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达比加群酯的合成

刘晓君,陈国华*   

  1. (中国药科大学药物化学教研室 南京 210009)
  • 收稿日期:2012-08-27 修回日期:2012-10-21 出版日期:2013-04-10 发布日期:2013-04-10
  • 通讯作者: 陈国华，副研究员; Tel:025-83271552; Fax:025-83271564; E-mail:cgh63@163.com; 研究方向：新药研究与开发

Synthesis of Dabigatran Etexilate

LIU Xiaojun, CHEN Guohua*   

  1. (Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing 210009,China)
  • Received:2012-08-27 Revised:2012-10-21 Published:2013-04-10 Online:2013-04-10
  • Contact: guohua chen

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摘要： 3-硝基-4-氯苯甲酸(2)经甲胺化得3-硝基-4-甲氨基苯甲酸(3)，2-氨基吡啶与丙烯酸乙酯经迈克尔加成得3-[(吡啶-2-基)氨基]丙酸乙酯(5),化合物3与5经缩合、催化氢化得3-{[(3-氨基-4-甲胺基)苯甲酰基](吡啶-2-基)氨基}丙酸乙酯(7)，化合物7再与N-(4-氰基苯基)甘氨酸(8)酰化、环合和Pinner反应，最后与氯甲酸正己酯反应得到达比加群酯(1)，总收率约40%(以3-硝基-4-氯苯甲酸计)，结构经IR、1H NMR和MS测试技术确证。

关键词: 达比加群酯, 非肽类凝血酶抑制剂, 合成

Abstract: 4-Methylamino-3-nitrobenzoic acid(3) was prepared from 3-nitro-4-chlorobenzoic acid by methylamination. 3-[(Pyridin-2-yl)amino]propinoic acid ethyl ester(5) was prepared from 2-aminopyridine and ethyl acrylate by Michael addition. Dabigatran etexilate was synthesized from compounds 3 and 5 via condensation, catalytic hydrogenation, acylation with N-(4-cyanophenyl)glycine(9), cyclization, Pinner reaction, followed by reaction with n-hexyl chlorofomate. The overall yield is about 40% and the structure of the product was determined by IR, 1H NMR and MS.

Key words: dabigatran etexilate, non-peptide thrombin inhibitors, synthesis

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