西格列汀中间体(R)-3-叔丁氧羰基氨基-4-(2,4,5-三氟苯基)丁酸的合成工艺研究  

Study on synthetic process of(R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid, an intermediate of sitagliptin

作　　者：高浩凌 查娟 刘建红[1] 盛力[1] GAO Hao-ling;ZHA Juan;LIU Jian-hong;SHENG Li(Research&Development Center,Zhejiang Medicine Co.,Ltd.,Shaoxing312300,China;Changhai Biological Compamy,Zhejiang Medicine Co.,Ltd.,Shaoxing312300,China;Zhejiang Novus Pharmaceuticals Co.,Ltd.,Shaoxing312300,China)

机构地区：[1]浙江医药股份有限公司研究院,浙江绍兴312300 [2]浙江医药股份有限公司昌海生物分公司,浙江绍兴312300 [3]浙江创新生物有限公司,浙江绍兴312300

出　　处：《中国药物化学杂志》2022年第1期28-31,共4页Chinese Journal of Medicinal Chemistry

摘　　要：目的优化(R)-3-叔丁氧羰基氨基-4-(2,4,5-三氟苯基)丁酸的合成工艺。方法以2,4,5-三氟苯乙酸为起始原料,经缩合、醇解、氨化"一锅法"得到(Z)-3-氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯,再经氨基乙酰化、不对称氢化、水解、氨基保护制得(R)-3-叔丁氧羰基氨基-4-(2,4,5-三氟苯基)丁酸。结果与结论目标产物的结构经质谱和核磁共振谱确证,总收率53.1%(以2,4,5-三氟苯乙酸计),纯度为99.7%(HPLC法)。该工艺步骤少、操作简单、反应条件温和,可为西格列汀的工业化生产提供有效方法。(R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid is an important intermediate for the synthesis of sitagliptin.2,4,5-Trifluorophenylacetic acid was used as the raw material, and(Z)-methyl 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate was obtained by the "one-pot method" of condensation, alcoholysis, and amination.Then(R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid was prepared via amino acetylation, asymmetric hydrogenation, hydrolysis, and amino protection from(Z)-methyl 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate.The total yield was 53.1% with the purity of 99.7%(HPLC).The process has fewer steps, simple operation and mild reaction conditions, and provides an effective method for the industrial production of sitagliptin.

关 键 词：西格列汀 (R)-3-叔丁氧羰基氨基-4-(2 4 5-三氟苯基)丁酸 不对称氢化 合成工艺 

分 类 号：R914[医药卫生—药物化学]