Substituted piperazines as central nervous system agents

Substituted piperazines and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of same, which are useful as central nervous system agents and are particularly useful as dopaminergic, antipsychotic, and antihypertensive agents as well as for treating hyperprolactinaemia-related conditions and central nervous system disorders.

BACKGROUND OF THE INVENTION 
The present invention relates to novel substituted piperazines and 
derivatives thereof useful as pharmaceutical agents, to methods for their 
production, to pharmaceutical compositions which include these compounds 
and a pharmaceutically acceptable carrier, and to pharmaceutical methods 
of treatment. The novel compounds of the present invention are central 
nervous system agents. More particularly, the novel compounds of the 
present invention are dopaminergic agents. 
A series of 1-pyridinyl-1-butanones, 1-indolyl-1-butanones, and related 
compounds were synthesized by Sato, M., et al, Chemical Pharmaceutical 
Bulletin, Volume 26, pages 3296-3305 (1978) as potential psychotropic 
agents. 
A series of piperazinylbutane derivatives useful as depressants for the 
central nervous system is disclosed in JP 48004478. 
A series of 1-phenyl-4-pyridylethyl-piperazines possessing tranquilizing 
and appetite depressant properties and also an effect on blood pressure is 
disclosed in U.S. Pat. No. 3,177,219. 
A series of 1-pyridylalkyl-4-phenylpiperazines were synthesized by 
Bacciarelli, C., et al, Boll. Chem. Farm, Volume 119, pages 608-618 (1980) 
as hypotensive, antihistaminic and adrenolytic agents. 
A series of 1-alkyl-4-arylpiperazines is disclosed in ES 452530. 
A series of substituted 1-alkyl-4-phenylpiperazines is disclosed in United 
Kingdom Patent 1,551,993. 
A series of phenyl piperazines useful in the treatment of a schistosomiasis 
is disclosed in U.S. Pat. No. 4,515,793. 
A series of 1-[(heterocyclyl)-lower-alkyl]-4-substituted-piperazines useful 
as depressants on the autonomic nervous system, the cardiovascular system, 
and the skeletal muscular system is disclosed in U.S. Pat. No. 3,362,956. 
However, the compounds disclosed in the aforementioned references do not 
disclose or suggest the combination of structural variations of the 
compounds of the present invention described hereinafter. 
SUMMARY OF THE INVENTION 
Accordingly, the present invention is a compound of Formula I 
##STR1## 
wherein R is 
##STR2## 
X is 
##STR3## 
or --CH.sub.2 --; 
n is an integer of 2 to 4; 
R.sup.1 is 2- or 3-1H-indolyl, or 2- or 3-1H-indolyl substituted by lower 
alkyl, lower alkoxy, or halogen, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 
4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, 
or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, 
lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower 
alkyl, lower alkoxy, or halogen, 2- or 3-thienyl, or 2- or 3-thienyl 
substituted by lower alkyl or halogen, 2- or 3-furanyl, or 2- or 3-furanyl 
substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl, or 2-, 4-, 
or 5-thiazolyl substituted by lower alkyl or halogen; or a 
pharmaceutically acceptable acid addition salt thereof. 
As dopaminergic agents, the compounds of Formula I are useful as 
antipsychotic agents for treating psychoses such as schizophrenia. They 
are also useful as antihypertensives and for the treatment of disorders 
which respond to dopaminergic activation. Thus, other embodiments of the 
present invention include the treatment, by a compound of Formula I, of 
hyperprolactinaemia-related conditions, such as galactorrhea, amenorrhea, 
menstrual disorders and sexual dysfunction, and several central nervous 
system disorders such as Parkinson's disease, Huntington's chorea, and 
depression. 
A still further embodiment of the present invention is a pharmaceutical 
composition for administering an effective amount of a compound of Formula 
I in unit dosage form in the treatment methods mentioned above. 
