (63.0 mmol) of 
4-hydroxy-trans-3-p-fluoro-phenyl(hydroxy)methyl-4-p-fluorophenylpiperidin 
e in a mixture of 250 ml of toluene and 25 ml of dimethylformamide were 
mixed with 20.6 ml (125 mmol) of .omega.-chloro-4-fluorobutyrophenone and 
with finely powdered potassium carbonate in addition to 1.0 g of potassium 
iodide and refluxed while stirring vigorously for 8 h. After cooling, the 
mixture was evaporated in a rotary evaporator, the residue was taken up in 
a little dimethylformamide, and the solution was poured into vigorously 
stirred ice-water. The precipitated solid was filtered off with suction, 
thoroughly washed with water and recrystallized from ethanol to give 23.5 
g (78%) of product of melting point 175.degree.-177.degree. C. 
The following can be prepared in a similar way: 
7. 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-p-fluoro-phenyl(hydroxy)methyl-4-p 
-fluorophenyl-1-piperidinyl!butane, melting point 170.degree.-171.degree. 
C. 
8. 
1-Phenyl-4- 4-hydroxy-trans-3-p-fluorophenyl-(hydroxy)methyl-4-p-fluorophe 
nyl-1-piperidinyl!-1-butanone 
9. 
1-Phenyl-4- 4-hydroxy-trans-3-p-fluorophenyl-(hydroxy)methyl-4-p-fluorophe 
nyl-1-piperidinyl!-butane 
EXAMPLE 10 
a) Preparation of the starting material 
4-hydroxy-cis-3-acetyl-4-methylpiperidine 
20.1 g (81.0 mmol) of 4-hydroxy-1-benzyl-cis-3-acetyl-4-methylpiperidine in 
700 ml of methanol were catalytically hydrogenated with the addition of 
2.5 g of palladium (10%) on carbon at room temperature for 8 h. After 
filtration and washing with methanol, the filtrate was evaporated to 
dryness. 11.9 g (94%) of product were isolated, melting point 
91.degree.-93.degree. C. The hydrochloride melts at 
118.degree.-199.degree. C. 
The trans isomer can be prepared in a similar way: decomposition above 
133.degree. C. (hydrochloride). 
b) Preparation of the final product 
1-(4-Fluorophenyl)-4- 4-hydroxy-cis-3-acetyl-4-methyl-1-piperidinyl)-1-buta 
none 
20.5 g (131 mmol) of 4-hydroxy-cis-3-acetyl-4-methylpiperidine in a mixture 
of 250 ml of toluene and 25 ml of dimethylformamide were mixed with 21.4 
ml (131 mmol) of .omega.-chloro-4-fluorobutyrophenone and with 18 g (131 
mmol) of finely powdered potassium carbonate in addition to 1.0 g of 
potassium iodide and refluxed while stirring vigorously for 3 h. After 
cooling, the mixture was evaporated in a rotary evaporator, and the 
residue was partitioned between methylene chloride and water. The aqueous 
phase was extracted with methylene chloride, and then the organic phase 
was dried with sodium sulfate and evaporated. The crude product was 
purified by column chromatography (silica gel, methylene chloride/methanol 
98/2). 9.5 g (22%) of product were isolated, decomposition above 
90.degree. C. (tartrate). 
The following can be prepared in a similar way: 
11. 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-acetyl-4-methyl-1-piperidinyl!-1-b 
utanone, Melting point 174.degree.-175.degree. C. (hydrochloride) 
12. 
1-(4-Fluorophenyl)-4- 4-hydroxy-cis-3-acetyl-4-methyl)-1-piperidinyl!-1-bu 
tanol, Alkylating reagent: 1-hydroxy-1-(p-fluorophenyl)-4-chlorobutane 
13. 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-acetyl-4-methyl-1-piperidinyl!-1-b 
utanol, melting point 97.degree.-99.degree. C., Alkylating reagent: 
1-hydroxy-1-(p-fluorophenyl)-4-chlorobutane 
14. 
1-(4-Fluorophenyl)-4- 4-hydroxy-cis-3-acetyl-4-methyl-1-piperidinyl!butane 
, melting point 85.degree.-88.degree. C. (hydrochloride) 
15. 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-acetyl-4-methyl-1-piperidinyl!buta 
ne, melting point 105.degree.-107.degree. C. (hydrochloride) 
16. 
