An improved Process for the preparation of Clopidogrei Hydrogen
bromide

Field of the Invention
The present invention relates to novel process for the preparation of Clopidogrel hydrogen bromide. Clopidogrel hydrogen bromide chemically known as methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate hydrogen bromide. Clopidogrel hydrogen bromide shown below as Formula-I

Clopidogrel hydrogen bromide may be used, in particular, for inhibiting platelet aggregation or for treating, preventing or managing thrombosis, atherothrombosis, an atherothrombotic event, ischaemic stroke, myocardial infarction, non-Q-wave myocardial infarction, atherosclerosis, peripheral arterial disease, or unstable angina.

Background of the Invention
Clopidogrel is currently marketed as the hydrogen sulfate. Previous preparations of Clopidogrel are reported in patent applications EP 0420706, EP 0099802, WO 98/51689, WO 98/51682, WO 98/51681, EP 0466569 and EP 0281459..
Polymorphic forms of Clopidogrel hydrogen bromide is disclosed in WO 2005/026174. Process for the preparation of Polymorphic Form-1 of Clopidogrel hydrogen bromide is disclosed in WO 2005/026174 by using mixture of solvents (2-propanol and diisopropyl ether), mixture of solvents are not suggestible for industrial scale up and the use of diisopropyl ether is not recommendable for scale up.
The main object of the present invention is to provide a Novel process for the preparation of Clopidogrel hydrogen bromide, which is cost effective and easy to scale up.
Brief description of the Invention
The present invention relates to novel process for the preparation of Clopidogrel
hydrogen bromide.
Which comprising of the following steps
a) Dissolving the Clopidogrel crude in acetone at 25-35°C
b) Adding aqueous hydrobromic acid to the above solution at 25-35°C
c) Stirring the reaction mixture for 1 to 15 hours at 25-35°C
d) Isolating the solid by filtration and dry the material at 40-45°C under reduced pressure.
Brief description of the drawings :
1. DSC Thermogram of Clopidogrel hydrogen bromide (Figure-1)
2. XRD Difractogram of Clopidogrel hydrogen bromide (Figure-2)

Detailed description of the Invention
The present invention relates to novel process for the preparation of Clopidogrel
hydrogen bromide.
Which comprising of the following steps
a) Dissolving the Clopidogrel crude in a solvent selected from ketone solvents like acetone, propanone, butanone, methyl iso butyl ketone, preferably acetone at a temperatrue ranges from 10-50°C, preferably at 30-35°C.
b) Adding aqueous hydrobromic acid to the reaction mixture at a temperature ranges from 5-50°C, preferably at 30-35°C.
c) Stirring the reaction mixture for 1 to 15 hours, preferably for 10-12 hours at a temperature ranges from 5-45°C, preferably at 30-35°C.
d) Isolating the solid by filtration and dry the material at 40-45°C under reduced pressure.
This invention further disclosed by the following non limiting examples
Examples
Example- 1 : Preparation of methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate hydrogen bromide (Clopidogrel hydrogen bromide)
Aqueous hydrogen bromide (42%) solution (25ml) is slowly added to the solution of Clopidogrel freebase (50gr) and acetone (250ml) at a temperature 25-3 5°C in 45 minutes duration. Stirred the reaction mixture for 10-12 hours at 25-35°C. Cooled the reaction mixture to 0-5°C and stirred for another l-2hours. Filtered the solid and washed the solid with Acetone(2xl5ml). Dried the material at 40-45°C under reduced pressure. Yield 25 gr.

We Claim
1. Process for the preparation of Clopidogrel hydrogen bromide

Which comprising of the following steps
a) Dissolving the Clopidogrel crude in a solvent selected from ketone solvents like acetone, propanone, butanone, methyl iso butyl ketone, preferably acetone at a temperatrue ranges from 10-50°C, preferably at 30-35°C.
b) Adding aqueous hydrobromic acid to the reaction mixture at a temperature ranges from 5-50°C, preferably at 30-35°C.
c) Stirring the reaction mixture for 1 to 15 hours, preferably for 10-12 hours at a temperature ranges from 5-45°C, preferably at 30-35°C.
d) Isolating the solid by filtration and dry the material at 40-45°C under reduced pressure.
2. Solvent according to claim 1 (a) is Acetone
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