CA1325215C

CA1325215C - Process for the preparation of n-(2-chloro-benzyl)2- (2-thienyl) ethylamine and intermediate compounds in this preparation

Info

Publication number: CA1325215C
Application number: CA000580875A
Authority: CA
Inventors: Joel Radisson
Original assignee: Sanofi SA
Current assignee: Sanofi Aventis France
Priority date: 1987-10-22
Filing date: 1988-10-21
Publication date: 1993-12-14
Anticipated expiration: 2010-12-14
Also published as: JPH01159389A; ES2032334T3; JP2664438B2; PT88788B; EP0313472B1; DE3869318D1; FR2622191B1; FR2622191A1; EP0313472A1; ATE73794T1

Abstract

Company named : SANOFI

Inventor : RADISSON Jo?l Process for the preparation of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine and intermediate compounds in this preparation A B S T R A C T

The invention relates to a process for the preparation of the product of the formula I
wherein an imine of formla II

Ar1-CH2 -N = CH-Ar2 II

in which Ar1 and Ar2 are different and represent a 2-thenyl group or a 2-chlorophenyl group, is reduced by chemical or electrochemical means or by catalytic hydrogenation.

Fig. None.

Description

132~215 The present invention relates to a process for the preparation of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine, starting from an imine.
This secondary amine was described for the first time in the patent FR-A 2 300 090 as an intermediate in the synthesis of the compound of formula:

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a platelet aggregation inhibitor, the international nonproprietar name Of which is ticlopidine.
The process for the preparation of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine of the formula :

.
~3_CH2--CH2--NH CH2 ~ I

. . .
~ described in the patent FR-A-2 300 090 consists in the reaction of : 2-chlorobenzylamine with 2-(2-thienyl)-ethyl benzenesulfonate according :' to the rea~tion scheme:
. - . .

~ CH2 2 ~ S02 _ 0 _ CH2 _ CH
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, _ .
~:~ The amine is available on an industrial scale but the sulfonate of formula II has to be prepared from 2-(2-thienyl) ethanol, obtained by , the action of ethylene oxide on the organolithium compound :
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Although the yields of the successive reactions are satisfactory, the overall process is expensive, especially as the first step implies working under rigorously anhydrous conditions.
It has now been found that the compound of formula I can be prepared in excellent yields by reduction of a Schiff base.
An object of the invention is thus a process for the preparation of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine by reduction by means of chemical or electrochemical means or by catalytic hydrogenation of an imine of the formula Ar -CH2-NzCH-Ar II

in which Arl and Ar2 are different and each represents a thenyl group (i.e. a 2-thienyl methyl group) or a 2-chlorophenyl group, i.e. compounds of the formula ~ CH2- CH2- N =C ~ IIA

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ZS l~1CH2--CH= N--CHz~ ~ IID

The compounds (II) are new products and another ob~ect of the - invention; they can be prepared in excellent yields by condensation of an aldehyde of formula ArlCH0 with a primary amine of formula Ar CH2NH2, ` 30 in which Ar and Ar have the same meanings as those in formula II.
The Schiff base of formula IIA is obtained by condensation of ~ 2-chlorobenzaldehyde with 2-(2-thienyl) ethylamine. The yields are ;1 sibst~t~ly quantitative when the reaction is carried out at temperatures between 20 C and 80 C.
The formation of the Schiff base IIB is also rapid and 5~b~=n~kL~
quantitative.Itis sufficientto mix t~ n~n~ the 2-thiophene acetaldehyde ~eing preferably ~d, to the 2-chlorobenzylamine,pure or in solution.
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One of the two reagents may be in slight excess. It is preferable to use an excess of from O to 10 % of 2-chlorobenzylamine, expressed as moles.
The reaction is preferably carried out between 0 C and 40 C, and preferably between 0 C and 5 C.
The reactions leading to the formation of the Schiff bases IIA
and IIB can be carried out in an inert solvent such as the methyl, ethyl, propyl and butyl alcohols, the ethyl and isopropyl ethers,tetrahydrofuran, dioxane, the aromatic hydrocarbons such as benzene, toluene and xylene.
It is not necessary to add a dehydrating agent to the reaction medium.
The Schiff bases of the formulae IIA and IIB can be reduced in a standard manner by catalytic hydrogenation or by chemical reduction, - either by hydrogen in the presence of a catalyst such as finely divided nickel or cobalt, platinum, palladium, rhodium and ruthenium;
- or by a metal hydride such as lithium aluminium hydride or sodium borohydride;
- - or by a sufficiently electropositive metal such as sodium, magnesium or zinc, or by any other reducing agent such as sodium dithionite.
The Schiff bases can also be reduced by electrochemical means.
The reduction can be performed after isolation of the Schiff bases from the reaction medium or simultaneously with their preparation by adding, for example, the aldehyde to the reaction medium containing the amine and the reducing agent.
The product of formula I is isolated by distillation or by crystallization of one of its salts, in par~icular its hydrochloride.
The following examples illustrate the invention.
EXAMPLE No. 1 : N-(o-chlorobenzylidene) 2-(thienyl) ethylamine (compound of formula IIA) 127.5 g (1 mole) of 2-(2-thienyl) ethylamine are dissolved in 200 ml of isopropyl ether. 148 g (1.05 mole) of 2-chlorobenzaldehyde ` dissolved in 200 ml of isopropyl ether are added in one portion. After . 30 min., the water of reaction is decanted and the solution is stirredfor a further 30 min. in the presence of 20 g of magnesium~sulfate.
The magnesium sulfate is filtered off, the ether is evaporated and the residue is distilled under reduced pressure.

