依替米贝合成新工艺的研究

New Synthesis Process for the Synthesis of Ezetimibe

依替米贝(Ezetimibe)是一种新型选择性胆固醇吸收抑制剂,在参考相关文献的基础上,以4-羟基苯甲醛、4-氟苯胺和氯化苄为原料一步合成得到N-(4-氟苯基)-4-苄氧基苯亚甲胺(化合物2),4-(4-氟苯甲酰基)丁酸与特戊酰氯反应成混酐后在氯化锂存在下直接和(S)-4-苯基-噁唑烷酮反应再经过CBS/BH3体系还原得到(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基-1-氧代戊基]-4-苯基-2-噁唑烷酮(化合物4),经三甲基硅烷基保护羟基后直接和化合物2在TiCl2(OiPr)2催化下缩合后经三水合四丁基氟化铵催化环合和Pa/C催化氢化脱保护制得,总收率92.4%×91.6%×77.7%×85.3%=56%。最终产品和部分中间体经过熔点、MS和1H-NMR测定。该工艺路线不仅减少了关键原料的使用,提高了收率,同时也增强了有羟基保护基的中间体的稳定性,简化了反应操作,更加易于工业化。

Ezetimibe is a novel selective cholesterol absorption inhibitor which was developed by both Schering-Plough and Merck. An improved process for the preparation of ezetimibe was studied and was described as follows. N-（4-（benzyloxy）benzylidene）-4-fluorobenzenamine （Compound 2） was prepared from 4-hyd- roxybenzaldehyde, 4-fluorobenzenamine and benzyl chloride in one pot. 5-（4-Fluorophenyl）-5-oxopentanoic acid was reacted with pivaloyl chloride and directly condensed with （S）-4-phenyloxazolidin-2-one promoted with LiCI, and then reduced by CBS/BH3 to get （4S）-3-[（5S）-5-（4-fluoror）-5-hydrox-l-oxo-pentyl]-4-phenyl- oxazolidin-2-one （Compound 4）. It was condensed with compound 2 catalyzed with Lewis acid after being protected by TMS to afford the condensation intermediate. Finally it was cyclized by TBAF.3H2O and deprotected with Pd/C to get the title compound with a total yield of 56%. Compared with the current technology, the present process shows advantage in high yield, less raw material consumed, and easy production on industrial scale. The specific rotation and melting point of the prepared title compound is the same as that reported in literature, and the structure of the prepared title compound and some intermediates were confirmed by MS and ^1H-NMR.