MXPA99008089A - Method for preparing 2-thienylethylamine derivatives - Google Patents

Abstract

The invention concerns a method for preparing 2-thienyl-ethylamine derivatives of general formula (I) and their acid additive salts, in which R represents a halogen atom and R1 represents a C1-C4 alkyl group, characterised in that it consists in reacting a thienyglycidic acid derivative of general formula (II) in which M represents an alkaline metal atom or an alkaline-earth metal fraction, with a phenylglycine ester, optionally in the form of a strong acid salt, of general formula (III) in which R and R1 have the same meaning as above, in the presence of an alkaline metal borohydride of general formula (IV):X-Y in which X represents an alkaline metal atom and Y represents a group of general formula (a):-BH3CN or (b):BH(4-w)Zw in which Z represents a carboxylic acid radical and optionally in the presence of a C1-C4 carboxylic acid, which results in the required compound in the form of a free base which can be treated if necessary, with an acid to obtain the additive salt of this compound.

Description

PROCEDURE FOR PREPARING DERIVATIVES OF 2-TIENIL-E ILAMINE DESCRIPTION OF THE INVENTION The present invention relates, in a general manner, to a novel process for the preparation of the 2-thienyl-ethylamine derivatives. In particular, the invention relates to a novel process for the preparation of N-phenylacetic derivatives of 2-thienyl-ethylamine of the general formula: as well as their acid addition salts, in which R represents a halogen atom such as chlorine or bromine and Rx represents an alkyl group of 1 to 4 carbon atoms, preferably methyl. These compounds of the formula I possess an asymmetric carbon represented by the asterisk and, consequently, can be presented in the form of REF .: 31242 racemic mixture or optically individual isomers (-) R and (+) - (S). Thus, the invention relates to the preparation of the 2-thienyl-ethylamine derivatives of the formula I which are in the form of a racemic mixture or dextrorotatory or individual levorotatory enantiomers. In formula I above, the group R can be in the ortho, meta or para position of the acetate group, preferably in the ortho position. On the other hand, chlorine represents a preferred R group. Accordingly "and according to a preferred aspect, the invention relates to a process for the preparation of the (+) - (S) -enantiomer of the compounds of the formula I, in particular the (+) - (S) enantiomer of the a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetic acid methyl ester These compounds of the formula I are known products and can be used for the preparation of pharmacologically active compounds. (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetic acid methyl ester has been described in European Patent EP 466569 as well as its use for the preparation of (+) - (S) -a- (4, 5, 6, 7-tetrahydro-thieno [3,2-c] -5-pyridyl) -a- (2-chloro-phenyl) -methyl acetate or clopidogrel This enantiomer of formula developed It is known for its interest in therapy, mainly for its anti-platelet and anti-thrombotic activities. A process for the preparation of clopidogrel by means of a racemic compound, namely (R, S) -a- (4, 5, 6, 7-tetrahydro-thieno [3, 2], has been described in this European Patent EP 466569. -c] -5-pyridyl) -a- (2-chloro-phenyl) -acetic acid methyl ester which is subjected to a resolution process. According to this process, a tereoisomeric salt of this racemic compound is crystallized selectively with (-) - (R) -10-camphorsulfonic acid, which leads to the chiral canfosulfonate of clopidogrel and the base is then released by displacement of the (-) - (R) -10-camphorsulfonic acid.

