FR2614619A1 - Process for the preparation of N-(2-chlorobenzyl)-2-(2-thienyl)ethylamine - Google Patents

Abstract

Process for the preparation of N-(2-chlorobenzyl)-2-(2-thienyl)ethylamine, characterised in that 2-(2-thienyl)ethylamine is reacted with a compound of formula III in which X represents a halogen atom, a (C1-C6)alkylsulphonate group or a (C6-C13)arylsulphonate group, or a nitrate group. The product obtained is an intermediate in the synthesis of a medicament.

Description

 The present invention relates to a process for the preparation of N - [(chloro-2)] - benzyl (2-thienyl) ethylamine from (2-thienyl-2-ethylamine.

antiagrégant plaquettaire, dont la dénomination commune internationale est ticlopidine.This secondary amine has been described for the first time in FR-A-2,300,090 as an intermediate for synthesizing the compound of formula

antiplatelet agent, the international nonproprietary name of which is ticlopidine.

décrit dans le brevet FR-A-2 300 090 comprend la réaction de la (chloro-2)-benzylamine sur le benzènésul- fonate de (thiényl-2)-2 éthyle selon le schéma reactionnel :

The process for the preparation of N- (chloro2) -benzyl (thienyl-2) -2-ethylamine of formula

described in FR-A-2 300 090 comprises the reaction of (chloro-2) -benzylamine on benzenesulfonate of (2-thienyl) ethyl according to the reaction scheme:

The amine is available in industrial quantities but the sulfonate must be prepared from 2-thienyl-2-ethanol, obtained by the action of ethylene oxide on the organolithium:

 Although the yields of the successive reactions are satisfactory, the whole process is expensive, especially since it involves working, for the first step, in a rigorously anhydrous mile.

dans laquelle X représente un groupe partant tel qu'un atome d'halogène, un groupement alkyi (en C1-C6) ou
aryl (en C6 -C13) sulfonate ou un groupe nitrate.It has now been found that the compound of formula I can be prepared in excellent yields by reacting 2-thienyl-2-ethylamine with a benzyl derivative of formula III

in which X represents a leaving group such as a halogen atom, a (C 1 -C 6) alkyl group or
aryl (C 6 -C 13) sulfonate or a nitrate group.

 The reaction is carried out in a particularly polar solvent, preferably in the presence of a mineral or organic base.

Preferred X groups are Cl, Br, CH 3 SO 3 and C 6 H 5 SO 3 -
All solvents generally used in nucleophilic substitution reactions, and in which thienylethylamine and the compound of formula
III are sufficiently soluble can be used as a reaction medium.At mention may be made of anhydrous or non-anhydrous alcohols, such as methanol, ethanol, propanols and ethylene glycol; etheroxides such as isopropyl ether, tetrahydrofuran, dioxane, ethylene glycol mono and diethers; ketals, such as methylal and 1,3-dioxane; ketones such as acetone, methyl ethyl ketone; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; esters, such as acetates and alkyl formates. Ethanol and methyl ethyl ketone are preferred solvents, especially for reasons of cost.

 The temperature of the reaction medium may be between 10 ° C. and the reflux temperature of the solvent: a temperature ranging from 60 ° C. to 80 ° C. is preferred.

 The reaction time is a function of the reactants present and the temperature; it is usually 4 to 6 hours but can be between 1 hour and 24 hours. The bases that can be used can be inorganic, such as oxides, hydroxides and carbonates of alkali and alkaline earth metals, or organic such as tertiary amines, such as diisopropylethylamine, triethylamine and pyridine. In the medium is introduced up to 1 to 1.5 molar equivalents of base relative to the compound of formula III. The base may also be (2-thienyl) -2-ethylamine itself.

The operation is generally carried out with an excess of 2-ethyl-2-ethylamine relative to the compound of formula
III, from 2 to 5 molar equivalents and preferably from 3 to 4 equivalents, to avoid the formation of tertiary amine; the excess amine can be removed by distillation or by selective solubilization of one of its salts, and particularly of its hydrochloride, which makes it possible to recycle it.

 The product of formula I is isolated by distillation or by crystallization of one of its salts, in particular its hydrochloride. In these conditions, there is no difficulty in separating it from the tertiary amine which could have formed.

 The reaction can also be carried out according to a known principle in biphasic medium, preferably in the presence of a phase transfer catalyst. The aqueous phase contains a mineral base such as a hydroxide or an alkali carbonate; the organic solvent may be chosen from water-immiscible solvents such as aliphatic hydrocarbons such as cyclohexane or petroleum ether, or aromatics such as benzene and toluene; ethers such as ethyl or isopropyl ether; alkyl halides such as methylene chloride or chloroform. Preferably, from 0.5 to 2 volumes of aqueous phase relative to the organic phase, in which the starting materials are solubilized, in a proportion of 2 to 5 molar equivalents of amine relative to the compound of formula III.

