高等学校化学学报

高等学校化学学报 ›› 2011, Vol. 32 ›› Issue (10): 2331.

• 研究论文 • 上一篇    下一篇

(S,S)-TsDPEN-Ru催化不对称氢转移还原β-胺基酮及在度洛西汀合成中的应用

赵金凤, 窦海建, 周宇涵, 曲景平   

  1. 大连理工大学制药科学与技术学院,  精细化工国家重点实验室, 大连  116024
  • 收稿日期:2010-10-28 修回日期:2011-01-25 出版日期:2011-10-10 发布日期:2011-09-11
  • 通讯作者: 曲景平 E-mail:qujp@dlut.edu.cn
  • 基金资助:

    国家自然科学基金(批准号:   20572011)和大连市留学回国人员科研基金(批准号:   2005J22JH021)资助.

Asymmetric Transfer  Hydrogenation of β-Amino Ketone Catalyzed by (S,S)-TsDPEN-Ru Complex and Its Application in the Synthesis of Duloxetine

ZHAO Jin-Feng, DOU Hai-Jian, ZHOU Yu-Han, QU Jing-Ping*   

  1. State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, China
  • Received:2010-10-28 Revised:2011-01-25 Online:2011-10-10 Published:2011-09-11
  • Contact: QU Jing-Ping E-mail:qujp@dlut.edu.cn
  • Supported by:

    国家自然科学基金(批准号:   20572011)和大连市留学回国人员科研基金(批准号:   2005J22JH021)资助.

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摘要： 报道了甲酸/三乙胺体系中, (S,S)-TsDPEN-Ru络合物催化的不对称氢转移反应合成(S)-γ-胺基醇的方法. 考察了不同底物的反应性能, β-单/二烷基胺基-2-噻吩酮在该还原体系中氢解得到1-(2-噻吩基)-1-丙酮; 氮原子上吸电子基取代的底物以高收率、高立体选择性(>95% e.e.)得到还原产物. 将这一反应用于度洛西汀的合成, 以乙酰噻吩为原料, 经五步反应合成度洛西汀, 收率69％, 91.7% e.e..

关键词: 度洛西汀, 不对称氢转移, (S,S)-TsDPEN-Ru 络合物

Abstract: (S)-γ-aminoalcohol is a key intermediate for the preparation of Duloxetine. In this paper, we describe an effective method to obtain (S)-γ-aminoalcohol through asymmetric transfer hydrogenation with an easy accessible (S,S)-TsDPEN-Ru complex as catalyst in HCOOH/Et3N system. A variety of β-amino ketones were examined. β-Amino ketones with donating groups(3a~3c) decomposed to give 1-(2-thienyl)-1-propanone during the reaction. On the other hand, (S)-γ-aminoalcohols with withdrawing groups(4e,4f) were obtained in high e.e. values(>95% e.e.) and good yields under optimal reaction conditions. This novel procedure was applied in the asymmetric total synthesis of Duloxetine as a key step. Starting from acetyl thiophene, Duloxetine was obtained in 69% yield and 91.7% e.e..

Key words: Duloxetine, Asymmetric transfer hydrogenation, (S,S)-TsDPEN-Ru complex

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