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【结 构 式】 
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【药物名称】 【化学名称】2-tert-Butyl-9-fluoro-6,7-dihydro-3H-benzo[h]imidazo[4,5-f]isoquinolin-7-one 【CA登记号】 【 分 子 式 】C18H16FN3O 【 分 子 量 】309.34612 |
【开发单位】Merck & Co. (Originator) 【药理作用】ONCOLYTIC DRUGS, Jak1 Inhibitors, Jak2 Inhibitors, Jak3 Inhibitors, Tyk2 Inhibitors |
合成路线1
Condensation of 2-fluoro-4-methylpyridine (I) with ethyl 4-fluorobenzoate (II) by means of sodium bis(trimethylsilyl)amide provides the diaryl ethanone (III). Subsequent nitrosation of ketone (III) with tert-butyl nitrite under acidic conditions furnishes oxime (IV). Cyclization of keto oxime (IV) with trimethylacetaldehyde (V) in the presence of ammonium acetate in boiling AcOH proceeds with concomitant hydrolysis of the fluoro group to produce the N-hydroxy imidazole (VI). Reduction of (VI) employing TiCl3 gives imidazole (VII). Finally, the photochemical cyclization of diarylimidazole (VII) leads to the target tetracyclic compound (1, 2).
| 【1】 Thompson, J.E.; Cubbon, R.M.; Cummings, R.T.; Wicker, L.S.; Franksun, R.; Cunningham, B.R.; Cameron, P.M.; Meinke, P.T.; Liverton, N.; Weng, Y.; DeMartino, J.A.; Photochemical preparation of a pyridone containing tetracycle: A jak protein kinase inhibitor. Bioorg Med Chem Lett 2002, 12, 8, 1219. |
| 【2】 Sinclair, P.J.; Goulet, J.L.; Hong, X.; Thompson, J.E.; Cubbon, R.M.; Cummings, R.T. (Merck & Co., Inc.); Benzimidazo[4,5-f]isoquinolinone derivs.. WO 0311285 . |
| 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) | 18296 | 2-Fluoro-4-methylpyridine | 461-87-0 | C6H6FN | 详情 | 详情 |
| (II) | 22830 | ethyl 4-fluorobenzoate | 451-46-7 | C9H9FO2 | 详情 | 详情 |
| (III) | 63664 | 1-(4-fluorophenyl)-2-(2-fluoro-4-pyridinyl)-1-ethanone | C13H9F2NO | 详情 | 详情 | |
| (IV) | 63665 | 1-(4-fluorophenyl)-2-(2-fluoro-4-pyridinyl)-1,2-ethanedione 2-oxime | C13H8F2N2O2 | 详情 | 详情 | |
| (V) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VI) | 63666 | 4-[2-(tert-butyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]-2(1H)-pyridinone | C18H18FN3O2 | 详情 | 详情 | |
| (VII) | 63667 | 4-[2-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2(1H)-pyridinone | C18H18FN3O | 详情 | 详情 |