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【结 构 式】 
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【分子编号】20387 【品名】1-(4-methylphenyl)hydrazine 【CA登记号】 |
【 分 子 式 】C7H10N2 【 分 子 量 】122.16988 【元素组成】C 68.82% H 8.25% N 22.93% |
合成路线1
该中间体在本合成路线中的序号：(I)Stobadine is obtained in a 3-step synthesis including the resolution of one of the enantiomers (V) Treatment of p-tolylhydrazine (I) with N-methyl-4-piperidone (II) yields 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (III). After catalytic hydrogenation of (III), the (±)-cis isomer (IV) is obtained. In the following phase the resolution of (IV) is carried out with (+)-dibenzyoltartaric acid. After several recrystallizations, the optically pure (-)-cis-enantiomer is obtained. Treatment of the optically pure base with hydrochloric or another acid yields the corresponding salts.
| 【1】 Benes, L.; Stolc, S.; STOBADINE. Drugs Fut 1989, 14, 2, 135. |
| 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) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (III) | 20389 | 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole | C13H16N2 | 详情 | 详情 | |
| (IV) | 20390 | (4aR,9bS)-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole | C13H18N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The title hydrazide was prepared from 4-chlorobenzoic acid (I) via conversion to the corresponding acid chloride (II), followed by condensation with 4-methylphenylhydrazine (III).
| 【1】 Sui, Z.; et al.; 1,3-Diarylcycloalkano-[1,2-d]-pyrazoles and diphenyl hydrazides as selective inhibitors of cyclooxygenase-2. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 202. |
| 【2】 Ferro, M.P.; Sui, Z.; Guan, J.; et al.; 1,3-Diarylcycloalkanopyrazoles and diphenyl hydrazides as selective inhibitors of cyclooxygenase-2. Bioorg Med Chem Lett 2000, 10, 6, 601. |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(VII)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5
该中间体在本合成路线中的序号：(VIII)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 |