RACEMIZATION PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF CLOPIDOGREL HYDROGEN SULPHATE

Field of the invention

The invention relates to a new industrial process for the preparation of the pharmaceutically applicable methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulphate (also known as S-(+)-clopidogrel hydrogen sulphate) of formula (I) comprising racemizing methyl (R)-(-)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate (known as (R)-(-)-clopidogrel) or methyl

(S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyrid ine-5(4H)-acetate (known as

(S)-(+)-clopidogrel), or a mixture thereof in any proportion with a weak base in the presence of an organic solvent, converting the methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate of fomula (II) obtained to its sulphuric acid addition salt methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyrid ine-5(4H)- acetate hydrogen sulphate (also known as racemic clopidogrel hydrogen sulphate) and converting it to methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine -5(4H)- acetate hydrogen sulphate of formula (I) by known manner.

II

Background of the invention

The (S)-(+)-clopidogrel hydrogen sulphate of formula (I) is a known valuable pharmaceutical substance used as platelet aggregation inhibitor and anti-thrombotic agent. The (S)-(+)-clopidogrel hydrogen sulphate and a process for the preparation thereof was originally disclosed in EP 281 459.

A large number of chemical processes have been developed for the preparation of the racemic clopidogrel hydrogen sulphate by racemization.

In EP 281 459 patent specification the methyl (R,S)-( ±)- α -(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate is formed with (R)-(-)-camphor-10-sulphonic acid to obtain camphor- 10-sulphonie acid salt of methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate. After separation the so obtained salt is treated with sodium hydrogen carbonate to obtain methyl (S)-(+)-α-(2-chlorophenyl-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate. Then addition of sulphuric acid to the methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine -5(4H)-acetate results in S-(+> clopidogrel hydrogen sulphate.

The camphor- 10-sulphonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2c]pyridine-5(4H)-acetate or the mixture in any proportion of camphor-10- sulphonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrotieno[3,2-c]pyridine- 5(4H)-acetate and camphor- 10-sulphonic acid salt of methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate that remained in the mother liquor is converted to methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine -5(4H)-acetate or 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]ρyridin e-5(4H)-acetate.

From the so obtained composition the methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate may be synthetized by racemization to give a further mass of S-(+)clopidogrel hydrogen sulphate.

WO 2000/027840 published patent application is directed to a racemization process of the optically active (-)-[2-(2-thienyl)-ethylamino]-(2-chlorophenyl)-acetamide. In this racemization procedure the R(-)-amide is converted to racemic amide {another named to [2-(2-thienil)-ethylamino]-(2-chlorophenyl)-acetamide} by using organic or inorganic basic compounds (alkali metal hydroxides, alkali metal alcoholates).

WO 2004/074215 published patent application discloses a process for the racemization of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]-pyridin e-5(4H)- acetate. Accordingly, the base is liberated from the camphor-sulphonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]-pyridin e-5(4H)-acetate then the so obtained base is treated with an acid (hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid) to obtain methyl (R,S)-(±)-α-(2chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate.

WO 2003/000636 published patent application discloses a process for the preparation of racemic 2-hydroxy-2(2-chlorophenyl) acetic acid by racemizing its S-(+) isomer with an alkali metal hydroxide. The racemic 2-hydroxi-2(2-chlorophenyl)acetic acid is one of the starting materials of the S-(+)-clopidogrel hydrogen sulphate. According to the process disclosed in US 6 737 411 patent specification methyl (R)-

(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate is racemized using a strong base (potassium-tert-butoxide, sodium-fe/Y-butoxide, diizopropylamide, potassium hydroxide, sodium hydroxide, potassium methoxide, sodium methoxide) similarly to those written in US 6 800 759 patent specification.

According to WO 2002/059128 published international patent specification racemization of (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine -5(4H)-acetate is also carried out with a base (potassium-fert-butoxide, lithium diisopropylamide, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium hydride, sodium hydride).

Summary of the invention

The invention relates to a new process for the preparation of the pharmaceutically applicable methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine -5(4H)-acetate hydrogen sulphate of formula (I) comprising racemizing methyl (R)-(-)-α-(2-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate, or a mixture thereof in any proportion with a weak base in the presence of an organic solvent, converting the (R,S)-(±)-α-(2-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate of fomula (II) obtained to its sulphuric acid addition salt methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyrid ine-5(4H)- acetate hydrogen sulphate and converting it to methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) by known manner.

