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【结 构 式】 
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【分子编号】36691 【品名】(4aS,8aS)-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one 【CA登记号】 |
【 分 子 式 】C17H19NO3 【 分 子 量 】285.3428 【元素组成】C 71.56% H 6.71% N 4.91% O 16.82% |
合成路线1
该中间体在本合成路线中的序号：(XI)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：(I)The reduction of (-)-narwedine (I) with BuLi, D2, tris(sec-butyl)borane and N,N,N',N'-tetramethylethylenediamine in hexane gives the target deuterated compound.
合成路线3
该中间体在本合成路线中的序号：(I)The reduction of (-)-narwedine (I) with BuLi, 3H2, tris(sec-butyl)borane and N,N,N',N'-tetramethylethylenediamine in hexane gives the target tritiated compound.
合成路线4
该中间体在本合成路线中的序号：(VII)The oxidative cyclization of the formamide derivative (I) with iodosobenzene bis(trifluoroacetate) (PIFA) gives the tricyclic semiquinone (II), which is debenzylated by means of TFA and Me2S and cyclized with Ms-OH to yield the tetracyclic ketone (III). Elimination of the extra OH group of (III) by means of Tf2O, Pd(OAc)2 and TEA affords the intermediate (IV), which is reduced by means of L-Selectride and LiAlH4 to provide racemic galanthamine (V). Finally, this compound is submitted to optical resolution to furnish the target (-)-galanthamine. Alternatively, the protection of the ketonic group of (IV) with ethyleneglycol and PPTS gives the spiroketal (VI), which is selectively reduced with LiAlH4 and hydrolyzed with HCl to yield racemic narwedine (VII). Finally, the reduction of (VII) with L-Selectride affords the already described racemic galanthamine.
| 【1】 Node, M.; et al.; An efficient synthesis of (±)-narwedine and (±)-galanthamine by an improved phenolic oxidative coupling. Angew Chem. Int Ed Engl 2001, 40, 16, 3060. |
| 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) | 50307 | 3,5-bis(benzyloxy)-4-methoxybenzyl(4-hydroxyphenethyl)formamide | C31H31NO5 | 详情 | 详情 | |
| (II) | 50308 | C31H29NO5 | 详情 | 详情 | ||
| (III) | 50309 | (4aS,8aS)-2-hydroxy-3-methoxy-6-oxo-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carbaldehyde | C17H17NO5 | 详情 | 详情 | |
| (IV) | 50310 | (4aS,8aS)-3-methoxy-6-oxo-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carbaldehyde | C17H17NO4 | 详情 | 详情 | |
| (V) | 41226 | (4aS,6R,8aS)-3-methoxy-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol | 357-70-0 | C17H21NO3 | 详情 | 详情 |
| (VI) | 50311 | C19H21NO5 | 详情 | 详情 | ||
| (VII) | 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 |