WO2008046792A1

WO2008046792A1 - CRISTALLINE FORM OF THE RACEMIC METHYL-α-(2-CHLORPHENYL)-2-(6,7-DIHYDROTHIENO[3,2-C]PYRIDINE-5(4H)) ACETATE, METHOD FOR THE PRODUCTION AND USE THEREOF

Info

Publication number: WO2008046792A1
Application number: PCT/EP2007/060905
Authority: WO
Inventors: Zbigniew Majka; Andrzej Wojciech Sawicki; Andrzej Trzepalka
Original assignee: Adamed Sp. Z O.O.
Priority date: 2006-10-17
Filing date: 2007-10-12
Publication date: 2008-04-24
Also published as: PL380849A1

Abstract

The present invention relates to the crystalline form of the racemic methyl-α-(2-chlorphenyl)-2-(6, 7-dihydrothieno [3,2-c] pyridine-5(4H)) acetate, which has characteristic peaks indicated on X-ray powder diffractogram (XRPD) in the degree 2ϑ (± 02°ϑ) being: 14.1, 16.2, 17.0, 18.6, 19.4, 19.8, 21.0, 25.2, 25.5, 27.3, 32.0. The invention further relates to a method for the production of the crystalline form thereof. The present invention further relates to the use of the crystalline racemate of the methyl-α-(2-chlorphenyl)-2-(6, 7-dihydrothieno [3,2-c] pyridine-5(4H))acetate for the production of the (+)-(S)-methyl-α-(2-chlorphenyl)-2-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)) acetate (Clopidogrel) and/or the salts thereof.

Description

Crystalline form of the racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate, process for its preparation and its use

The present invention relates to a crystalline form of the racemic methyl-α- (2-chlorophenyl) -2 - (6, 7-dihydrothieno [3, 2-c] pyridine-5 (4H)) acetate, a process for their preparation and their use.

Racemic methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is the most important intermediate in the preparation of clopidogrel.

Clopidogrel is a generic name of the (+) - (S) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate, a Substance known as an antithrombotic drug.

clopidogrel

The manufacturing process of clopidogrel has been in many

Publications presented. The group of substances with antithrombotic activity, which also includes clopidogrel, was first described in the publication of European patent EP 099802. The preparation of the racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) acetate is described in Example 1 of the abovementioned publication. This product has the form of a yellow oil which has been converted into hydrochloride acid addition salt for purification and isolation.

In EP 281459, pharmaceutically acceptable salts of (+) - (S) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) - acetate (the clopidogrel). It was found to be under many proven salts, the most beneficial properties of clopidogrel bisulfate. The separation of the racemate on the individual enantiomers was carried out here by their conversion into the diastereomeric salts with (-) - camphorsulfonic acid. The mixture, after separation of the diastereomeric Clopidogrelsalzes with

Camphorsulfonic acid, contained 35% clopidogrel and 65% of its levorotatory isomers. This mixture was used for the secretion of this left-handed isomer.

As described in the specification EP 281459, according to the toxicological information, the left-rotating isomer of clopidogrel has a toxic effect on the central nervous system. Therefore, it is useless for the therapy and represents after the secretion stage of clopidogrel from Razemate a waste product.

For the recovery of this waste, several processes of racemization of methyl α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) acetate.

International Publication WO 2002/59128, which describes a preparation process of the clopidogrel and the intermediates used in this synthesis, reveals that the link-rotating enantiomers of the intermediates as well as the unwanted link-rotating enantiomer of the clopidogrel itself undergo racemization can be. This process is carried out in an appropriate solvent using a base in an equimolar amount relative to the substrate. As examples of the bases, lithium diisopropylamide LDA, KOH, NaOH, tert-BuOK, MeONa, NaH, KH were listed.

