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目的合成2型糖尿病治疗药西他列汀的关键手性中间体。方法以2,4,5-三氟苯乙酸为原料,与2,2-二甲基-1,3-二烷-4,6-二酮缩合、脱羧得到3-氧代-4-(2,4,5-三氟苯基)丁酸甲酯,然后与R-α-苯乙胺缩合、不对称还原、脱除苄基保护基,再经Boc保护、水解得到西他列汀关键手性中间体(R)-3-(叔丁氧羰基氨基)-4-(2,4,5-三氟苯基)丁酸。结果与结论以总收率59.5%合成了西他列汀关键手性中间体,该合成路线具有步骤少、操作简便、收率高、立体选择性好、反应条件温和的特点。
Objective To synthesize the key chiral intermediate of sitagliptin for the treatment of type 2 diabetes mellitus. Methods 2,4,5-trifluorophenylacetic acid was used as starting material to condense with 2,2-dimethyl-1,3-dioxane-4,6-dione to obtain 3-oxo-4- 2,4,5-trifluorophenyl) butanoate, and then condensation with R-α-phenylethylamine, asymmetric reduction, removal of the benzyl protective group, and then by Boc protection, hydrolysis of sitagliptin key Chiral intermediate (R) -3- (tert-butoxycarbonylamino) -4- (2,4,5-trifluorophenyl) butanoic acid. Results and Conclusion The key chiral intermediate of sitagliptin was synthesized in a total yield of 59.5%. The synthetic route has the advantages of few steps, simple and convenient operation, high yield, good stereoselectivity and mild reaction conditions.