1-(4-Phenyl)-4- 4-hydroxy-cis-3-acetyl-4-methyl-1-piperidinyl!-1-butanone 
17. 
1-(4-Phenyl)-4- 4-hydroxy-trans-3-acetyl-4-methyl-1-piperidinyl!-1-butanon 
e 
18. 1-(4-Phenyl)-4- 4-hydroxy-cis-3-acetyl-4-methyl-1-piperidinyl !butane 
19. 1-(4-Phenyl)-4- 4-hydroxy-trans-3-acetyl-4-methyl-1-piperidinyl !butane 
20. 1- 
(4-Fluorophenyl)-4- 4-hydroxy-trans-3-propionyl-4-ethyl-1-piperidinyl!-1-b 
utanone 
EXAMPLE 21 
1,1-Bis (4-fluorophenyl)-4- 4-hydroxy-trans-3-phenyl(hydroxy) 
methyl-4-phenyl-1-piperidinyl!butane 
22.8 g (80.6 mmol) of 
4-hydroxy-trans-3-phenyl-(hydroxy)methyl-4-phenylpiperidine (Example 1a) 
in 400 ml of xylene mixed with 40 ml of DMF were mixed with 22.6 g (80.6 
mmol) of 1,1-bis (4-fluorophenyl)-4-chlorobutane and with 18.6 g (132 
mmol) of finely powdered potassium carbonate in addition to 0.3 g of 
potassium iodide and refluxed while stirring vigorously for 8 h. The 
mixture was cooled and then evaporated to dryness. The residue was 
dissolved in DMF, and the solution was poured into 2.5 l of vigorously 
stirred ice-water. After stirring for 1 hour, the precipitated solid was 
filtered off with suction to give 40.1 g (95%) of product of melting point 
60.degree.-162.degree. C. 
The following can be prepared in a similar way: 
22. 1,1-Bis (4-fluorophenyl)-4- 4-hydroxy-trans-390 
3-p-fluorphenyl(hydroxy)methyl-4-p-fluorophenyl-1-piperidinyl!butane 
23. 1,1-Bis(4-fluorophenyl)-4- cis-3-acetyl-4-hydroxy-1-piperidinyl!butane, 
melting point 116.degree.-119.degree. C. (hydrochloride) 
24. 
1,1-Bis(4-fluorophenyl)-4- trans-3-acetyl-4-hydroxy-1-piperidinyl!butane, 
melting point 93.degree.-96.degree. C. (hydrochloride) 
EXAMPLE 25 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-phenyl(hydroxy)-methyl-4-phenyl-1-p 
iperidinyl!-1-butanol 
5.0 g (11.6 mmol) of 
1-(4-fluorophenyl)-4- 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1pi 
peridinyl!-1-butanone (Example 1b) were dissolved in a mixture of 80 ml of 
methanol and 100 ml of tetrahydrofuran, and 0.6 g (16 mmol) of sodium 
boranate was added. The mixture was stirred at room temperature for 2 h 
and then concentrated in a rotary evaporator. The residue was partitioned 
between methylene chloride and water at pH 10, and the organic phase was 
dried with sodium sulfate and evaporated to give 4.6 g (88%) of product of 
melting point 90.degree.-92.degree. C. (decomposition). 
The following can be prepared in a similar way: 
26. 1-Phenyl-4- 4-hydroxy-trans-3-phenyl (hydroxy)methyl-4-phenyl- 
1-piperidinyl!-1-butanol Melting point: 90.degree.-92.degree. C. 
27. 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-p-fluoro-phenyl(hydroxy)methyl-4-p 
-fluorophenyl-1-piperidinyl!1-butanol 
28. 1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-p-fluorophenyl 
(hydroxy)methyl-4-p-fluorophenyl-1-piperidinyl!butane 
29. 1-Phenyl-4- 4-hydroxy-trans-3-p-fluorophenyl 
(hydroxy)methyl-4-p-fluorophenyl-1-piperidinyl!-1 -butanol 
30. 1-(4-Fluorophenyl)-4- 4-hydroxy-cis-3-.alpha.-hydroxyethyl-4-methyl- 
1-piperidinyl!-1-butanol 
31. 1- (4-Fluorophenyl)-4- 
4-hydroxy-trans-3-.alpha.-hydroxyethyl-4-methyl- 1-piperidinyl!- 
1-butanol 
32. 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-.alpha.hydroxy-ethyl-4-methyl-1-pi 
peridinyl!butane 
33. 
