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

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.