Research On Preparation Of CLOPIDOGREL

This thesis focused on the optimization of the process for preparation Clopidogrel bisulphate that is an antiplatelet drug.2-chlorophenyl glycine methyl ester (4) which was esterified from 2-(2-chlorophenyl) glycine (3) in methanol. Resolved by L-(+)-tartaric acid to give S-(+)-2-chlorophenyl glycine methyl ester L-tartrate (5). Directly condensation reaction of (2) and (5) to give S-(+)-methyl-2-(2-thienylethamino) (2-chlorophenyl) acetate (6). Then cyclization reaction with formaldehyde, and salt forming reaction with concentrated sulfuric acid, form I Clopidogrel bisulfate salt (1) was obtained as target product. The total yield of the whole process reached above 52%.The main improved steps were as following:In the condensation step, optimized the process for preparation compound (6), obtained (6) by directly condensation reaction of (2) and (5) in yield of 82% with 99.86% ee value; by control the evaporation rate of water, to avoid racemization product; after the scale-up, the yield and optical rotation is satisfactory.After the condensation reaction step, through the wastewater treatment, recovery of the tartaric acid and recycling.In the cyclization step, through the use of paraformaldehyde, reduce the hydrolysis.In the salt forming step, optimized the reaction conditions, reduce the impurity, made the product fit for USP standard; by control the concentration and temperature, avoid the mixed crystals; study the impact of factors of the drug particle size, in order to control the particle size distribution of drug powder within a certain range.