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【结 构 式】 
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【分子编号】31702 【品名】2-[(2-chloro-3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-ethanol 【CA登记号】 |
【 分 子 式 】C19H24ClNO4 【 分 子 量 】365.8566 【元素组成】C 62.38% H 6.61% Cl 9.69% N 3.83% O 17.49% |
合成路线1
该中间体在本合成路线中的序号：(III)The condensation of 2-chloro-3,4-dimethoxyphenylethylamine (I) with 4-methoxystyrene oxide (II) in refluxing THF gives the hydroxy phenylethylamine (III). The yield of this reaction is only 19%. In a better sequence (I) is heated with methyl 4-methoxymandelate (IV) to give the mandelamide (V), which is then reduced without purification by B2H6 in THF to give (III). The latter is cyclized by treatment with trifluoroacetic acid - sulfuric acid yielding 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-(1H)-3-benzazepine (VI). Finally, this compound is demethylated by treatment with BBr3 in methylene chloride and treated with methanesulfonic acid.
| 【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645. |
| 【2】 Weinstock, J.; Method for 6-bromination of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds. BE 0860774; DD 2751258; DE 133563; FR 2371430; JP 53063335; NL 7712567; US 4160765; ZA 7705910 . |
| 【3】 Kuo, G.Y.; Holden, K.G.; Tobia, A.J.; Hahn, R.A.; Sarau, H.M.; Ladd, D.L.; Ridley, P.T.; Wilson, J.W.; Setler, P.E.; Bush, C.K.; Yim, N.C.F.; Pfieffer, F.R.; Wardell, J.R.; Weinstock, J.; Separation of potent central and renal dopamine agonist activity in substituted 6-chloro-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepines. J Med Chem 1980, 23, 9, 973-975. |
| 【4】 Weinstock, J. (SmithKline Beecham plc); Benz-tetrasubstituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines. EP 0004794; JP 54135787; JP 63065663B; US 4171359 . |
| 【5】 Castaner, J.; Serradell, M.N.; Blancafort, P.; SKF-82,526-J. Drugs Fut 1982, 7, 1, 32. |
| 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) | 42037 | 2-chloro-3,4-dimethoxyphenethylamine; 2-(2-chloro-3,4-dimethoxyphenyl)-1-ethanamine | 67287-36-9 | C10H14ClNO2 | 详情 | 详情 |
| (II) | 31703 | Methyl 4-(2-oxiranyl)phenyl ether; 4-Methoxystyrene oxide; 2-(4-Methoxyphenyl)oxirane | C9H10O2 | 详情 | 详情 | |
| (III) | 31702 | 2-[(2-chloro-3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-ethanol | C19H24ClNO4 | 详情 | 详情 | |
| (IV) | 31700 | Methyl 2-hydroxy-2-(4-methoxyphenyl)acetate; Methyl 4-methoxymandelate | C10H12O4 | 详情 | 详情 | |
| (V) | 31701 | N-(2-chloro-3,4-dimethoxyphenethyl)-2-hydroxy-2-(4-methoxyphenyl)acetamide | C19H22ClNO5 | 详情 | 详情 | |
| (VI) | 31704 | 4-(6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether; 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine | C19H22ClNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The bromination of 4-methoxystyrene (I) with Br2 gives the alpha,beta-dibromo derivative (II), which by selective debromination with potassium tert-butoxide yields the tert-butyl ether (III). The condensation of (III) with 2-(2-chloro-3,4-dimethoxyphenyl)ethylamine (IV) affords the secondary amine (V), which is deprotected with H2SO4 to provide the substituted ethanolamine (VI). The cyclization of (VI) by means of Ms-OH and trifluoroacetic acid gives the 3-benzazepine (VII), which is finally demethylated with BBr3 and treated with methanesulfonic acid to afford the target mesylate.
