HUP0700809A2 - Racemisation process for producing methyl (r,s)-(+)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4h)-acetate hydrogene sulfate intermediate - Google Patents

Description

The subject of the invention is a new industrial process for the preparation of methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of formula (I) (also known as (S)-(+)-clopidogrel hydrogen sulfate) by the sulfuric acid separation of methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate of formula (II) (also known as (R,S)-(+)-clopidogrel or racemic clopidogrel), which is formed by the racemization of optically active methyl α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, in such a way that methyl The racemization reaction of (R)-(-)-α-(2-chlorophenyl)6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate (also known as (R)-(-)-clopidogrel), or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate (also known as (S)-(+)-clopidogrel), or mixtures of these compounds in any ratio, is carried out with weak bases in the presence of an organic solvent.

CH ₃ oog ch ₃ ooc

This allows for the preparation of methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of formula (I) by further resolution.

(S)-(+)-clopidogrel hydrogen sulfate of formula (I) is a known compound, a therapeutic agent with platelet aggregation inhibitory and antithrombotic effects.

Several methods for the preparation of racemic clopidogrel hydrogen sulfate by racemization have become known in the literature.

The first preparation of (S)-(+)-clopidogrel hydrogen sulfate of formula (I) is described in European patent specification No. 281 459, according to which the camphorsulfonic acid salt of methyl (S)-(+)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate of formula (II) is separated from the methyl (R,S)-(±)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate with the resolving agent (R)-(-)-camphor-10-sulfonic acid, then after separation it is converted into methyl (S)-(+)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate with sodium bicarbonate, and then the S-(+)-clopidogrel hydrogen sulfate.

The camphorsulfonic acid salt of methyl (R)-(-)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate remaining in the resolving mother liquor, or the mixture of methyl (R)-(-)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate camphorsulfonic acid salt and methyl (S)-(+)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate camphorsulfonic acid salt, is converted into methyl (R)-(-)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, or methyl It is converted into a mixture of (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate.

The mixture thus obtained provides an opportunity to prepare methyl (R,S)-(±)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate by racemization, which thus enables the further preparation of S-(+)-clopidogrel hydrogen sulfate.

During the racemization of (-)-[2-(2-thienyl)ethylamino]-(2-chlorophenyl)acetamide described in patent application WO 2000/027840, the racemic amide, also known as [2-(2-thienyl)ethylamino]-(2-chlorophenyl)acetamide, is obtained from the R(-)-amide using an organic or inorganic base (alkali metal hydroxides, alkali metal alcoholates).

In patent application WO 2004/074215, the base is liberated from the camphorsulfonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate, and then converted back to methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate with acid (hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid).

Patent application WO 2003/000636 describes the racemization of the S-(+) isomer of 2-hydroxy-2-(2-chlorophenyl)acetic acid, a possible starting compound for the preparation of S-(+)-clopidogrel hydrogen sulfate, with a base, using an alkali metal hydroxide as the base.

According to U.S. Patent No. 6,737,411, the authors racemize methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate in the presence of a strong base (potassium tert-butoxide, sodium tert-butoxide, diisopropylamide, potassium hydroxide, sodium hydroxide, potassium methylate, sodium methylate), similar to those described in U.S. Patent Applications Nos. 2004/024012 and 2004/024011, WO 2004/013147, and U.S. Patent No. 6,800,759.

In patent application WO 2002/059128, the racemization of (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate is also carried out with a base (potassium tert-butoxide, lithium diisopropylamide, potassium hydroxide, sodium hydroxide, sodium methylate, potassium hydride, sodium hydride).

The process according to the invention is the preparation of methyl (R,S)-(±)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate of formula (II) by separating methyl (R)-(+)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of formula (I) for pharmaceutical use, after resolution with (R)-(-)-camphor-10-sulfonic acid, the methyl (R)-(-)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate remaining in the mother liquor or any ratio thereof. by racemization of a mixture of weak bases in the presence of an organic solvent, creating the possibility of further resolution to prepare methyl (S)-(+)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine5(4H)-acetate hydrogen sulfate.