Drawback of the procedures described in the foregoing is that the use of strong

Bronsted-Lowry acids or bases in the racemization step results in other catalytic actions (ester hydrolysis, condensation reactions, etc.) therefore the product obtained requires further purifying actions. The procedures are also disadvantageous from the environmental point of view due to use of strong acids or bases.

In the course of our experience we have surprisingly found that performing the racemization procedure described in the aforesaid patent applications the racemization

procedure can be carried out by using weak bases (alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, alkali metal carbonates, alkali earth metal carbonates, organic bases with non-nucleophile character, particularly cyclic organic bases) instead of strong bases. The so obtained (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3.2-c] pyridine-5(4H)-acetate of formula (II) can be converted to (S)-(+)-clopidogrel hydrogen sulphate without further purifying procedure.

In the new process according to the invention the starting methyl (R)-(-)-α- (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acet ate or methyl (S)-(+)~α- (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acet ate or a mixture thereof can be obtained according to the resolvation process described in EP 281 459 .

Detailed description of the invention

Definitions of terms and abbreviations as used herein have the following meanings: As used herein the term ,,room temperature" refers to temperatures between about 20 and 25°C.

As used herein the abbreviation "DSC" means differential scanning calorimetric test. As used herein the abbreviation ,,TG" means thermogravimetric analysis. As used herein the term abbreviation ,,IR" means infrared spectra.

Using the EP 281 459 procedure for the preparation of methyl (S)-(+)-α-

(2-chlorophenyl)-6,7-dyhidrothieno[3,2-c]pyridine-5(4H)-a cetate hydrogen sulphate of formula (I), the starting material of our invention is methyl (R)-(-)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]ρyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chloroρhenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate or a mixture thereof in any ratio remained in the

mother liquor after resolution with (R)-(-)-camphor-10-sulphonic acid is racemized using a weak base in the presence of an organic solvent to obtain (R,S)-(±)-α-(2~chlorophenyl)-6,7- dihydrothieno[3.2-c]pyridine-5(4H)-acetate of formula (II). This compound is converting to its sulphuric acid addition salt methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulphate (also known as racemic clopidogrel hydrogen sulphate) and converting it to methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) by known manner.

Performing the new process according to the invention for the preparation of methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine -5(4H)-acetate hydrogen sulphate of formula (I) the starting methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chloroρhenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate or a mixture thereof is prepared according to the EP 281 459 procedure. Accordingly, after resolving with (R)-(-)-camphor-10-sulphonic acid the camphor- 10-sulphonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate or the camphor- 10-sulphonic acid salt of methyl (S)-(+)-α- (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acet ate or a mixture thereof in any ratio remained in the mother liquor is extracted with aqueous alkali hydrogen carbonate or alkali earth metal hydrogen carbonate to liberate the acetate compounds. Then the so obtained methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine -5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine -5(4H)-acetate or a mixture thereof in any ratio is racemized with a weak base as catalyst in the presence of an organic solvent. The methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3.2-c]pyrid ine-

5(4H)-acetate of formula (II) obtained is treated with sulphuric acid to obtain the racemic clopidogrel hydrogen sulphate.

The racemization process according to the invention affords the possibility of further resolution steps to give further amounts of (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I).

Suitable weak base which can be used in the racemization process according to the invention include alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, or a mixture thereof, particularly sodium hydrogen carbonate, potassium hydrogen carbonate, preferably sodium hydrogen carbonate. Suitable weak base which can be used in the racemization process according to the invention include alkali metal carbonates, alkali earth metal carbonates, or a mixture thereof, particularly lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, preferably potassium carbonate.

Suitable weak base which can be used in the racemization process according to the invention include organic bases with non-nucleophile character, particularly cyclic organic bases, or a mixture thereof, particularly l,5,7-triazabicyclo[4.4.0]dec-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5~ene, preferably l,8-diazabicyclo[5.4.0]undec-7-ene.

