公斤级沙库必曲半钙盐的合成  

Synthetic Process of Sacubitril Hemicalcium in Kg Scale

作　　者：孙光祥 张云然 单环宇 

机构地区：[1]浙江大学化学系,浙江杭州310027 [2]上药集团-常州制药厂有限公司,江苏常州213018

出　　处：《中国医药工业杂志》2017年第9期1264-1269,共6页Chinese Journal of Pharmaceuticals

摘　　要：本研究报道了一条成本低、环境友好、适合产业化的沙库必曲半钙盐合成路线。以价廉易得的D-苯丙氨酸为原料,经碘代、甲酯化、氨基保护和Negishi偶联得(R)-3-([1,1'-联苯]-4-基)-2-[(叔丁氧羰基)氨基]丙酸甲酯,经硼氢化锂还原、TEMPO催化氧化、缩合、氢氧化锂水解得(R,E)-5-([1,1'-联苯]-4-基)-4-[(叔丁氧羰基)氨基]-2-甲基-2-戊烯酸,再经钯炭催化氢化、脱保护、乙酯化、与丁二酸酐缩合并成半钙盐得目标化合物。本工艺反应条件温和,后处理操作简便;革除了价昂或有基因毒性的试剂以及易燃易爆等危险试剂的使用。总收率22.8%,产品纯度99.7%,光学纯度99.8%。This study reported a process for the preparation of sacubitril hemicalcium, which was low-cost, environmental-friendly and suitable for industrialization as well. D-（＋）-phenylalanine, which was easy obtained, was used as the starting material. It was subjected to iodonation, methyl esterification, amino protection and Negishi coupling to give methyl （R）-3-（ E 1,1＇-biphenyl]-4-yl）-2-[ （tert-butoxycarbonyl）amino] propanoate, then after reduction by lithium borohydride, oxidation catalyzed by TEMPO, condensition and lithium hydroxide hydrolysis, （R,E） -5- （ [ 1, 1＇-biphenyl1-4-yl） -4- E （tert-butoxycarbonyl） amino] -2-methylpent-2-enoic acid was obtained. The latter was subjected to catalytic hydrogenation, deprotection, ethyl esterification, condensition with butanedioic anhydride and salt-forming with calcium chloride to prepare the target compound. The total yield of the process was 22.8% , the HPLC purity and optical purity reached 99.7% and 99.8%, respectively. The process not only involves mild reaction conditions, easy work-up methods, but also avoids the use of expensive reagent, genotoxic and explosive chemicals.

关 键 词：沙库必曲 抗心衰 D-苯丙氨酸 Negishi偶联 合成 

分 类 号：R972.1[医药卫生—药品] R914.5[医药卫生—药学]