This access path, although it is of classic use to prepare a chiral compound, can be considered as impractical in the economic plane since it needs both the recycling of the unwanted isomer and that of the salt of the chiral acid (-) - (R) -1 O-canfosul phonic used for resolution. A more convergent method for the preparation mainly of clopidogrel, has been proposed in the European Patent EP 466569, method according to which is treated, in a first stage, the (+) -2-chloro-phenylglycinate methyl with a halogenide or sulfonate of 2-thienyl-yl and this, in a solvent, for several hours, at a temperature between 50 ° C and 100 ° C and in the presence of a base, to give after salification, the hydrochloride of (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetic acid methyl ester with a yield of approximately 50%. ~ However, it has been noted that the choice of solvent, in this method is not indifferent if only one of the enantiomers of α- (2-t-enyl-2-ethylamino) -a- (2) is to be obtained. methyl-chloro-phenyl) -acetate by reaction of one of the enantiomers of methyl 2-chloro-phenylglycinate, a partial racemization would occur in certain solvents. On the other hand, this method has the drawback of needing a very long contact time at a temperature higher than the ambient temperature, for example during 40 hours at 80 ° C, to obtain the (+) - (S) -a- (t ienil) -2- Ethylamino-a- (2-chloro-phenyl) -acetic acid methyl ester, these operating conditions can not unfavorably influence the selling price of the final product. Ethyl amine of the formula I thus obtained, remain relatively modest since they are of the order of 50%. ~~ The search for an industrial process for the preparation of the 2-thienyl-ethylamine derivatives of the formula I whether they are under the racemic form or individual enantiomers, which puts into operation the synthesis intermediates according to a low-cost operating procedure and which provides a satisfactory yield of the desired product, are of unquestionable interest. Now surprisingly found, it is possible to obtain the 2-thienyl-ethylamine derivatives of the formula I, mainly their right-handed enantiomers, avoiding the drawbacks described above, and according to the yields higher than those obtained with the above procedure, since that the formation of at least 90% of these compounds is recorded in the form of a free base in relation to the theoretical yield. Thus, according to the invention, the 2-thienyl-ethylamine derivatives of the formula I are prepared by reacting a thienylglycidic derivative of the general formula: II wherein M represents an alkali metal atom such as lithium, potassium or preferably sodium or a fraction of an alkaline earth metal atom such as calcium or magnesium? * _-, with phenylglycine ester of the general formula: I I I in which R and Ri have the same meaning as described above for I, optionally in the form of a strong acid salt, for example, the hydrochloride or the methanesulfonate, in the presence of an alkali metal borohydride of the general formula: X-Y IV in which X represents an alkali metal atom, preferably sodium, and Y represents a group of the formula: -BH3CN or -BH (4 -w) w wherein Z represents a carboxylic acid residue, generally a residue of the general formula: R2-C02- in which R2 represents alkyl of 1 to 10 carbon atoms, for example methyl, and w represents 1, 2 or 3, which provides the desired compound in the form of the free base which can be reacted, if necessary, with an acid to obtain an addition salt of this compound. The compound of the general formula III can be in the racemic form or, conversely, in the form of (+) - (S) or (-) - (R) enantiomers. In fact, it has been possible to demonstrate that the method of the invention is carried out with the retention of the configuration when the phenylglycine ester of the formula III is in the form of a dextrorotatory or separated levorotatory enantiomer, the optical purity of the enantiomer of the compound of Formula I depends exclusively on the optical purity of the enantiomer of the starting compound of formula III. By virtue of this stereospecificity of the process of the invention, the esters of formula III in the form of individual enantiomers, in particular ( +) - (S) -a-amino-a- (2-chloro-phenyl) -acetic acid methyl ester, can be considered as preferred. When the alkali metal borohydride corresponds to a cyanoborohydride, ie a compound of the formula IV in which Y represents the group -BH 3 CN, the process of the invention is advantageously and preferably carried out in the presence of a weak acid such as an acid alkylcarboxylic acid of 1 to 4 carbon atoms, for example, acetic acid and preferably at a concentration not exceeding 0.50 mol / 1. By way of indication, a maximum yield of the compound of the formula I has been recorded, at a concentration of 0.30 to 0.35 mol / l of weak acid, such as the acetic acid in the organic solvent used, for example, methanol. Similarly, when the compound of the formula IV is an alkaline cyanoborohydride, the following is used: a) a strong acid salt of the compound of the formula III in particular of a compound of the formula III in which R represents a halogen atom eh ortho position, in general a strong acid salt of a 2-chloro-phenyl derivative of the formula III and more particularly a strong acid salt of the methyl a-amino-a- (2-chloro-phenyl) -acetate . b) the thienyl derivative of the formula II, preferably in a slight excess relative to the compound of the formula I II, up to 0.5 mol in excess per mol of the compound of the formula III. Similarly, when the alkali metal borohydride corresponds to an acyloxy borohydride, that is, a compound of the formula IV in which Y represents the group -BH (- ") ZW, the process of the invention is put into operation preferably in a weak acid as a solvent, such as an alkylcarboxylic acid of 1 to 4 carbon atoms, for example acetic acid in the absence of another solvent. However, it is also possible to use a reaction medium formed from an organic solvent such as alcohol, for example methanol or a halogenated hydrocarbon, such as benzene, toluene or a xylene or even dichloromethane, and a weak acid such as the one described above. In this case, the weak acid in question is present, preferably, at a rate of at least 50% by volume with respect to the organic solvent.