The publication WO 2004/013147 describes the racemization of the left-rotating isomer of clopidogrel or of a mixture containing this enantiomer in excess in the presence of a catalytic amount of an organic or inorganic base. The process is carried out in a solvent. After the reaction, the base used for the racemization is neutralized with acid, the reaction mixture is rinsed for the purpose of leaching the neutralization products, the organic layer is dried and concentrated, and then the recovered Methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate as an oily racemate. This racemate is subjected to further work-up for the purpose of isolating the clopidogrel.

The next publication WO 2004/074215 describes the racemization of (-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H )) - acetate in the presence of the acid, which is carried out in a solvent. After the reaction, the racemate is precipitated in the form of an addition salt with acid used for racemization (sulfuric acid, hydrochloric acid, acetic acid, phosphoric acid). Before separation of the racemate to individual enantiomers, it should be isolated from the addition salt, by-products of neutralization should be extracted and the organic phase should be narrowed. The racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is recovered in the form of an oil. In the publication WO 2005/077958 the conversion of the unwanted left-rotating enantiomer of clopidogrel into the racemate in the presence of a base in the organic solvent is described. Both the neutralization of the basic agent and the method of working the reaction mixture have not been described. In the publication WO 2006/087729 the racemization of the left-rotating clopidogrel enantiomer in the solvent in the presence of the basic agent (metal alcoholate) is described. After the reaction, the alcoholate is neutralized with acid, the mixture is washed with water, the organic layer is added to obtain the oily racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2 -c] pyridine-5 (4H) -acetate dried and concentrated. The racemate is defaults, i. separated by the method known from the prior art (EP 281495, camphorsulfonic acid).

The next publication WO 2006/094468 describes the racemization of the left-handed clopidogrel enantiomer, which is carried out in the presence of various ammonium hydroxides. For the purpose of separating out the racemic product after the reaction extract the reaction mixture with water, dry the organic layer and evaporate the solvent.

The processes described in the prior art are laborious. Their main drawback is the need to remove the agent that affects the process of racemization. Before the separation process, the reaction mixture is usually neutralized, extracted and dried and the solvent is evaporated. The further disadvantage is the form of the racemate itself. The viscous oil is not a desirable form in many technological operations. The prior art has not described any crystalline form of the racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) acetate.

The inventors have found that clopidogrel, both in the form of individual enantiomers and in racemic form, despite its basic character, does not form any crystalline precipitating addition salts with some acid. These acids include carboxylic acids. Some of those added to the solution of clopidogrel in the organic solvent to convert it to salt crystallize from this system in an unchanged form. The pharmaceutically acceptable acids such as: ascorbic acid, malic acid, tartaric acid and mandelic acid do not form clopidogrel salts leaving the solutions, nor do they cause changes in the configuration of the clopidogrel.

It has surprisingly been found that some of the acids have extraordinary properties. Formic acid and acetic acid were found to racemize the individual enantiomers of methyl α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) acetate and Mixtures of predominantly one of the enantiomers cause the racemic product to crystallize from the reaction mixture in high yield and not as an acid addition salt but as a free base. The product is easy to separate, eg by filtration, and is suitable for further processing, including separation of enantiomers. The product does not need to be cleaned of any by-products. It was found that the crystalline methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2- c] pyridine-5 (4H)) - acetate after drying less than 1% of the

Razemization used acid contains.

Of course, the racemization of mixtures with excess of the left-handed clopidogrel enantiomer and the pure link-rotating enantiomers is of practical importance because it enables the recovery of the waste.

The racemization process according to the invention achieves special effects which confirm the unobviousness of both the process of preparation and of the new product to be produced. The inventive method is very simple to implement and much more economical, because it ensures time and energy savings, lower device requirements compared to the prior art. The crystalline racemate of the present invention is more advantageous in handling operations associated with separation of the enantiomers for clopidogrel secretion. The new crystalline form racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is characterized by the melting temperature in the range of 56- 60 ⁰ C. the Crystalline racemate also has the characteristic peaks in the powder diffractogram Röentgen-(XRPD) in degrees 2Θ (± 0.2 ° θ): 14.1, 16.2, 17.0, 18.6, 19.4, 19.8, 21.0, 25.2, 25.5, 27.3, 32.0. The powder diffractogram is shown in attached Figure 1 and a detailed list of peaks is presented in Table 1. Table 1. Characteristic XRPD peaks, the lattice spacings d and relative intensities 1/1 ° of the interference lines for the crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3, 2-c] pyridine-5 (4H)) -acetate

