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【结 构 式】

【分子编号】21122

【品名】[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methanol

【CA登记号】

【 分 子 式 】C15H19Cl2NO

【 分 子 量 】300.2274

【元素组成】C 60.01% H 6.38% Cl 23.62% N 4.67% O 5.33%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VII)

The hydrolysis of (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (I) with refluxing 1M HCl gives the corresponding hydroxy acid (II), which is dehydrated with refluxing POCl3 and treated with methanol to the unsaturated methyl ester (III). The reaction of (III) with 3,4-dichlorophenylmagnesium bromide in ether yields a mixture of (1R,2S,3S,5S)- and (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl esters (V) and (VI), respectively. Enantiomer (V) is isomerized to (VI) by treating the mixture with sodium methoxide in refluxing methanol. The reduction of (VI) with LiAlH4 in ethyl ether gives (1R,2R,3S,5S)-[3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]methanol (VII), which is oxidized with oxalyl chloride in dichloromethane, affording aldehyde (VIII). Finally, this compound is treated with methoxyammonium chloride and Na2CO3 in methanol, giving brasofensine as an oil. Several salts of brasofensine were obtained by addition of the acid to a solution of brasofensine in ethanol and recrystallization from either water or isopropanol.

1 Castañer, J.; Graul, A.; Brasofensine Sulfate . Drugs Fut 1999, 24, 2, 128.
2 Moldt, P.; Watjen, F.; Scheel-Kruger, J. (NeuroSearch A/S); Tropane-2-aldoxine derivs. as neurotransmitter reuptake inhibitors. EP 0756596; JP 1997505607; US 5736556; WO 9528401 .
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) 21116 methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate C17H21NO4 详情 详情
(II) 21117 (1R,2R,3S,5S)-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid C9H15NO3 详情 详情
(III) 21118 methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate C10H15NO2 详情 详情
(IV) 10069 Bromo(3,4-dichlorophenyl)magnesium 79175-35-2 C6H3BrCl2Mg 详情 详情
(V) 21120 methyl (1R,2S,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate C16H19Cl2NO2 详情 详情
(VI) 21121 methyl (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate C16H19Cl2NO2 详情 详情
(VII) 21122 [(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methanol C15H19Cl2NO 详情 详情
(VIII) 21123 (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde C15H17Cl2NO 详情 详情
Extended Information