FIELD OF INVENTION

The invention relates to a novel process for the preparation of (S)-Methyl-2-amino-2-(2-chlorophenyl) acetate hydrochloride of Formula I
which is useful as an Intermediate in the preparation of Clopidogrel bisulphate.

BACKGROUND OF INVENTION

Clopidogrel bisulphate is an oral antiplatelet agent, it is a prodrug whose action may be
related lo adenosine diphospatc (ADP) receptor on platelet cell membranes, and is important in platelet aggregation and cross-linking of platelets by fibrin. Platelet inhibition can be demonstrated two hours after a single dose of oral Clopidogrel bisulphate.

The synthesis of Clopidogrcl and its pharmaceutically acceptable salts are disclosed in US 4,847,265 and the corresponding HP 0281459 Bl.

OBJECTIVE OF THE INVENTION

An object of the present invention is to provide a process for the preparation of (S)-Mcthyl-2-amino-2-(2-chlorophcnyl) acetate hydrochloride.

SUMMARY OF THE INVENTION

The instant invention discloses a novel and efficient method for the preparation of (S)-Mcthyl-2-amino-2-(2-chlorophcnyl) acetate hydrochloride which comprises

(i) Converting (S)-Methyl-2-amino-2-(2-chlorophenyl)acetate to (S)-Methyl-2-amino-2-(2-chlorophenyl)acetate hydrochloride salt by employing Ethyl acetate 1 TCI in Ethyl acetate solvent medium at 0-5°C.

(ii) Cooling the reaction mixture at 0-5°C to precipitate the product.

(iii)Isolating the product by conventional techniques to yield compound of Formula I.

BRIEF DESCRIPTION OF THE INVENTION

(S)-Mcthyl 2-amino-2-(2-chlorophenyl) acetate HCl salt is an important intermediate for manufacturing of Clopidogrcl bisulphatc. During our laboratory studies at lOOgms size we used protic solvents like IPA for the formation of HCl salt from the corresponding free base. No raccmization was observed.

But during scale up reaction raccmization was observed in protic solvents like IPA. Immediately we switched over to non protic solvents like Ethyl acetate and minimized the raccmi/ation. Raccmization was not observed in Kthyl acetate.

This unusual raccmization was observed only in the scale up in pilot plant batches with protic solvents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns novel process for the preparation of compound of Formula I which is used in the preparation of Clopidogrcl. The process provides a novel procedure employing Kthyl acetate & Kthyl acetate hydrochloride to give compound of Formula I.

In this process, the (S)-Methyl-2-amino-2-(2-chlorophcnyl)acctatc was dissolved in Ethyl acetate and then the reaction mixture was stirred to obtain a clear solution. Subsequently the reaction mass is cooled to 15°C and pII is adjusted to 2.5 with Ethyl acetate HCl over a period of 1-2 hrs. This reaction mixture is cooled to 0-5°C and then the product is seperatcd. The separated products arc filtered and wash with Ethyl acetate. The obtained product is dried in spin drier and finally dried under vacuum to obtain (S)-Methyl-2-amino-2-(2-chlorophenyl)acetate IIC1 salt.

While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the spccillc embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention.

EXAMPLE I

Preparation of (S)-Mcthyl 2-amino-2-(2-chlorophenyl) acetate HC1 salt

In a 250 1 glass reactor (S)-Mcthyl 2-amino-2-(2-chlorophenyl) acetate 25 Kg was dissolved in Kthyl acetate. The reaction mixture was stirred to obtain clear solution. The reaction mixture was cooled to 15°C and adjusts pH 2.5 with Ethyl acetate HC1 over a period of 1 -2 hrs. Then the reaction mixture was cooled to 0-5 °C to get the product out. The separated product was filtered and washed with 20 1 of Ethyl acetate, spin dried and dried under vacuum to obtain 23-26 kg (S)-Methyl 2-amino-2-(2-chlorophenyl) acetate IIC1 salt with R-isomcr 0.3 %.

EXAMPLE 11

Preparation of (S)-Mcthyl 2-amino-2-(2-chlorophenyl) acetate HO salt

In a 250 1 glass reactor (S)-Mcthyl 2-amino-2-(2-chlorophenyl) acetate 25 Kg was dissolved in Acetone. The reaction mixture was stirred to obtain clear solution. The reaction mixture was cooled to 15°C and adjusts pII 2.5 with Acetonic HC1 over a period of 1 -2 hrs. Then the reaction mixture was cooled to 0-5 °C to get the product out. The separated product was filtered and washed with 20 1 of Acetone, spin dried and dried under vacuum to obtain 22-24 kg (S)-Methyl 2-amino-2-(2-chlorophenyl) acetate HC1 salt with R-isomcr 0.9 %.

EXAMPLE III

Preparation of (S)-Mcthyl 2-amino-2-(2-chIorophenyI) acetate HCI salt

In a 250 1 glass reactor (S)-Mcthyl 2-amino-2-(2-chlorophenyl) acetate 25 Kg was dissolved in Isopropyl alcohol. The reaction mixture was stirred to obtain clear solution. The reaction mixture was cooled to 15°C and adjusts pII I 2.5 with IPA HCl over a period of 1-2 hrs. Then the reaction mixture was cooled to 0-5 °C to get the product out. The separated product was filtered and washed with 20 1 of IPA, spin dried and dried under vacuum to obtain 21-23 kg (S)-Mcthyl 2-amino-2-(2-chlorophenyl) acetate HCl salt with R-isomcr 3 %.

CLAIMS:

Wc claim:

1) A process for the preparation of (S)-mcthyl-2-amino-2-(2-chlorophenyl) acetate
and its pharmaceutically acceptable salts comprising

a) Dissolving (S)-mcthyl-2-amino-2-(2-chlorophcnyl)acetate in an organic solvent.

b) Adjusting pII with Kthyl acetate / Hydrochloric acid.

c) Isolating the product as Hydrochloride Salt.

2) The process according to Claim 1, Step (a) is wherein the organic solvent employed is Kthyl acetate.

3) The process according to Claim 1, Step (b) wherein pH of the reaction mixture is adjusted to 2-2.5.