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【结 构 式】 
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【分子编号】35450 【品名】3,3-dibromo-1,1,1-trifluoroacetone 【CA登记号】431-67-4 |
【 分 子 式 】C3HBr2F3O 【 分 子 量 】269.8435496 【元素组成】C 13.35% H 0.37% Br 59.22% F 21.12% O 5.93% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 3-cyanobenzaldehyde (I) with trifluoroacetone (II) in piperidine gives 3-(4,4,4-trifluoro-3-oxo-2-butenyl)benzonitrile (III). The condensation of cyclohexane-1,3-dione (IV) with 1(R)-phenylethylamine (V) in refluxing toluene or THF yields the secondary enamine (VI), which is condensed with benzonitrile (III) by means of Tms-Cl in hot acetonitrile to afford the chiral adduct (VII). The cyclization of (VII) by means of NH3 in hot acetonitrile provides the chiral octahydroquinolone (VIII), which is finally dehydrated by means of TFA, MsOH, TsOH or HCl in refluxing acetonitrile to give the target hexahydroquinolone.
| 【1】 Patel, I.; Hopes, P. (AstraZeneca AB); Process for synthesis of alpha,beta-unsaturated ketones. WO 0210103 . |
| 【2】 Patel, I.; Ashworth, I.; Levin, D. (AstraZeneca AB); Process for asymmetric synthesis of substd. 1,4-dihydropyridines. WO 0210134 . |
| 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) | 13245 | 3-Formylbenzonitrile; 3-Cyanobenzaldehyde | 24964-64-5 | C8H5NO | 详情 | 详情 |
| (II) | 35450 | 3,3-dibromo-1,1,1-trifluoroacetone | 431-67-4 | C3HBr2F3O | 详情 | 详情 |
| (III) | 62031 | 3-[(E)-4,4,4-trifluoro-3-oxo-1-butenyl]benzonitrile | C11H6F3NO | 详情 | 详情 | |
| (IV) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
| (V) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (VI) | 62032 | 3-{[(1R)-1-phenylethyl]amino}-2-cyclohexen-1-one | C14H17NO | 详情 | 详情 | |
| (VII) | 62033 | 3-[(1S)-4,4-dimethyl-3-oxo-1-(6-oxo-2-{[(1R)-1-phenylethyl]amino}-1-cyclohexen-1-yl)pentyl]benzonitrile | C28H32N2O2 | 详情 | 详情 | |
| (VIII) | 62034 | 3-[(4S)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-4-quinolinyl]benzonitrile | C17H15F3N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The bromination of 1,1,1-trifluoroacetone (I) according to McBee and Burton gives 3,3-dibromo-1,1,1-trifluoroacetone (II), which is hydrolyzed with aqueous NaOAc to the glyoxal (III). The cyclization of (III) with benzaldehyde (IV) and ammonia in methanol yields 2-phenyl-4-(trifluoromethyl)-1H-imidazole (V), which is converted into the carbonitrile (VI) by reaction with hot aqueous ammonium hydroxide. The reduction of (VI) with diisobutylaluminum hydride in THF affords the carbaldehyde (VII), which is finally condensed with N-tert-butylhydroxylamine (VIII) by means of NaHCO3 in hot ethanol.
| 【1】 Dhainaut, A.; et al.; Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones. J Med Chem 2000, 43, 11, 2165. |
| 【2】 Dhainaut, A.; Lestage, P.; Lockhart, B.; Tizot, A.; Goldstein, S. (ADIR et Cie.); Nitrone derivs., process for their preparation and pharmaceutical compsns. containing them. CA 2274621; EP 0967207; FR 2780404; JP 2000026428; US 6034250 . |
| 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) | 35449 | 1,1,1-trifluoroacetone | 421-50-1 | C3H3F3O | 详情 | 详情 |
| (II) | 35450 | 3,3-dibromo-1,1,1-trifluoroacetone | 431-67-4 | C3HBr2F3O | 详情 | 详情 |
| (III) | 35451 | 3,3,3-trifluoro-2-oxopropanal | C3HF3O2 | 详情 | 详情 | |
| (IV) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (V) | 35452 | 2-phenyl-4-(trifluoromethyl)-1H-imidazole | C10H7F3N2 | 详情 | 详情 | |
| (VI) | 35435 | (1R)-2-[12-[(2R)-2-(benzoyloxy)propyl]-2,4,6,7,9,11-hexamethoxy-3,10-dioxo-3,10-dihydro-1-perylenyl]-1-methylethyl benzoate | C46H42O12 | 详情 | 详情 | |
| (VII) | 35454 | 2-phenyl-1H-imidazole-4-carbaldehyde | C10H8N2O | 详情 | 详情 | |
| (VIII) | 35455 | N-(tert-butyl)hydroxylamine; 2-(hydroxyamino)-2-methylpropane | C4H11NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)1,1-Dibromo-3,3,3-trifluoroacetone (I) is treated with a hot aqueous solution of sodium acetate, and subsequently condensed with 4-(trifluoromethyl)benzaldehyde (II) in the presence of ammonium hydroxide to furnish the trifluoromethyl imidazole (III). The imidazole trifluoromethyl group of (III) is then selectively converted to nitrile (IV) upon heating with a methanolic solution of ammonium hydroxide. Reduction of the cyano group of (IV) employing DIBAL in cold THF leads to aldehyde (V). This is finally converted to the target nitrone by condensation with N-tert-butyl hydroxylamine.
| 【1】 Dhainaut, A.; et al.; Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones. J Med Chem 2000, 43, 11, 2165. |
| 【2】 Dhainaut, A.; Lestage, P.; Lockhart, B.; Tizot, A.; Goldstein, S. (ADIR et Cie.); Nitrone derivs., process for their preparation and pharmaceutical compsns. containing them. CA 2274621; EP 0967207; FR 2780404; JP 2000026428; US 6034250 . |
| 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) | 35450 | 3,3-dibromo-1,1,1-trifluoroacetone | 431-67-4 | C3HBr2F3O | 详情 | 详情 |
| (II) | 13380 | 4-(Trifluoromethyl)benzaldehyde; alpha,alpha,alpha-Trifluoro-p-tolualdehyde | 455-19-6 | C8H5F3O | 详情 | 详情 |
| (III) | 57671 | 4-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]-1H-imidazole | C11H6F6N2 | 详情 | 详情 | |
| (IV) | 57672 | 2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carbonitrile | C11H6F3N3 | 详情 | 详情 | |
| (V) | 57673 | 2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carbaldehyde | C11H7F3N2O | 详情 | 详情 |