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2023 , Vol. 43 >Issue 8: 2961 - 2967

DOI: https://doi.org/10.6023/cjoc202301029

研究简报

[RuCl(p-cymene)-(S)-BINAP]Cl催化不对称合成反式-3-氨基-双环[2.2.2]辛烷-2-甲酸乙酯

  • 周章涛 ,
  • 王杨 ,
  • 程冰心 ,
  • 叶伟平
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  • 深圳市华先医药科技有限公司 广东深圳 518118

收稿日期: 2023-01-31

  修回日期: 2023-03-14

  网络出版日期: 2023-04-26

基金资助

深圳市科技计划(KQTD20190929172447117)

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[RuCl(p-cymene)-(S)-BINAP]Cl Catalyzed Asymmetric Preparation of trans-3-Amino-bicyclo[2.2.2]octane-2-carboxylic Acid Ethyl Ester

  • Zhangtao Zhou ,
  • Yang Wang ,
  • Bingxin Cheng ,
  • Weiping Ye
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  • Shenzhen HwaGen Pharmacuticial Co., Ltd, Shenzhen, Guangdong 518118
*E-mail:

Received date: 2023-01-31

  Revised date: 2023-03-14

  Online published: 2023-04-26

Supported by

The Shenzhen Science and Technology Program(KQTD20190929172447117)

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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.

关键词： 流感; 钌催化; 不对称转移氢化; β-氨基酸酯

本文引用格式

周章涛 , 王杨 , 程冰心 , 叶伟平 . [RuCl(p-cymene)-(S)-BINAP]Cl催化不对称合成反式-3-氨基-双环[2.2.2]辛烷-2-甲酸乙酯[J]. 有机化学, 2023 , 43(8) : 2961 -2967 . DOI: 10.6023/cjoc202301029

Abstract

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.

Key words： influenza; Ru catalysis; asymmetric transfer hydrogenation; β-amino acid ester

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