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234.7 g of N-(o-chlorobenzylidene) 2-(2-thienyl) ethylamine distilling between 140 C and 150 C at 0.4-0.5 mm of mercury (53 to 66 Pa) are obtained.
The product is characterized by infra-red spectroscopy as a thin film (~ C N at 1640 cm ) and proton NMR : 1 triplet (2H) at 3.25 ppm, 1 triplet (2H) at 3.95 ppm, aromatic protons (7H) between 6.8 and 8.2 ppm, 1 singlet at 8.65 ppm (lH) (solvent : CDC13; internal reference : tetra-methylsilane).
EXAMPLE 2 : N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride.
26.0 g (0.20 mole) of 2-(2-thienyl) ethylamine are added to a solution of 28.1 g (0.20 mole) of 2-chiorobenzaldehyde in 140 ml of ethanol and the mixture is heated for 40 min. at 55 C. 15.1 g (0.40 mole) of sodium borohydride are then added at 55 C during 10 min. and stirring is continued for a further 5 min. The solution is cooled to ambient temperature. 200 g of ice and 60 ml of concentrated hydrochloric acid (d: 1.18) are added. The product which crystallized is filtered off, washed with water and alcohol and dried to constant weight at 60 C.
52.2 g of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride are thus obtained.
M.p. = 148 C. NMR as expected. Yield : 90.6 %.
EXAMPLE 3 : N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride 30.9 g (0.22 mole) of 2-chlorobenzaldehyde are added to a solution of 26.0 g (0.20 mole) of 2-(2-thienyl) ethylamine in 150 ml of methanol. The mixture is stirred for 30 min. at 25 C, then refluxed for 30 min. 8.3 g (0.22 mole) of NaBH4 are added to the solution after it has ` been cooled to 10 C. and the mixture is stirred at ambient temperature - for 30 min.
After evaporation of the methanol, the residue is taken up in 100 g of ice and 60 ml of concentrated hydrochloric acid. The product which crystallized is filtered off, washed wit~ water, acetone and ether, and dried to constant weight at 50 C.
54.75 g of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydro-chloride are thus obtained.
M.p. = 148 C. Yield : 95.0 %

