高等学校化学学报 ›› 2013, Vol. 34 ›› Issue (4): 858.doi: 10.7503/cjcu20120862

• 有机化学 • 上一篇    下一篇

盐酸决奈达隆合成新工艺

李峰1, 田拴红2, 宋晓峰3, 李文远3, 程花英1, 雷灵芝1, 朱勤丰1, 金春华1, 李少华2   

  1. 1. 浙江大学宁波理工学院生化分院, 宁波 315100;
    2. 南昌大学药学院, 南昌 330006;
    3. 山东省诸城人民医院, 潍坊 262200
  • 收稿日期:2012-09-19 出版日期:2013-04-10 发布日期:2013-03-21
  • 通讯作者: 金春华,男,副研究员,主要从事新药开发及药物合成研究.E-mail:chjin641@163.com E-mail:chjin641@163.com
  • 基金资助:

    宁波市工业重大(重点)择优委托科技攻关项目(批准号:2011B1019)资助.

New Process for Preparation of Dronedarone Hydrochloride

LI Feng1, TIAN Shuan-Hong2, SONG Xiao-Feng3, LI Wen-Yuan3, CHENG Hua-Ying1, LEI Ling-Zhi1, ZHU Qin-Feng1, JIN Chun-Hua1, LI Shao-Hua2   

  1. 1. School of Biological & Chemical Engineering, Ningbo Institute of Technology, Zhejiang University, Ningbo 315100, China;
    2. School of Pharmacy, Nanchang University, Nanchang 330006, China;
    3. Zhucheng People's Hospital, Weifang 262200, China
  • Received:2012-09-19 Online:2013-04-10 Published:2013-03-21

摘要:

设计了一条全新的盐酸决奈达隆(1)的合成路线, 该路线以价廉易得的对氨基苯酚(2)为起始原料, 经N-甲磺酰化、 氧化得到对甲磺酰亚氨基苯醌(4)后, 再与3-氧代庚酸甲酯缩合、 环化制得关键中间体2-丁基-5-甲磺酰胺基苯并呋喃-3-甲酸甲酯(6), 然后经水解、 酰氯化, 继而与1-苯氧基-3-二正丁胺基丙烷盐酸盐进行傅-克酰基化反应, 成盐后即得化合物1, 总收率达33%.

关键词: 盐酸决奈达隆, 抗心律失常药, 新工艺

Abstract:

Dronedarone hydrochloride(1), a potent blocker of multiple ion, was approved for atrial fibrillation by Food and Drug Administration(FDA) in 2009. It's a modified synthetic analogue of amiodarone, which decreases lipophilicity and results in a shorter lifetime and lower tissue accumulation. Here a new process for compound 1 was achieved with 33% overall yield starting from commercial p-aminophenol(2). N-(4-oxocyclohexa-2,5-dien-1-yl)-methanesulfonamide(4) which was obtained by mesylation and oxidization from compound 2 reacted with methyl 3-oxoheptanoate followed by cyclization to afford N--methanesulfonamide(6). The inversion of compound 6 into the desired compound 1 was realized by hydrolyzation and chlorination followed by Friedel-Crafts reaction with N-butyl-N-(3-phenoxypropyl)-1-butanamine hydrochloride. This process is characterized by cheap and readily available materials, shorter procedures, mild reaction conditions and convenient work-up, making it practical in industry.

Key words: Dronedarone hydrochloride, Antiarrhythmics, New process

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