1-(4-Bromophenyl)-4- 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-pi 
peridinyl!-1-butanol, Melting point 92.degree.-93.degree. C. 
34. 
1,1-Bis(4-fluorophenyl)-4- 4-hydroxy-cis-3-.alpha.-hydroxyethyl-4-methyl-1 
-piperidinyl!butane 
35. 
1,1-Bis(4-fluorophenyl)-4- 4-hydroxy-trans-3-.alpha.-hydroxyethyl-4-methyl 
-1-piperidinyl!butane 
EXAMPLE 36 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-benzoyl-4-phenyl-1-piperidinyl!-1-b 
utanone 
22.6 g (50.7 mmol) of 
1-(4-fluorophenyl)-4- 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-p 
iperidinyl)-1-butanone (Example 1b) were suspended in 500 ml of acetone and 
then, while stirring vigorously, 21 ml (56 mmol) of Jones reagent were 
added dropwise. The temperature rose to 32.degree. C. during this. The 
mixture was stirred at room temperature for 12 h and then evaporated in a 
rotary evaporator. The mixture was then poured into ice-water, methylene 
chloride was added, dilute sodium hydroxide solution was added until 
alkaline, and the precipitated chromium oxide was filtered off with 
suction. The aqueous phase was extracted with methylene chloride and then 
the organic phase was dried with sodium sulfate and concentrated to give 
21.1 g (95%) of product of melting point 128.degree.-130.degree. C. 
The following can be prepared in a similar way: 
37. 
1-(4-Fluorophenyl)-4- 4-hydroxy-trans-3-P-fluorobenzoyl-4-p-fluorophenyl-1 
-piperidinyl!-1-butanone, Melting point 111.degree.-113.degree. C. 
38. 
1-Phenyl-4- 4-hydroxy-trans-3-p-fluorobenzoyl-4-p-fluorophenyl-1-piperidin 
yl!-1-butanone 
EXAMPLE 39 
1,1-Bis(4-fluorophenyl)-4- 4-hydroxy-trans-3-benzoyl 
4-phenyl-1-piperidinyl!butane 
4.0 g (7.6 mmol) of 1,1-bis(4-fluorophenyl)-4- 4-hydroxy-trans-3-phenyl 
(hydroxy) methyl-4-phenyl-1-piperidinyl !butane (Example 21) were 
dissolved in 50 ml of glacial acetic acid and then, while stirring 
vigorously, 4.3 ml (11.4 mmol) of Jones reagent were added dropwise. The 
mixture was stirred at 60.degree. C. for 12 h and then the solution was 
decanted off the precipitated chromium salts. The mixture was then poured 
into ice-water, methylene chloride was added, and sodium hydroxide 
solution was added until alkaline. The aqueous phase was extracted with 
methylene chloride and then the organic phase was dried with sodium 
sulfate and concentrated. The crude product was purified by column 
chromatography (silica gel, methylene chloride/methanol 98/2) to give 1.0 
g (50%) of product (oil). 
The following can be prepared in a similar way: 
40. 1,1-Bis 
(4-fluorophenyl)-4- 4-hydroxy-trans-3-p-fluorobenzoyl-4-p-fluorophenyl- 
1-piperidinyl !butane 
EXAMPLE 41 
a) Preparation of the starting material 
1. 4-Hydroxy-trans-3-benzoyl-4-phenylpiperidine 
8 ml (21.4 mmol) of Jones reagent were added dropwise to 6.0 g (21.2 mmol) 
of 4-hydroxy-trans-3phenyl (hydroxy) methyl-4-phenylpiperidine (Example 
1a) in 150 ml of acetone. The temperature rose to 30.degree. C. during 
this. The mixture was stirred at room temperature for 1 h, and the 
solution was decanted off the precipitated chromium oxide and evaporated 
to half the volume in a rotary evaporator. The mixture was then poured 
into ice-water, dilute sodium hydroxide solution was added until alkaline, 
the mixture was extracted several times with methylene chloride, and the 
organic phase was dried with sodium sulfate and evaporated. 5.2 g (87%) of 
product were isolated and, after recrystallization from ethyl acetate, 
melted at 128.degree.-129.degree. C. 
