伊潘立酮有关物质的合成
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摘要
为对伊潘立酮原料药进行质量控制,分别合成6种有关物质:4-[3-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]-丙氧基]-3-甲氧基-a-甲基苯甲醇(P88)、4-[3-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯甲酸(P95)、1,1'-[1,3-丙二基-双[氧代(3-甲氧基-1,4-亚苯基)]]双-乙酮(A)、(E)-2,4-二氟苯基-4-哌啶基甲酮肟(B)、1-[4-[3-[4-(6-乙氧基-1,2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮(C)、1-[3-(4-乙酰基-2-甲氧基苯氧基)丙基]-4-(6-氟-1,2-苯并异噁唑-3-基)哌啶-N-氧化物(D),结构经MS、1H NMR和13C NMR确证。
To perform the quality control of iloperidone, six related substances: 4-[3-[4-(6-fl uoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-ɑ-methylbenzenemethanol(P88), 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxybenzoic acid(P95), 1,1'-[1,3-propanediylbis[oxy(3-methoxy-1,4-phenylene)]]bis-ethanone(A),(E)-(2,4-difluorophenyl)(piperidin-4-yl)methanone oxime(B), 1-[4-[3-[4-(6-ethoxy-1,2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone(C) and 1-[3-(4-acetyl-2-methoxyphenoxy)propyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine-N-oxide(D) were synthesized. The chemical structures were confi rmed by MS, 1H NMR and 13C NMR.
To perform the quality control of iloperidone, six related substances: 4-[3-[4-(6-fl uoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-ɑ-methylbenzenemethanol(P88), 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxybenzoic acid(P95), 1,1'-[1,3-propanediylbis[oxy(3-methoxy-1,4-phenylene)]]bis-ethanone(A),(E)-(2,4-difluorophenyl)(piperidin-4-yl)methanone oxime(B), 1-[4-[3-[4-(6-ethoxy-1,2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone(C) and 1-[3-(4-acetyl-2-methoxyphenoxy)propyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine-N-oxide(D) were synthesized. The chemical structures were confi rmed by MS, 1H NMR and 13C NMR.
引文
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[12]Slanina P,Bartl J.Process for making risperidone and intermediates therefor:US,2008262227A1[P].2008-10-23.
[13]谢峰,龚恒源,罗杰,等.一种伊潘立酮的杂质及其制备方法:中国,102952123A[P].2013-03-06.
[2]王志宏,郑宇静.伊潘立酮的药理作用与临床评价[J].中国新药杂志,2010,19(15):1293-1295.
[3]陆维君.抗精神分裂药物的临床应用[J].中国现代药物应用,2010,4(8):222-223.
[4]Strupczewski JT,Allen RC,Gardner BA,et al.Synthesis and neuroleptic activity of 3-(1-substituted-4-piperidinyl)-1,2-benzsoxazoles[J].J Med Chem,1985,28(6):761-769.
[5]胡文浩,徐勤耀,任白燕,等.伊潘立酮的合成[J].中国医药工业杂志,2011,42(2):88-89.
[6]郑立刚,尚振华,哈婧,等.伊潘立酮的制备方法:中国,20110226361.4[P].2013-02-13.
[7]Jia MM,Li J,He XM,et al.Simultaneous determination of iloperidone and its two active metabolites in human plasma by liquid chromatography-tandem mass spectrometry:application to a pharmacokinetic study[J].J Chromatogr B,2013,928:52-57.
[8]Mutlib AE,Strupczewski JT,Chesson SM.Application of hyphenated LC/NMR and LC/MS techniques in rapid identification of in vitro and in vivo metabolites of iloperidone[J].DMD,1995,23(9):951-964.
[9]Wolfgang CD,Polymeropoulos MH.Methods for the administration of iloperidone:WO,2006039663A[P].2006-04-13.
[10]Strupczewski JT,Bordeau KJ,Chiang YL,et al.3-[[(Aryloxy)alkyl]piperdinyl]-1,2-benzisoxazoles as D2/5-HT2 antagonists with potential atypical antipsychotic activity:antipsychotic profile of iloperidone[J].J Med Chem,1995,38(7):1119-1131.
[11]Mutlib AE,Strupczewski JT.Picogram determination of iloperidone in human plasma by solid-phase extraction and by high-performance liquid chromatography-selectedion monitoring electrospray mass spectrometry[J].J Chromatogr B,1995,669:237-246.
[12]Slanina P,Bartl J.Process for making risperidone and intermediates therefor:US,2008262227A1[P].2008-10-23.
[13]谢峰,龚恒源,罗杰,等.一种伊潘立酮的杂质及其制备方法:中国,102952123A[P].2013-03-06.