On the other hand, when the compound of the formula IV is an alkali aciloxyborohydride, it is generally used in equimolar amounts of this compound of the formula IV and of the phenylglycine ester of the formula III, this compound of the formula III is put into operation preferably in excess, ie up to 2.2 molar equivalents per molar equivalent of the thienylglycidal derivative of the formula II. As for the alkali metal borohydrides of the formula IV, these mainly include the alkali metal cyanoborohydrides, preferably sodium cyanoborohydride (NaBH3CN) but also the borohydrides of carboxylic acid residues, which can be obtained extemporaneously in a solvent suitable such as dichloromethane by mixing a borohydride of the general formula: XBH VI in which X has the same meaning as described above, for example sodium, with a carboxylic acid of the general formula: R2-C02H VII in which R2 has the same meaning as described above. According to the usual operations, the borohydrides of the formula IV are prepared in which Y represents a group -BH (4-W) ZW either _ a) by the slow addition and low agitation of an alkali metal borohydride of the formula XBH4 in which X has the same meaning as described above, for example sodium borohydride, to an acid of formula VII, which may be in stoichiometric excess, for example acetic acid, this acid being cooled to a temperature below room temperature, or b) by slow addition and low agitation of 1 to 3 molar equivalents of acid of formula VII to a suspension of alkali metal borohydride of the formula XBH as described above and this, in the organic solvent chosen, for example dichloromethane.

After removal of the solvent, the residue is taken up in an acid of formula VII and can constitute an appropriate reaction medium for the operation of the process of the invention. The borohydrides of the formula IV used in the process of the invention are generally put into operation at a concentration not exceeding 0.40 mol / 1, which corresponds substantially to the saturation concentration, ie the concentration beyond which the yield of the reaction no longer increases. The thienylglycid derivatives of the formula II can be prepared according to known methods. For example, it can be obtained by applying the procedure proposed in European Patent EP 465358 which is based on a Darzens reaction. According to this method, 2-thienylcarboxaldehyde is reacted in isopropanol with an isopropyl haloacetate, for example isopropyl chloroacetate in the presence of an alkali metal isopropylate, preferably sodium isopropylate, which provides the isopropyl 2-thienylglycidate which is then saponified by means of an alkali metal or alkaline earth metal hydroxide to finally obtain the desired glycidic ester or glycidate of the formula II. More generally, this method can be put into operation from a methyl haloacetate such as methyl chloroacetate, the reaction being developed in an alkanol of 1 to 4 carbon atoms, for example, methanol. As for the glycine esters of the formula III, these are also the known compounds or those which can be prepared by known methods, which are either in the form (-) - (R), (+) - (S) or under the racemic form. For this purpose, the method described in European Patent EP 466569 according to which the corresponding racemic amino acid or its individual enantiomers are esterified can be used, by reaction with thionyl chloride and an alkanol of 1 to 4 carbon atoms. Similarly, the strong acid salts of the enantiomers of the esters of the formula III can also be obtained by recrystallization of the salt formed by the racemate of the same compound of the formula III, with an optically active acid such as (+) or (-) tartaric acid in isopropanol, or even acids (+) or (-) -10-camphorsulfonic acid in acetone in the presence or absence of methyl ethyl ketone, then by treatment with an appropriate strong acid to obtain the desired salt. Alternatively, the individual enantiomers of the esters of the formula III can be prepared under the formula of a strong acid salt from the enantiomer of opposite configuration of said ester, optionally of a mixture with the desired enantiomer of said ester, This ester is in the form of a base or a weak acid addition salt, for example in the form of acetate, In accordance with this process, the enantiomer or mixture of starting enantiomers is treated optionally in the presence of a polar cosolvent. or apolar such as isopropanol or a mixture of such cosolvents, with ketone compound, preferably acetone and with an N-protected amino acid, namely N- (2,4-dinitrobenzoyl) -phenylglycine in the form of an enantiomer , the treatment being carried out in the presence of a carboxylic acid, preferably acetic acid, in order to induce a total racemization and the concomitant precipitation of a salt Tereoisomeric days of the ester of formula III and of N- (2,4-dinitrobenzoyl) -phenylglycine. It is hydrolyzed, subsequently, in the presence of a strong acid such as hydrochloric acid, the tereoisomeric day salt in question to obtain the desired enantiomer of formula III in the form of a strong acid salt. The following non-limiting examples illustrate the process of the invention.