A major disadvantage of previous processes is that strong Brønsted-Lowry acids or bases are used for racemization, which also induce other catalytic processes (ester hydrolysis, condensation reactions and other reactions depending on the solvent), due to which the pharmaceutical use of the resulting product can only occur through additional purification processes, and the use of these strong acids or bases is dangerous in an industrial environment.

During our experiments, we came to the unexpected and surprising realization that these strong bases are not necessary for racemization, and instead, racemization can be achieved with weaker bases (alkali metal, alkaline earth metal hydrogen carbonates, alkali metal, alkaline earth metal carbonates, non-nucleophilic organic bases, especially cyclic structures), and the resulting methyl (R,S)-(±)a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate of formula (II) can be converted into (S)-(+)-clopidogrel hydrogen sulfate of formula (I) without further purification, which can be used in the pharmaceutical industry.

The invention is described in detail below.

For a better understanding of the invention, the following definitions are provided:

···«···· ···· ·· · «*·· J

The term "room temperature" means a temperature of around 20-25 °C.

The abbreviation “DSC” stands for differential scanning calorimetry.

The abbreviation “TG” stands for thermo gravimetric analysis.

The abbreviation “IR” stands for infrared spectrum.

In the new industrial process according to the invention, first, during the preparation of the pharmaceutical methyl (S)-(+)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of formula (I) (- according to the method found in European patent specification No. 281 459 -), the methyl (R)-(-)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate remaining in the mother liquor after resolution with (R)-(-)-camphor-10-sulfonic acid or a mixture of these in any ratio with weak bases in the presence of an organic solvent, the methyl (II)-acetate is prepared. (R,S)-(±)a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate; then the racemic clopidogrel hydrogen sulfate is separated from the methyl (R,S)-(±)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate thus obtained with sulfuric acid.

This opens up the possibility of preparing further methyl (S)-(+)-α(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of formula (I) by further resolution.

In the process according to the invention, the racemization is carried out after the separation of the camphorsulfonic acid salt of methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate from the camphorsulfonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate remaining in the mother liquor, or from the camphorsulfonic acid salt of methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate, or from a mixture of these in any ratio.

In the process according to the invention, the racemization is generally carried out by liberating methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)acetate, or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)acetate, or a mixture thereof in any ratio, from their camphorsulfonic acid salt by extraction with aqueous alkali metal bicarbonate or alkali metal carbonate, and then the racemization of the resulting base is carried out using a weak base as a catalyst and an organic solvent as a solvent. The racemic clopidogrel hydrogen sulfate is separated from the methyl (R,S)-(±)a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate thus obtained with sulfuric acid.

In the racemization process according to the invention, alkali metal bicarbonates, alkaline earth metal bicarbonates, or mixtures thereof, especially sodium bicarbonate, potassium bicarbonate, preferably sodium bicarbonate, are used as weak bases.

In the racemization process according to the invention, alkali metal carbonates, alkaline earth metal carbonates, or mixtures thereof, especially lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, preferably potassium carbonate, are used as weak bases.

In the racemization process according to the invention, non-nucleophilic organic bases, in particular those with a cyclic structure, or mixtures thereof, are used as weak bases, mainly 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene.

In the racemization process according to the invention, mixtures of the listed alkali metal hydrogen carbonates, alkaline earth metal hydrogen carbonates, alkali metal carbonates, alkaline earth metal carbonates, non-nucleophilic organic bases, especially those with a cyclic structure, can also be used as weak bases.

In the racemization process according to the invention, a weak base is used in an amount of 0.1-1.0 molar equivalent, preferably 0.1 molar equivalent, per mole of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate, or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate, or a mixture thereof in any ratio.

In the racemization process according to the invention, one or more straight or branched, aliphatic or cyclic, saturated or unsaturated, mono- or polysubstituted, primary, secondary or tertiary, C _r C6 alcohols, preferably methanol, are used as organic solvents.

In the racemization process according to the invention, an organic solvent is used in an amount of 1-20 times, preferably 10 times, by weight of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate, or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate, or a mixture thereof in any ratio.

In the racemization process according to the invention, the reaction is carried out between 0°C and the boiling point of the solvent or solvent mixture used, preferably at the boiling point of the solvent or solvent mixture used.

