FIELD OF THE INVENTION

The present invention relates to a process for racemisation of optically active
isomer of 2-halo-2-(2-chlorophenyl) acetic acid methyl ester of formula (I). More
particularly the present invention relates to S (+) 2-bromo-2-(2-chIorophenyl) acetic acid
methyl ester of Formula (la). -

BACKGROUND OF THE INVENTION

Clopidogrel bisulfate is chemically known as methyl (+)-(S)-a-(2-chlorophenyl)-6, 7-dihydrothieno [3S 2-c] pyridine-5-(4H) acetate hydrogen sulfate (1:1) of Formula A.

Clopidogrel is an inhibitor of platelet aggregation. Clopidogrel platelets inhibiting activity makes it an effective drug for reducing the induced ischemic strokes or heart attacks. By inhibiting platelet aggregation, Clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks. Recent studies have shown that Clopidogrel is more effective in blocking platelet aggregation than Aspirin. Clopidogrel is much effective than Aspirin even at much lower dosage. In addition to being more effective, Clopidogrel produces much less gastrointestinal bleeding than Aspirin.

Clopidogrel is marketed under the brand name Plavix® in the US. It has been approved for the treatment of Recent Stroke or Established Peripheral Arterial Disease and Acute Coronary Syndrome.

There are several processes reported in the prior art for the preparation of Clopidogrel, for example US patent 4,847,265 discloses a method for resolving racemic Clopidogrel of formula (Ha) using R-(-) camphor- 10-sulfonic acid. The process is as shown in Scheme-I below:

WO 02/059128 discloses a process for the preparation of Clopidogrel which is shown in Scheme-II. This patent publication involves the racemisation of unwanted stereo isomer of Clopidogrel intermediate of Formula (III) using base as shown in Scheme-IIA.

WO 98/39286 discloses a racemisation process for phenyl glycine esters.

US 6,737,411 disclose a process for racemisation of enriched (R)-(-)-Clopidogrel, which is left in the mother liquor, after removal of (S)-(+)-Clopidogrel. The process comprises reacting (R)-(-)-Clopidogrel with a catalytic amount of a base in a solvent to convert a portion of the (R)-(-)-Clopidogrel to (S)-(+)-Clopidogrel. .

WO 2004/074215 discloses a process, which comprises treating R-(-)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5-(4H)acetate with an acid in a solvent at a temperature in the range of 60-100° C to produce racemic methyl ct-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetate acid salt. This salt is neutralised with a base to give racemic Clopidogrel.

WO 2007/126258 discloses a process for the preparation of optically active 2-bromo-2-(2-chloro phenyl)acetic acid alkyl ester and 2-bromo-2-(2-chloro phenyl)acetic acid from racemic 2-bromo-2-(2-chloro phenyl)acetic acid alkyl ester by using hydrolases or hydrolase producing micro organisms as biocatalysis. The process is as shown in Scheme-IV below:

WO 2009/121946 discloses the racemisation of (R)-Clopidogrel by treating with acetic acid without solvent.

US 2008/0182869 disclose the racemisation process of (R)-Clopidogrel by treating with a base selected from alkyl, aryl, or cycloalkyl ammonium hydroxides in a solvent selected from alcohol, ester, ketone or ethers..

The main drawbacks of the above cited processes are that the resolution is carried out at the late stage and affects the overall yield. The late stage resolutions of chiral products are regarded as unfavorable as loss of material at a later stage is disadvantageous commercially.

Considering the need of Clopidogrel in the health industry, there is a need to develop an improved process for the preparation of Clopidogrel bisulfate. We focused our research and found that the resolution in initial stage helps to enhance the overall productivity.

Combining this early stage resolution under dynamic kinetic conditions affords the increased potential benefit of 100% yield from the resolution process, rather than the 50% maximum yield which is a feature of the existing technology.

OBJECTIVE OF INVENTION

The objective of the present invention is to provide a dynamic kinetic resolution process for Clopidogrel utilizing racemisation of optically active isomer of 2-halo-2-(2-chlorophenyl) acetic acid methyl ester formula (I), in particular S (+) 2-bromo-2-(2-ch!orophenyl)acetic acid methyl ester of formula (la) to increase the yield of optically enhanced S (+) 2-bromo-2-(2-chlorophenyl)acetic acid methyl ester of formula (la)

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to racemisation of optically active isomer of 2-halo-2-(2-chlorophenyl) acetic acid methyl ester of general formula (I) which comprises treating a solution of optically active isomer of 2-halo-2-(2-chlorophenyl) acetic acid methyl ester of formula (I) in a solvent with a halide source.