PREPARATIONS a) Sodium 2-thienylglicidate In a 250 ml flask, 100 ml of methylene chloride, 8.3 ml of 98% 2-thienyl carboxaldehyde and 9.3 ml of methyl chloroacetate are introduced and then homogenized by magnetic stirring. The mixture is placed in a 0 ° C (water / ice) bath, then 18 ml of 30% sodium methylate is added slowly in one hour. The stirring is continued for 2 hours in the cold and it is then allowed to reach room temperature. 50 g of ice are then added to the reaction medium and stirred until the Itotal solution. The medium is transferred to another container for decanting and the two phases are separated. The organic phase is washed with 50 ml of 0.5 N hydrochloric acid and then once with distilled water. Dry over anhydrous sodium sulfate and filter. It is concentrated under vacuum at a temperature below 30oC, then the temperature is allowed to rise to 0 ° C in an ice bath. Then, 50 ml of absolute ethanol and 16 ml of 30% sodium methylate are added to the oily residue, then 1.6 ml of distilled water are added slowly, which causes the immediate formation of a precipitate. This precipitate is placed in a cold chamber for 12 hours and then drained, washed with absolute ethanol and then with ethyl ether. It dries immediately in a desiccator. In this way, 14.6 g of sodium 2-thienylglycidate are obtained. b) (R, S) -a-amino- (2-chloro-phenyl) -acetic acid In a 500 ml flask, 6.88 g of ammonium chloride, 11.64 g of potassium cyanide and 200 ml of 30% ammonia are introduced. Under low magnetic stirring, 200 ml of methanol containing 11.2 ml of 99% 2-chlorobenzaldehyde are added, then under occasional stirring, the reaction medium is brought to 45 ° C for one hour. It is then diluted with 200 ml of distilled water and extracted twice with 200 ml of ethyl acetate. The organic phases are combined and then washed with distilled water. Dry over anhydrous sodium sulfate, filter and evaporate to dryness, which provides an oily residue. This residue is then hydrolyzed by the addition of 200 ml of 6N hydrochloric acid, refluxed and the mixture left for a minimum of 4 hours. The hydrolyzate is washed with chloroform until a yellow shot, due to excess reagent and then the excess hydrochloric acid is evaporated reducing the volume by half, by evaporation in vacuum. 100 ml of hot distilled water are added and the pH is adjusted to 5.27 with ammonia, which causes a start of the precipitation of (R, S) -a-amino-a- (2-chloro-phenyl) -acetic acid. The medium is then left in a cold room for 12 hours, drained and dried under vacuum in the presence of phosphoric anhydride to obtain 8.45 g of acid (R, S) -a-amino-a- (2-chloro) phenyl) -acetic in the form of white crystals. c) Methyl (R, S) -a-amino-a- (2-chloro-phenyl) -acetate hydrochloride Under magnetic stirring and in an ice bath, 5 ml of thionyl chloride in 100 ml of methanol are slowly added. The crystals of (R, S) -a-amino-a- (2-chloro-phenyl) -acetic acid, obtained above, are then dissolved in this mixture and the reaction medium is filled at 40 ° C. The reaction is left to proceed for 48 hours at 40 ° C and then evaporated to dryness. The residue is dissolved in methanol and evaporated again under reduced pressure. 200 to 300 ml of ethyl ether are added immediately and the mixture is left for 15 hours at 5-6 ° C, which causes the formation of crystals. These crystals are then drained, washed with ethyl ether and dried in vacuo. In this way, 9.5 g of methyl (R, S) -a-amino-a- (2-chloro-phenyl) -acetate hydrochloride are obtained. d) (-) - (2,4-dinitrobenzoyl) phenylglycinate of (+) - (S) -a-amino-a- (2-chloro-phenyl) -acetic acid methyl ester.

