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有机化学
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有机化学 ›› 2013, Vol. 33 ›› Issue (05): 1100-1103.DOI: 10.6023/cjoc201211034 上一篇    下一篇

研究简报

利斯的明消旋体的高效实用合成

张恩, 李聪, 张保寅, 吕爱桥, 方园, 冯思琦, 刘宏民   

  1. 郑州大学药学院 新药研究开发中心 郑州 450001
  • 收稿日期:2012-11-17 修回日期:2013-01-10 发布日期:2013-01-21
  • 通讯作者: 刘宏民,liuhm@zzu.edu.cn E-mail:liuhm@zzu.edu.cn
  • 基金资助:

    国家自然科学基金(Nos. 81172937, U1204206)、教育部博士点新教师基金(No. 20114101120013)和博士后基金(Nos. 20100480857, 201104402)资助项目.

A Practical and Efficient Synthesis of (±)-Rivastigmine

Zhang En, Li Cong, Zhang Baoyin, Lü Aiqiao, Fang Yuan, Feng Siqi, Liu Hongmin   

  1. New Drug Research & Development Center and School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001
  • Received:2012-11-17 Revised:2013-01-10 Published:2013-01-21
  • Supported by:

    Project supported by the National Natural Science Foundation of China (Nos. 81172937, U1204206), the New Teachers' Fund for Doctor Stations, Ministry of Education (No. 20114101120013) and the China Postdoctoral Science Foundation (Nos. 20100480857, 201104402).

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利斯的明作为氨基甲酸酯类乙酰胆碱酯酶抑制剂在60多个国家被批准用于治疗老年痴呆症, 是临床最重要的治疗药物之一. 从3-乙基苯酚出发, 以3步反应高效实用地合成了利斯的明消旋体. 关键步骤是以NBS为试剂的N-甲基-N-乙基胺基甲酸-3-乙基苯酯的苄位溴代反应. 目标分子能够以71%的总产率得到, 并且整个实验不需要传统的柱层析或者重结晶分离. 整个合成包括酯化、苄位溴代和取代3种反应.

关键词: 利斯的明, 苄位溴代, 3-乙基苯酚, 合成, Wohl-Ziegler反应

A practical and efficient synthesis of (±)-rivastigmine, which is an acetyl cholinesterase inhibitor of the carbamate family and has been approved for the treatment of Alzheimer's disease in more than 60 countries, was developed in three steps from cheap and commercially available 3-ethylphenol. The key step of the synthesis involved the NBS-promoted benzylic bromination of 3-ethylphenyl ethyl(methyl)carbamate. The target molecular was obtained in 71% overall yield without any traditional purification (column chromatography or crystallization). The reactions include esterification, benzylic bromination, substitution reaction.

Key words: rivastigmine, benzylic bromination, 3-ethylphenol, synthesis, Wohl-Ziegler reaction