 The phase transfer catalysts that may be used may be chosen from quaternary ammonium and phosphonium salts. Tetra (n-butyl) ammonium hydrogen sulfate, triethylbenzylammonium chloride and trioctylmethylammonium chloride are preferred. The reaction time is 24 to 72 hours, and preferably 24 to 48 hours.

ou par réduction catalytique du (thiényl-2)acétonitrile.The starting thienylethylamine can be prepared, as described in FR-A-2,299,332, by phthalimide of the formula

or by catalytic reduction of (2-thienyl) acetonitrile.

 The following examples illustrate the invention.

EXAMPLE 1
A solution in 200 ml of ethanol of 76.2 g (0.6 mol) of (2-thienyl-2-yl) ethylamine and 32.2 g (0.2 mol) of hexane is maintained at reflux temperature for 5 hours. (2-chlorobenzyl) chloride in the presence of 27.6 g of K 2 CO 3.

 After cooling to room temperature, the mixture is filtered off and the ethanol is then removed under reduced pressure and the residue is taken up in 100 ml of water and 300 ml of methylene chloride. The aqueous phase is then separated and the organic solvent removed under reduced pressure.

 The residue is distilled under reduced pressure. The excess (499) of (2-thienyl) -2-ethylamine distilled at 87 ° C. under 200 mmHg (2.66 kPa), and the compound of formula I distilled at 136-144 ° C. under 0.4 mmHg (53 Pa). .

 45.82 g of pure N- (2-chloro-2-benzylthienyl) ethylamine are thus isolated, which corresponds to 91% yield relative to the chlorinated derivative and 85% yield relative to the unrecovered thienylethylamine.

 The centesimal analysis and the infrared spectrum of the isolated product are in conformity.

Example 2
In this example, the reaction is carried out under the same conditions as those described in Example 1, but the isolation conditions of the final product are modified to obtain the hydrochloride directly.

 After removal of 1 ethanol, the residue is taken up in 200 ml of 6N hydrochloric acid. The hydrochloride of the final product precipitates; it is isolated by filtration, washed with water and then resuspended twice in 100 ml of a mixture of isopropyl ether and acetone (90/10).

 Elemental analysis and NMR spectrum conform. F 145-C. Yield: 90.4Z relative to the chloride.

 The excess of (2-thienyl) ethylamine is extracted with isopropyl ether from the acidic aqueous solution after alkalinization. Two volume-to-volume extractions and vacuum distillation make it possible to recover the majority of the unreacted product.

Examples 3 to 8
The procedure is as in Example 2 starting from 0.6 mole of amine and 0.2 mole of (chloro) benzyl chloride. at the reflux temperature of the solvent.

 In Table 1 are mentioned the solvent, the base, the duration of the reaction and the yield of pure hydrochloride relative to the chloride (chloro-2) benzyl introduced.

TABLE 1

<tb> Example <SEP> no <SEP> Solvent <SEP> base <SEP> time <SEP> Yield
<tb><SEP> (volume) <SEP> (weight) <SEP> of <SEP> the <SEP> reaction
<tb><SEP> 3 <SEP> methylethylketone- <SEP> - <SEP> 5 <SEP> h <SEP> 85.9 <SEP>%
<tb><SEP> (200 <SEP> ml) <SEP>
<tb><SEP> 4 <SEP> acetonitrile <SEP> a <SEP> 4 <SEP> h <SEP> 92.1 <SEP> X
<tb><SEP> (150 <SEP> ml) <SEP>
<tb><SEP> 5 <SEP> tetrahydrofuran <SEP> - <SEP> 6 <SEP> h <SEP> 95.7 <SEP>% <SEP>
<tb><SEP> (200 <SEP> ml) <SEP>
<tb><SEP> 6 <SEP> acetate <SEP> ethyl <SEP> - <SEP> 4 <SEP> h <SEP> 92.6 <SEP> X
<tb><SEP> (200 <SEP> ml) <SEP>
<tb><SEP> 7 <SEP> ethanol <SEP> (C2H5) 3N <SEP> 4 <SEP> h <SEP> 89.7 <SEP> X
<tb><SEP> (200 <SEP> ml) <SEP> (22.2 <SEP> g)
<tb><SEP> 8 <SEP> ethanol <SEP> (isoC3H7 <SEP>) <SEP> 2NC2H5 <SEP> 4 <SEP> h <SEP> 89.5 <SEP> X
<tb><SEP> (200 <SEP> ml)
<Tb>
Example 9
A solution of 76.2 g (0.6 mole) of (thienyl) -2-ethylamine and 32.2 g of (chloro-2) benzyl chloride in 200 ml of toluene with 200 ml is maintained under vigorous stirring for 48 hours. 5N aqueous NaOH solution in the presence of 1.5 g of methyltrioctylammonium chloride.

