沙库巴曲钙盐的合成工艺优化

Improved Synthetic Process of Sacubitril Calcium

本研究对沙库巴曲钙盐(1)的合成工艺进行了改进。固体氧化剂二氧化硅负载氯铬酸吡啶(PCC/SiO2)将(2R)-1-[(1,1’-联苯)-4-基]-3-羟基丙烷-2-基-氨基甲酸叔丁酯(2)氧化为(2R)-1-[(1,1’-联苯)-4-基]-3-氧代丙烷-2-基-氨基甲酸叔丁酯(3),反应液过滤除去PCC/SiO2后可直接与乙氧甲酰基亚乙基三苯膦经Wittig反应得(R,E)-5-[(1,1’-联苯)-4-基]-4-[(叔丁氧羰基)氨基]-2-甲基-2-戊烯酸乙酯(4)。4经氢氧化锂水解后以活性白土吸附三苯氧膦,使(R,E)-5-[(1,1’-联苯)-4-基]-4-[(叔丁氧羰基)氨基]-2-甲基-2-戊烯酸(5)中三苯氧膦含量低于0.01%。5经手性加氢还原、乙酰化、酰胺化及成盐得1。优化后的工艺操作简单,仅5需重结晶精制,产品纯度99.91%,总收率60%(以2计),适合工业化生产。

The synthetic process of sacubitril calcium(1) was improved.(2 R)-1-[(1,1’-Biphenyl)-4-yl]-3-hydroxypropane-2-yl-carbamate tert-butyl ester(2) was oxidized to(2 R)-1-[(1,1’-biphenyl)-4-yl]-3-oxopropane-2-ylcarbamate tert-butyl ester(3) with pyridinium chlorochromate loaded on silica(PCC/SiO2) as solid oxidant. PCC/SiO2 was removed from reaction solution and then the filtrate was reacted with(carbethoxyethylidene)triphenylphosphorane to give(R,E)-5-[(1,1’-biphenyl)-4-yl]-4-[(tert-butoxycarbonyl)amino]-2-methyl-2-pentenoic acid ethyl ester(4) via Wittig reaction. Compound 4 was hydrolyzed with lithium hydroxide, and triphenyl phosphorus oxide was adsorbed by activated clay and its content in(R,E)-5-[(1,1’-biphenyl)-4-yl]-4-[(tert-butoxycarbonyl)amino]-2-methyl-2-pentenoic acid(5) was less than 0.01%. Sacubitril calcium(1) was prepared via chiral hydrogenation reduction, acetylation, amidation and salt formation from 5, with a purity of 99.91% and a total yield of 60%(based on 2). This improved process was easy to operate, and only recrystallization of 5 was needed, which was suitable for industrial production.