摘要
反式-3-氨基-双环[2.2.2]辛烷-2-甲酸乙酯是以RNA聚合酶PB2亚基作为靶点的一类抗流感新药(如匹莫地韦和ZSP1273)的关键手性片段.目前,该片段的市场需求量在数百公斤到吨级级别,与之相对应的多个创新药已经处于临床研究阶段.采用[RuCl(p-cymene)-(S)-BINAP]Cl为催化剂,通过不对称转移氢化的方式一步构建了反式构型3-氨基-双环[2.2.2]辛烷-2-甲酸乙酯,对映选择性最高可达98%ee以上,从而避免了构型翻转及脱保护等工艺过程,具备工业化放大生产的潜质与商业价值.
trans-3-Amino-bicyclo[2.2.2]octane-2-carboxylic acid ester is the key common chiral fragment of some novel antiviral drugs(like Pimodivir and ZSP1273),which targets the PB2 subunit of RNA polymerase.Now,the market demand of this molecule is at level of hundreds kilograms to tons,and there are several related innovative drugs in clinical study.Here a asymmetric transfer hydrogenation strategy to directly construct trans-3-amino-bicyclo[2.2.2]octane-2-carboxylic acid ethyl ester using[RuCl(p-cymene)-(S)-BINAP]Cl as catalyst with excellent enantioselectivity(over 98%ee)and without tautomerization and protecting/de-protecting process is developed,which holds the potential of scale up production and commercial value.
作者
周章涛
王杨
程冰心
叶伟平
Zhou Zhangtao;Wang Yang;Cheng Bingxin;Ye Weiping(Shenzhen HwaGen Pharmacuticial Co.,Ltd,Shenzhen,Guangdong 518118)
出处
《有机化学》
SCIE
CAS
CSCD
北大核心
2023年第8期2961-2967,共7页
Chinese Journal of Organic Chemistry
基金
深圳市科技计划(No.KQTD20190929172447117)资助项目。
关键词
流感
钌催化
不对称转移氢化
β-氨基酸酯
influenza
Ru catalysis
asymmetric transfer hydrogenation
β-amino acid ester