The great advantage of the process according to the invention is that it is industrially applicable and provides economical production of the active ingredient methyl (S)-(+)-oc-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of formula (I) suitable for pharmaceutical use.

The results of the rotational ability, IR, DSC, and TG tests of methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate sulfate obtained by the process according to the invention are consistent with those described in the literature.

Further details of the invention are illustrated by the following examples. The listed examples do not limit the scope or extent of the invention.

Example 1

Process for preparing methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate camphorsulfonic acid salt by resolving methyl (R,S)-(±)-α-(2chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate of formula (II)

123.53 g of compound (Π) is dissolved in 560.0 ml of acetone and 40.6 g of (R)-(-)-camphor-10-sulfonic acid are added while stirring at room temperature. After dissolution, the resulting solution is seeded with (S)-(+)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)acetate (R)-(-)-camphor-10-sulfonic acid salt. The reaction mixture is stirred for another 22 hours at room temperature, then the resulting crystals are filtered, washed with acetone and dried.

Thus, 43.7 g of (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate camphorsulfonic acid salt product is obtained, the specific rotation of which is: [α] _D ²⁰ = 24.71° (C _Me0 H=1)· Yield: 22.5%.

Example 2

Process for preparing a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate

The acetone mother liquor obtained in Example 1 was evaporated in vacuo. 280.0 ml of ethyl acetate was added to the oil obtained and extracted with 90.0 ml of 8% aqueous sodium hydrogen carbonate solution. The organic phase was washed with aqueous sodium chloride solution and dried over sodium sulfate. The thus dried organic phase was evaporated in vacuo.

Thus, 76.5 g of a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetate are obtained, the specific rotation of which is [oc]n — (-15 )-(-16 ) (CMeOH=1)·

Example 3

Process for the preparation of methyl (R,S)-(±)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate of formula (II)

A mixture of 15.8 g of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate prepared in Example 2 was dissolved in 158.0 ml of methanol and 0.41 g of sodium bicarbonate was added. The reaction mixture was refluxed for 3 hours, and the organic solvent was evaporated in vacuo. 40.0 ml of ethyl acetate was added to the resulting residue and extracted with 40 ml of water. The organic phase was dried over sodium sulfate and evaporated in vacuo.

Thus, 14.8 g of the product of formula (II) are obtained, the specific rotation of which is: [α] _D ²⁰ : 0°-(-1°) (C _Me 0H=1)· Yield: 94%.

Example 4

Process for the preparation of methyl (R,S)-(±)-a-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine5(4H)-acetate of formula (II) * ·«· ««t « ♦ «

A mixture of 15.78 g of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate prepared in Example 2 was dissolved in 158.0 ml of methanol and 0.63 g of potassium carbonate was added. The reaction mixture was refluxed for 3 hours, and the organic solvent was evaporated under vacuum. 40.0 ml of ethyl acetate was added to the resulting residue and extracted with 40 ml of water. The organic phase was dried over sodium sulfate and evaporated under vacuum.

Thus, 15.1 g of the product of formula (II) are obtained, the specific rotation of which is: [a] _D ²⁰ : 0°-(-1°) (C _Me oH=1)· Yield: 96%.

Example 5

Process for preparing methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate of formula (II)

A mixture of 10.54 g of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate prepared in Example 2 was dissolved in 105.4 ml of methanol and 0.49 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene was added. The reaction mixture was refluxed for 3 hours, and the organic solvent was evaporated under vacuum. 40.0 ml of ethyl acetate was added to the resulting residue and extracted with 40 ml of water. The organic phase was dried over sodium sulfate and evaporated under vacuum.

Thus, 9.7 g of the product of formula (II) are obtained, the specific rotation of which is: [a] _D ²⁰ : 0°-(-1°) (C _Me0 H=1)· Yield: 92%.

Example 6

Process for preparing methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate of formula (II)

15.8 g of methyl (R)-(-)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetate, with a specific rotation: [α]d ² °: (-47.1°) (C _Me oH=1); are dissolved in 158.0 ml of methanol and 0.41 g of sodium bicarbonate are added. The reaction mixture is refluxed for 3 hours, then the organic solvent is evaporated in vacuo. 40.0 ml of ethyl acetate are added to the resulting residue and extracted with 40 ml of water. The organic phase is dried over sodium sulfate and then evaporated in vacuo.