Finally, the present invention is directed to methods for production of a 
compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION 
In the compounds of Formula I, the term "lower alkyl" means a straight or 
branched hydrocarbon radical having from one to six carbon atoms and 
includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, 
sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. 
"Lower alkoxy" is O-alkyl of from one to six carbon atoms as defined above 
for "lower alkyl." 
"Halogen" is fluorine, chlorine, bromine, or iodine. 
"Alkali metal" is a metal in Group IA of the periodic table and includes, 
for example, lithium, sodium, potassium, and the like. 
"Alkaline-earth metal" is a metal in Group IIA of the periodic table and 
includes, for example, calcium, barium, strontium, magnesium and the like. 
"Noble metal" is platinum, palladium, rhodium, ruthenium, and the like. 
Pharmaceutically acceptable acid addition salts of the compounds of Formula 
I include salts derived from nontoxic inorganic acids, such as 
hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, 
phosphorous, and the like, as well as the salts derived from nontoxic 
organic acids, such as aliphatic mono- and dicarboxylic acids, 
phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic 
acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such 
salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, 
nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, 
metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, 
propionate, caprylate, isobutyrate, oxalate, malonate, succinate, 
suberate, sebacate, fumarate, maleate, mandelate, benzoate, 
chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, 
benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, 
maleate, tartrate, methanesulfonate, and the like. Also contemplated are 
salts of amino acids such as arginate and the like and gluconate, 
galacturonate (see, for example, Berge, S. M., et al, "Pharmaceutical 
Salts," Journal of Pharmaceutical Science, Vol. 66, pages 1-19 (1977)). 
The acid addition salts of said basic compounds are prepared by contacting 
the free base form with a sufficient amount of the desired acid to produce 
the salt in the conventional manner. The free base form may be regenerated 
by contacting the salt form with a base and isolating the free base in the 
conventional manner. The free base forms differ from their respective salt 
forms somewhat in certain physical properties such as solubility in polar 
solvents, but otherwise the salts are equivalent to their respective free 
base for purposes of the present invention. 
Certain of the compounds of the present invention can exist in unsolvated 
forms as well as solvated forms, including hydrated forms. In general, the 
solvated forms, including hydrated forms, are equivalent to unsolvated 
forms and are intended to be encompassed within the scope of the present 
invention. 
A preferred compound of Formula I is one wherein R.sup.1 is 2- or 
3-1H-indolyl, or 2- or 3-1H-indolyl substituted by lower alkyl, lower 
alkoxy, or halogen, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl 
substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 
5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, 
lower alkoxy, or halogen, 2-, or 3-thienyl or 2- or 3-thienyl substituted 
by lower alkyl or halogen. 
Another preferred embodiment is a compound of Formula I wherein R.sup.1 is 
2- or 3-1H-indolyl, 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-pyrimidinyl, or 
2- or 3-thienyl. 
Particularly valuable are: 
1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-(piperazinyl)]-1-butanone; 
1-(2-Pyridinyl)-4-[4-(3-pyridinyl)butyl]piperazine; 
1-(4-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone; 
2-[4-[4-(4-Pyridinyl)butyl]-1-piperazinyl]pyridine; 
2-[4-[4-(4-Pyridinyl)butyl]-1-piperazinyl]pyrimidine; 
1-(2-Pyridinyl)-4-[3-(3-pyridinyl)propyl]piperazine; 
1-(3-Quinolinyl)-4-[4-(2-pyridinyl)-1-(piperazinyl)]-1-butanone; 
3-[4-[4-(2-Pyridinyl)-1-piperazinyl]butyl]quinoline; 
3-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]quinoline; 
1-(4-Quinolinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone; 
1-(3-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]-1-butanone; 
1-(4-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]-1-butanone; and 
4-[4-[4-(2-Pyridinyl)-1-piperazinyl]butyl]quinoline; 
or a pharmaceutically acceptable acid addition salt thereof. 
