Clopidogrel Synthesis

Clopidogrel is one of thieno [3,2-c]pyridine derivatives, which can inhibit ADP-induced platelet aggregation. A new route consisting of resolution, esterification, sulfonylation and nucleophilic substitution is studied in this paper because of the available raw materials, mild reaction conditions and high yield.HPLC and NMR are used as analytical methods and the single-factor optimization is adopted. When the ratio of racemic 2-chloromandelic acid to resolution agent N is 1:0.6, cooling temperature is 28 ℃, A and B are resolving solvent and washing solvent respectively, the salt yield for the first step is 74.4% and the optical purity is 99%. The washing mother liquid can be recycled. The two enantiomers are obtained by recrystallisation from solvent C. The yield of the second step is 84.8% when the ratio of methanol to racemic acid to sulfuric acid equals to 18:1:0.1. Above reaction conditions can also be used in synthesis of (R)-ester and the yield is 84.5%. In the third step, when the ratio of racemic ester to benzenesulfonyl chloride to triethylamine to catalyst 4-DMAP is 1:1:1:0.1 in 10℃, the yield is 82.9% and high purity is obtained by crystallisation. Above reaction conditions can also be used in synthesis of (R)-sulfonate and the yield is 80.5%, but we can't get high purity through crystallisation. In the final step, the yield is 91.7% when the ratio of thieno [3,2-c]pyridine hydrochloride to racemic sulfonate is 1.2:1 in solution of sodium bicarbonate and methanol. Clopidogrel is obtained and its optical purity reaches 100% when the ratio of thieno [3,2-c]pyridine hydrochloride to (R)-sulfonate is 1.2:1 in the solvent D and 30% potassium carbonate solution. Clopidogrel hydrogen sulfate is also obtained when clopidogrel reacts with concentrated sulphuric acid.