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【结 构 式】 
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【药物名称】Doramapimod, BIBR-796, BIRB-796 BS, BIRB-0796, BIRB-796 【化学名称】N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-[4-[2-(4-morpholinyl)ethoxy]naphthalen-1-yl]urea 【CA登记号】285983-48-4 【 分 子 式 】C31H37N5O3 【 分 子 量 】527.67224 |
【开发单位】Boehringer Ingelheim (Originator) 【药理作用】Antiarthritic Drugs, Antipsoriatics, DERMATOLOGIC DRUGS, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, p38 Protein Kinase Inhibitors, TNF-alpha Production Inhibitors |
合成路线1
The cyclization of 4-methylphenylhydrazine (I) with pivaloylacetonitrile (II) in refluxing methanol gives the aminopyrazole (III), which is treated with Troc-Cl and NaOH in water/ethyl acetate to yield the carbamate (IV). Finally, this compound is condensed with 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (V) by means of DIEA in hot DMSO to afford the target urea. The intermediate 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (V) is obtained by condensation of 2-(4-morpholinyl)ethanol (VI) with 4-nitro-1-naphthol (VII) by means of NaOH and K2CO3 in hot 1-methyl-2-pyrrolidone to yield the corresponding ether (VIII), which is finally reduced with H2 over Pd/C in methanol.
| 【1】 Zhang, L.-H.; Zhu, L. (Boehringer Ingelheim Pharmaceuticals Inc.); Novel process for synthesis of heteroaryl-substd. urea cpds.. WO 0104115 . |
| 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) | 20387 | 1-(4-methylphenyl)hydrazine | C7H10N2 | 详情 | 详情 | |
| (II) | 44248 | 4,4-dimethyl-3-oxopentanenitrile | 59997-51-2 | C7H11NO | 详情 | 详情 |
| (III) | 55425 | 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-amine; 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylamine | C14H19N3 | 详情 | 详情 | |
| (IV) | 55426 | 2,2,2-trichloroethyl 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylcarbamate | C17H20Cl3N3O2 | 详情 | 详情 | |
| (V) | 55427 | 4-[2-(4-morpholinyl)ethoxy]-1-naphthalenamine; 4-[2-(4-morpholinyl)ethoxy]-1-naphthylamine | C16H20N2O2 | 详情 | 详情 | |
| (VI) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VII) | 55428 | 4-nitro-1-naphthol | C10H7NO3 | 详情 | 详情 | |
| (VIII) | 55429 | 2-(4-morpholinyl)ethyl 4-nitro-1-naphthyl ether; 4-{2-[(4-nitro-1-naphthyl)oxy]ethyl}morpholine | C16H18N2O4 | 详情 | 详情 |
合成路线2
The N-protection of 4-amino-1-naphthol (I) with Boc2O by means of BuLi in THF gives the carbamate (II), which is condensed with 4-(2-chloroethyl)morpholine (III) by means of K2CO3 in hot acetonitrile, yielding the corresponding aryl ether (IV). The deprotection of the amino group of (IV) with HCl in dioxane affords the naphthylamine (V), which is finally condensed with 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazole-5-amine (VI) by means of COCl2 in toluene/dichloromethane and aq. NaHCO3 to provide the target urea. The intermediate 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazole-5-amine (VI) is obtained by cyclization of 4-methylphenylhydrazine (VII) with 4,4-dimethyl-3-oxopentanenitrile (VIII) by means of HCl in refluxing ethanol.
| 【1】 Regan, J.R.; Zhang, L.-H.; Cirillo, P.F.; Hickey, E.R.; Gilmore, T.A. (Boehringer Ingelheim Pharmaceuticals Inc.); Aromatic heterocyclic cpds. as antiinflammatory agents. EP 1147104; US 6319921; WO 0043384 . |
| 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) | 55430 | 4-Amino-1-naphthol | C10H9NO | 详情 | 详情 | |
| (II) | 55431 | tert-butyl 4-hydroxy-1-naphthylcarbamate | C15H17NO3 | 详情 | 详情 | |
| (III) | 27355 | 4-(2-chloroethyl)morpholine | 3647-69-6 | C6H12ClNO | 详情 | 详情 |
| (IV) | 55432 | tert-butyl 4-[2-(4-morpholinyl)ethoxy]-1-naphthylcarbamate | C21H28N2O4 | 详情 | 详情 | |
| (V) | 55427 | 4-[2-(4-morpholinyl)ethoxy]-1-naphthalenamine; 4-[2-(4-morpholinyl)ethoxy]-1-naphthylamine | C16H20N2O2 | 详情 | 详情 | |
| (VI) | 55425 | 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-amine; 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylamine | C14H19N3 | 详情 | 详情 | |
| (VII) | 20387 | 1-(4-methylphenyl)hydrazine | C7H10N2 | 详情 | 详情 | |
| (VIII) | 44248 | 4,4-dimethyl-3-oxopentanenitrile | 59997-51-2 | C7H11NO | 详情 | 详情 |
合成路线3
The reaction of 4-amino-1-naphthol (I) with Boc2O in THF gives the carbamate (II), which is condensed with 4-(2-chloroethyl)morpholine (III) by means of K2CO3 in hot acetonitrile to yield ether (IV). The hydrolysis of the carbamate group of (IV) by means of HCl in dioxane affords the naphthylamine (V), which is finally condensed with 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (VI) and phosgene (VII) in THF to provide the target urea. The intermediates 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (VI) and phosgene (VII) are obtained by cyclization of 4-methylphenylhydrazine (VIII) with 4,4-dimethyl-3-oxopentanenitrile (IX) in refluxing toluene or by means of HCl in refluxing ethanol.
| 【1】 Regan, J.; et al.; Pyrazole urea-based inhibtitors of p38 MAP kinase: From lead compound to clinical candidate. J Med Chem 2002, 45, 14, 2994. |
| 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) | 55430 | 4-Amino-1-naphthol | C10H9NO | 详情 | 详情 | |
| (II) | 55431 | tert-butyl 4-hydroxy-1-naphthylcarbamate | C15H17NO3 | 详情 | 详情 | |
| (III) | 27355 | 4-(2-chloroethyl)morpholine | 3647-69-6 | C6H12ClNO | 详情 | 详情 |
| (IV) | 55432 | tert-butyl 4-[2-(4-morpholinyl)ethoxy]-1-naphthylcarbamate | C21H28N2O4 | 详情 | 详情 | |
| (V) | 55427 | 4-[2-(4-morpholinyl)ethoxy]-1-naphthalenamine; 4-[2-(4-morpholinyl)ethoxy]-1-naphthylamine | C16H20N2O2 | 详情 | 详情 | |
| (VI) | 55425 | 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-amine; 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylamine | C14H19N3 | 详情 | 详情 | |
| (VII) | 56933 | carbonic dichloride | CCl2O | 详情 | 详情 | |
| (VIII) | 20387 | 1-(4-methylphenyl)hydrazine | C7H10N2 | 详情 | 详情 | |
| (IX) | 44248 | 4,4-dimethyl-3-oxopentanenitrile | 59997-51-2 | C7H11NO | 详情 | 详情 |