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对氟苯甲酰丁酸(2)经乙二硫醇保护羰基得4-[2-(4-氟苯基)-1,3-二硫戊环-2-基]丁酸(3),与手性助剂(S)-4-苯基-2-噁唑烷酮经缩合反应得(S)-3-[4-[2-(4-氟苯基)-1,3-二硫戊环-2-基]丁酰]-4-苯基-2-噁唑烷酮(5),经路易斯酸催化的不对称Mannich反应得(S)-3-[(R)-[2-[(S)-(4-氟苯胺基)[4-(三甲基硅氧基)苯基]甲基]-4-[2-(4-氟苯基)-1,3-二硫戊环-2-基]]丁酰]-4-苯基-2-噁唑烷酮(7),再经成环、脱保护、手性催化还原得依折麦布(1),总收率49%(以2计)。本研究采用乙二硫醇作为羰基保护试剂,增加中间体3、5和7的结晶性能,提高中间体的纯化效果,使终产物只需经一次重结晶便可达到纯度要求(99.9%);还优化了手性还原步骤的反应温度和加料顺序,提高了手性选择性,将成品中RRS、SSR和RSR-构型异构体杂质均控制在≤0.05%,光学纯度达99.9%以上。
P-Fluorobenzoylbutyric acid (2) is protected by ethanedithiol to give 4- [2- (4-fluorophenyl) -1,3-dithiolan-2-yl] (S) -3- [4- [2- (4-fluorophenyl) -1,3-disulfide by the condensation reaction with the chiral auxiliary (S) 2-yl] butanoyl] -4-phenyl-2-oxazolidinone (5) was subjected to Lewis acid-catalyzed asymmetric Mannich reaction to obtain (S) -3 - [(R) [(S) - (4-fluoroanilino) [4- (trimethylsiloxy) phenyl] methyl] -4- [2- Cycloheptan-2-yl]] butanoyl] -4-phenyl-2-oxazolidinone (7) which is then cyclized, deprotected and chirally reduced to give ezetimibe (1) 49% (calculated as 2). In this study, ethanedithiol was used as a carbonyl protecting reagent to increase the crystallization performance of intermediates 3, 5 and 7 and to improve the purification effect of the intermediates, so that the purity of the final product could reach 99.9% after only one recrystallization. The reaction temperature and the order of addition of the chiral reduction step were also optimized to improve the chiral selectivity. The impurities of the RRS, SSR and RSR-isomers in the finished product were both controlled at ≤0.05% and the optical purity was over 99.9%.