LCZ696的合成工艺改进

Improved synthesis of LCZ696

目的优化抗心衰药物LCZ696的合成工艺。方法以(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,经酯化、脱保护得到(2R,4S)-5-((1,1′-联苯)-4-基))-4-氨基-2-甲基戊酸乙酯盐酸盐,其与丁二酸酐经酰化反应得到沙库比曲,进一步制成AHU377-钙盐后,经游离与缬沙坦反应,成盐析晶得到LCZ696。结果与结论目标化合物的结构经1H-NMR、13C-NMR、MS谱确证,收率为69.5%,纯度为99.98%。优化后的合成工艺简化了反应操作、降低了生产成本,有较高的实用价值,适合于工业化生产。

An optimal process has been developed after summarizing all the synthetic methods of LCZ696 reported in literatures.Taking(2R,4S)-5-(1,1′-biphenyl)-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid as starting material,the key intermediate(2R,4S)-4-amino-5-(1,1′-biphenyl)-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride(3)was synthesized by the esterification reaction.The key intermediate sacubitril calcium salt(5)was synthesized by acylation reaction and alkalization from compound 3,and then was cocrystallized with valsartan to obtain LCZ696.The structure of the target compound was identified by 1H-NMR,13C-NMR and MS.The total yield(69.5%)and purity(99.98%)of the target product have been improved significantly compared to previously reported methods.The improved synthetic process of LCZ696 has many advantages such as low cost,simple operation and high purity of the target product which is more suitable for industrial production.