Thus, 15.0 g of the product of formula (II) are obtained, the specific rotation of which is: [a] _D ²⁰ : 0°-(-1°) (C _Me0 H=1)· Yield: 95%.

Example 7

Process for preparing methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate of formula (II)

15.78 g of methyl (R)-(-)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetate, with a specific rotation: [α]d ² °: (-47.1°) (C _Me oH=1); are dissolved in 158.0 ml of methanol and 0.63 g of potassium carbonate are added. The reaction mixture is refluxed for 3 hours, then the organic solvent is evaporated in vacuo. 40.0 ml of ethyl acetate are added to the resulting residue and extracted with 40 ml of water. The organic phase is dried over sodium sulfate and then evaporated in vacuo.

Thus, 15.0 g of the product of formula (II) are obtained, the specific rotation of which is: [α] _D ²⁰ : 0°-(-1°) (C _MeOH =1)· Yield: 95%.

Example 8

Process for preparing methyl (R,S)-(±)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate

16.6 g of compound (II) was dissolved in 48.0 ml of acetone and 2.17 ml of 98% sulfuric acid were added while stirring. The resulting suspension was stirred for another 2 hours at room temperature, then filtered and washed with acetone.

Thus, 15.17 g of methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate product is obtained, the specific rotation of which is: [α] _D ²⁰ : 0°-(-1°) (C _Me0H =1). Yield: 91%.

Claims (10)

PATENT CLAIMS 1. Process for the preparation of methyl (S)-(+)a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of formula (I) suitable for medical use by separating methyl (R,S)-(±)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate of formula (II) formed by racemization of optically active methyl a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate with sulfuric acid, characterized in that methyl (R)-(-)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, or methyl (S)-(+)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, or the racemization reaction from any mixture of these compounds, is weak. 2. The process according to claim 1, characterized in that alkali metal hydrogen carbonates and alkaline earth metal hydrogen carbonates are used as weak bases in the racemization reaction. 3. The method according to claim 2, characterized in that sodium bicarbonate, potassium bicarbonate, preferably sodium bicarbonate is used as the bicarbonate. 4. The process according to claim 1, characterized in that alkali metal carbonates and alkaline earth metal carbonates are used as weak bases in the racemization reaction. 5. The method according to claim 4, characterized in that the carbonate used is lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, preferably potassium carbonate. 6. The process according to claim 1, characterized in that non-nucleophilic organic bases, in particular those with a cyclic structure, are used as weak bases in the racemization reaction. 7. The process according to claim 6, characterized in that the organic base used is 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene. 8. The process according to any one of claims 1-7, characterized in that a mixture of the listed alkali metal hydrogen carbonates, alkaline earth metal hydrogen carbonates, alkali metal carbonates, alkaline earth metal carbonates, non-nucleophilic organic bases, especially those with a cyclic structure, is used as a weak base in the racemization reaction. 9. The process according to any one of claims 1-8, characterized in that in the racemization reaction, methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine5(4H)-acetate, or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine5(4H)-acetate, or a mixture thereof in any ratio is used. A weak base is used in an amount of 0.1 to 1.0 molar equivalents, preferably 0.1 molar equivalents. 10. The process according to any one of claims 1-9, characterized in that in the racemization reaction one or more straight or branched, aliphatic or cyclic, saturated or unsaturated, mono- or polysubstituted, primary, secondary or tertiary, C 1 -C ₆ carbon chain alcohols, preferably methanol, are used as organic solvent. r. ,, 1-3. The process according to any one of claims 1-1Z, characterized in that in the racemization reaction, an organic solvent is used in an amount of 1-20 times, preferably 10 times, by weight of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate, or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate, or a mixture thereof in any ratio. (2 ü , i χ The process according to any one of claims 1-6, characterized in that the racemization reaction is carried out between 0 °C and the boiling point of the solvent or solvent mixture used, preferably at the boiling point of the solvent or solvent mixture used. department head