The compounds of Formula I are valuable dopaminergic agents. The tests 
employed indicate that compounds of Formula I possess dopaminergic 
activity. Thus, the compounds of Formula I were tested for their ability 
to inhibit locomotor activity in mice according to the assay described by 
J. R. McLean, et al, Pharmacology, Biochemistry and Behavior, Volume 8, 
pages 97-99 (1978); for their ability to inhibit [.sup.3 H]spiroperidol 
binding in a receptor assay described by D. Grigoriadis and P. Seeman, 
Journal of Neurochemistry, Volume 44, pages 1925-1935 (1985); and for 
their ability to inhibit dopamine synthesis in rats according to the 
protocol described by J. R. Walters and R. H. Roth, Naunyn-Schmiedeberg's 
Archives of Pharmacology, Volume 296, pages 5-14 (1976). The above test 
methods are incorporated herein by reference. The data in the table show 
the dopaminergic activity of representative compounds of Formula I. 
TABLE 1 
__________________________________________________________________________ 
Biological Activity of Compounds of Formula 1 
% Reversal of Brain 
Inhibition of 
Inhibition of Locomotor 
Dopamine Synthesis 
[.sup.3 H]Spiroperidol 
Example Activity in Mice 
in Rats at Binding 
Number 
Compound ED.sub.50, mg/kg, IP 
10 mg/kg, IP 
IC.sub.50, 
__________________________________________________________________________ 
.mu.M 
2 1-(3-Pyridinyl)-4-[4-(2-pyridinyl)- 
6.3 43 2.87 
1-(piperazinyl)]-1-butanone 
8 1-(2-Pyridinyl)-4-[4-(2-pyridinyl)- 
2.7 67 -- 
butyl]piperazine 
4 1-(4-Pyridinyl)-4-[4-(2-pyridinyl)-1- 
7.6 35 2.13 
piperazinyl]-1-butanone 
9 2-[4-[4-(4-Pyridinyl)butyl]-1-pipera- 
4.0 79 0.835 
zinyl]pyridine 
10 2-[4-[4-(4-Pyridinyl)butyl]-1-pipera- 
10.1 35 4.18 
zinyl]pyrimidine 
1 1-(2-Pyridinyl)-4-[3-(3-pyridinyl)- 
3.1 -- -- 
propyl]piperazine 
6 1-(3-Quinolinyl)-4-[4-(2-pyridinyl)- 
2.8 -- 0.486 
1-(piperazinyl)]-1-butanone 
11 3-[4-[4-(2-Pyridinyl)-1-piperazinyl]- 
2.2 100 0.155 
butyl]quinoline 
12 3-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]- 
1.2 -- -- 
butyl]quinoline 
7 1-(4-Quinolinyl)-4-[4-(2-pyridinyl)- 
13 -- -- 
1-piperazinyl]-1-butanone 
13 4-[4-[4-(2-Pyridinyl)-1-piperazinyl]- 
3.2 -- 0.279 
butyl]quinoline 
__________________________________________________________________________ 
A compound of Formula Ia 
##STR4## 
wherein R is 
##STR5## 
n is an integer of 2 to 4; 
R.sup.1 is 2- or 3-1H-indolyl, or 2- or 3-1H-indolyl substituted by lower 
alkyl, lower alkoxy, or halogen, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 
4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, 
or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, 
lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower 
alkyl, lower alkoxy, or halogen, 2- or 3-thienyl, or 2- or 3-thienyl 
substituted by lower alkyl or halogen, 2- or 3-furanyl, or 2- or 3-furanyl 
substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl, or 2-, 4-, 
or 5-thiazolyl substituted by lower alkyl or halogen; or a 
pharmaceutically acceptable acid addition salt thereof may be prepared by 
reacting a compound of Formula Ib 
##STR6## 
wherein R, R.sup.1, and n are as defined above with a reducing agent such 
as, for example, hydrazine, in the presence of an alkaline catalyst such 
as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium 
ethoxide and the like, and a solvent such as, for example, ethylene glycol 
and the like, or amalgamated zinc and an acid such as, for example, 
concentrated hydrochloric acid and the like optionally in the presence of 
a solvent such as, for example, ethanol, acetic acid, dioxane, toluene and 
the like, or treating a compound of Formula Ib with hydrogen in the 
presence of a catalyst such as a noble metal, for example, palladium on 
charcoal in the presence of a solvent such as, for example, ethanol and 
the like to give a compound of Formula Ia. Preferably, the reaction is 
carried out with hydrazine in the presence of potassium hydroxide and 
ethylene glycol. 