A suspension of 7.1 g of (R, S) -a-amino-a- (2-chloro-phenyl) -acetate hydrochloride in 50 ml of ethyl acetate is added, 50 ml of ammonia 2 to 3 are added. molars and extracted. The organic phase is separated and dried over anhydrous sodium sulfate. It is filtered directly in a container 500 ml, then evaporated to dryness at a temperature below 40 ° C. Under magnetic stirring, 45 ml of isopropanol and 10 g of (-) - (2> 4-dinitrobenzoyl) -phenylglycine previously solubilized in 60 ml of acetone containing 5% acetic acid are added. It is then seeded with some crystals of the desired compound, 120 ml of hexane are added and the stirring is maintained for 15 minutes. The reaction medium is left for 18 hours at 35 ° C and then for 24 hours at 5-6 ° C, which causes the formation of crystals that drain, rinsed with a mixture of acetone / hexane vol. / vol. and they dry up.

In this way, 9.5 g of (-) - (2,4-dinitrobenzoyl) -phenylglycinate of (+) - (S) -a-amino-a- (2-chloro-phenyl) -acetic acid methyl ester are obtained. Optical purity: 98% (gas chromatography).

(+) - (S) -a-amino-a- (2-chloro-phenyl) -methyl acetate hydrochloride 3 g of (-) - (2,4-dinitrobenzoyl) -phenylglycinate of (+) - (S) -a-amino-a- (2-chloro-phenyl) -acetic acid methyl ester are introduced into 20 ml of a solution 1 M in sodium carbonate and extracted twice with 10 ml of ethyl acetate. The regrouped organic phases are dried over anhydrous sodium sulfate, treated with 10 ml of 1N hydrochloric acid in methanol and concentrated in vacuo. The residue is dissolved in a minimum amount of methanol and crystallization is caused by the addition of diethyl ether. In this way, the hydrochloride of (+) - (S) -a-amino-a- (2-chloro-phenyl) -acetic acid methyl ester with a practically quantitative yield.

+) - (S) -a-amino-a- (2-chloro-phenyl) -methyl acetate 2.36 g (10 ~ 2 mol) of (+) - (S) -a-amino-a- (2-chloro-phenyl) -acetic acid hydrochloride in 50 ml of ethyl acetate or methylene chloride are introduced. and add 20 ml of 1.5 M ammonia or 5% sodium bicarbonate. The mixture is stirred, the organic phase is separated out and the aqueous phase is extracted with 10 ml of ethyl acetate. The organic phases are combined, treated with anhydrous sodium sulfate and concentrated at reduced pressure until the absence of distillation. The residue formed from (+) - (S) -a-amino-a- (2-chloro-phenyl) -acetic acid in 50 ml of acetic acid is then collected.

EXAMPLE 1 (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetic acid methyl chloride In a 100 ml flask, 1.92 g (10 ~ 2 mol) of sodium 2- thienylglycidate, 2.36 g of (+) - (S) -a-amino-a- (2-chloro-phenyl) hydrochloride are placed. -methyl acetate 0.63 (10 mol) of sodium cyanoborohydride (NaBH3CN) as well as 40 ml of methanol and 0.8 ml of acetic acid, this reaction medium is immediately maintained under magnetic stirring in a bath at 18 ° C. ~ the course of the reaction, aliquots (10 μl) of the mixture are obtained and analyzed by high performance liquid chromatography (CLAP) to follow the formation of the desired compound at the same time as the disappearance of the (+) - (S) -a- amino-a- (2-chloro-phenyl) -acetic acid methyl ester. After 3 to 4 hours, the reaction is stabilized and the analysis shows a yield of 66% in (+) - (S) -a-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetate. methyl. Then add 0.96 to 1 g (0.5 x 10-2 mol) of sodium 2-thienylglycidate, 0.3 g (0.5 x 10 ~ 2 mol) of NaBH3CN and 0.4 ml of acetic acid. After 3 hours of reaction, the analysis shows a yield of 98% in the desired compound, in the form of a free base and the disappearance of the starting ester. The reaction mixture is then diluted with 250 to 300 ml of 1 to 2 M ammonia and extracted twice with ethyl acetate. The organic phases are then combined, dried over sodium sulphate and evaporated. The residue is taken up in 40 to 50 ml of methanol and treated with 15 to 20 ml (excess) of 1 M hydrochloric acid in methanol. After evaporation, methyl (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetate hydrochloride crystallizes by addition of acetone. Yield: 2.56 g or 75%.

