Chemical process

A process is disclosed for the preparation of a compound of formula (I): ##STR1## where Ar is aryl or substituted aryl and R.sup.3 and R.sup.4 are the same or different and each is alkyl, which process comprises hydrognating a compound of formula (II): ##STR2## wherein Ar, R.sup.3 and R.sup.4 are as defined with respect to formula (I) and Hal is a halogen atom. Compounds of formula (I) are useful as chemical intermediates.

This invention relates to a novel chemical process for preparing 
aryl-piperidine esters and to novel intermediates used in that process. 
British patent No. 1422263 and U.S. Pat. No. 4007196 disclose compounds of 
formula A 
##STR3## 
in which R.sup.1 represents hydrogen, trifluoro (C.sub.1-4) alkyl, alkyl 
or alkynyl, R.sup.2 represents an alkyl or alkynyl group having 1-4 carbon 
atoms, or a phenyl group optionally substituted by C.sub.1-4 alkyl, 
alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or 
methylenedioxy, or represents tetrahydronaphthyl, and X represents 
hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, 
halogen, methylthio, or aralkyloxy. 
The compounds of formula A are disclosed as having pharmacological 
properties that make them useful as anti-depressants. 
One compound that has proved especially valuable is paroxetine (R.sup.1 =H, 
R.sup.2 =5-(1,2-benzdioxylyl), X=4-F) which is in the )-)-trans 
configuration. 
In the above-mentioned patents, the compounds of formula A are prepared 
using an intermediate of formula B 
##STR4## 
in which R.sup.1 and X are as defined above. 
The piperidine carbinols of formula B are prepared by reduction of an ester 
of formula C 
##STR5## 
with a complex metal hydride reducing agent. 
The compound of formula C is obtained by reacting arecoline (when R.sup.1 
=methyl) or arecoline homologues with phenyl (or substituted phenyl) 
magnesium bromide. This procedure has the disadvantages that arecoline is 
a powerful irritant and that the ester of formula C is obtained as a 
mixture of cis and trans configuration compounds. 
We have now discovered a new process for preparation of piperidine carbinol 
esters which advantageously avoids the use of arecoline and selectively 
produces the cis-isomer in a good overall yield. 
Accordingly, the present invention provides a process for preparing a 
compound of formula I 
##STR6## 
in which Ar represents an aryl or substituted aryl group and R.sup.3 and 
R.sup.4 each represents an alkyl group, by hydrogenation of a compound of 
formula II 
##STR7## 
in which Ar, R.sup.3 and R.sup.4 are as defined for formula (I), and Hal 
represents a halogen atom. 
In formulae I and II, Ar may be 
##STR8## 
where X is as defined for formula A. Preferably X is fluorine or hydrogen 
and R.sup.3 is methyl. The halogen Hal is preferably chloride or bromide. 
The hydrogenation may be carried out conventionally as a catalytic 
hydrogenation, for example using a platinum oxide catalyst. 
The compounds of formula I are obtained in the cis-configuration but as a 
mixture of enantiomers. The compounds may be resolved into their 
enantiomeric forms by conventional methods, such as by use of an optically 
active acid. 
The compounds of formula I may optionally be converted to the 
trans-configuration by treatment with a base, for example sodium 
methoxide, in an inert solvent such as toluene. 
The esters of formula I may be converted to the corresponding carbinols by 
conventional reduction, for example using a metal hydride such as lithium 
aluminium hydride. The cis-ester gives the cis-carbinol, and the 
trans-ester gives the trans-carbinol. 
The carbinols obtained from the compounds of formula I may be used as 
intermediates in the preparation of compounds of formula A making use of 
the procedures set out in British Patent No. 1422263 or U.S. Pat. No. 
4,007,196. 
For example, to prepare paroxetine, the carbinol in which 
##STR9## 
and R.sup.3 =Me in the (+)-cis or )-)-trans configuration is reacted with 
thionyl chloride or benzenesulphonyl chloride and then with sodium 
3,4-methylenedioxyphenoxide. 
Subsequently the N-methyl group is replaced by reaction with phenyl 
chloroformate followed by de-acylation with KOH to obtain R.sup.3 =H. 
The present invention also provides the intermediates of formula II as 
novel compounds. Preferred substituents are as exemplified for formula I. 
The quaternary pyridines of formula II may be prepared from aryl-pyridines 
of formula III 
##STR10## 
by quaternization under conventional conditions with an alkyl halide of 
formula R.sup.3 -Hal. 
The aryl-pyridines of formula III may be prepared by reacting an alkyl, 
preferably methyl, nicotinate (formula IV) with a chloroformate ester, 
such as ethyl or phenyl chloroformate, and an aryl magnesium halide to 
give a dihydropyridine of formula V. The dihydropyridine (formula V) is 
then aromatized and the nitrogen atom de-protected in conventional manner, 
for example by heating with sulphur in decalin, to give the compounds of 
formula III. The procedure is illustrated in the following reaction scheme 
in which Ar, R.sup.4 and Hal are as defined above and R.sup.5 is an alkyl 
or aryl group. 
##STR11## 
Certain of the intermediates described above are novel and, together with 
the above described processes for their preparation, they form part of the 
present invention. 
In particular the present invention provides as novel compounds the 
compound of formula III in which Ar=4-fluoro-phenyl and R.sup.4 =methyl, 
and the compound of formula V in which Ar=4-fluoro-phenyl, R.sup.4 =methyl 
and R.sup.5 =ethyl. 
As used herein, the terms alkyl, alkoxy, aralkyloxy and aryl include, but 
are not limited to, groups in which the alkyl moiety, when present, is a 
straight or branched alkyl group containing from 1 to 6 carbon atoms, more 
especially from 1 to 4 carbon atoms, and the aryl moiety when present, is 
phenyl. 
The following Examples illustrate the preparation of novel intermediates of 
this invention (Example 1) and the novel process of this invention 
(Example 2a).

