新产品编号:182439
Chemical Name: 1-[1-[5-[3,5-Bis(trifluoromethyl)benzyloxy]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl]piperidin-4-yl]pyrrolidin-2-one
CAS No. 184967-93-9 (undefined isomer)
项目整合开发状态: Biological Testing
项目研究机构: Schering-Plough (Originator)
合成路线:Conjugate addition of the lithium enolate of ethyl 1,3-dithiolane-2-carboxylate (II) to methyl 3,4-dichlorocinnamate (I) afforded the diester adduct (III).Reduction of (III) with LiAlH4 gave diol (IV),which was selectively monosilylated with tert-butyldimethylsilyl chloride,yielding (V).Condensation of the potassium alkoxide of (V) with 3,5-bis(trifluoromethyl)benzyl bromide (VI) provided ether (VII).After desilylation of (VII) with HF in acetonitrile to alcohol (VIII),the hydrolysis of its thioketal function with mercuric perchlorate and CaCO3 furnished ketone (IX).Treatment of (IX) with methoxyamine gave rise to a mixture of (E)- and (Z)-oximes from which the desired (Z)-isomer (X) was isolated by flash chromatography.Swern oxidation of the alcohol functionality of (X) produced the corresponding aldehyde,which was reductively condensed with piperidinyl pyrrolidone (XI) in the presence of NaBH3CN to afford the title compound.
📌 参考资料/链接：
参考文献标题:Substd.oximes,hydrazones and olefins useful as neurokinin antagonists
文献作者:Shankar,B.B.(Schering Corp.)
参考来源:EP 0823896; EP 0937064; JP 1998506923; JP 2000504341; US 5688960; US 5696267; WO 9634857; WO 9818785
📄 详细内容
合成路线:Conjugate addition of the lithium enolate of ethyl 1,3-dithiolane-2-carboxylate (II) to methyl 3,4-dichlorocinnamate (I) afforded the diester adduct (III).Reduction of (III) with LiAlH4 gave diol (IV),which was selectively monosilylated with tert-butyldimethylsilyl chloride,yielding (V).Condensation of the potassium alkoxide of (V) with 3,5-bis(trifluoromethyl)benzyl bromide (VI) provided ether (VII).After desilylation of (VII) with HF in acetonitrile to alcohol (VIII),the hydrolysis of its thioketal function with mercuric perchlorate and CaCO3 furnished ketone (IX).Treatment of (IX) with methoxyamine gave rise to a mixture of (E)- and (Z)-oximes from which the desired (Z)-isomer (X) was isolated by flash chromatography.Swern oxidation of the alcohol functionality of (X) produced the corresponding aldehyde,which was reductively condensed with piperidinyl pyrrolidone (XI) in the presence of NaBH3CN to afford the title compound.
参考文献标题:Synthesis of substituted 4(Z)-(methoxyimino)penthyl-1-piperidines as dual NK1/NK2 inhibitors
文献作者:Ting,P.C.; Lee,J.F.; Anthes,J.C.; Shih,N.-Y.; Piwinski,J.J.
参考来源:Bioorg Med Chem Lett 2001,11(4),491