福沙吡坦二甲葡胺及其光学异构体的合成研究
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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。
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.
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.
引文
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[9]丁军,吴忠玉,孙敬勇,等.阿瑞吡坦合成工艺研究进展[J].食品与药品,2015,17(1):68-71.
[10]BRANDS K M,PAYACK J F,ROSEN J D,et al.Efficient synthesis of NK1 receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation[J].J Am Chem Soc,2003,125(8):2129-2135.
[11]Mc NAMARA J M,MATTY L,ROSEN J D,et al.Process for preparation of fosaprepitant dimeglumine:WO,2006060110(A2)[P].2006-06-08.
[12]杨玉雷,潘红娟,朱雪淼,等.制备福沙吡坦的方法:中国,102850398(A)[P].2013-01-02.
[13]ELATI C R,KOLLA N,GANGULA S,et al.A convergent approach to the synthesis of aprepitant:a potent human NK-1 receptor antagonist[J].Tetrahedron Lett,2007,484(45):8001-8004.
[2]王训强.肿瘤化疗所致恶心呕吐的药物治疗[J].世界临床药物,2008,29(6):362-365.
[3]孙丹霞,邱焱,侯源源,等.NK-1受体拮抗剂在癌症化疗止吐中的应用[J].中国肿瘤临床,2012,39(20):1572-1574.
[4]张童童,李青.神经激肽1受体阻断剂——缓解化疗所致恶心呕吐的新选择[J].癌症进展,2013,11(4):351-354.
[5]聂映,毕小玲,尤启冬.阿瑞吡坦[J].中国新药杂志,2006,l5(3):238-239.
[6]HESKETH P J,GRUNBERG S M,GRALLA R J,et al.The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting:a multinational,randomized,double-blind,placebo-controlled trial in patients receiving highdose cisplatin——the aprepitant protocol 052 study group[J].J Clin Oncol,2003,21(22):4112-4119.
[7]GANGULA S,ELATI C R,MUDUNURU S V,et al.Synthesis of all enantiomerically pure diastereomers of aprepitant[J].Synth Commun,2010,40(15):2254-2268.
[8]WAN W L,HE Y,GUAN M,et al.Synthesis of the major isomers of aprepitant and fosaprepitant[J].Chin Chem Lett,2013,24(12):1118-1122.
[9]丁军,吴忠玉,孙敬勇,等.阿瑞吡坦合成工艺研究进展[J].食品与药品,2015,17(1):68-71.
[10]BRANDS K M,PAYACK J F,ROSEN J D,et al.Efficient synthesis of NK1 receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation[J].J Am Chem Soc,2003,125(8):2129-2135.
[11]Mc NAMARA J M,MATTY L,ROSEN J D,et al.Process for preparation of fosaprepitant dimeglumine:WO,2006060110(A2)[P].2006-06-08.
[12]杨玉雷,潘红娟,朱雪淼,等.制备福沙吡坦的方法:中国,102850398(A)[P].2013-01-02.
[13]ELATI C R,KOLLA N,GANGULA S,et al.A convergent approach to the synthesis of aprepitant:a potent human NK-1 receptor antagonist[J].Tetrahedron Lett,2007,484(45):8001-8004.