CAJ | 학술논문

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.
의체미패(Ezetimibe)시일충신형선택성담고순흡수억제제,재삼고상관문헌적기출상,이4-간기분갑철、4-불분알화록화변위원료일보합성득도N-(4-불분기)-4-변양기분아갑알(화합물2),4-(4-불분갑선기)정산여특무선록반응성혼항후재록화리존재하직접화(S)-4-분기-오서완동반응재경과CBS/BH3체계환원득도(4S)-3-[(5S)-5-(4-불분기)-5-간기-1-양대무기]-4-분기-2-오서완동(화합물4),경삼갑기규완기보호간기후직접화화합물2 재TiCl2(OiPr)2최화하축합후경삼수합사정기불화안최화배합화Pa/C최화경화탈보호제득,총수솔92.4%×91.6%×77.7%×85.3%=56%.최종산품화부분중간체경과용점、MS화1H-NMR측정.해공예로선불부감소료관건원료적사용,제고료수솔,동시야증강료유간기보호기적중간체적은정성,간화료반응조작,경가역우공업화.
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 LiCl, and then reduced by CBS/BH3 to get (4S)-3-[(5S)-5-(4-fluoror)-5-hydrox-1-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.