SGLT2抑制剂3-脱氧达格列净简便的汇聚式合成方法  

A Facile Convergent Synthetic Procedure for 3-Deoxydapagliflozin as SGLT2 Inhibitor

作　　者：高志刚[1] 张大同[1] 魏鹏[1] 王哲[2] 谢亚非[3] 刘钰强 徐为人[3] 汤立达[3] 赵桂龙[1,3] 

机构地区：[1]齐鲁工业大学化学与制药工程学院,济南250353 [2]山东中医药大学第一临床医学院,济南250014 [3]天津药物研究院天津市新药设计与发现重点实验室,天津300193

出　　处：《有机化学》2014年第9期1829-1839,共11页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.21302141);天津市科技支撑计划重点项目(No.10ZCKFSH01300);天津市自然科学基金(No.14JCQNJC12900)资助项目~~

摘　　要：3-脱氧达格列净(1)是一个高选择性的强效钠依赖性葡萄糖转运子2(SGLT2)抑制剂.本研究发现了一条以廉价的α-D-甲基吡喃葡萄糖(2)为起始原料的简便的3-脱氧达格列净(1)的汇聚式合成路线,共13步,总产率38%.在此过程中系统研究了4,6-O-苄叉-α-D-甲基吡喃葡萄糖苷(3)中2-OH和3-OH的选择性保护策略,使用NOE(nuclear overhauser effect)技术对区域异构体进行了结构鉴定,并对区域异构体的相对比例和相对极性提出了合理解释;在此过程中对4,6-O-苄叉-2-O-叔丁基二苯基硅基-α-D-甲基吡喃葡萄糖(4)中葡萄糖片段上位阻较大3-OH的脱氧策略也进行了系统研究,最终获得了最优的脱氧策略.该路线为一条汇聚式路线,具有廉价、操作简便的特点,可以作为一种高效合成3-脱氧苯基C-葡萄糖苷类化合物的通用方法.3-Deoxydapagliflzoin （1） is a highly selective, potent sodium-dependent glucose transporter 2 （SGLT2） inhibitor discovered earlier. A facile convergent synthetic procedure for 3-deoxydapagliflzoin （1） was developed in 13 steps and in 38% overall yield starting from inexpensive methyl a-D-glucopyranoside 2. Regioselective protection of 2-OH and 3-OH in the key intermediate methyl 4,6-O-benzylidene-a-D-glucopyranoside 3 was systematically studied; the regioisomers thus obtained were distinguished from each other with nuclear overhauser effect （NOE） and their ratios and relative polarities were rationally explained. The strategy for deoxygenation of the sterically hindered 3-OH in another key intermediate 4,6-O-benzylidene-2-O-t-butyldiphenylsilyl-a-D-glucopyranoside （4） was also systematically studied. The facile synthetic route is characterized by convergence characteristics and inexpensive starting material, also representing an alternative general synthetic approach to phenyl 3-deoxy-C-glucosides.

关 键 词：SGLT2抑制剂 3-脱氧达格列净 区域选择性 脱氧 汇聚式合成 

分 类 号：TQ463[化学工程—制药化工]