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【结 构 式】

【分子编号】36486

【品名】(4aS,6R,8aS)-1-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol

【CA登记号】

【 分 子 式 】C16H18BrNO3

【 分 子 量 】352.22786

【元素组成】C 54.56% H 5.15% Br 22.69% N 3.98% O 13.63%

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:(VIII)

The bromination of 3,4-dimethoxybenzaldehyde (I) with Br2 in acetic acid gives 2-bromo-4,5-dimethoxybenzaldehyde (II), which is selectively demethylated with H2SO4 yielding 2-bromo-5-hydroxy-4-methoxybenzaldehyde (III). The reductocondensation of (III) with 2-(4-hydroxyphenyl)ethylamine (IV) by means of NaBH4 affords the secondary amine (V), which is formylated with ethyl formate in dioxane/DMF giving the formamide (VI). The cyclization of (VI) by means of potassium hexacyanoferrate (III) and K2CO3 in hot toluene yields racemic N-formylbromonarwedine (+/-)(VII), which is reduced with lithium tri-tert-butoxyaluminum hydride furnishing a mixture of N-demethylbromogalanhamine (+/-)(VIII) and N-demethylepibromogalanthamine (+/-)(IX). After chromatographic separation of the two racemic epimers, resolution of racemic (+/-)(VIII) is carried out employing di-p-toluoyl tartaric acid to afford the required levo isomer. Alkylation of (-)(VIII) with 1-(3-chloropropyl)piperidine (X) gives (XI), which is finally converted to the title compound by reductive debromination in the presence of Zn and CaCl2.

1 Kuenburg, B.; et al.; Development of a pilot scale process for the anti-Alzheimer drug (-)-galanthamine using large-scale phenolic oxidative coupling and crystallisation-induced chiral conversion. Org Process Res Dev 1999, 3, 6, 425.
2 Kuenburg, B.; Frohlich, J.; Jordis, U.; Czollner, L. (Sanochemia Pharmazeutika AG); New benzazepine derivs., medicaments containing the same and their use to prepare medicaments. WO 9740049 .
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) 18304 3,4-Dimethoxybenzaldehyde; Veratraldehyde 120-14-9 C9H10O3 详情 详情
(II) 36481 2-bromo-4,5-dimethoxybenzaldehyde 5392-10-9 C9H9BrO3 详情 详情
(III) 36482 2-bromo-5-hydroxy-4-methoxybenzaldehyde 2973-59-3 C8H7BrO3 详情 详情
(IV) 19988 4-(2-Aminoethyl)phenol; Tyramine 51-67-2 C8H11NO 详情 详情
(V) 36483 4-bromo-5-[[(4-hydroxyphenethyl)amino]methyl]-2-methoxyphenol C16H18BrNO3 详情 详情
(VI) 36484 2-bromo-5-hydroxy-4-methoxybenzyl(4-hydroxyphenethyl)formamide C17H18BrNO4 详情 详情
(VII) 36485 1-bromo-3-methoxy-6-oxo-3a,5,6,9,10,12b-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carbaldehyde C17H18BrNO4 详情 详情
(VIII) 36486 (4aS,6R,8aS)-1-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol C16H18BrNO3 详情 详情
(IX) 36487 (4aS,6S,8aS)-1-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol C16H18BrNO3 详情 详情
(X) 36488 1-(3-chloropropyl)piperidine 5472-49-1 C8H16ClN 详情 详情
(XI) 36489 (4aS,6R,8aS)-1-bromo-3-methoxy-11-[3-(1-piperidinyl)propyl]-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol C24H33BrN2O3 详情 详情
Extended Information