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Identification of unknown impurities of S-(+)-Clopidogrel bisulfate

IP.com Disclosure Number: IPCOM000200435D
Publication Date: 2010-Oct-12
Document File: 3 page(s) / 86K

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Abstract

An improved, scalable and cost effective process described for S-(+)-Clopidogrel, identification of impurities and the way of controlling these novel impurities.

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Identification of unknown impurities of S-(+)-Clopidogrel bisulfate

(S)-(+)-Clopidogrel bisulfate (Plavix, Figure 1) is an orally active inhibitor of platelet aggregation often used in the treatment of coronary artery, peripheral vascular and cerebrovascular diseases.

Figure 1. (S)-(+)-Clopidogrel bisulfate

An improved, scalable and cost effective process described for S-(+)-Clopidogrel1 by utilizing a robust resolution strategy for the key intermediate (+)-methyl-2-chloro phenyl glycinate in patent

US

2007/0225320 A1. Herein, we disclosed identification of impurities of compound 3 and 4 and the way of controlling these novel impurities.

During the synthesis of clopidogrel, compounds 3 and 4 were expected in the formylation and cyclization reaction (Scheme 1).

 

Scheme 1. Synthesis of S-(+)-clopidogrel 1 bisulfate.

Based on the detailed investigation on formylation and LC-MS data, we proposed the structure 3 for unknown impurity. Hydroxy impurity 3 found to be difficult to remove it during isolation of the desired product. Dihydroxy impurity 4 was not detected in the LCMS and this impurity might be formed under higher temperature/harsh reaction conditions, but may not be formed during the lower temperatures of reaction up to 40 oC. (Figure 2).

Figure 2.S-(+)-Clopidogrel bisulfate (1) related impurities

Formation of impurity 3 was steadily increased by increasing the reaction temperature up to 55 oC and impurity 3 enhanced drastically beyond 55 oC.  By increasing the reaction time impurity 3 was gradually increased accordingly. There is no significant change in the purity of compound 1 and impurity 3 percentages with the amount water addition during the purification of compound 1.

In summary, compound...