|
【结 构 式】 
|
【分子编号】36624 【品名】bromo(4-chloro-3-methoxyphenyl)magnesium 【CA登记号】 |
【 分 子 式 】C7H6BrClMgO 【 分 子 量 】245.78574 【元素组成】C 34.21% H 2.46% Br 32.51% Cl 14.42% Mg 9.89% O 6.51% |
合成路线1
该中间体在本合成路线中的序号：(X)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 |
合成路线2
该中间体在本合成路线中的序号：(XXXIVb)The reaction of L-homophenylalanine (XXXIX) with methyl chloroformate, NaHCO3 and NaOH gives N-(methoxycarbonyl)-L-homophenylalanine (XXXI), which is treated with SOCl2 yielding the acyl chloride (XXXII). The cyclization of (XXXII) by means of AlCl3 in dichloromethane affords the chiral tetralone (XXXIII), which is condensed with the aryllithium (or arylmagnesium bromide) (XXXIV) to give the intermediate alcohol (XXXV). Elimination of the OH group of (XXXV) by means of Et3SiH and TFA yields the carbamate (XXXVI) as a 3.6:1 mixture of cis- and trans-isomers, which is reduced with LiAlH4 in refluxing THF providing the secondary amine (XXXVII). The alkylation of (XXXVII) with 2-bromoacetaldehyde dimethylacetal (XXV) by means of KF/Al2O3 in refluxing acetonitrile affords the tertiary amine (XXXVIII), also as a mixture of cis- and trans-isomers. The 1:3 trans/cis ratio of isomers in (XXXVIII) is improved up to 50:1 by treatment with t-BuOK in DMSO/DMF providing the desired trans(1R,2S)-isomer (XXVIII) already reported.
| 【1】 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): 2. L-homophenylalanine-based syntheses. Org Process Res Dev 1998, 2, 3, 186. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (XXXIVb) | 36624 | bromo(4-chloro-3-methoxyphenyl)magnesium | C7H6BrClMgO | 详情 | 详情 | |
| (XXXIVa) | 36646 | (4-chloro-3-methoxyphenyl)lithium | C7H6ClLiO | 详情 | 详情 | |
| (XXV) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XXVIII) | 63422 | (2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXXI) | 36643 | (2S)-2-[(methoxycarbonyl)amino]-4-phenylbutyric acid | C12H15NO4 | 详情 | 详情 | |
| (XXXII) | 36644 | methyl (1S)-1-(chlorocarbonyl)-3-phenylpropylcarbamate | C12H14ClNO3 | 详情 | 详情 | |
| (XXXIII) | 36645 | methyl (2S)-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C12H13NO3 | 详情 | 详情 | |
| (XXXV) | 36647 | methyl (1R,2S)-1-(4-chloro-3-methoxyphenyl)-1-hydroxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C19H20ClNO4 | 详情 | 详情 | |
| (XXXVI) | 36648 | methyl (2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C19H20ClNO3 | 详情 | 详情 | |
| (XXXVII) | 36649 | (2S)-1-(4-chloro-3-methoxyphenyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-methylamine | C18H20ClNO | 详情 | 详情 | |
| (XXXVIII) | 36640 | N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine; (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXXIX) | 36642 | (2S)-2-amino-4-phenylbutyric acid | 943-73-7 | C10H13NO2 | 详情 | 详情 |