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【结 构 式】 
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【药物名称】SB-203580 【化学名称】4-(4-Fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-5-(4-pyridyl)-1H-imidazole 【CA登记号】152121-47-6 【 分 子 式 】C21H16FN3OS 【 分 子 量 】377.44357 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antiarthritic Drugs, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Calcium Channel Activators, p38 Protein Kinase Inhibitors, Stress-Activated Protein (SAP/Jun) Kinase Inhibitors |
合成路线1
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.
| 【1】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazole derivs. and their use as cytokine inhibitors. EP 0623126; EP 0943616; JP 1995503017; US 5686455; WO 9314081 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 32835 | 4-pyridinylmethanol | 586-95-8 | C6H7NO | 详情 | 详情 |
| (II) | 22829 | 4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether | C12H21NOSi | 详情 | 详情 | |
| (III) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (IV) | 55081 | 2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanol | C19H26FNO2Si | 详情 | 详情 | |
| (V) | 55082 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1,2-ethanediol | C13H12FNO2 | 详情 | 详情 | |
| (VI) | 37913 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1,2-ethanedione | C13H8FNO2 | 详情 | 详情 | |
| (VII) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (VIII) | 55083 | 4-{5-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1H-imidazol-4-yl}pyridine; 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazol-2-yl]phenyl methyl sulfide | C21H16FN3S | 详情 | 详情 |
合成路线2
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.
| 【1】 Gallagher, T.F.; et al.; Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg Med Chem 1997, 5, 1, 49. |
| 【2】 Gallagher, T.F.; et al.; 2,4,5-Triarylimidazole inhibitors of IL-1 biosynthesis. Bioorg Med Chem Lett 1995, 5, 11, 1171. |
| 【3】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazole derivs. and their use as cytokine inhibitors. EP 0623126; EP 0943616; JP 1995503017; US 5686455; WO 9314081 . |
| 【4】 Adams, J.L.; Gallagher, T.F.; Lee, J.C.; White, J.R. (GlaxoSmithKline plc); Imidazoles for treating cytokine mediated disease. WO 9503297 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 22829 | 4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether | C12H21NOSi | 详情 | 详情 | |
| (VII) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (VIII) | 55083 | 4-{5-(4-fluorophenyl)-2-[4-(methylsulfanyl)phenyl]-1H-imidazol-4-yl}pyridine; 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazol-2-yl]phenyl methyl sulfide | C21H16FN3S | 详情 | 详情 | |
| (IX) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (X) | 29514 | 4-fluoro-N-methoxy-N-methylbenzamide | C9H10FNO2 | 详情 | 详情 | |
| (XI) | 22831 | 2-[[tert-butyl(dimethyl)silyl]oxy]-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C19H24FNO2Si | 详情 | 详情 |