2. 3-Benzoyl-4 -phenyl-.DELTA..sup.4 -dehydropiperidine 
400 ml of methylene chloride and then 112.6 g (304 mmol) of 
4-hydroxy-trans-3-benzoyl-4-phenyl-piperidine dissolved in 350 ml of 
methylene chloride were added dropwise to 186 g (1.9 mol) of concentrated 
sulfuric acid while cooling in ice to 0.degree.-5.degree. C. The mixture 
was stirred while cooling in ice for 2-3 h and then poured into ice-water, 
concentrated sodium hydroxide solution was added (to pH 10). The mixture 
was partitioned between methylene chloride and water, and the organic 
phase was dried over sodium sulfate and concentrated. The crude product 
was purified by column chromatography (silica gel, methylene chloride+5% 
methanol) to give a yield of 61 g (57%) of melting point 
118.degree.-119.degree. C.) 
b) Preparation of the final product 
1-(4-Fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.4 
-dehydro-1-piperidinyl!-1-butanone 
15.4 g (59 mmol) of 3-benzoyl-4-phenyl-.DELTA..sup.4 -dehydropiperidine in 
90 ml of xylene were mixed with 11.5 ml (70 mmol) of 
e-chloro-4-fluorobutyrophenone and with 12.1 g (88 mmol) of finely 
powdered potassium carbonate together with 0.5 g of potassium iodide and 
refluxed while stirring vigorously for 15 h. The mixture was concentrated 
in a rotary evaporator and then the residue was partitioned between 
ice-water and methylene chloride, making alkaline with dilute sodium 
hydroxide solution. The aqueous phase was extracted with methylene 
chloride and then the organic phase was dried with sodium sulfate and 
concentrated. The crude product was purified by column chromatography 
(silica gel, methylene chloride/methanol 98/2) to give 5.2 g (21%) of 
product of melting point 89.degree.-91.degree. C. (hydrochloride). 
The following can be prepared in a similar way: 
42. 1-(4-Fluorophenyl)-4- 3-benzoyl-4-Phenyl-.DELTA..sup.4 
-dehydro-1-piperidinyl!-1-butanol 
EXAMPLE 43 
1-(4-Fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.4 
-dehydro-1-piperidinyl!-1-butanone 
100 ml of methylene chloride and then 10.0 g (22.4 mmol) of 
1-(4-fluorophenyl)-4- 4-hydroxy-trans-3-benzoyl-4-phenyl-1-piperidinyl!-1- 
butanone (Example 36) dissolved in 50 ml of methylene chloride were added 
dropwise to 18.0 ml (336 mmol) of concentrated sulfuric acid while cooling 
in ice to 0.degree.-5.degree. C. The mixture was stirred while cooling in 
ice for 2 h and then poured into ice-water, adjusted to pH 10 with 
concentrated sodium hydroxide solution and partitioned between methylene 
chloride and water, and the organic phase was dried over sodium sulfate 
and concentrated. The crude product was purified by column chromatography 
(silica gel, methylene chloride 99/1) to give a yield of 4.2 g (44%) of 
pale oil. The hydrochloride melts at 89.degree.-91.degree. C. 
The following can be prepared in a similar way: 
44. 1-(4-Fluorophenyl)-4- 
3-benzoyl-4-phenyl-.DELTA.4-dehydro-1-piperidinyl !butane 
45. 1-(4-Fluorophenyl)-4- 3-p-fluorobenzoyl-4-fluorophenyl-.DELTA..sup.4 
-dehydro- 1-piperidinyl !- 1-butanone 
46. 1- (4-Fluorophenyl)-4- 3-p-fluorobenzoyl-4-fluorophenyl-.DELTA..sup.4 
-dehydro- 1-piperidinyl !butane 
47. 1-Phenyl-4- 
3-benzoyl-4-phenyl-.DELTA.-dehydro-1-piperidinyl!-1-butanone 
48. 1-Phenyl-4- 3-p-fluorobenzoyl-4-P-fluorophenyl-.DELTA..sup.4 
-dehydro-1-piperidinyl!- 1-butanone 
49. 1,1-Bis(4-fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.4 
-dehydro-1-piperidinyl!butane, Melting point 85.degree.-87.degree. C. 