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132~215 EXAMPLE 4 : N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride By repeating the experiment described in Example 3, except that 5.9 g (0.15 mole) of sodium borohydride are used, 54.5 g of N-(2-chloro-benzyl) 2-(2-thienyl) ethylamine hydrochloride are obtained.
Yield : 94.6 %
EXAMPLE 5 : N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride 28.1 g (0.20 mole) of 2-chlorobenzaldehyde dissolved in 50 ml of isopropyl ether are added to a solution of 26.0 g (0.20 mole) of 2-(2-thienyl) ethylamine in 50 ml of isopropyl ether. After 10 min. of heating under reflux the water of reaction is decanted, the ethereal phase is dried over MgS04 and filtered. A solution of 7.6 g (0.2 mole) of LiAlH4 in 100 ml of anhydrous ether are then added during 30 min. and the mixture i B ref~d again for 1 h. Subsequently, 50 ml of ethyl acetate, 13 ml of water, 3 ml of 15 % NaOH and again 40 ml of water are added.
The mineral salts are filtered off and rinsed with 200 ml of isopropyl ether. 100 ml of 4N hydrochloric acid are added to the filtrate.
After being stirred for 1/2 h, the product which has crystallised is ' filtered off, rinsed with water and ether, and dried to constant weight at 60 C.
; 20 50.7 g of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride are thus obtained.
M.p. = 147 C. Yield : 88 %
EXAMPLE 6 : N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride 25 g (0.196 mole) of 2-(2-thienyl) ethylamine are mixed with 30.3 g (0.215 mole) of 2-chlorobenzaldehyde in 100 ml toluene. After 15 min.
the water of reaction is decanted and the toluene is evaporated under reduced pressure. The residue (consisting essentially of the Schiff base IIA) is taken up in 200 ml of ethanol and is hydrogenated in the presence of 5 g of Raney nickel at 50 C at a pressure of 20 bars ( 2M~a ). When the stoichiometric amount of hydrogen has been absorbed, the hydrogen isdriven ~ut , the Raney nickel is filtered off and the alcohol is evaporated.
The concentrate is stirred with 200 ml of isopropyl ether, 100 g of ice and 60 ml of concentrated hydrochloric acid. The product which-crystallized is filtered off, washed with water, acetone and ether, then dried at 60 C to constant weight.
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132~215 52.3 g of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride are obtained.
M.p. = 148 C. Yield : 92.9 %.
EXAMPLE 7 : N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride 12.7 g (0.10 mole) of 2-(2-thïenyl) ethylamine are mixed with 14.0 g (0.10 mole) of 2-chlorobenzaldehyde in 100 ml of toluene. After decantation of the water of reaction and evaporation of the toluene~ the Schiff base obtained is hydrogenated in 200 ml of ethanol in the presence of 5 g of palladium on charcoal at 40 C at a pressure of 10 bars (]~Pa ) -When the stoichiometric amount of hydrogen has been absorbed, the hydrogen . is imnedi:ately driven out and the catalyst filtered off. ~fter a final - work-up as described in Example 6, 24.5 g of N-(2-chlorobenzyl) 2-(2-thienyl)l ethylamine hydrochloride are obtained.
7 M.p. = 146 C. Yield : 85 %
EXAMPLE 8 : N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride 0.1 Mole of crude Schiff base (IIA), prepared as described in Example 6) are refluxed in 100 ml of anhydrous methanol in the presence of 5 g of dry magnesium; after 1 h, the mixture is diluted with an additional 50 ml of methanol, 3 g of magnesium are added and refluxing is continued for a further 2 h.
l The methanol is then evaporated and the residue is taken up in :i, 50 ml of concentrated hydrochloric acid and loog of ~ After being stirred for half an hour, the product is filtered off, washed with water, acetone and isopropyl ether, and dried at 60 C to constant weight.
27.7 g of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride are obtained.
~, M.p. = 147 C. Yield : 96.2 %.
j EXAMPLE 9 :
.~i 13 g of zinc powder are added in small portions to 0.1 mole of Schiff base (IIA),prepared as described in Example 6 and dissolved in 25 ml of sodium hydroxide (400 g/l) in 100 ml of ethanol,and stirred for `~ 18 h. The reaction mixture is then filtered and the alcohol is evaporated.
The residue obtained after evaporation is taken up in 100 g of ice and 50 ml of concentrated hydrochloric acid. The product which crystallized is filtered off, washed with water, acetone and isopropyl ether, and drie~
at 60 C to constant weight.

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22.7 g of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride are obtained.
M.p. = 147 C. Yield : 78.8 %
EXAMPLE 10 :
34.8 g (0.20 mole) of sodium dithionite are suspended in a mixture of 150 ml of ethanol and 50 ml of water in an atmosphere of nitrogen, then 0.1 mole of Schiff base (IIA), prepared according to ; Example 6, is added. After being stirred for 18 h at ambient temperature and refluxed for 1 h, the suspension is filtered, the insoluble material is washed with 100 ml of ethanol and the filtrate is evaporated to dryness.
; The residue is taken up in 100 g of ice, 60 ml of concentrated hydrochloric acid and 200 ml of isopropyl ether. The product which crystallized is filtered off, washed with water, acetone and ether, and dried at 60 C to constant weight.
24.8 g of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride are obtained.
M.p. = 148 C. Yield : 86.0 %
EXAMPLE 11 :
.
14.5 g (0.058 mole) of Schiff base (IIA), prepared in toluene as described in Example 6, are dissolved in a solution of potassium . acetate (30 g) in 160 ml of ethanol and 40 ml of water. The solution is :' placed in the cathode compartment of an electrolysis apparatus whereas~, the anode compartment contains a solution of 100 g of potassium acetate in 160 ml of ethanol containing 20 % water. The cathode is a layer of ;~ 25 mercury and the anode is made of graphite. Electrolysis is carried outfor 3 h at 20 C with a current of 2 amperes. The cathode solution is then diluted with 100 ml of water, extracted twice with 200 ml of isopropyl ether and then the ethereal phase is stirred with 100 ml of 6N hydrochloric acid. The product which precipitated is filtered off, washed with water, acetone and ether, and dried at 60 C to constant weight.
- 14.35 g of N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride are obtained.
M.p. = 147 C. Yield : 85.6 %

