Process for preparation of clopiodogrel bisulfate form-1
AssigneePharmaZell GmbH
InventorsWolfgang Burger, Omprakash Gudaparthi, Konda Srinivasa Reddy, Suneel K. Kumar, Venkata P. Ramana
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Abstract
An improved process for preparing crystalline form-1 of (S)-methyl 2-(2-chlorophenyl)-2-{6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl}acetate bisulfate (clopidogrel bisulfate) of formula I is provided The preparation comprises the straight conversion of an uncyclized material of (S)-methyl 2-[2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride into clopidogrel bisulfate crystalline form-1 without any degradation of clopidogrel base
Claims9
An improved process for the preparation of Clopidogrel bisulfate of general formula I comprising steps of:
- i. Treating (S)-methyl-2-(2-thiophen-2-yl) ethylamino)-2-(2-chlorophenyl) acetate hydrochloride of general formula II with 37-41% WN formaldehyde solution at a temperature of about 25-30° C. and then heated to a temperature of about 60-65° C., preferably in the range of 50-55° C.
- ii. Cooling the reaction mass to a temperature of about 25-30° C. and is continued until (S)-methyl-2-(2-thiophen-2-yl) ethylamino)-2-(2-chlorophenyl) acetate hydrochloride content reaches to <0.5%. The reaction is then cooled to a temperature range of 5-10° C.
- iii. Diluting the reaction mass with C14 alcohol, C1-5 carboxylic acid ester and then pH is adjusted to a range of about 7-8 by employing a base. The reaction mass is allowed to reach to a temperature of about 25-30° C.
- iv. Separating the aqueous and organic layers obtained from step (iii) and aqueous layer is further extracted with C1-5 carboxylic acid ester and then the organic layers are combined.
- v. Washing the combined organic layer with 1-20% sulphuric acid solution to remove the impurities.
- vi. Washing the combined layer with inorganic base solution followed by water.
- vii. Treating the organic layer with activated charcoal at a temperature of about 25-30° C. for about 20-30 minutes. The treated layer obtained is filtered to provide a filtered solution.
- viii. Adding sulfuric acid dissolved in C1-5 carboxylic acid ester to the filtered solution at a temperature of about −10-0° C. for 90-120 minutes.
- ix. Adding C1-5 carboxylic acid is added slowly to the solution obtained in step (viii) for about 30-45 minutes at the same temperature and then temperature is raised to about 25-30° C. and is maintained for about 20-24 hrs.
- x. Filtering the solid material obtained from step (xi), and washing with C1-5 carboxylic acid ester, acetone and kept under suck dry for 30-60 minutes to provide a crystalline solid material.
- xi. The crystalline solid material obtained is dried at about 50-55° C., preferably at 40-45° C. under vacuum.
Dependencies are inferred from the claim text.