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SB-203580

4-(4-氟苯基)-2-(4-甲基亚磺酰基苯基)-5-(4-吡啶基)-1H-咪唑Chemical Name: 4-(4-Fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-5-(4-pyridyl)-1H-imidazole
CAS No. 152121-47-6
项目整合开发状态: Preclinical
项目研究机构: GlaxoSmithKline (Originator)
合成路线:4-[(tert-Butyldimethylsilyloxy)methyl]pyridine (II) was prepared by silylation of 4-hydroxymethylpyridine (I) with tert-butyldimethylsilyl chloride and imidazole.Deprotonation of (II) by means of LDA in cold THF,followed by condensation with 4-fluorobenzaldehyde (III),furnished the protected diol adduct (IV),which was further desilylated upon treatment with tetrabutylammonium fluoride in THF.Oxidation of the resultant diol (V) under Swern conditions provided diketone (VI).The triaryl imidazole (VIII) was then obtained by condensation of diketone (VI) with 4-(methylsulfanyl)benzaldehyde (VII) in the presence of ammonium acetate in refluxing HOAc.Finally,oxidation of the thioether function of (VIII) with K-2S2O8 furnished the title sulfoxide.

合成路线:In a related procedure,4-fluorobenzoyl chloride (IX) was converted to the corresponding Weinreb amide (X) upon treatment with N,O-dimethylhydroxylamine.Condensation of (X) with the lithium derivative of 4-[(tert-butyldimethylsilyloxy)methyl]pyridine (II) furnished the silylated hydroxy ketone (XI).This was then condensed with 4-(methylthio)benzaldehyde (VII) in the presence of cupric acetate as oxidant and ammonium acetate to produce the intermediate triaryl imidazole (VIII),which was finally oxidized as above.
📌 参考资料/链接：
参考文献标题:Imidazole derivs.and their use as cytokine inhibitors
文献作者:Adams,J.L.; Gallagher,T.F.; Lee,J.C.; White,J.R.(GlaxoSmithKline plc)
参考来源:EP 0623126; EP 0943616; JP 1995503017; US 5686455; WO 9314081

📄 详细内容


合成路线:In a related procedure,4-fluorobenzoyl chloride (IX) was converted to the corresponding Weinreb amide (X) upon treatment with N,O-dimethylhydroxylamine.Condensation of (X) with the lithium derivative of 4-[(tert-butyldimethylsilyloxy)methyl]pyridine (II) furnished the silylated hydroxy ketone (XI).This was then condensed with 4-(methylthio)benzaldehyde (VII) in the presence of cupric acetate as oxidant and ammonium acetate to produce the intermediate triaryl imidazole (VIII),which was finally oxidized as above.

参考文献标题:Imidazoles for treating cytokine mediated disease
文献作者:Adams,J.L.; Gallagher,T.F.; Lee,J.C.; White,J.R.(GlaxoSmithKline plc)
参考来源:WO 9503297


合成路线:In a related procedure,4-fluorobenzoyl chloride (IX) was converted to the corresponding Weinreb amide (X) upon treatment with N,O-dimethylhydroxylamine.Condensation of (X) with the lithium derivative of 4-[(tert-butyldimethylsilyloxy)methyl]pyridine (II) furnished the silylated hydroxy ketone (XI).This was then condensed with 4-(methylthio)benzaldehyde (VII) in the presence of cupric acetate as oxidant and ammonium acetate to produce the intermediate triaryl imidazole (VIII),which was finally oxidized as above.

参考文献标题:2,4,5-Triarylimidazole inhibitors of IL-1 biosynthesis
文献作者:Gallagher,T.F.; et al.
参考来源:Bioorg Med Chem Lett 1995,5(11),1171


合成路线:In a related procedure,4-fluorobenzoyl chloride (IX) was converted to the corresponding Weinreb amide (X) upon treatment with N,O-dimethylhydroxylamine.Condensation of (X) with the lithium derivative of 4-[(tert-butyldimethylsilyloxy)methyl]pyridine (II) furnished the silylated hydroxy ketone (XI).This was then condensed with 4-(methylthio)benzaldehyde (VII) in the presence of cupric acetate as oxidant and ammonium acetate to produce the intermediate triaryl imidazole (VIII),which was finally oxidized as above.
参考文献标题:Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase
文献作者:Gallagher,T.F.; Seibel,G.L.; Kassis,S.; Laydon,J.T.; Blumenthal,M.J.; Lee,J.C.; Lee,D.; Boehm,J.C.; Fier-Thompson,S.M.; Abt,J.W.; Soreson,M.E.; Smietana,J.M.; Hall,R.F.; Garigipati,R.S.; Bender,P.E.; Erhard,K.F.; Krog,A.J.; et al.
参考来源:Bioorg Med Chem 1997,5(1),49


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