The present invention also relates to the process for preparing the crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate. The process for the preparation of the crystalline racemate of

Methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) -acetate defined as above, characterized by being based on (-) - (R ) -Methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) -acetate or to the mixture of the enantiomer of methyl-α- (2- chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) - acetate is treated with formic acid or acetic acid.

The process for preparing the crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is advantageously characterized in that the (- ) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) -acetate or the mixture of the enantiomers of the methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) - acetate with excess of the left-handed enantiomer until the consistency which allows stirring is heated, formic acid or acetic acid added with stirring and the mixture is heated to the temperature of about 70 ⁰ C to about 1 10 ⁰ C, then it is cooled to the temperature of about 40 ⁰ C to about 80 ⁰ C, the organic solvent added and it is further cooled with stirring to the temperature of about 0 ⁰ C to about 20 ⁰ C and the precipitate is separated.

Further variants of the process are advantageous, characterized in that the (-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H ) acetate or the mixture of the enantiomers of the methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate with excess of the left-handed enantiomer in the dissolved organic solvent and formic acid or acetic acid added thereto, the mixture is heated to the boiling point, cooled to the temperature of 40 ⁰ C to 80 ⁰ C, the organic solvent is added and it further with stirring on the Temperature of about 0 ⁰ C cooled to about 15 ° C and the precipitate is separated.

Advantageously used as the organic solvent is a solvent selected from the group of alcohols, ketones, ethers, and most advantageously methanol or ethanol.

The subject of the invention is also the crystalline form of the racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate obtained by any one of was prepared as described above. The invention further relates to the process for the preparation of

(+) - (S) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) -acetate (clopidogrel) and / or its salts characterized by using, as a starting racemate, the crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) acetate as described in U.S. Pat as defined above.

The invention further provides the use of the inventive crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate as defined above, for the preparation of the (+) - (S) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate (clopidogrel) and / or its salts.

The process according to the invention for the preparation of the racemate is carried out as follows.

In the first variant of the inventive method link rotatory enantiomer of clopidogrel or the mixture of enantiomers with excess of the link rotating enantiomer to the temperature of at least 50 ⁰ C for the purpose of reducing the viscosity and facilitating the stirring, is heated, because the substrates oily forms of liquids are. To the heated substrate, formic acid or acetic acid is added thereto with stirring in an amount of 0.05 to 3 times, preferably 0.1 to 1 times, per mole of racemized substrate. The whole is stirred at the temperature of 70 to 110 ^° C., preferably at 110 ^° C., for 1.5 to 3 hours, preferably for 2 hours. Then the mixture is cooled to 40-80 ⁰ C, advantageously to 70 ⁰ C, the organic solvent is added and with stirring to 0-20 ⁰ C, advantageously on 4- 10 ⁰ C cooled. After 0.5 to 10 hours, advantageously 1-2 hours of cooling, the product is filtered off, washed with a small amount of the solvent and dried. The drying can be carried out on the air as well as in the usual dryer or vacuum dryer at the temperature up to 35 ° C, advantageously at room temperature.

Second variant of the method according to the invention consists in dissolving the substrate: the left-rotating enantiomer of clopidogrel or the mixture of enantiomers with excess of the left-rotating isomer in the organic solvent and the addition of formic acid or acetic acid in the amount of 0.05 to 3 (advantageously 0, 1 to 1-fold of one mole) based on racemized substrate. The mixture is then heated to the boiling point and kept under these conditions for 10-24 hours, preferably 12 hours. After this time, the whole is cooled to the temperature of 0- 15 ⁰ C, 1-10 hours, advantageously mixed for 1-2 hours at this temperature and the precipitate formed is filtered off. The thus prepared crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is dried under conditions as in the first variant.