EXAMPLE 2 (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetic acid methyl chloride In a 100 ml flask, a 0.25 molar methanolic solution in sodium 2-thienyl glycidate, 0.25 molar in (+) - (S) -a-amino-a- (2-chloro-phenyl) hydrochloride - is introduced. methyl acetate, 0.25 molar in NaBH3CN and X molar acetic acid. This reaction medium is maintained immediately under magnetic stirring in a bath at 18 ° C. In the course of the reaction, aliquots (10 μl) of the mixture are obtained and analyzed by CLAP to follow the formation of the desired compound at the same time as the disappearance of the (+) - (S) -a-amino- a- (2-chloro-phenyl) -acetic acid methyl ester. After 3 to 4 hours, the reaction is stabilized and the analysis shows the following yields in (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetate of methyl calculated on the conversion of the starting ester.

X (molar) Yield (%) 0 50 0., 125 52.5 0. .167 57.4 0., 330 66 0. .420 56 The reaction is then continued as described in Example 1 to obtain first the methyl (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetic acid the basic form according to the yields that vary from 80 to 98% by CLAP, then the hydrochloride of this compound according to the yields of 60 to 80% after isolation.

EXAMPLE 3 (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl methyl acetate) This compound has been prepared according to the method described in Example 1, replacing the 0.37 molar solution in NaBH3CN (0.9 g in 40 ml of methanol) with a methanol solution of molarity indicated below, in order to obtain, by means of CLAP, the following yields of (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-faehyl) -methyl acetate not isolated.

Molarity in NaBH3CN Performance s (% 0.22 90 0.30 97 EXAMPLE 4 (+) - (S) -a- (2-1-Ethyl-2-ethylamino) -a- (2-chloro-phenyl) -acetic acid methyl chloride Under cooling (water bath 14 a ° C and under magnetic stirring, 1 g of sodium borohydride in 100 ml of dichloromethane is suspended. Then 4.5 ml of acetic acid is added slowly in 5 to 10 minutes. From the end of hydrogen liberation, dichloromethane is completely evaporated under reduced pressure and the residue obtained is dissolved in the acetic solution of (+) - (S) -a-amino-a- (2-chloro-phenyl) methyl acetate obtained in preparation f) above. Under mechanical agitation, 3 fractions are added, namely 1.54; 1.54 g and 1.34 g of sodium 2-thienylglycidate at 5 minute intervals, at a temperature of 15 to 18 ° C, then reacted for 20 minutes after the last addition. The reaction mixture is then diluted with 200 ml of ethyl acetate and 400 ml of water, then 70 ml of 30% ammonia are slowly added. It is stirred, the organic phase is decanted (the pH of the aqueous phase must be basic) and the aqueous phase is extracted again with 100 ml of ethyl acetate. The organic phases are combined, washed with water, dried over sodium sulphate and concentrated in vacuo under reduced pressure. The residue obtained is dissolved in 20 ml of 1 M hydrochloric acid in methanol and again evaporated. The residue is taken up in 60 ml of acetone and is kept at room temperature until the formation of crystals. 100 ml of tert-butyl methyl ether are then added, allowed to crystallize for 10 to 12 hours in a cold room and then the crystals formed are drained. In this way, 2.42 g of the '(+) - (S) -a-amino-a- (2-chloro-phenyl) -acetic acid hydrochloride are recovered. Analytical performance: 95% Weight yield: 70% _ (the analysis of the mother liquor of crystallization shows the presence of the desired compound not precipitated).

EXAMPLE 5 (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -methyl acetate hydrochloride The acetic solution of methyl (+) - (S) -a-amino-a- (2-chloro-phenyl) -acetate obtained in preparation f) above is added, with stirring and cooling and in about 10 minutes , 1 g of sodium borohydride. 4.42 g of sodium 2-thienylglycidate are then introduced in 3 fractions and at a temperature of 15 to 18 ° C and then allowed to react for 20 minutes after the last addition. The procedure is followed as described in Example 4 to obtain methyl (+) - (S) -a- (2-thienyl-2-ethylamino) -a- (2-chloro-phenyl) -acetate hydrochloride. Analytical performance: 95% by weight: 70% _ (the analysis of the mother liquor of crystallization shows the presence of the desired compound not precipitated).

