4'-氨甲酰基-N-叔丁氧羰基-2',6'-二甲基-L-苯丙氨酸甲酯的合成  

Synthesis of 4'-Carbamoyl-N-(tert-butoxycarbonyl)-2',6'-dimethyl-L-phenylalanine Methyl Ester

作　　者：汪小兵 尹先清[1] 许方亮 李俊 李立威[2] WANG Xiaobing;YIN Xianqing;XU Fangliang;LI Jun;LI Liwei(College of Chemistry ＆ Environmental Engineering, Yangtze University, Jingzhou 434023;HubeiJingmen Institute of Pharmaceutical Industry Technology, Jingehu University of Technology, Jingmen 448000)

机构地区：[1]长江大学化学与环境工程学院,湖北荆州434023 [2]荆楚理工学院湖北省荆门医药工业技术研究院,湖北荆门448000

出　　处：《中国医药工业杂志》2018年第5期600-603,共4页Chinese Journal of Pharmaceuticals

基　　金：湖北省高等学校优秀中青年科技创新团队计划项目(T200911)

摘　　要：本研究报道了一条新路线合成伊卢多啉的关键中间体4'-氨甲酰基-N-叔丁氧羰基-2',6'-二甲基-L-苯丙氨酸甲酯。以2,6-二甲基苯胺为起始原料,经对位溴取代制得4-溴-2,6-二甲基苯胺,再和氰化亚铜在高温下发生氰基取代生成4-氨基-3,5-二甲基苯腈,然后经重氮化反应及碘置换反应制得4-碘-3,5-二甲基苯腈,再在碱性条件下水解氰基得4-碘-3,5-二甲基苯甲酰胺,最后和N-叔丁氧羰基-3-碘-L-丙氨酸甲酯经Negishi偶联制得目标化合物,总收率55.5%,纯度97.3%。A new route for the synthesis of 4＇-carbamoyl-N- （tert-butoxycarbonyl）-2＇,6＇-dimethyl-L- phenylalanine methyl ester, a key intermediate of eluxadoline, was reported. 4-Bromo-2,6-dimethylaniline was prepared from 2,6-dimethylaniline by bromination. After that, it reacted with cuprous cyanide at a high temperature to give 4-amino-3,5-dimethylbenzonitrile. Then the latter was subjected to diazotization and iodine substitution to afford 4-iodo-3,5-dimethylbenzonitrile, which was followed by cyano hydrolysis under alkaline condition to give 4-iodo-3,5- dimethylbenzamide （6）. Finally, the target compound was obtained from the Negishi coupling of compound 6 and N- （tert-butoxycarbonyl） -3-iodo-L-alanine methyl ester with a total yield of 55.5 % and a purity of 97.3 %.

关 键 词：伊卢多啉 4’-氨甲酰基-N-叔丁氧羰基-2’ 6’-二甲基-L-苯丙氨酸甲酯 关键中间体 2 6-二甲基苯胺 Negishi偶联 

分 类 号：R975.3[医药卫生—药品] R914.5[医药卫生—药学]