| 【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645. |
| 【2】 US 4321195 . |
| 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) | 44049 | 1-methoxy-4-vinylbenzene; methyl 4-vinylphenyl ether | 637-69-4 | C9H10O | 详情 | 详情 |
| (II) | 44050 | 4-(1,2-dibromoethyl)phenyl methyl ether; 1-(1,2-dibromoethyl)-4-methoxybenzene | C9H10Br2O | 详情 | 详情 | |
| (III) | 44051 | 4-[2-bromo-1-(tert-butoxy)ethyl]phenyl methyl ether; 1-[2-bromo-1-(tert-butoxy)ethyl]-4-methoxybenzene | C13H19BrO2 | 详情 | 详情 | |
| (IV) | 42037 | 2-chloro-3,4-dimethoxyphenethylamine; 2-(2-chloro-3,4-dimethoxyphenyl)-1-ethanamine | 67287-36-9 | C10H14ClNO2 | 详情 | 详情 |
| (V) | 44052 | 2-(tert-butoxy)-N-(2-chloro-3,4-dimethoxyphenethyl)-2-(4-methoxyphenyl)-1-ethanamine; N-[2-(tert-butoxy)-2-(4-methoxyphenyl)ethyl]-N-(2-chloro-3,4-dimethoxyphenethyl)amine | C23H32ClNO4 | 详情 | 详情 | |
| (VI) | 31702 | 2-[(2-chloro-3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-ethanol | C19H24ClNO4 | 详情 | 详情 | |
| (VII) | 31704 | 4-(6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether; 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine | C19H22ClNO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The bromination of labeled 4'-methoxyacetophenone (I) with CuBr2 gives 4'-methoxyphenacyl bromide (II), which is reduced with NaBH4, yielding the carbinol (III). The protection of (III) with DHP affords the tetrahydropyranyl ether (IV), which is condensed with 2-(2-chloro-3,4-dimethoxyphenyl)ethylamine (V) and acidified to provide the aminoalcohol (VI). The cyclization of (VI) with MsOH and trifluoroacetic acid furnishes labeled 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (VII), which is finally demethylated with BBr3 and MsOH.
| 【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645. |
| 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) | 11041 | 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone | 100-06-1 | C9H10O2 | 详情 | 详情 |
| (I) | 44616 | 1-(4-methoxyphenyl)-1-ethanone | C9H10O2 | 详情 | 详情 | |
| (II) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (II) | 44617 | 2-bromo-1-(4-methoxyphenyl)-1-ethanone | C9H9BrO2 | 详情 | 详情 | |
| (III) | 44053 | 2-bromo-1-(4-methoxyphenyl)-1-ethanol | C9H11BrO2 | 详情 | 详情 | |
| (III) | 44618 | 2-bromo-1-(4-methoxyphenyl)-1-ethanol | C9H11BrO2 | 详情 | 详情 | |
| (IV) | 44054 | 2-bromo-1-(4-methoxyphenyl)ethyl tetrahydro-2H-pyran-2-yl ether; 2-[2-bromo-1-(4-methoxyphenyl)ethoxy]tetrahydro-2H-pyran | C14H19BrO3 | 详情 | 详情 | |
| (IV) | 44619 | 2-bromo-1-(4-methoxyphenyl)ethyl tetrahydro-2H-pyran-2-yl ether; 2-[2-bromo-1-(4-methoxyphenyl)ethoxy]tetrahydro-2H-pyran | C14H19BrO3 | 详情 | 详情 | |
| (V) | 42037 | 2-chloro-3,4-dimethoxyphenethylamine; 2-(2-chloro-3,4-dimethoxyphenyl)-1-ethanamine | 67287-36-9 | C10H14ClNO2 | 详情 | 详情 |
| (VI) | 31702 | 2-[(2-chloro-3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-ethanol | C19H24ClNO4 | 详情 | 详情 | |
| (VI) | 44620 | 2-[(2-chloro-3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-ethanol | C19H24ClNO4 | 详情 | 详情 | |
| (VII) | 31704 | 4-(6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether; 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine | C19H22ClNO3 | 详情 | 详情 | |
| (VII) | 44621 | 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 4-(6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether | C19H22ClNO3 | 详情 | 详情 |