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【结 构 式】

【药物名称】Fenoldopam mesilate, SK&F-82526J, Corlopam

【化学名称】6-Chloro-7,8-dihydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine methanesulfonate
　　　　　　6-Chloro-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol methanesulfonate

【CA登记号】67227-57-0, 67287-54-1 (HBr salt), 67227-56-9 (racemic; free base)

【 分 子 式 】C17H20ClNO6S

【 分 子 量 】401.86905

【开发单位】GlaxoSmithKline (Originator), Abbott (Not Determined), Elan (Licensee), Neurex (Licensee)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Dopamine D1 Agonists

合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

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.

参考文献 中间体
【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

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.

参考文献 中间体
【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

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.

参考文献 中间体
【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

合成路线4

The optical resolution of the racemic 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (I) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (R)-isomer (II), which is N-demethylated by means of BrCN to yield 6-chloro-7,8-dimethoxy-1(R)-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with BBr3. The optical resolution can also be performed by treatment of racemic (III) with (+)- or (-)-dibenzoyltartaric acid.

参考文献 中间体
【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】 Webb, R.L.; Horodniak, J.W.; Dandridge, P.A.; Sarau, H.M.; Setler, P.E.; Weinstock, J.; Ackerman, D.M.; Kaiser, C.; Matz, E.D.; Stereoselectivity of some new dopamine receptor agonists. Acta Pharm Suec 1983, 2, 132-150.
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) 44055 4-(6-chloro-7,8-dimethoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether; 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine C20H24ClNO3 详情 详情
(II) 44056 (1R)-6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 4-[(1R)-6-chloro-7,8-dimethoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]phenyl methyl ether C20H24ClNO3 详情 详情
(III) 44057 (1R)-6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 4-[(1R)-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]phenyl methyl ether C19H22ClNO3 详情 详情

合成路线5

The optical resolution of the racemic 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (I) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (S)-isomer (II), which is N-demethylated by means of BrCN to yield 6-chloro-7,8-dimethoxy-1(S)-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with BBr3. The optical resolution can also be performed by treatment of racemic (III) with (+)- or (-)-dibenzoyltartaric acid.

参考文献 中间体
【1】 Webb, R.L.; Horodniak, J.W.; Dandridge, P.A.; Sarau, H.M.; Setler, P.E.; Weinstock, J.; Ackerman, D.M.; Kaiser, C.; Matz, E.D.; Stereoselectivity of some new dopamine receptor agonists. Acta Pharm Suec 1983, 2, 132-150.
【2】 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) 44055 4-(6-chloro-7,8-dimethoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether; 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine C20H24ClNO3 详情 详情
(II) 44058 4-[(1S)-6-chloro-7,8-dimethoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]phenyl methyl ether; (1S)-6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine C20H24ClNO3 详情 详情
(III) 44059 (1S)-6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 4-[(1S)-6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]phenyl methyl ether C19H22ClNO3 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)