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【结 构 式】

【药物名称】SK&F-38393

【化学名称】2,3,4,5,-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
　　　　　　2,3,4,5-Tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol

【CA登记号】20012-10-6 (HBr), 62717-42-4 (HCl), 62751-59-1 (R-(+)-isomer)

【 分 子 式 】C16H17NO2

【 分 子 量 】255.31939

【开发单位】GlaxoSmithKline (Originator), National Institute on Drug Abuse (Codevelopment)

【药理作用】Treatment of Cocaine Dependency, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, 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1

The condensation of 3,4-dimethoxyphenethylamine (I) with styrene oxide (II) by heating at 100 C gives N-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenyl-2-hydroxyethylamine (III), which can be cyclized with H2SO4 in refluxing trifluoroacetic acid yielding 2,3,4,5-tetrahydro-7,8-dimethoxy-1-phenyl-1H-3-benzazepine (IV). Finally, intermediate (IV) is demethylated with refluxing 48% HBr (III) can also by cyclized and demethylated simultaneously by refluxing with 48% HBr.

参考文献 中间体
【1】 Kaiser, C.; et al.; DE 2629887 .
【2】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645.
【3】 Castaner, J.; Hillier, K.; SKF-38393. Drugs Fut 1980, 5, 10, 507.
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) 10098 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine 120-20-7 C10H15NO2 详情 详情
(II) 23017 2-phenyloxirane 96-09-3 C8H8O 详情 详情
(III) 39206 2-[(3,4-dimethoxyphenethyl)amino]-1-phenyl-1-ethanol C18H23NO3 详情 详情
(IV) 39207 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C18H21NO2 详情 详情

合成路线2

The bromination of labeled acetophenone (I) with Br2 and AlCl3 gives the phenacyl bromide (II), which is reduced with NaBH4, yielding 2-bromo-1-phenylethanol (III). The condensation of (III) with N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]amine (IV) affords the tertiary amine (V), which is debenzylated by hydrogenolysis with H2 over Pd/C to provide the substituted ethanolamine (VI). Finally, this compound is cyclized and demethylated by treatment with 48% HBr to provide the target benzazepine.

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】 Bass, L.S.; Dandridge, P.A.; Setler, P.E.; Sarau, H.M.; Garvey, E.; Clardy, J.; Hanhn, R.A.; Kaiser, C.; Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine. J Med Chem 1982, 25, 6, 697-703.
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) 10317 Acetophenone 98-86-2 C8H8O 详情 详情
(I) 44572 acetophenone C8H8O 详情 详情
(II) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(II) 44573 2-bromo-1-phenyl-1-ethanone C8H7BrO 详情 详情
(III) 44060 2-bromo-1-phenyl-1-ethanol C8H9BrO 详情 详情
(III) 44632 2-bromo-1-phenyl-1-ethanol C8H9BrO 详情 详情
(IV) 44061 N-benzyl-2-(3,4-dimethoxyphenyl)-1-ethanamine; N-benzyl-N-(3,4-dimethoxyphenethyl)amine C17H21NO2 详情 详情
(V) 44062 2-[benzyl(3,4-dimethoxyphenethyl)amino]-1-phenyl-1-ethanol C25H29NO3 详情 详情
(V) 44633 2-[benzyl(3,4-dimethoxyphenethyl)amino]-1-phenyl-1-ethanol C25H29NO3 详情 详情
(VI) 39206 2-[(3,4-dimethoxyphenethyl)amino]-1-phenyl-1-ethanol C18H23NO3 详情 详情
(VI) 44634 2-[(3,4-dimethoxyphenethyl)amino]-1-phenyl-1-ethanol C18H23NO3 详情 详情

合成路线3

The optical resolution of the racemic 7,8-dimethoxy-3-methyl-1-phenyl-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 CN-Br to yield 7,8-dimethoxy-1(S)-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with MsOH and methionine. An earlier alternative route to demethylation of (III) involves its conversion to the N-benzyl derivative (V) with benzyl bromide (IV), followed by demethylation with BBr3, yielding (VI), and final debenzylation with H2 over Pd/C.

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】 Bass, L.S.; Dandridge, P.A.; Setler, P.E.; Sarau, H.M.; Garvey, E.; Clardy, J.; Hanhn, R.A.; Kaiser, C.; Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine. J Med Chem 1982, 25, 6, 697-703.
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) 44063 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C19H23NO2 详情 详情
(II) 44064 (1S)-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether; (1S)-7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine C19H23NO2 详情 详情
(III) 44065 (1S)-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (1S)-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C18H21NO2 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 44066 (1S)-3-benzyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether; (1S)-3-benzyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine C25H27NO2 详情 详情
(VI) 44067 (1S)-3-benzyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol C23H23NO2 详情 详情

合成路线4

The optical resolution of the racemic 7,8-dimethoxy-3-methyl-1-phenyl-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 CN-Br to yield 7,8-dimethoxy-1(R)-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with Ms-OH and methionine. An earlier alternative route to demethylation of (III) involves its conversion to the N-benzyl derivative (V) with benzyl bromide (IV), followed by demethylation with BBr3, yielding (VI), and final debenzylation with H2 over Pd/C.

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】 Bass, L.S.; Dandridge, P.A.; Setler, P.E.; Sarau, H.M.; Garvey, E.; Clardy, J.; Hanhn, R.A.; Kaiser, C.; Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine. J Med Chem 1982, 25, 6, 697-703.
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) 44063 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C19H23NO2 详情 详情
(II) 44068 (1R)-7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (1R)-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C19H23NO2 详情 详情
(III) 44069 (1R)-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (1R)-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C18H21NO2 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 44070 (1R)-3-benzyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (1R)-3-benzyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether C25H27NO2 详情 详情
(VI) 44071 (1R)-3-benzyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol C23H23NO2 详情 详情
Extended Information