In another aspect the present invention relates to racemisation of S (+) 2-bromo-2-(2-chlorophenyl) acetic acid methyl ester of formula (la) or its salts,

which comprises treating a solution of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl
ester (la) in a solvent with a bromide source.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, the present invention provides a process for the racemisation of optically active isomer of 2-halo-2-(2-chlorophenyl) acetic acid methyl ester of formula (I) using a halide source in a solvent.

In another embodiment of the present invention, the halide source used for racemisation is selected from bromide source or chloride source.

In still another embodiment of the present invention, optically active isomer of 2-halo-2-(2-chlorophenyl) acetic acid methyl ester of formula (I) is selected from (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (la), (R)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (lb), (S)-2-chloro-2-(2-chlorophenyl) acetic acid methyl ester (Ic) or (R)-2-chloro-2-(2-chlorophenyl) acetic acid methyl ester (Id).

In yet another embodiment of the present invention, the present invention provides a process for the racemisation of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (la) or (R)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (lb) using a bromide source in a solvent..

In another embodiment of the present invention, the solution of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (la) is obtained either by dissolving the (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (la) in a solvent or directly from the reaction mass.

In still another embodiment of the present invention the solution of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (la) may optionally contain (R)-2-bromo-2-(2-chlorophenyl) acetic. Accordingly the present invention provides a racemisation process for (S)-2-bromo-2-(2-chlorophenyl)acetic acid methyl ester (la) from a mixture containing variable amounts of (S)-2-bromo-2-(2-chlorophenyl)acetic acid methyl ester (la) and (R)-2-bromo-2-(2-chlorophenyl)acetic acid using a bromide source. The reaction mixture may contain 50-99 % of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (la) and 1-50 % of (R)-2-bromo-2-(2-chlorophenyl) acetic acid.
^ . ■ ■

In yet another embodiment of the present invention, the bromide source used for racemisation is selected from potassium bromide (KBr), cesium bromide (CsBr), triethylamine hydrogen bromide (Et3NHBr), a quaternary ammonium bromide (Bu4NBr), quaternary phosphonium bromide (Bu4PBr), cetyltriphenylphosphonium bromide (Ci6H33PPh3Br), wang polymer-CH2PPh3Br or mixtures thereof

In another embodiment of the present invention, the chloride source used for racemisation is selected from alkali metal chloride (e.g. KC1), quaternary ammonium chloride (e.g. NH4Br, Bu4NCl, Et3NHCl, Et3(Bn)NCl, ET3(Ci6H33)NCl), quaternary phosphonium chloride (Bu4PBr) or mixture thereof.

In one more embodiment of the present invention, the solvent used in the reaction comprises ether, ester, halogenated hydrocarbon, aromatic hydrocarbon, amide, nitrile, ketone, or mixtures thereof.

For the purpose of illustrationexamples of solvents are provided below, but the
present invention is not restricted to these solvent lists. Ether comprises tetrahydrofuran
(THF), diethyl ether, methyl ter-butyl ether, 1,4-dioxane or mixtures thereof; halogenated
hydrocarbon comprises dichloromethane, ethylene dichloride, chloroform or mixtures
thereof; aromatic hydrocarbon comprises benzene, toluene, xylene or mixtures thereof;
amide comprises dimethylacetamide, dimethylformamide or mixtures thereof; nitrile
comprises acetonitrile, propionitrile or mixtures thereof; alcohol comprises methanol,
ethanol, propanol, butanol, isopropano\or mixtures thereof; ester comprises methyl
acetate, ethyl acetate or mixtures thereof.

The reaction is carried put at a temperature ranges from 0°C to reflux temperature of solvent used. After the completion of reaction, the racemate compound is isolated by conventional manner and reused in the production of Clopidogrel. Accordingly the racemic 2-bromo-2-(2-chlorophenyl)acetic acid methyl ester is selectively hydrolysed by using hydrolytic biocatalysts (enzymes) under kinetic resolution conditions to provide (R)-2-bromo-2-(2-chlorophenyI)acetic acid and (S)-2-bromo-2-(2-chIorophenyl)acetic acid methyl ester (la). The obtained (R)-2-bromo-2-(2-chlorophenyl) acetic acid is reacted with thienylpiperidine and subsequent esterification yields Clopidogrel hydrogen sulfate (1:1).

1
The unwanted (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (la) is further converted to racemic compound of formula (I) in in situ manner.

Accordingly the present invention, the optically active isomer of 2-bromo-2-(2-. chlorophenyl)acetic acid methyl ester is raciemised and resolved in a in situ way to get homochiral 2-bromo-2-(2-chlorophenyl) acetic acid (IA) which in then converted to Clopidogrel.