Alternatively, a compound of Formula Ia may be prepared from a compound of 
Formula II 
EQU R--CH.sub.2 --(CH.sub.2).sub.n --L II 
wherein L is a halogen, or a leaving group such as, for example, 
methanesulfonyloxy, toluenesulfonyloxy and the like, and R and n are as 
defined above, and a compound of Formula III 
##STR7## 
wherein R.sup.1 is as defined above in the presence of a base such as, for 
example, an alkali metal or alkaline earth metal hydroxide, carbonate or 
bicarbonate, for example, sodium hydroxide, sodium carbonate, sodium 
bicarbonate, potassium hydroxide, potassium carbonate, potassium 
bicarbonate and the like in the presence of a solvent such as, for 
example, acetonitrile and the like to give a compound of Formula Ia. 
Preferably, the reaction is carried out in the presence of potassium 
bicarbonate and acetonitrile. 
A compound of Formula Ib is prepared from a compound of Formula IV 
##STR8## 
wherein R, n, and L are as defined above and a compound of Formula III 
using the methodology used to prepare a compound of Formula Ia from a 
compound of Formula II and a compound of Formula III. 
Compounds of Formula II, Formula III, and Formula IV are either known or 
capable of being prepared by methods known in the art. 
The compounds of the present invention can be prepared and administered in 
a wide variety of oral and parenteral dosage forms. It will be obvious to 
those skilled in the art that the following dosage forms may comprise as 
the active component, either a compound of Formula I or a corresponding 
pharmaceutically acceptable salt of a compound of Formula I. 
For preparing pharmaceutical compositions from the compounds of the present 
invention, pharmaceutically acceptable carriers can be either solid or 
liquid. Solid form preparations include powders, tablets, pills, capsules, 
cachets, suppositories, and dispersible granules. A solid carrier can be 
one or more substances which may also act as diluents, flavoring agents, 
solubilizers, lubricants, suspending agents, binders, preservatives, 
tablet disintegrating agents, or an encapsulating material. 
In powders, the carrier is a finely divided solid which is in a mixture 
with the finely divided active component. 
In tablets, the active component is mixed with the carrier having the 
necessary binding properties in suitable proportions and compacted in the 
shape and size desired. 
The powders and tablets preferably contain from five or ten to about 
seventy percent of the active compound. Suitable carriers are magnesium 
carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, 
starch, gelatin, tragacanth, methylcellulose, sodium 
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The 
term "preparation" is intended to include the formulation of the active 
compound with encapsulating material as a carrier providing a capsule in 
which the active component, with or without other carriers, is surrounded 
by a carrier, which is thus in association with it. Similarly, cachets and 
lozenges are included. Tablets, powders, capsules, pills, cachets, and 
lozenges can be used as solid dosage forms suitable for oral 
administration. 
For preparing suppositories, a low melting wax, such as a mixture of fatty 
acid glycerides or cocoa butter, is first melted and the active component 
is dispersed homogeneously therein, as by stirring. The molten homogenous 
mixture is then poured into convenient sized molds, allowed to cool, and 
thereby to solidify. 
Liquid form preparations include solutions, suspensions, and emulsions, for 
example, water or water propylene glycol solutions. For parenteral 
injection liquid preparations can be formulated in solution in aqueous 
polyethylene glycol solution. 