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EXAMPLE 12 :
17.8 g (0.10 mole) of 2-chlorobenzylamine hydrochloride and 28.2 g (0.2 mole) 2-chlorobenzylamine are dissolved in 150 ml of methanol.
4.4 g (0.07 mole) of sodium cyanoborohydride are added, followed by 12.6 g (0.10 mole) of 2-thiophene acetaldehyde-A~ithin 30 min. with the temperature maintained between 10 C and 20 C, and the mixture was stirred for 30 hours at 25 C. The reaction mixture is then poured onto 200 g of ice and 200 ml of concentrated hydrochloric acid. After the mixture has been stirred for 15 min. , 200 ml of isopropyl ether are added and stirring is then continued for 15 min. The N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride which crystallized is filtered off, washed with water, acetone and ether, and dried to constant weight. 21.9 g of the expected product are obtained.
Yield : 76 % (with respect to the thiophene acetaldehyde).
EXAMPLE 13 :
22.7 g (0.18 mole) of 2-thiophene acetaldehyde are addedwlthin 30 min. to 28.2 g (0.2 mole) of 2-chlorobenzylamine cooled to 0 C while the temperature is maintained between 0 C and 10 C. N-2-(2-thienyl) ethylidene 2-chlorobenzylamine (formula IIB) is thus obtained and characterized by infra-red spectroscopy (~ C N at 1640 cm 1) and proton ¦ 20 NMR spectroscopy : 1 methylene singlet at 3.8 ppm, 1 methylene doublet at 3.75 ppm, aromatic protons between 6.7 and 7.4 ppm and 1 methine proton at 7.75 ppm (solvent : CDC13; internal reference : tetramethylsilane).
The Schiff base (IIB) is dissolved in 200 ml of methanol and ~ hydrogenated in the presence of 5 g of Raney nickel at 20 C at a hydrogen :1 25 pressure of 5 bars (50~ kPa3 .
:' The Raney nickel is filtered off, the methanol is evaporated, ; the residue is taken up in 200 ml of isopropyl ether and stirred for 30 min.
i in the presence of 200 ml of 6N hydrochloric acid.
The N-(2-chlorobenzyl) 2-(2-thienyl) ethylamine hydrochloride ` 30 which crystallized is filtered off, washed with water, acetone and ether, ' and dried to constant weight. 45.6 g of the expected product are obtained.
J Yield : 88 %.

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Claims

1.A process for the preparation of the product of the formula:

wherein an imine of formula II

Ar1-CH2-N=CH-Ar2 II

in which Ar1 and Ar2 are different and each represents a 2-thenyl group or 2-chlorophenyl group, is reduced by chemical or electrochemical means or by catalytic hydrogenation.

2.A process according to Claim 1, wherein the imine (II) is reduced by hydrogen in the presence of a catalyst,

3.A process according to Claim 1, wherein the imine (II) is reduced by means of a metal hydride.

4.A process according to Claim 1, wherein the imine (II) is reduced by sodium dithionite.

5.A process according to Claim 1, wherein the imine (II) is reduced by an electropositive metal.

6.A process according to Claim 1, wherein the reduction of the imine (II) is carried out simultaneously with its preparation from an aldehyde Ar1CHO and an amine Ar2CH2NH2, in which Ar1 and Ar2 have the same meanings as in formula I.

7.A process according to Claim 1, wherein the imine (II) is reduced by electrochemical means.

8.A product of the formula Ar1-CH2-N=CH-Ar2 II

in which Ar1 and Ar2 are different and each represents a 2-thenyl group or a 2-chlorophenyl group.

9.A process for the preparation of the product of the formula II
according to Claim 8, wherein an aldehyde Ar1CHO is condensed with an amine Ar2CH2NH2, in which Ar1 and Ar2 have the same meanings as in formula II.