Suitable weak base which can be used in the racemization process according to the invention include also a mixture of the above listed alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, alkali metal carbonates, alkali earth metal carbonates, organic bases with non-nucleophilic character, particularly cyclic organic bases. hi the racemization process according to the invention 0,1-1,0 mol equivalents, preferably 0,1 mol equivalents of the weak base is applied per one mol of methyl

(R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyrid ine-5(4H)-acetate or methyl

(S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2c]pyridi ne-5(4H)-acetate or a mixture thereof at any rate.

As organic solvent for the racemization process according to the invention one or more straight or branched chain aliphatic or cyclic saturated or unsaturated mono- or polisubstituted primary, secondary or tertiary C ₁ -C ₆ alcohol, preferably methanol can be used.

In the racemization process according to the invention the solvent is applied in 1-20 fold, preferably in 10 fold amount based on the weight of the methyl (R)-(-)-α- (2-chloroρhenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-ac etate or methyl (S)-(+)-α-

(2-chlorophenyl)-6,7-dihydrothieno[3,2c]pyridine-5(4H)-ac etate or a mixture thereof at any rate.

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

The advantage of the invention appears in that the racemization process according to the invention is suitable for the economical preparation of methyl (S)-(+)-α-(2-chlorophenyl)- 6,7-dihydrothieno[3,2c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) in industrial scale. The specific rotation, IR ₅ DSC, TG data of methyl (R,S)-(±)-α-(2-chlorophenyl)-

6,7-dihydrothieno[3 ₅ 2c]pyridine-5(4H)-acetate hydrogen sulphate obtained in the procedure according to the invention correspond with data described in the literature.

The invention is illustrated by the following non-limiting Examples. Example 1

Preparation of camphor-sulfonic acid salt of methyl (S)-(+)-α-(2-chIorophenvD- 6,7-dihydrothienof3,2-c]pyridine-5(4H)-acetate by resolution of methyl (R ₁ S)-(J-Va- (2-chlorophenyl)-6,7-dihydrothienor3,2-clpyridine-5(4H)-acet ate of formula (II)

123.53 g of compound of formula (II) was dissolved in 560.0 ml of acetone at room temperature during stirring and 40.6 g of (R)-(-)-camphor-10-sulphonic acid was added to this mixture. After dissolution of the compound of formula (II) the solution obtained was seeded with (R)-(-)-carnphor-10-sulphonic acid salt of (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate. The reaction mixture was stirred for further 22 hours at room temperature and the crystals precipitated were filtered washed with acetone and dried.

In this manner 43.7 g of the camphor-sulphonic acid salt of (S)-(+)-α- (2-chlorophenyl)-6,7-dihydrothieno[3 ,2-c]pyridine-5(4H)-acetate was obtained. Yield: 22.5%

Specific rotation: [α]D ² °=(24.71 ^° ) (C=I, in methanol)

Example 2 Preparation of a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7- dihydrothienof3,2-clpyridine-5(4H)-acetate and methyl (SH+)-q-(2-chlorophenyl)-6,7- dihydrothieno [3,2-d pyridine-5(4HV acetate

The acetonic mother liquor, obtained according to Example 1, was evaporated in vacuum. 280.0 ml of ethyl acetate was added to the oil obtained above and the mixture was

extracted with 90.0 ml of eight percent aqueous sodium hydrogen carbonate. The organic phase was washed with aqueous sodium chloride and dried on sodium sulphate. The dried organic phase was evaporated in vacuum. hi this manner, 76.5 g of product was obtained as a mixture of methyl (R)-(-)-α-(2-chloroρhenyl)-6,7-dihydrothieno[3,2-c]ρyridi ne-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine -5(4H)-acetate. Specific rotation: [α] _D ²⁰ =(-15 ^o )-(-16°) (C=I, in methanol)

Example 3

Preparation of methyl (R,SV(±Vα-(2-chlorophenyl)-6,7-dihydrothieno [3,2-clpyridine-5(4H)-acetate of formula (ID

15.8 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 obtained in Example 2 was dissolved in 158,0 ml of methanol and 0.41 g of sodium hydrogen carbonate was added. The reaction mixture was heated to reflux temperature for 3 hours then the organic solvent was evaporated in vacuum. To the residue obtained 40.0 ml of ethyl acetate was added and the mixture was extracted with 40 ml of water. The organic phase was dried on sodium sulphate then evaporated in vacuum. hi this manner 14.8 g of compound of formula (II) was obtained.