(hydrochloride) 
50. 
1,1-Bis(4-fluorophenyl)-4- 3-p-fluorobenzoyl-4-p-fluorophenyl-.DELTA..sup. 
4 -dehydro- 1-piperidinyl!butane 
EXAMPLE 51 
1-(4-Fluorophenyl)-4- 3-acetyl-4-methyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!-1-butanone 
200 ml of methylene chloride and then 22.0 g (68.5 mmol) of 
1-(4-fluorophenyl)-4- 4-hydroxy-cis,trans-3-acetyl-4-methyl- 1-piperidinyl 
!- 1-butanone (Example 10,11) dissolved in 100 ml of methylene chloride 
were added dropwise to 40 ml (747 mmol) of concentrated sulfuric acid 
while cooling in ice to 0.degree.-5.degree. C. The mixture was stirred 
while cooling in ice for 2 h and then at 30.degree.-35.degree. C. for 1 h, 
and was then poured into ice-water, adjusted to pH 10 with concentrated 
sodium hydroxide solution and partitioned between methylene chloride and 
water, and the organic phase was dried with sodium sulfate and 
concentrated. The crude product was purified by column chromatography 
(silica gel, methylene chloride 99/1) to yield 9.8 g (45%) of melting 
point 67.degree.-70.degree. C. (tartrate). 
The following can be prepared in a similar way: 
52. 1-(4-Fluorophenyl)-4- 3-acetyl-4-methyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!butane 
53. 1-Phenyl-4- 3-acetyl-4-methyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!-1-butanone 
54. 1-Phenyl-4- 3-acetyl-4-methyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!butane 
EXAMPLE 55 
1-(4-Fluorophenyl)-4- 3-phenyl(hydroxy)methyl-4-phenyl-.DELTA..sup.4 - 
dehydro-1-piperidinyl!-1-butanone 
4.0 g (9.0 mmol) of 1-(4-fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.4 
-dehydro-1-piperidinyl!-1-butanone (Example 41, 43) were suspended in 50 
ml of methanol and, at 30.degree. C., 0.34 g (9.0 mmol) of sodium boronate 
was slowly added. The mixture was stirred at room temperature for 2 h and 
then evaporated in a rotary evaporator. The residue was partitioned 
between methylene chloride and water at pH 10, and the organic phase was 
dried with sodium sulfate and concentrated to give 3.8 g (95%) of product 
of melting point 191.degree.-192.degree. C. (hydrochloride). 
EXAMPLE 56 
a) Preparation of the starting material 
3-Benzoyl-4-phenyl-.DELTA..sup.3 -dehydropiperidine 
12.0 g (66 mmol) of 30% sodium methylate solution were added to 4.2 g (16.0 
mmol) of 3-benzoyl-4- phenyl-.DELTA..sup.4 -dehydropiperidine (Example 
41a) in 60 ml of methanol, and the mixture was refluxed for 8 h and then 
stirred at room temperature overnight and evaporated to dryness in a 
rotary evaporator. The residue was poured into ice-water, the mixture was 
extracted several times with methylene chloride, and the organic phases 
were dried with sodium sulfate and evaporated. The crude product was 
purified by column chromatography (silica gel, methylene chloride+1% 
methanol) to yield 1.9 g (45%) of melting point 189.degree.-192.degree. C. 
b) Preparation of the final product 
1-(4-Fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!-1-butanone 
2.8 g (10.6 mmol) of 3-benzoyl-4-phenyl-.DELTA..sup.3 -dehydropiperidine in 
50 ml of xylene were mixed with 2.6 ml (15.4 mmol) of 
.omega.-chloro-4-fluorobutyrophenone and with 2.2 g (16 mmol) of finely 
powdered potassium carbonate together with 0.5 g of potassium iodide and 
refluxed while stirring vigorously for 13 h. The mixture was partitioned 
between methylene chloride and water, and the organic phase was dried with 
sodium sulfate and concentrated. The crude product was purified by column 
chromatography (silica gel, methylene chloride+5% methanol) to yield 1.4 g 
(31%) of product with melting point 171.degree.-172.degree. C. 
