【摘要】 目的合成福沙吡坦及其所有光学异构体,提供福沙吡坦生产过程中杂质检测样品,以保证药物的安全性和有效性。方法以N-苄基乙醇胺为起始原料,经过缩合、醚化、加成、取代等反应,合成阿瑞吡坦;阿瑞吡坦进一步磷酰化并成盐得到福沙吡坦二甲葡胺盐,总收率约为30.8%。结果与结论选择不同的原料和不同的合成策略,获得了福沙吡坦及另外七个光学异构体的二甲葡胺盐,所有光学异构体的结构均经~1H-NMR、LC-MS谱及比旋光度确证,并通过单晶X光衍射对具有代表性的中间体进行了绝对构型确证。更多还原

【Abstract】 Fosaprepitant dimeglumine is the pro-drug of aprepitant as an antagonist of NK-1 receptor,which is clinically used in treatment or prevention acute or tardive chemotherapy induced nausea and vomiting(CINV). In this study,N-benzylethanolamine was employed as starting material and reacted with glyoxylic acid to afford N-benzyl-2-hydroxymorpholin-3-one. The absolute configuration of all the chiral centers was confirmed through the condensation of 2-hydroxyl with R-1-[3,5-bis(trifluoromethyl) phenyl]ethanol and the nucleophilic addition of 3-carbonyl with(4-fluorophenyl) magnesium bromide orderly.Accordingly,the 2,3-cis key intermediate 5(1’ R,2 R,3 S) was converted into aprepitant by the substitution of an alkyl halide,methyl 2-(1-amino-2-chloroethylidene) hydrazine-1-carboxylate with N-atom in morpholine ring, following a cyclization of this side chain. Fosaprepitant dimeglumine was finally obtained by phosphorylation of aprepitant and saltification with meglumine in the yield of 30. 8% overall. At the same time,different starting materials and synthetic strategies were utilized to synthesize all the other seven optical isomers of fosaprepitant. The structures of all isomers were characterized by ~1H-NMR,LC-MS and their specific rotation. The absolute configuration of one representative intermediate(5-RRR) was confirmed by X-ray crystal diffraction. It is of great significance that the preparation of all optical isomers of fosaprepitant can provide reference for the related material detection,quality control,and drug safety evaluation.更多还原