The process uses concentrated formic acid (99.9%) and concentrated acetic acid (glacial acetic acid) (at least 99%).

According to the inventive method is advantageously used organic solvent selected from the group of alcohols, for example, methanol, ethanol, n-propanol, isopropanol, butanol; from the group of ketones, for example acetone, isobutyl methyl ketone; from the group of ethers, for example diethyl ether, diisopropyl ether, isobutyl methyl ether, tetrahydrofuran. The most advantageous group are alcohols, especially ethanol.

Crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate can be used to prepare the clopidogrel, according to methods known from the prior art Known in the art, for example from EP 281459. Conditions of the analyzes

The powder diffractogram was carried out using Rigaku's X-ray powder diffractometer MiniFlex, Cu-Ka radiation and Kβ filter. The lamp parameters were determined to be 30 kV and 15 mA. The divergence aperture and the grit shutter were set at 4.2 ° and the reception slit at 0.3 mm. The diffraction radiation was detected by NaI scintillation counter. Scanning Θ / 2Θ was performed continuously: 1 ° / min with the step 0.02 ° in the range of 2.0 to 40 ° for 2Θ-angle. The sample was prepared by injecting the preparation into the quartz sample holder.

The enantiomeric purity was determined by HPLC method: Alliance 2695 chromatograph from Waters, with UV detection, chiral column 150x4.0 mm was used.

The acidity in the product was determined by titration with the aid of the titration machine 736 GP Titrino from Metrohm. Examples

(-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) - acetate and the mixture of enantiomers of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate with excess of the left-hand isomer was prepared by the methods known in the art, including below the description of EP 281459. Example 1.

(-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H) -acetate (32 g, 0.1 mol ) was preheated to the consistency which allows stirring. Then 2 ml of formic acid (0.05 mol) is added and the mixture is preheated to 100 ⁰ C. The whole is stirred under these conditions for 2 hours, then it is cooled to 70 ⁰ C, added 50 ml of ethanol, cooled to 4 ° C and held at this temperature for 1.5 hours. The white crystalline precipitate of the racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is then filtered off (30 g, yield: 94%) %) Content of individual enantiomers (HPLC):

(-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) -acetate: 50%, (+) - (S) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H) -acetate: 50%.

Measurement result of the elemental analysis of the product:% C = 59.7; % H = 5, 1,% N = 4.3,

% S = 9.8,% C1 = 1 1, 3 is consistent with the theoretical calculations for methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H )) acetate.

Content of formic acid in the product: 0.8%.

The results of the analysis - diffractogram XRPD are presented in Table 1. Example 2

(-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H) -acetate (30 g, 0.094 mol) until the consistency, which allows stirring, preheated. Then 5.3 ml of acetic acid (0.094 mol) is added and the

Mixture preheated to 100 ⁰ C. The whole is mixed under these conditions for 2 hours after it is cooled to 70 ⁰ C, added 50 ml of ethanol, cooled to 4 ° C and held at this temperature for 4 hours.

Then the white crystalline precipitate of the racemic

Methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate filtered off (26 g, yield: 87%) Enantiomeric purity (HPLC) and elemental analysis and the

Measurement result after XRPD were basically the same as those for after

Example 1 product.

Content of acetic acid in the product: 0.7%.

Example 3 160 g (0.5 mol) of the mixture of enantiomers: (-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine -5 (4H)) - acetate 70% and the

(+) - (S) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) -acetate 30% is added until the consistency, the allows stirring, preheated.

Then 2 ml of formic acid (0.05 mol) is added and stirred after preheating to 100 ⁰ C for 2 hours. After that time it will be

Cooled to 70 ⁰ C, added 150 ml of ethanol, and to 0 ⁰ C under

Stirring cooled. At this temperature, it is stirred for 1, 5 hours, then The white crystalline precipitate of the racemic clopidogrel is filtered off (145 g, yield: 90%).