Aqueous solutions suitable for oral use can be prepared by dissolving the 
active component in water and adding suitable colorants, flavors, 
stabilizing and thickening agents as desired. 
Aqueous suspensions suitable for oral use can be made by dispersing the 
finely divided active component in water with viscous material, such as 
natural or synthetic gums, resins, methylcellulose, sodium 
carboxymethylcellulose, and other well-known suspending agents. 
Also included are solid form preparations which are intended to be 
converted, shortly before use, to liquid form preparations for oral 
administration. Such liquid forms include solutions, suspensions, and 
emulsions. These preparations may contain, in addition to the active 
component, colorants, flavors, stabilizers, buffers, artificial and 
natural sweeteners, dispersants, thickeners, solubilizing agents, and the 
like. 
The pharmaceutical preparation is preferably in unit dosage form. In such 
form, the preparation is subdivided into unit doses containing appropriate 
quantities of the active component. The unit dosage form can be a packaged 
preparation, the package containing discrete quantities of preparation, 
such as packeted tablets, capsules, and powders in vials or ampoules. 
Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge 
itself, or it can be the appropriate number of any of these in packaged 
form. 
The quantity of active component in a unit dose preparation may be varied 
or adjusted from 1 mg to 1000 mg preferably 10 mg to 100 mg according to 
the particular application and the potency of the active component. The 
composition can, if desired, also contain other compatible therapeutic 
agents. 
In therapeutic use as antipsychotic agents, the compounds utilized in the 
pharmaceutical method of this invention are administered at the initial 
dosage of about 1 mg to about 50 mg per kilogram daily. A daily dose range 
of about 5 mg to about 25 mg per kilogram is preferred. The dosages, 
however, may be varied depending upon the requirements of the patient, the 
severity of the condition being treated, and the compound being employed. 
Determination of the proper dosage for a particular situation is within 
the skill of the art. Generally, treatment is initiated with smaller 
dosages which are less than the optimum dose of the compound. Thereafter, 
the dosage is increased by small increments until the optimum effect under 
the circumstances is reached. For convenience, the total daily dosage may 
be divided and administered in portions during the day if desired. 
The following nonlimiting examples illustrate the inventors' preferred 
methods for preparing the compounds of the invention. 
EXAMPLE 1 
1-(2-Pyridinyl)-4-[3-(3-pyridinyl)propyl]piperazine 
A solution of 3-pyridinylpropylchloride (Example A) (3.0 g, 0.0193 mol), 
1-(2-pyridinyl)piperazine (3.15 g, 0.0193 mol), potassium iodide (0.8 g, 
0.005 mol) is dissolved in N,N-dimethylformamide (80 mL) and heated to 
80.degree. C. for 12 hours. The reaction is cooled and the precipitate is 
filtered. The filtrate is washed with sodium carbonate and extracted with 
dichloromethane. The organic layer is evaporated in vacuo and the residue 
is purified by column chromatography (silica gel, 10% ethanol/ethyl 
acetate). The major product is taken up in diethyl ether and the 
precipitate is filtered. The filtrate is evaporated in vacuo to give 0.8 g 
of 1-(2-pyridinyl)-4-[3-(3-pyridinyl)propyl]piperazine as a white solid; 
mp 51-52.degree. C. 
EXAMPLE 2 
1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone 
A solution of 4-chloro-1-(3-pyridinyl)-1-butanone (Example B) (9 g, 0.049 
mol), 1-(2-pyridinyl)piperazine (24 g, 0.147 mol), and potassium iodide 
(0.8 g, 0.005 mol) is heated to 120.degree. C. for 5 minutes. The residue 
is taken up in chloroform (40 mL) and the precipitate is filtered. The 
filtrate is evaporated in vacuo and purified by column chromatography 
(silica gel, 2% methanol/dichloromethane). The major product is 
crystallized from 2-propanol/diethyl ether to give 6.7 g 
1-(3-pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone as a white 
solid; mp 89.degree. C. 