The optically pure (S)-Clopidogrel is converted into its bisulfate salt using sulfuric acid in an appropriate solvent at suitable temperature to afford (-t-)-Clopidogrel bisulfate. The obtained (S)-Clopidogrel bisulfate by the above process shows crystalline Form-I.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the ' invention.

EXAMPLES:

Example 1: Racemisation of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester

To a solution of a mixture of (S)-2-bromo-2-(2-chlorophenyl)acetic acid methyl ester and (R)-2-bromo-2-(2-chlorophenyl) acetic acid (1 g) in THF (10 ml) was added tetrabutylammoinum bromide (TBAB) (1 g) at 25° C and stirred. Sample was analysed by chiral HPLC. After that THF was removed by distillation, added acetonitrile (10 ml) to the residue and stirred at 25°C. Enantiomeric excess of (R)-2-bromo-2-(2-chlorophenyl) acetic acid and (S)-2-bromo-2-(2-chlorophenyI) acetic acid methyl ester was measured by HPLC. A table of results is provided below:

The above table clearly shows that TBAB helps in racemisation of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester.

HPLC method for analysing enantiomeric excess of (R)-2-bromo-2-(2-chlorophenyl) acetic acid and (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester.

The chromatographic separation was carried out in an Ultron ES-OVM (150 mm x 4.6 nrimO 5 (a).column at a temperature of 25-35°C, using a UV detector at wave length of 220 nm. The mobile phase was prepared by mixing a suitable quantity of degassed mixture of acetonitrile and buffer (potassium phosphate in water) in the ratio 20:80 (v/v). The analysis was carried out by injecting 10 JIL of the test sample into the column, and running the chromatogram for 25 minutes. The retention time for (R)-2-bromo-2-(2-ch!orophenyl)acetic acid was observed to be about 8.03 minutes, and the retention time for (S)-2-bromo-2-(2-chlorophenyl)acetic acid methyl ester was observed to be 2.714 minutes.

Example 2: Resolution of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester using hydrolase

In PTFE vials placed hydrolase enzyme (20 mg) and phosphate buffer (1 mL, pH 7.5). Each vials were added with a solution of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (20 mg) in tert. butyl methyl ether (TBME) (0.2 mL). The vials were agitated in shaker at 25°C for 20h. Reactions were analysed with chiral HPLC. The following table illustrates the resolution of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester using various enzymes.

The following table illustrates the resolution of (R/S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester using various enzymes.

Example 3: Dynamic kinetic resolution of (S)-2-bromo-2-(2-chIorophenyI) acetic acid methyl ester using lipase TL

To a round bottom flask that was equipped with an overhead stirrer and a temperature probe was added a solution of TBAB (22.42g ) in 2M Tris buffer (900ml) was added and followed by addition of methyl-2- bromo-2-(2-chlorophenyl) acetate (18g ) in TBME (72ml) and lipase TL (18 g). Resulting reaction mixture was stirred at 100°C. Reaction progress was analysed by HPLC. After complete hydrolysis of ester, the mass was filtered through Hyflo. Reaction mixture was extracted with TBME. Then pH of the reaction mixture was adjusted to 2.0 to 2.5 with aq. hydrochloric acid. Reaction mixture was extracted with n-butanol to separate the product (R)-2- bromo-2-(2-chlorophenyl) acetic acid. Product purity (>95%) and chiral purity was analysed by HPLC (>95%).

Example 4: Dynamic kinetic resolution of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester using immobilised enzyme (AZL-1600)

To a round bottom flask that was equipped with an overhead stirrer and a temperature probe was added immobilised hydrolase AZL-1600 (94.8g). A solution of TBAB (22.42g in Tris buffer was added followed by addition of methyl-2- bromo-2-(2-chlorophenyl)

acetate (18g ) in TBME (72ml). Resulting reaction mixture was stirred at 100°C. Reaction progress was analysed by HPLC. After complete conversion of ester, the reaction mixture was filtered to separate immobilised enzyme. Reaction mixture was. extracted with TBME. Then pH of the reaction mixture was adjusted to 2.0 to 2.5 with aq. hydrochloric acid. Reaction mixture was extracted with n-butanol to separate the product (R)-2-bromo-2-(2-chlorophenyl) acetic acid with purity (>95%) and ee (>95%). The product was carried over to next step without further isolation.

