首页    期刊浏览 2024年12月11日 星期三
登录注册

文章基本信息

  • 标题:The Design, Synthesis and Preliminary Pharmacokinetic Evaluation of d3-Poziotinib Hydrochloride
  • 本地全文:下载
  • 作者:Shuchao Ma ; Linan Wang ; Ben Ouyang
  • 期刊名称:Biological and Pharmaceutical Bulletin
  • 印刷版ISSN:0918-6158
  • 电子版ISSN:1347-5215
  • 出版年度:2019
  • 卷号:42
  • 期号:6
  • 页码:873-876
  • DOI:10.1248/bpb.b19-00153
  • 出版社:The Pharmaceutical Society of Japan
  • 摘要:To establish a synthetic route to d3 -poziotinib hydrochloride. Treatment of 4-chloro-7-hydroxyquinazolin-6-yl pivalate ( 1 ) with d3 -methyliodide afforded the etherization product, which reacted with 3,4-dichloro-2-fluoroaniline to generate the key intermediate d3 -4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl pivalate ( 3 ). Followed the de-protection reaction, the nucleophilic substitution ( S N 2) reaction with tert -butyl 4-(tosyloxy)piperidine-1-carboxylate ( TSP ), and the de-protection reaction of t -butoxycarbonyl (Boc) group, and the amide formation reaction with acrylyl chloride, d3 -poziotinib was obtained, which was converted to hydrochloride salt by treatment with concentrated hydrochloric acid (HCl). Starting from a known compound 4-chloro-7-hydroxyquinazolin-6-yl pivalate ( 1 ), after 7 steps transformation, d3 -poziotinib hydrochloride was obtained with a total yield of 9.02%. The structure of d3 -poziotinib hydrochloride was confirmed by 1H-NMR, 13C-NMR, and high resolution (HR)-MS. Meanwhile, the in vitro microsomal stability experiment showed that d3 -poziotinib had a longer half time ( t 1/2 = 4.6 h) than poziotinib ( t 1/2 = 3.5 h).
  • 关键词:poziotinib;d3-poziotinib;metabolic closure
国家哲学社会科学文献中心版权所有