抗2型糖尿病药西他列汀杂质A的合成研究  

Synthesis of Impurity A of Sitagliptin,an Anti-diabetes Drug

作　　者：董世超 陈固洲 韩耀天 朱坤芳[1] 刘晓平[1] 胡春[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,沈阳110016

出　　处：《中国药学杂志》2017年第6期438-441,共4页Chinese Pharmaceutical Journal

基　　金：国家"重大新药创制"科技重大专项(2009ZX09301-012)

摘　　要：目的合成西他列汀杂质A。方法将2,4,5-三氟苯乙酸、米氏酸和3-三氟甲基-5,6,7,8-四氢-1,2,4-三唑[4,3-α]吡嗪盐酸盐以"一锅法"反应得到中间体1-{3-三氟甲基-5,6-二氢-1,2,4-三唑并[4,3-a]吡嗪-7(8H)-基}-4-(2,4,5-三氟苯基)-1,3-丁二酮,再经硼氢化钠还原得到西他列汀杂质A。结果目标化合物的结构经IR、MS和1H-NMR确证。结论该方法未见文献报道,具有成本低、操作简单、反应温和、收率高等优点。OBJECTIVE To synthesize the impurity A of sitagliptin which is a highly selective DPP-4 inhibitor used for treatment of type 2 diabetes. METHODS 1-{3-Trifluoromethyl-5,6-dihydro-1,2,4-triazo[4,3-a] piperazin-7 （8H） -ylt -4-（2,4,5-triiluorophe- nyl） butane-1,3-dione was prepared from 2,4,5-triflurophenylacetic acid, meldrum＇s acid and 3-trifluromethyl-5,6,7,8-tetrahydro-1, 2,4-triazolo[4,3-a] pyrazine hydrochloride with one-pot reaction, followed by reduction with sodium borohydride to yield the impurity A of sitagliptin. RESULTS The structure of the impurity A of sitagliptin was characterized by IR, MS, and 1H-NMR. CONCLUSION The established synthetic route of the impurity A in this study has not been reported in the literature, and has the advantages of low-cost, easy operation, mild reaction, and high overall yield.

关 键 词：西他列汀 杂质 合成 表征 

分 类 号：R97[医药卫生—药品]