In a process analogous to Example 2 using appropriate starting materials 
the corresponding compounds of Formula I (Examples 3 to 7) are prepared as 
follows: 
EXAMPLE 3 
1-(3-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]-1-butanone 
mp 109-112.degree. C. 
EXAMPLE 4 
1-(4-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone 
mp 89.degree. C. 
EXAMPLE 5 
1-(4-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]-1-butanone 
mp 100.degree. C. 
EXAMPLE 6 
1-(3-Quinolinyl)-4-[4-(2-pyridinyl)-1-(piperazinyl)]-1-butanone 
mp 96-97.degree. C. 
EXAMPLE 7 
1-(4-Quinolinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone 
mp 198-199.degree. C. 
EXAMPLE 8 
1-(2-Pyridinyl)-4-[4-(3-pyridinyl)butyl]piperazine 
A solution of 1-(3-pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone 
(Example 2) (5.2 g, 0.0168 mol), hydrazine hydrate (1.9 g, 0.0603 mol), 
and potassium hydroxide (3 g, 0.0538 mol) in ethylene glycol (100 mL) is 
refluxed 12 hours removing the water formed with a Dean-Stark trap. The 
cooled reaction mixture is diluted with water (100 mL) and extracted with 
dichloromethane. The organic layer is dried (sodium sulfate) and the 
solvent evaporate in vacuo. The resulting residue is crystallized from 
2-propanol and diethyl ether to give 2 g of 
1-(2-pyridinyl)-4-[4-(3-pyridinyl)butyl]piperazine as a white solid; mp 
54-64.degree. C. 
In a process analogous to Example 8 using appropriate starting materials 
the corresponding compounds of Formula I (Examples 9 to 13) are prepared 
as follows: 
EXAMPLE 9 
2-4-[4-(4-Pyridinyl)butyl]-1-piperazinyl]pyridine 
mp 56-58.degree. C. 
EXAMPLE 10 
2-[4-[4-(4-Pyridinyl)butyl]-1-piperazinyl]pyrimidine 
mp 49.degree. C. 
EXAMPLE 11 
3-[4-[4-(2-Pyridinyl-1-piperazinyl]butyl]quinoline 
mp 89-90.degree. C. 
EXAMPLE 12 
3-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]quinoline 
mp 70-71.degree. C. 
EXAMPLE 13 
4-[4-[4-(2-Pyridinyl)-1-piperazinyl]butyl]quinoline 
mp 70-71.degree. C. 
PREATION OF STARTING MATERIALS 
EXAMPLE A 
3-Pyridinylpropylchloride 
A solution of 3-(3-pyridinyl)-1-propanol in concentrated hydrochloric acid 
(60 mL) is refluxed for 12 hours. The solution is made basic with sodium 
hydroxide and extracted with dichloromethane. The organic layer is dried 
(sodium sulfate) and the solvent is evaporated in vacuo to give 11.3 g of 
3-pyridinylpropylchloride. 
EXAMPLE B 
4-Chloro-1-(3-pyridinyl)-1-butanone (Sato, M., et al, Chem. Pharm. Bull., 
26, 3296 (1978)). 
A solution of methyl nicotinate (59 g, 0.43 mol), 4-hydroxybutyric acid 
lactone (51.8 g, 0.602 mol), and sodium methoxide (70 g, 1.29 mol) in 
dioxane (500 mL) is refluxed for 1 hour and then cooled. Concentrated 
hydrochloric acid (650 mL) is added, and the reaction mixture refluxed for 
12 hours. The resulting solution is neutralized with solid sodium 
bicarbonate and extracted with chloroform. The organic phase is dried 
(sodium sulfate), and the solvent evaporated in vacuo. The residue is 
taken up in 2-propanol (50 mL) and treated with a saturated solution of 
hydrogen chloride in 2-propanol. The hydrochloride salt of 
4-chloro-1-(3-pyridinyl)-1-butanone is obtained as a white solid (30 g); 
mp 73-76.degree. C.