Yield: 94% Specific rotation: [α] _D ²⁰ =(0°)-(-l ^o ) (Ol , in methanol)

Example 4

Preparation of methyl (R,SH±Vα-(2-chlorophenvi)-6,7-dihydrothieno f3,2-c1pyridine-5(4ϊDacetate of formula (IB

15.78 g of a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2c]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 heated to reflux temperature for additional 3 hours then the organic solvent was evaporated in vacuum. 40.0 ml of ethyl acetate was added to the residue obtained and the mixture was extracted with 40 ml of water. The organic phase was dried on sodium sulphate then evaporated in vacuum, hi this manner 15.1 g of compound of formula (II) was obtained. Yield: 96% Specific rotation: [α] _D ²⁰ =(0°)-(-l ^o ) (O=I, in methanol)

Example 5

Preparation of methyl (R,SV(±Vα-(2-chlorophenylV6J-dihydrothieno [3.,2-c1pyridine-5(4H)acetate of formula (ID

10.54 g of a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2c]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 l,8-diazabicyclo[5.4.0]undec-7-ene was added. The reaction mixture was heated to reflux temperature for additional 3 hours then the organic solvent was evaporated in vacuum. 40.0 ml of ethyl acetate was added to the residue obtained and

the mixture was extracted with 40 ml of water. The organic phase was dried on sodium sulphate then evaporated in vacuum.

In this manner 9.7 g of compound of formula (II) was obtained.

Yield: 92%. Specific rotation: [α] _D ²⁰ =(0°)-(-l °) (C=I , in methanol)

Example 6

Preparation of methyl (R,SV(±Vα-(2-chIorophenylV6,7-dihvdrothieno r3.2-clpyridine-5(4EDacetate of formula (ID

15.8 g of methyl (R)-(-)-α-(2-chloroρhenyl)-6,7-dihydrothieno[3,2-c]pyridin e-5(4H)- acetate {Specific rotation: [α] _D ²⁰ =(-47.1°) (C=I, in methanol)} was dissolved in 158.0 ml of methanol and 0.41 g of sodium hydrogen carbonate was added. The reaction mixture was heated to reflux temperature for additional 3 hours then the organic solvent was evaporated in vacuum. 40.0 ml of ethyl acetate was added to the residue obtained and the mixture was extracted with 40 ml of water. The organic phase was dried on sodium sulphate then evaporated in vacuum.

In this manner 15.0 g of compound of formula (II) was obtained. Yield: 95% Specific rotation: [α] _D ²⁰ =(0 ^o H-P) (C=I , in methanol)

Example 7

Preparation of methyl rR-SH±Vα-(2-chIorophenyiy6,7-dihydrothieno [3,2-c1pyridine-5(4H)acetate of formula (ID

15.78 g of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine - 5(4H)-acetate {Specific rotation: [α] _D ²⁰ =(-47,l°) (C=I, in methanol)} was dissolved in 158.0 ml of methanol and 0.63 g of potassium carbonate was added. The reaction mixture was heated to reflux temperature then the organic solvent was evaporated in vacuum. To the residue obtained 40.0 ml of ethyl acetate was added and the mixture was exacted with 40 ml of water. The organic phase was dried on sodium sulphate and evaporated in vacuum. In this manner 15.0 g of compound of formula (II) was obtained.

Yield: 95% Specific rotation: [α] _D ²⁰ =(0°)-(-l°) (C=I, in methanol)

Example 8

Preparation of methyl (R.SV(±)-α-(2-chlorophenyl)-6J-dihydrothieno[3.,2-c1 pyridine-5(4H)acetate hydrogen sulphate

16.6 g of compound of formula (II) was dissolved in 48.0 ml of acetone and 2.17 ml of 98 % sulphuric acid was added under stirring. The suspension obtained was stirred for additional 2 hours at room temperature then filtered and washed with acetone. hi this manner 15.17 g of methyl (R,S)-(±)-α-(2-chloroρhenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)acetate hydrogen sulphate was obtained. Yield: 91% Specific rotation: [α] _D ²⁰ =(0°)-(-P) (C=I, in methanol)