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【结 构 式】 
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【分子编号】36483 【品名】4-bromo-5-[[(4-hydroxyphenethyl)amino]methyl]-2-methoxyphenol 【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% |
合成路线1
该中间体在本合成路线中的序号：(V)The bromination of 3,4-dimethoxybenzaldehyde (I) with Br2 in methanol gives the 6-bromo-3,4-dimethoxybenzaldehyde (II), which is regioselectively demethylated with conc. H2SO4 yielding 6-bromo-3-hydroxy-4-methoxybenzaldehyde (III). The reductocondensation of (III) with 2-(4-hydroxyphenyl)ethylamine (IV) by means of NaBH4 in ethanol affords the secondary amine (V), which is formylated with ethyl formate and formic acid in dioxane furnishing the formamide (VI). The oxidative cyclization of (VI) by means of potassium ferricyanide and K2CO3 in toluene/water gives the (+/-)-bromoformylnarwedine (VII), which is protected with propyleneglycol (VIII) and TsOH in hot toluene yielding the ketal (IX). The reduction of the formyl group of (IX) with LiAlH4 in THF affords racemic narwedine (X), which is submitted to a crystallization-induced chiral transformation using a catalytic amount of seed crystals of (-)-narwedine in refluxing ethanol containing TEA, an 80% of (-)-narwedine (XI) is obtained. Finally, this compound is stereoselectively reduced to the target compound by means of L-selectride in THF.
| 【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】 Chaplin, D.A.; et al.; A concise, scaleable synthesis of narwedine. Tetrahedron Lett 1997, 38, 45, 7931. |
| 【3】 Czollner, L.; et al.; New kilogram-synthesis of the anti-Alzheimer drug (-)-galanthamine. Tetrahedron Lett 1998, 39, 15, 2087. |
| 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) | 36689 | 1-bromo-3-methoxy-6-oxo-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carbaldehyde | C17H16BrNO4 | 详情 | 详情 | |
| (VIII) | 36692 | 1,2-Propanediol; 1,2-Propylene glycol; 1,2-Dihydroxypropane; Monopropylene glycol; (+/-)-1,2-Propanediol; (+/-)-Propylene glycol; Propan-1,2-diol; propylene glycol | 57-55-6 | C3H8O2 | 详情 | 详情 |
| (IX) | 36690 | C20H22BrNO5 | 详情 | 详情 | ||
| (X) | 26837 | 3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one | C17H19NO3 | 详情 | 详情 | |
| (XI) | 36691 | (4aS,8aS)-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one | C17H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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 |