沃拉帕沙中间体手性氨基环己烯基丙烯酸的合成工艺改进

Improved Synthesis of (R,E)-3-(5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylicacid, the Intermediate of Vorapaxar

摘要:

摘要：以(E)-3-(5-硝基-1-环己烯基)丙烯酸(Ⅱ)为原料，经酯化、硝基还原、拆分、缩合、水解等反应制备了(R,E)-3-(5-乙氧羰基氨基-1-环己烯基)丙烯酸(Ⅰ)。就Ⅰ合成的各歩反应条件进行了优化。其中，(R,E)-3-(5-氨基-1-环己烯基)丙烯酸乙酯的制备采用D-苹果酸作为拆分剂，甲醇:丙酮=1:1作为溶剂，收率为35.6%。改进后目标产物的总收率达到了27.4%。新合成路线操作简便，反应条件温和，使用的原料和试剂成本都比较低廉，适合工业化生产。目标化合物及中间体的结构经1HNMR、ESI-MS等确证。

Abstract:

Abstract: (R,E)-3-(5-((ethoxycarbonyl)amino)cyclohex-1-en-1-yl)acrylicacid(Ⅰ), the key intermediate of vorapaxar was prepared from (E)-3-(5-nitrocyclohex-1-en-1-yl) acrylicacid(Ⅱ) via esterification, reduction, chiral resolution, condensation and hydrolysis. The reaction conditions were optimized for the synthesis of I. The results showed that ethyl(R,E)-3-(5-amino-cyclohex-1-en-1-yl)acrylate was obtained with a yield of 35.6%, using D-malic acid as separation agent and V(Methanol):V(acetone)=1:1 as solvent. The total yield of this target compound was improved to 27.4%. The structure of target compound was identified by 1HNMR and ESI-MS. The improved process is facile with relatively convenient operation procedures and suitable for industrial production.