特拉匹韦中间体(3aS,6aR)-1,3a,4,5,6,6a-六氢环戊并[c]吡咯的合成工艺研究

Synthetic process research of an intermediate of telaprevir,(3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole

目的优化抗丙肝药物特拉匹韦中间体(3aS,6aR)-1,3a,4,5,6,6a-六氢环戊并[c]吡咯的合成工艺。方法通过有机小分子催化不对称迈克尔加成反应,以1,6-己二醇为起始原料,经氧化、催化环合、不对称迈克尔加成、缩醛保护、催化氢化、脱保护环合等反应制得目标化合物。结果与结论新工艺路线能够高效构建手性中心,避免了拆分过程,采用"一锅法"提高了产品收率。

A feasible synthetic method for( 3aS,6aR)-1,3 a,4,5,6,6 a-hexahydrocyclopenta[c]pyrrole w hich w as the important intermediate of anti-HCV drug telaprevir w as developed. The key process w as a"one pot"process to synthesize( 1R,2R)-1-diethoxymethyl-2-( nitromethyl) cyclopentane catalyzed by an asymmetric M ichael addition reaction. The organo-catalyst reaction can make the chiral purity high so the resolution process can be omitted. The detail synthetic route w as as follow ed. 1,6-Hexanediol w as oxidized to 1,6-hexanedial by NaClO. The organo-catalyst w as added to catalyze the cyclization reaction and asymmetric M ichael addition reaction. After acetal protecting reaction,the intermediate w as obtained by distillation,and then hydrogenated and acidized to generate( 3aS,6 aR)-1,3 a,4,5,6,6 a-hexahydrocyclopenta[c]pyrrole with the total yield of 30. 9%. This process increased the yield and was suitable for the commercial production.