EXAMPLE 1 
4-(4'-Fluorophenyl)-3-methoxycarbonyl-1-methylpyridinium bromide 
Ethyl chloroformate (3.5 ml) was added to a stirred suspension of cuprous 
chloride (0.33 g) in dry tetrahydrofuran (100 ml) under nitrogen. After 
cooling to 0.degree., a solution of methyl nicotinate (5.0 g) in 
tetrahydrofuran (10 ml) was added slowly followed by the addition of 
4-fluorophenyl magnesium bromide solution [from 4-bromo-fluorobenzene (4.4 
ml) and magnesium (0.93 g) in tetrahydrofuran (25 ml)]. After stirring for 
20 minutes, the mixture was diluted with ethyl acetate and decomposed by 
the addition of a saturated ammonium chloride/ammonia solution (1:1, 100 
ml). The organic phase was washed with dilute acid and brine and dried 
over anhydrous sodium sulphate. Evaporation of the solvent gave 
1,4-dihydro-1-ethoxycarbonyl-4-(4'-fluorophenyl)-3-methoxycarbonylpyridine 
as an off-white solid (10.37 g, 93%). A sample crystallised from ethyl 
acetate had m.p. 83-85.degree.. 
The crude dihydropyridine (10.37 g) was dissolved in warm decalin (25 ml) 
and sulphur (1.04 g) added. The mixture was refluxed under nitrogen for 16 
hours, then cooled and diluted with ethyl acetate (100 ml) and extracted 
with dilute hydrochloric acid (4.times.25 ml, 2M). The aqueous acid 
extracts were washed with ethyl acetate (20 ml), basified with 20% sodium 
hydroxide solution and extracted with dichloromethane (50 ml and 
3.times.25 ml). The organic solutions were dried (potassium carbonate) and 
evaporated to give 4-(4'-fluorophenyl)-3-methoxycarbonylpyridine as an oil 
which rapidly crystallized (5.98 g, 76%). A sample crystallized from ethyl 
acetate had m.p. 94.degree.-95.degree.. 
The crude pyridine (5.95 g) was treated with methyl bromide (2.2 ml) in 
acetone (25 ml). After heating in a sealed vessel at 53.degree. for 60 
hours and cooling to 0.degree., the title pyridinium salt was collected by 
filtration, washed with acetone and dried (7.4 g, 88%), m.p. 
165.degree.-170.degree. (decomp.). 
______________________________________ 
.sup.1 H-n.m.r. (CDCl.sub.3) 
______________________________________ 
.delta. = 3.84 
(s, 3H) 
4.86 (s, 3H) 
7.23 (m, 2H) 
7.44 (m, 2H) 
8.08 (d, J = 7 Hz, 1H) 
9.58 (s, 1H) 
9.88 (d, J = 7 Hz, 1H) 
______________________________________ 
EXAMPLE 2 
(a) (.+-.)-cis-4-(4'-Fluorophenyl)-3-methoxycarbonyl-1-methyl-piperidine 
4-(4'-Fluorophenyl)-3-methoxycarbonyl-1-methylpyridinium bromide (15.90 g), 
prepared as in Example 1, in ethanol (250 ml) was hydrogenated at 
atmospheric pressure and 45.degree. for 24 hours, in the presence of 
platinum oxide (0.5 g). Evaporation of the filtrate after removing the 
catalyst gave a dark oil which was partitioned between 10% sodium 
carbonate solution (100 ml) and dichloromethane (30 ml). After separation, 
the aqueous phase was extracted with dichloromethane (3.times.20 ml) and 
the organic solutions dried (potassium carbonate) and evaporated to give 
an off-white solid (12.1 g). Crystallisation from ethyl acetate gave the 
title compound as white crystals (8.32 g, 72%), m.p. 
88.degree.-89.degree.. 
______________________________________ 
.sup.1 H n.m.r. (CDCl.sub.3) 
______________________________________ 
.delta. = 1.75 - 3.30 
(m, 8H) 
2.27 (s, 3H) 
3.50 (s, 3H) 
6.75 - 7.40 
(m, 4H) 
______________________________________ 
(b) Isomerisation to 
(.+-.)-trans-4-(4'-fluorophenyl)-3-methoxycarbonyl-1-methylpiperidine 
(.+-.)-cis-4-(4'-Fluorophenyl)-3-methoxycarbonyl-1-methylpiperidine (2.0 
g), prepared as in Example 2(a), in dry toluene was added to sodium 
methoxide in toluene and refluxed for 7 hours. After cooling to 0.degree. 
and filtration, evaporation gave the title compound as an oil (1.97 g, 
99%), purity 85-90%. 
______________________________________ 
.sup.1 H-n.m.r. (CDCl.sub.3) 
______________________________________ 
.delta. = 1.15 - 1.95 
(m, 4H) 
2.30 (s, 3H) 
2.50 - 3.25 
(m, 4H) 
3.40 (s, 3H) 
6.80 - 7.30 
(m, 4H) 
______________________________________