The enantiomeric purity (HPLC) and elemental analysis as well as the measurement result according to XRPD were basically the same as those for the product obtained according to Example 1.

The content of formic acid in the product: 0.7%.

Example 4

40 g (0.12 mol) of the mixture of enantiomers: (-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 ( 4H)) - acetate 70% and (+) - (S) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) -acetate Dissolve 30% in 40 ml of ethanol, add 2.3 ml (0.06 mol) of formic acid and heat to the boiling point. Under these conditions, it is kept under stirring for 20 hours, after being cooled to the temperature of 4 ° C, and allowed to stand overnight. Then, the white crystalline precipitate of the racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate is filtered off (30 g, yield: 75 %) The enantiomeric purity (HPLC) and elemental analysis as well as the measurement result after XRPD were basically the same as those for the product obtained in Example 1. Content of formic acid in the product: 0.8%. Example 5

A crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate (27 g. 0.084 mol) is dissolved in 150 ml of acetone. It is added camphorsulfonic acid (19.5 g, 0.084 mol) and preheated to complete dissolution with stirring, then cooled to room temperature and allowed to crystallize overnight. Filtration and drying of the precipitate gives 6.3 g of clopidogrel camphorsulfonate (yield: 37% based on racemate).

Claims

claims

1. Crystalline form of the racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate.

2. Crystalline form of the racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) - acetate according to claim 1, characterized in that it has characteristic Peaks X-ray diffractogram (XRPD) peaks at 2Θ (+ 0.2 ° θ) indicated: 14.1, 16.2, 17.0, 18.6, 19.4, 19.8, 21.0, 25.2, 25.5, 27.3, 32.0.

A process for producing the crystalline racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate as claimed in any one of claims 1 to 2, characterized in that on (-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) - acetate or on the mixture of enantiomers of methyl α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) acetate is treated with formic acid or acetic acid.

4. Process for the preparation according to Claim 3, characterized in that (-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine)

5 (4H)) - acetate or the mixture of enantiomers of methyl α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) acetate with excess of link rotating enantiomers until the consistency that allows stirring, heated, adding formic acid or acetic acid with stirring and the mixture is heated to temperatures of about 70 ⁰ C up to about 1 10 ⁰ C, then heated to temperatures of about 40 ⁰ C to Cools to about 80 ⁰ C, adding an organic solvent and further cooled to the temperature of about 0 ⁰ C to about 20 ⁰ C with stirring and the precipitate separated.

5. Process for the preparation according to claim 3, characterized in that (-) - (R) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine) 5 (4H)) - acetate or the mixture of the enantiomers of the methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) - acetate with Excess of the left-rotating enantiomer in the organic solvent dissolves and adds formic acid or acetic acid, the mixture is heated to boiling point, cooled to temperatures of about 40 ⁰ C up to about 80 ⁰ C, adding an organic solvent and further to temperatures of about 0 ⁰ C is cooled to about 15 ° C with stirring and the precipitate separated.

6. A process for the preparation according to any one of claims 3 to 5, characterized in that the organic solvent used is a solvent selected from groups: alcohols, ketones, ethers, most advantageously methanol or ethanol.

A crystalline form of the racemic methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate prepared by the process of any of claims 3 to 6 ,

8. A process for the preparation of (+) - (S) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydro-thieno [3,2-c] pyridine-5 (4H)) -acetate (Clopidogrel ) and / or its salts, characterized in that the starting material is the crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) Acetate according to one of claims 1, 2 or 7, is used.

9. Use of the crystalline racemate of methyl α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) - acetate according to any one of claims 1, 2 or 7 for the preparation of the (+) - (S) -methyl-α- (2-chlorophenyl) -2- (6,7-dihydrothieno [3,2-c] pyridine-5 (4H)) acetate (clopidogrel) and / or its salts.