依折麦布的合成工艺改进  

Improved synthesis of ezetimibe

作　　者：刘春池[1] 罗昌群 郝晨洲[1] 宋帅[1] 赵冬梅[1] 程卯生[1] 

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

出　　处：《中国药物化学杂志》2016年第1期37-40,44,共5页Chinese Journal of Medicinal Chemistry

基　　金：教育部创新团队发展计划;辽宁省高校创新团队支持计划资助

摘　　要：目的改进依折麦布的合成工艺。方法以4-羟基苯甲醛为起始原料,经苄基保护、缩合得到中间体N-（4-氟苯基）-4-苄氧基苯亚甲胺（4）;以氟苯为起始原料,经傅克酰化、还原、酯化反应得到中间体6-（4-氟苯基）四氢-2H-吡喃-2-酮（9）;中间体4与中间体9经环合、氧化、还原、脱保护、拆分共10步反应得到依折麦布。结果与结论目标化合物依折麦布的结构经MS、~1H-NM R谱确证,反应总收率达6.2%（以4-羟基苯甲醛计）,化学纯度大于99.5%。Ezetimibe is a cholesterol absorption inhibitor developed by Merck Corporation and Schering- Plough Corporation. In this paper, a new synthetic route for preparing ezetimibe was designed on the base of several references, synthesized from a convergent synthesis. Intermediate 4, N- （ 4-fluorophenyl ） -4-benzy- loxybenzimide, was obtained via benzyl protection, condensation reaction, using 4-hydroxybenzaldehyde as the starting material; Intermediate 9,6- （ 4-fluorophenyl ） tetrahydro-2H-pyran-2-one, was obtained via Friedel- Crafts alkylation, reduction, esterification ,using fluorobenzene as the starting material. The final product was prepared via cyclization of intermediates 4 and 9, oxidation, reduction, deprotection, chiral separation, with an overall yield of 6.2%. The structure of the target compound was confirmed by MS and ^1H-NMR.

关 键 词：依折麦布 胆固醇吸收抑制剂 工艺改进 

分 类 号：R914.5[医药卫生—药物化学]