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【结 构 式】 
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【分子编号】36625 【品名】4-(4-chloro-3-methoxyphenyl)-1,2-dihydronaphthalene; 2-chloro-5-(3,4-dihydro-1-naphthalenyl)phenyl methyl ether 【CA登记号】 |
【 分 子 式 】C17H15ClO 【 分 子 量 】270.7582 【元素组成】C 75.41% H 5.58% Cl 13.09% O 5.91% |
合成路线1
该中间体在本合成路线中的序号：(XI)The Grignard condensation of 1-tetralone (IX) with 4-chloro-3-methoxyphenylmagnesium bromide (X) in THF followed by a treatment with TsOH gives 4-(4-chloro-3-methoxyphenyl)-1,2-dihydronaphthalene (XI), which is oxidized with oxone and TsOH yielding the 2-tetralone (XII). The condensation of (XII) with 2-aminoacetaldehyde dimethylacetal (XIII) in toluene affords the enamine (XIV), which is reduced with BH3 / t-Bu-NH2 and AcOH in dichloromethane to give a 9:1 mixture of cis (XV) and trans (XVI) isomers that is epimerized with t-BuOK in DMSO/DMF to a 15:85 mixture from which the desired trans-diastereomer (XVI) is isolated. The cyclization of (XVI) with CH3SO3H in dichloromethane affords the tetracyclic compound (XVII), which is hydrogenated with BH3 / t-Bu-NH2 to provide the intermediate (XVIII). Finally, this compound is methylated with formaldehyde and formic acid to obtain the previously reported rac-(VIII) compound.
| 【1】 Berger, J.G.; Clader, J.W.; Chang, W.K.; Gold, E.H. (Schering Corp.); Fused benzazepines. EP 0230270; EP 0254737; JP 1988502348; WO 8704430 . |
| 【2】 Draper, R.W.; et al.; Novel stereoselective syntheses of the fused benzazepine dopamine D1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5-H-benzo[d]naphth[2,1-b]azepin-12-ol (Sch 39166): 1. Aziridinium salt based syntheses. Org Process Res Dev 1998, 2, 3, 175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 31779 | (3aS,9bR)-12-chloro-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine; (3aS,9bR)-12-chloro-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether | C20H22ClNO | 详情 | 详情 | |
| (IX) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (X) | 36624 | bromo(4-chloro-3-methoxyphenyl)magnesium | C7H6BrClMgO | 详情 | 详情 | |
| (XI) | 36625 | 4-(4-chloro-3-methoxyphenyl)-1,2-dihydronaphthalene; 2-chloro-5-(3,4-dihydro-1-naphthalenyl)phenyl methyl ether | C17H15ClO | 详情 | 详情 | |
| (XII) | 36626 | 1-(4-chloro-3-methoxyphenyl)-3,4-dihydro-2(1H)-naphthalenone | C17H15ClO2 | 详情 | 详情 | |
| (XIII) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XIV) | 36627 | N-[1-(4-chloro-3-methoxyphenyl)-3,4-dihydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine; 1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2-naphthalenamine | C21H24ClNO3 | 详情 | 详情 | |
| (XV) | 36628 | N-[(1R,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine; (1R,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-2-naphthalenamine | C21H26ClNO3 | 详情 | 详情 | |
| (XVI) | 36629 | (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine | C21H26ClNO3 | 详情 | 详情 | |
| (XVII) | 36630 | (3aS,9bR)-12-chloro-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepine | C19H18ClNO | 详情 | 详情 | |
| (XVIII) | 36631 | (3aS,9bR)-12-chloro-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine | C19H20ClNO | 详情 | 详情 |