The following can be prepared in a similar way: 
57. 1-(4-Fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!-1-butanol 
EXAMPLE 58 
1-(4-Fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!-1-butanone 
5.7 g (32 mmol) of 30% sodium methylate solution were added to 4.5 g (10.5 
mmol) of 1-(4-fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.4 
-dehydro-1-piperidinyl!-1-butanone (Example 41, 43) in 60 ml of methanol, 
and the mixture was refluxed for 1.5 h, then stirred at room temperature 
overnight and evaporated to dryness in a rotary evaporator. The residue 
was poured into ice-water, the mixture was partitioned between methylene 
chloride and water, the pH was adjusted to 10, and the organic phase was 
dried over sodium sulfate and concentrated. The crude product was purified 
by column chromatography (silica gel, methylene chloride+2.5% methanol) to 
yield 2.2 g (48%) of product whose maleate melts at 
171.degree.-172.degree. C. 
The following can be prepared in a similar way: 
59. 1-(4-Fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.3 
-dehydro1-piperidinyl!butane 
60. 1-(4-Fluorophenyl)-4- 3-p-fluorobenzoyl-4-p-fluorophenyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!-1-butanone, Melting point 211.degree.-213.degree. 
C. (hydrochloride) 
61. 1-(4-Fluorophenyl)-4- 3-p-fluorobenzoyl-4-p-fluorophenyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!butane 
62. 1-Phenyl-4- 3-benzoyl-4-phenyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!-1-butanone 
63. 1-Phenyl-4- 3-p-fluorobenzoyl-4-p-fluorophenyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!-1-butanone 
64. 1,1-Bis(4-fluorophenyl)-4- 3-benzoyl-4-phenyl-.DELTA..sup.3 
-dehydro-1-piperidinyl!butane Melting point 85.degree.-87.degree. C. 
(hydrochloride) 
65. 
1,1-Bis(4-fluorophenyl)-4- 3-p-fluorobenzoyl-4-p-fluorophenyl-.DELTA..sup. 
3 -dehydro-1-piperidinyl!butane. 
EXAMPLE 66 
a) Preparation of the starting material 
cis-3-phenyl(hydroxy)methyl-4-phenylpiperidine 
7.8 g (22.1 mmol) of 3-benzoyl-4-phenyl-1-benzyl-.DELTA..sup.4 
-dehydropiperidine (prepared as in Example 41a) in 300 ml of ethanol were 
catalytically hydrogenated with the addition of 1.6 g of palladium (10%) 
on carbon at room temperature under atmospheric pressure for 48 h. The 
mixture was filtered to remove the catalyst, evaporated to dryness, taken 
up in 40 ml of acetone with heating, and cooled while stirring. The 
precipitated product was filtered off with suction and washed with 
acetone. Yield: 2.3 g (39%); the hydrochloride melts at 
239.degree.-240.degree. C. 
b) Preparation of the final product 
1-(4-Fluorophenyl)-4- cis-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl!- 
1-butanone 
4.0 g (15.0 mmol) of cis-3-phenyl(hydroxy)methyl-4-phenylpiperidine in 50 
ml of toluene were mixed with 3.8 ml (23 mmol) of 
.omega.-chloro-4-fluorobutyrophenone and with finely powdered potassium 
carbonate in addition to 1.0 g of potassium iodide and refluxed while 
stirring vigorously for 25 h. After cooling, the filtrate was 
concentrated, the residue was partitioned at pH 10 between methylene 
chloride and water, and the organic phase was dried and concentrated. The 
crude product was purified by column chromatography (silica gel, methylene 
chloride+5% methanol) to isolate 3.5 g (54%) of product of melting point 
113.degree.-114.degree. C. 
The following can be prepared in a similar way: 
67. 
1-(4-Fluorophenyl)-4- cis-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl!b 
utane 
68. 
1-(4-Fluorophenyl)-4- cis-3-p-fluorophenyl(hydroxy)-methyl-4-p-fluoropheny 
l-1-piperidinyl!-1-butanone 
69. 1-(4-Fluorophenyl)-4- cis-3-acetyl-4-methyl-1-piperidinyl!-1-butanone 
70. 1-(4-Fluorophenyl)-4- cis-3-acetyl-4-methyl-1-piperidinyl!butane