(1S,3S,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]已烷-3-甲酰胺3个立体异构体的合成  

Synthesis of Three Stereo-isomers of(1S,3S,5S)-2-Tert-butoxycarbonyl-2-azabicyclo[3.1.0] hexane-3-amide

作　　者：于净平 刘飞[2] 郭雅俊 朱雪焱[1] 刘相奎[1] YU Jingping;LIU Fei;GUO Yajun;ZHU Xueyan;LIU Xiangkui(State Key Lab. of New Drug & Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203;Jiangsu Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing 210038)

机构地区：[1]中国医药工业总院上海医药工业研究院创新药物与制药工艺国家重点实验室,上海201203 [2]江苏正大天晴药业股份有限公司,江苏南京210038

出　　处：《中国医药工业杂志》2019年第5期520-523,共4页Chinese Journal of Pharmaceuticals

摘　　要：本研究设计合成了(1S,3S,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-甲酰胺(沙格列汀的关键中间体)的3 个异构体。以(1S,3S,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-羧酸乙酯为起始原料,经氢氧化锂水解得(1S,3S,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-羧酸,与羰基二咪唑反应后,在碳酸钾作用下消旋化,再经氯甲酸异丁酯活化、氨化后制得(1S,3R,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-甲酰胺。按照相同的方法,可由(1R,3R,5R)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-羧酸乙酯制得(1R,3R,5R)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-甲酰胺和(1R,3S,5R)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-甲酰胺。这3 个异构体的结构均经MS、1H NMR 确证,可作为合成沙格列汀的立体异构体的重要中间体。In this study, three stereo-isomers of (1S,3S,5S)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]hexane-3- amide, the key intermediate of saxagliptin, were synthesized. Ethyl (1S,3S,5S)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]- hexane-3-carboxylate reacted with lithium hydroxide to give (1S,3S,5S)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]- hexane-3-carboxylic acid. After reacting with carbonyldiimidazole, the corresponding compound was subjected to racemization by potassium carbonate, activation by isobutyl chloroformate and ammoniation to afford (1S,3R,5S)-2- tert-butoxycarbonyl-2-azabicyclo[3.1.0]hexane-3-amide with a total yield of 40.4%. According to the same method,(1R,3R,5R)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]hexane-3-amide and (1R,3S,5R)-2-tert-butoxycarbonyl-2- azabicyclo[3.1.0]hexane-3-amide was obtained from ethyl (1R,3R,5R)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]- hexane-3-carboxylate in a total yield of 23.1% and 46.1%, respectively. These substances were confirmed by MS and 1H NMR. They may be used as the key intermediates for synthesis of the stereo-isomers of saxagliptin.

关 键 词：沙格列汀 中间体 立体异构体 合成 质量控制 

分 类 号：R914.5[医药卫生—药物化学]