钌催化烯胺酯的不对称氢化合成西格列汀手性中间体

doi: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^a, 廖海华^a, 汤文军^a,b,c,*

^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国科大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
基金资助:
国家重点研发计划（2022YFA1503702, 2021YFF0701601）,国家自然科学基金(No. 82188101 )资助项目.

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

Lv Yiwen^a, Liao Haihua^a, Tang Wenjun^a,b,c,*

^aEast China University of Science and Technology, School of Pharmacy, Shanghai, 200237;
^bState Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032;
^cSchool of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024

Received:2024-08-08 Revised:2024-08-31
Contact: *E-mail: tangwenjun@sioc.ac.cn.
Supported by:
National Key R&D Program of China (2022YFA1503702, 2021YFF0701601), NSFC (82188101).

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摘要/Abstract

本文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 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50个氢气大气压压力和60 ℃条件下反应 22 小时,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

This paper aims at developing a highly enantioselective ruthenium-catalyzed asymmetric hydrogenation of enamine 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 50 atm of hydrogen pressure and 60 ℃ for 22 hours. The use of Ru-BIBOP catalyst plays a key role in achieving high enantioselectivity for this transformation.

Key words: ruthnium, enamide easter, asymmetric hydrogenation, Sitagliptin

引用此文

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, doi: 10.6023/cjoc202408013.

Lv Yiwen, Liao Haihua, Tang Wenjun. Synthesis of a Sitagliptin Intermediate via Ruthenium-Catalyzed Asymmetric Hydrogenation of Enamine Ester[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202408013.

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