新型抗心衰药物Entresto的合成

Synthesis of a New Anti-heart Failure Drug Entresto

以(2R,4S)-5-([1,1'-联苯]-4-基)-4-[(叔丁氧羰基)氨基]-2-甲基戊酸为原料,经乙醇/氯化亚砜一步法进行酯化-脱保护反应得(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸乙酯盐酸盐,再与丁二酸酐经酰化反应得4-[[(2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基]氨基]-4-氧代丁酸(sacubitril,4),4与乙酸钠成钠盐纯化精制后,再与缬沙坦复合从而得到抗心衰药Entresto,总收率81%。

（2R,4S）-5-（[1,1＇-Biphenyl]-4-yl）-4-[（tert-butoxycarbonyl）amino]-2-methylpentanoic acid reacted with ethanol and thionyl chloride in one-pot via esterification-deprotection to afford （2R,4S）-ethyl 5-（[1,1＇-biphenyl]-4-yl）-4-amino-2-methylpentanoate hydrochloride, then the latter reacted with succinic anhydride via acylation to give 4-[[（2S,4R）-1-（[1,1＇-biphenyl]-4-yl）-5-ethoxy-4-methyl-5-oxopentan-2-yl]amino]-4-oxobutanoic acid （sacubitril, 4）, followed by salification with sodium acetate and combination with valsartan to obtain the anti-heart failure drug, Entresto, with an overall yield of 81%.