Optimized Asymmetric Synthesis Of Clopidogrel

Clopidogrel is one of thieno[3,2-c]pyridine derivatives, which can inhibit ADP- induced platelet aggregation. The treat effect is clear and the demand is increasing in domestic and abroad. Sanofi corporation has applied administrative protection, which is overdue in china. Because the product technique has some difficulties and most of the domestic products are imports, it will be to have practical importance and economic benefit to replace imports in the condition of getting through and improving the technology route.A new route consisting of sulfonylation, methylesterification, nucleophilic substitution, condensation ring closure and salification is studied in this paper. The single-factor optimization and the orthogonal test are adopted. Products of every step are monitored by TLC, analyzed by HPLC, identified by IR, MS, NMR and XRD and the process is optimized in this paper.During the sulfonylation, the yield is 95.7% when solvent is acetone, catalyst is DMAP, reaction temperature is 25℃and acid-binding agent is triethylamine. The result implied that the new technology reduced the reaction time and energy, increased the utilization of raw materials, reduced wastes.The yield of methylesterification reached 98% when the temperature of dropping thionyl chloride was between -5℃and 0℃, the molar ratio between (+)-alpha-amino (2-chlorophenyl)acetic acid and thionyl chloride was 1:2, the temperature after completion of dropping thionyl chloride was 50℃, the reaction time was 6 h, the optical purity is 98%. The result implied that the new technology reduced the reaction time, the consumption of raw materials and wastes. The yield is increased.In the third step, the yield is 80.9% when the ratio of amino ester to sulfonate is 2:1 in solution of acetonitrile and postassium hydrogen phosphate, the optical purity is 99%. The result implied that the new technology simplified the postprocessing, shortened the technology flow-sheet, the yield is increased by 30%.In the cyclization, the yield is 85% when raw material is D-(+)-Methyl-alpha -(2-thienylethamino)(2-chlorophenyl)acetate hydrochloride, concentration of HCl is 1.5 mol/L, solvent is ethanol. The result implied that the new technology shortened the technology flow-sheet, reduced the consumption of raw materials, and proposed the reaction mechanism.In the final step, the yield of the production of crystalline formⅠof clopidogrel hydrogen sulfate was 42% With tetrahydrofuran as solvent, reacting at -10～-16℃for 10～15h; the yield of crystalline formⅡwas 60% With ethyl acetate as solvent, reacting at 0～6℃for 25～30h. The optical purity is 96%. The result implied that the new technology adopted the cheap solvents.According to the above results of optimization, the overall yield of clopidogrel hydrogen sulfate is 39%. This new route is practical and economic because of the available raw materials, simple operation, mild reaction conditions, reduced wastes, simple postprocessing and high yield.