 The aqueous phase is then separated and the toluene phase is stirred with 90 ml of concentrated aqueous HCl solution (10 N) previously poured onto 200 g of crushed ice.

 The precipitate formed is filtered, drained and suspended in 200 ml of isopropyl ether and then in 200 ml of water.

 After drying, 43.7 g of N (2-chlorobenzyl) (2-thienyl) ethylamine hydrochloride are isolated.

M.p. 144-146 ° C. Yield: 75.82.

EXAMPLE 10
The procedure is as in Example 9, but allowing the reaction to continue for 72 hours before treating the reaction medium. The yield is then 84.8% pure hydrochloride.

EXAMPLE 11
A solution of 76.2 g of (2-thien-2-yl) ethylamine and 32.2 g of (chloro-2) benzyl chloride in 200 ml of toluene is stirred for 70 hours with 200 ml of aqueous 5N NaOH solution.

 It is then treated as in Example 9, to obtain 30.8 g of the final hydrochloride. Yield 53.4Z.

When using an aqueous solution of
K2CO3 (2.5 M) instead of 5N NaOH, the yield is 51.5X.

Example 12
a) o-Chlorobenzyl sulphonate
To a suspension of 28.3 g of NaH 502 in 500 ml of isopropyl ether is added, in 2 hours, 85.6 g of 2-chlorobenzyl alcohol.

 After stirring for 16 hours at ambient temperature, the suspension is cooled to -20 ° C. and 114.5 g of tosyl chloride are added in th.

 After the end of the addition, the suspension is stirred for a further 2 h while allowing to return to ambient temperature.

 The insoluble material is filtered off, washed twice with 200 ml of isopropyl ether and then extracted twice with 300 ml of toluene.

 The toluene solutions are evaporated to dryness and the residue is recrystallized from a mixture of benzene and petroleum ether. 119 g of crystallized product are obtained as PF = g4C needles. Yield = 66.8%.

 The product is characterized by proton NMR in CDCl3: 1 singlet (CH3) at 2.3 ppm, 1 singlet (CH2) at 5.0 ppm, aromatics centered at 7.3 ppm (6H) and 7.7 ppm (2H). ).

b) N- (2-chloro-benzyl) -2-ethyl-2-ethylamine hydrochloride
To a suspension of 13.8 g of K 2 CO 3 in 150 ml of tetrahydrofuran containing 38.2 g (0.30 mol) of 2- (2-thienyl) ethylamine and heated to reflux, a solution of 29 is added over a period of 3 hours. 7 g (0.10 mol) of 2-chloro-benzyl paratoluenesulphonate in 150 ml of tetrahydrofuran.

 After cooling, the insoluble material is filtered off, washed with 100 ml of tetrahydrofuran and the filtrate is evaporated to dryness. 49.6 g of oil are obtained, which is taken up in 200 ml of water and acidified with 40 ml of concentrated hydrochloric acid.

 The product which has crystallized is filtered, washed with water and with isopropyl ether.

 After drying at 50 ° C. under vacuum at constant weight, 27.4 g of N- (2-chloro) benzyl (2-thienyl) -2-ethylamine hydrochloride are obtained. Mp = 148 ° C. Yield: 95.1% (relative to the sulfonate).

 The filtrate is washed with 100 ml of isopropyl ether and then brought to basic pH with 50 ml of 10N sodium hydroxide and extracted twice with 200 ml of ethyl ether. After evaporation of the ether, 25.3 g of (2-thienyl-2-yl) ethylamine are obtained, which gives a recovery yield of 95%, taking into account the product which has reacted.

Claims (9)

 A process for the preparation of N- (2-chloro) benzyl (2-thienyl) -2-ethylamine, wherein (2-thienyl) -2-ethylamine is reacted with a compound of formula III

 wherein X represents a halogen atom, an alk, yl (C1-C6) or aryl (C6-C13) sulfonate group.  2. The method of claim 1 wherein X is Cl.  3. Method according to one of claims 1 and 2, characterized in that the reaction takes place in a polar solvent.  4. Process according to claim 3, characterized in that 2 to 5 molar equivalents of (2-thienyl) ethylamine are reacted with the derivative of formula III.  5. Method according to one of claims 1 to 4, characterized in that introduced into the reaction medium a mineral or organic base.  6. The process of claim 5 wherein the base is selected from alkali metal hydroxides and carbonates.  7. The process of claim 5 wherein the base is selected from tertiary amines.  8. Method according to one of claims 1 and 2, characterized in that the reaction takes place in a biphasic medium in the presence of a mineral base.  9. Process according to claim 8, characterized in that the reaction medium contains a phase transfer catalyst.