It is noted that with regard to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (20)

RE IVINDICATIONS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for the preparation of 2-thienyl-ethylamine derivatives of the general formula: as well as its acid addition salts, in which R represents a halogen atom and Ri represents an alkyl group of 1 to 4 carbon atoms, characterized in that a thienylglycidic derivative of the general formula is reacted: II in which M represents an alkali metal atom or a fraction of an alkaline earth metal atom, with a phenylglycine ester, optionally in the form of a strong acid salt, of the general formula: III wherein R and Ri have the same meaning as described above, in the presence of an alkali metal borohydride of the general formula: X-Y IV wherein X represents an alkali metal__atome and Y represents a group of the formula: -BH3CN -BH ((4.-ww)) in which Z represents a carboxylic acid residue and W represents 1, 2 or 3, which gives the desired compound in the form of free base that can be treated if necessary, with an -acid to obtain an addition salt of this compound. __

2. The process according to claim 1, characterized in that the halogen atom is located in the ortho position.

3. The process according to claim 1, characterized in that the halogen atom is chlorine.

4. The process according to any of claims 1 to 3, characterized in that Rx represents methyl.

The process according to any of claims 1 to 4, characterized in that the 7"2-thienyl-ethylamine derivative of the formula I and the phenylglycine ester of the formula III are each in the form of the enantiomer. (+) - (S).

6. The process according to any of claims 1 to 5, characterized in that M represents lithium, sodium, potassium, calcium or magnesium.

7. The process according to any of claims 1 to 6, characterized in that the phenylglycine ester of the formula III is in the form of a strong acid salt, chosen from the hydrochloride or the methansulphonate.

8. The process according to any of claims 1 to 7, characterized in that Z represents a carboxylic acid residue of the general formula: R2-C02- in which R2 represents an alkyl group of 1 to 10 carbon atoms.

9. The process according to any of claims 1 to 7, characterized in that the alkali metal borohydride corresponds to sodium cyanoborohydride.

10. The process according to claim 9, characterized in that the reaction is carried out in the presence of an alkylcarboxylic acid of 1 to 4 carbon atoms.

11. The process according to claim 10, characterized in that the carboxylic acid is used at a concentration not exceeding 0.50 mol / 1.

12. The process according to claim 11, characterized in that the carboxylic acid is used at a concentration of 0.30 to 0.35 mol / 1.

13. The process according to any of claims 9 to 12, characterized in that the carboxylic acid is acetic acid.

14. The process according to any of claims 9 to 13, characterized in that the phenylglycine ester of the formula III is in the form of a strong acid salt.

15. The process according to any of claims 1 to 14, characterized in that the thienylglycidic derivative of the formula II is used in excess, up to 0.5 additional mole per mole of phenylglycine ester of the formula III.

16. The process according to any of claims 1 to 7, characterized in that the alkali metal borohydride corresponds to a compound of the formula IV in which Y represents the group -BH (4-W) ZW.

17. The process according to claim 16, characterized in that the reaction is put into operation in an alkylcarboxylic acid of 1 to 4 carbon atoms.

18. The process according to claim 16 or claim 1 characterized in that the phenylglycine ester of the formula III is used in excess up to 2.2 molar equivalents per molar equivalent of the thienylglycidic derivative of the formula II.

19. The process according to any of claims 1 to 18, characterized in that the alkali metal borohydride of the formula IV is used in a concentration which does not exceed 0.40 mol / 1.

20. The process according to any of claims 1 to 19, characterized in that the (+) - (S) -a- (2-thienyl 1-2 -et i lamino) -a (2-chloro-phenyl) is prepared -methyl acetate. SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of 2-thienyl-ethylamine derivatives of the general formula: as well as its acid addition salts, in which R represents a halogen atom and Rx represents an alkyl group of 1 to 4 carbon atoms, characterized in that a thienylglycidic derivative of the general formula is reacted: II wherein M represents an alkali metal atom or a fraction of an alkaline earth metal atom, with a phenylglycine ester, optionally in the form of a strong acid salt, of the general formula: III in which R and Ri have the same meaning as described above, "~ in the presence of an alkali metal borohydride of the general formula: X-Y IV wherein X represents an alkali metal atom and Y represents a group of formula: -BH3CN or -BH (4-W) Zw wherein Z represents a carboxylic acid residue and optionally in the presence of a carboxylic acid of 1 to 4 carbon atoms, which provides the desired compound in the form of free base which can be treated if necessary, with an acid for obtain an addition salt of this compound.