硫酸氢氯吡格雷合成工艺研究

An Improved Synthesis of Clopidogrel Sulfate

以消旋的邻氯苯甘氨酸为原料,经酯化、光学拆分得到(+)-邻氯苯甘氨酸甲酯,与对甲苯磺酸-2-噻吩乙酯缩合制得氯吡格雷关键中间体(S)-2-(2-噻吩乙胺基)-(2-氯苯基)乙酸甲酯,然后在无水甲酸和多聚甲醛中环合反应得到硫酸氢氯吡格雷。该合成方法具有原料价廉易得、反应条件温和、收率较高,产品质量好的特点,适合于工业化。

（S）-methyl 2-amino-2-（2-chlorophenyl）acetate is obtained from racemic 2-amino-2-（2- chlorophenyl） acetic acid through esterification and optical resolution, which was subjected to condensation reaction with 2-（thiophen-2-yl）ethyl 4-methyl benzene sulfonate to afford the critical intermediate （S）-methyl 2- （2-chlorophenyl）-2-（2-（thiophen-2-yl）ethylamino） acetate. The cyclization of （S）-methyl 2-（2＂ehlorophenyl）-2- （2-（thiophen-2-yl）ethylamino） acetate with paraformaldehyde in the presence of anhydrous formic acid provided the Clopidogrel bisulfate. For this synthesis pathway, there are .some advantages such as readily available starting material, moderate condition, high yield and good quality. This process is suitable for industrialization.