Example 5: Preparation of (+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate

To the above solution from example 4 at l5°C , added 4s5,6,7-Tetrahydrothieno[3,2-c] pyridine hydrochloride (13.6 g) and triethyl amine and the reaction mass was stirred at 15°C for until consumption of (S)-2-bromo-2-(2-chlorophenyl) acetic acid. After completion of reaction, solvent was under reduced pressure followed by methyl tertiary butyl ether added to the residue. The solid obtained was separated by filtration and washed with additional tert. butyl methyl ether. Combined filtrate was concentrated under reduced pressure to obtain gummy mass. The gummy mass was dissolved in dichloromethane and cooled to 0°C. To the solution was added a solution of sodium hydroxide (2.25 g) in water, TBAB (2.4 g) and dimethyl sulphate (32.3 g). The reaction mass was stirred until complete conversion of acid to ester. Organic fraction was separated and washed with water and solvent was removed under vacuum to afford (H-)-(S)-methyl 2-(2-chlorophenyl)-2-(6, 7-dihydrothieno [3,2-c]pyridin-5(4H)-yl)acetate as oily mass.

Example 6: Preparation of (+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate dihydrogensulphate salt (Clopidogrel bisulphate).
To a solution of (+)-(S)-methyl 2-(2-chlorophenyI)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate free base (10 g) in acetone was added concentrated sulfuric acid (0.33g) was added slowly and stirred at 0°C.
The precipitate was separated by filtration. The filtrate was cooled to 0°C and added concentrated sulfuric acid (2.5 g). The mass was seeded with clopidogrel bisulphate and stirred at 0°C. Temperature was raised to 25°C and stirred. White precipitate was separated by filtration, washed with cold acetone and dried under vacuum to afford Clopidogrel bisulphate (ee: 99.1% by chiral HPLC)

We Claim:

1. A process for racemisation of optically active isomer of 2-halo-2-(2-chlorophenyl) acetic acid methyl ester of Formula (I) or its salts,

which comprises treating a solution of optically active isomer of 2-halo-2-(2-chlorophenyl) acetic acid methyl ester of formula (I) in a solvent with a halide source to yield racemic 2-halo-2-(2-chlorophenyl) acetic acid methyl ester.

2. The process according to claim 1, wherein the halide source is bromide or chloride.
3. The process according to claim 2, wherein the bromide source for racemisation is selected from potassium bromide (KBr), cesium bromide (CsBr), triethylamine hydrogen bromide (Et3NHBr), a quaternary ammonium bromide (Bu4NBr), quaternary phosphonium bromide (Bu4PBr)s cetyltriphenylphosphonium bromide fCi6H33PPh3Br), wang polymer-CH2PPh3Br or mixtures thereof.

4. The process according to claim 2, wherein chloride source for racemisation is selected from alkali metal chloride (KC1), quaternary ammonium chloride (NHUBr, B114NCI, Et3NHCl, Et3(Bn)NCl, ET3(CI6H33)NC1), quaternary phosphonium chloride (Bu4PBr) or mixture thereof.

5. The process according to claim 1, wherein optically active isomer of 2-halo-2-(2-chlorophenyl) acetic acid methyl ester of Formula (I) is selected from (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (la), (R)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester (lb), (S)-2-chloro-2-(2-chlorophenyl) acetic acid methyl ester (Ic) or (R)-2-chloro-2-(2-chlorophenyl) acetic acid methyl ester (Id).
6. The process according to claim 1, wherein the solvent used is selected from tetrahydrofuran, dichloromethane, ethylene dichloride, chloroform, benzene, toluene, xylene, dimethylacetamide, dimethylformamide, acetonitrile, propionitrile, methanol, ethanol, propanol, butanol, isopropanol, methyl acetate, ethyl acetate or mixtures thereof.

7. A process for racemisation of S (+) 2-bromo-2-(2-chlorophenyl) acetic acid methyl ester
of Formula (la) or its salts,

according to claim 1 comprises treating a solution of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester of formula (la) in a solvent with a bromide source.
8. The process according to claim 7, wherein bromide source is tetrabutylammoinum bromide (TBAB) and the solvent used is tetrahydrofuran.
9. The process as claimed in claim 7, farther comprising resolving the racemic compound of formula (I) into (R)-2-bromo-2-(2-chlorophenyl)acetic acid and (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester of formula (la) using biocatalyst; followed by converting the (R)-2-bromo-2-(2-chlorophenyl)acetic acid into clopidogrel and in situ
conversion of (S)-2-bromo-2-(2-chlorophenyl) acetic acid methyl ester of formula (la) in to racemic compound of formula.(I).

10. The process as claimed in claim 9, wherein the biocatalyst is selected from hydrolase AZL-1600, Lipase-TL , Lipase- OF, Novo COR AD L, Addzyme TL 165 G, Addzyme RD 165 G and Neutral protease.