达比加群酯-d_(3)的合成  

Synthesis of Dabigatran etexilate-d_(3)

作　　者：王昌 梁林辉 姚永秀[2] 梁大伟[2] 董金华[1] WANG Chang;LIANG Lin-hui;YAO Yong-xiu;LIANG Da-wei;DONG Jin-hua(Key Laboratory of Structure-based Drug Design&Discovery of Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110016,China;School of Pharmacy&Medical Laboratory Science,Ya′an Polytechnic College,Ya′an 625100,China)

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016 [2]雅安职业技术学院药学与检验学院,四川雅安625100

出　　处：《化学试剂》2024年第1期105-110,共6页Chemical Reagents

基　　金：雅安市应用技术研究与开发项目(21KJJH0080);雅安市科技创新创业苗子工程重点项目(YKZ20211307)。

摘　　要：研究抗凝血药物达比加群酯-d_(3)的合成工艺。以4-氯-3-硝基苯甲酸甲酯为起始原料,氘代甲胺盐酸盐为氘代试剂,经氘代甲基化、取代、还原、缩合、环合、水解、亲核等反应得到关键氘化中间体3-{[(2-{[(4-氰基苯基)氨基]甲基}-1-(甲基-d_(3))苯并咪唑-5-基)氧亚基](吡啶-2-基)氨基}丙酸乙酯,而后再经氨解和亲核反应,成功制备稳定的达比加群酯-d_(3),8步反应总产率为6.4%,目标化合物结构经NMR和MS确认,同位素丰度达99.7%。该合成方法原料简单易得、操作简便、重现性好,可用于达比加群酯-d_(3)的合成。To investigate the synthesis of the anticoagulant drug dabigatran etexilate-d_(3).Using Methyl 4-chloro-3-nitrobenzoate as the starting materials and deuteromethylamine hydrochloride as a deuterated reagent,the key deuterated intermediate ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-(methyl-d_(3))benzoimidazol-5-yl)oxylidene](pyridin-2-yl)amino}propanoate(8)was obtained through deuterylation,substitution,reduction,condensation,cyclization,hydrolysis and nucleophilic reaction.After ammonolysis and nucleophilic reaction,the stable dabigatran etexilate-d_(3) was synthesized.The total yield was 6.4%,and the structure was confirmed by NMR and MS.The isotopic enrichment of dabigatran etexilate-d_(3) was 99.7%.The synthetic method has several advantages,such as low cost of starting materials,facile operation process,and good reproducibility.The synthetic procedure is suitable for the laboratory production of dabigatran etexilate-d_(3).

关 键 词：抗凝血药物 达比加群酯-d_(3) 合成工艺 优化 同位素标记 

分 类 号：O62[理学—有机化学]