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2024 , Vol. 44 >Issue 12: 3720 - 3726

DOI: https://doi.org/10.6023/cjoc202408013

研究论文

钌催化烯胺酯的不对称氢化合成西格列汀手性中间体

  • 吕逸文 ,
  • 廖海华 ,
  • 汤文军
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  • a 华东理工大学药学院 上海 200237
    b 中国科学院上海有机化学研究所 生命过程小分子调控全国重点实验室 上海 200032
    c 中国科学院大学杭州高等研究院 化学和材料科学学院 杭州 310024

收稿日期: 2024-08-08

  修回日期: 2024-08-31

  网络出版日期: 2024-09-10

基金资助

国家重点研发计划(2022YFA1503702); 国家重点研发计划(2021YFF0701601); 国家自然科学基金(82188101)

收起

Synthesis of a Sitagliptin Intermediate via Ruthenium-Catalyzed Asymmetric Hydrogenation of Enamine Ester

  • Yiwen Lü ,
  • Haihua Liao ,
  • Wenjun Tang
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  • a School of Pharmacy, East China University of Science and Technology, Shanghai 200237
    b State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
    c School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024
*Corresponding authors. E-mail:

Received date: 2024-08-08

  Revised date: 2024-08-31

  Online published: 2024-09-10

Supported by

National Key R&D Program of China(2022YFA1503702); National Key R&D Program of China(2021YFF0701601); National Natural Science Foundation of China(82188101)

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摘要

发展了烯胺酯的高对映选择性钌催化不对称氢化合成西格列汀手性中间体. 通过对钌催化剂前体、手性配体、酸和铵盐添加剂、温度、压力和溶剂等全面考察, β-2,4,5-三氟苯基β-烯胺酯在双二氢苯并氧磷杂环戊烷(BIBOP)-钌催化剂作用下, 以对甲苯磺酸和对甲苯磺酸铵为添加剂, 二氯甲烷/甲醇作溶剂, 在5 MPa压力和60 ℃条件下反应22 h, 以97%收率以及99% ee值获得西格列汀关键中间体(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸异丙酯. 采用BIBOP-钌催化剂是实现该高对映选择性不对称氢化反应的关键.

关键词： 钌; 烯胺酯; 不对称氢化; 西格列汀

本文引用格式

吕逸文 , 廖海华 , 汤文军 . 钌催化烯胺酯的不对称氢化合成西格列汀手性中间体[J]. 有机化学, 2024 , 44(12) : 3720 -3726 . DOI: 10.6023/cjoc202408013

Abstract

This paper aims at developing a highly enantioselective ruthenium-catalyzed asymmetric hydrogenation of ena- mine ester to synthesize the chiral intermediate of sitagliptin. Through a comprehensive investigation of ruthenium catalyst precursors, chiral ligands, acids and ammonium salts as additives, temperature, pressure, and solvent, (R)-3-amino-4-(2,4,5- trifluorophenyl) isopropyl butyrate, the key intermediate of sitagliptin, was obtained in 97% yield and 99% ee by asymmetric hydrogenation from β-2,4,5-trifluorophenyl-β-enamine ester under the action of Ru-BIBOP catalyst, with p-toluenesulfonic acid and ammonium p-toluenesulfonate as additives, and dichloromethane/methanol as solvent, under 5 MPa of hydrogen pressure and 60 ℃ for 22 h. The use of Ru-BIBOP catalyst plays a key role in achieving high enantioselectivity for this trans- formation.

Key words： ruthnium; enamide easter; asymmetric hydrogenation; sitagliptin

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