|
【结 构 式】 
|
【分子编号】41226 【品名】(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 【CA登记号】357-70-0 |
【 分 子 式 】C17H21NO3 【 分 子 量 】287.35868 【元素组成】C 71.06% H 7.37% N 4.87% O 16.7% |
合成路线1
该中间体在本合成路线中的序号：(V)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 |
合成路线2
该中间体在本合成路线中的序号：(I)The N-demethylation of galantamine (I) by means of MCPBA and FeSO4 in dichloromethane gives the N-demethylated compound (II), which is then remethylated with 14C-methyl iodide and diisopropylamine (DIA) in methanol to obtain the target labeled compound.
| 【1】 Janssen, C.G.M.; et al.; Synthesis of 3H-, 14C-, and stable-isotope-labelled galantamine. J Label Compd Radiopharm 2002, 45, 10, 841. |
合成路线3
该中间体在本合成路线中的序号：(I)The O-demethylation of galantamine (I) by means of BuLi and butanethiol in HMPT gives the O-demethylated compound (II), which is then remethylated with 14C-methyl iodide, KOH and 1,3-dimethylimidazolidin-2-one (DMIO) to obtain the target labeled compound.
| 【1】 Janssen, C.G.M.; et al.; Synthesis of 3H-, 14C-, and stable-isotope-labelled galantamine. J Label Compd Radiopharm 2002, 45, 10, 841. |
合成路线4
该中间体在本合成路线中的序号：(I)The O-demethylation of galantamine (I) by means of BuLi and butanethiol in HMPT gives the O-demethylated compound (II), which is then remethylated with fully deuterated 13C-methanol, DIAD and PPh3 in THF to obtain the target labeled compound.
| 【1】 Janssen, C.G.M.; et al.; Synthesis of 3H-, 14C-, and stable-isotope-labelled galantamine. J Label Compd Radiopharm 2002, 45, 10, 841. |
合成路线5
该中间体在本合成路线中的序号：(I)The demethylation of galanthamine (I) with ethyl mercaptane sodium salt in hot DMF gives 6-demethylgalanthamine (II), which is selectively monoesterified at the phenolic OH with N-methylcarbamic acid and CDI yielding the target monoester. The selective monoesterification of (II) can also be performed with N-methylcarbamic anhydride and TEA or DMAP, with N-methylcarbamoyl chloride and DBU, with N-methylisocyanate and K2CO3 or with CDI and methylamine in HOAc.
| 【1】 Bores, G.M.; Kosley, R.W. Jr.; Galanthamine derivatives for the treatment of Alzeimer's disease. Drugs Fut 1996, 21, 6, 621. |
合成路线6
该中间体在本合成路线中的序号：(I)The demethylation of galanthamine (I) with ethyl mercaptane sodium salt in hot DMF gives 6-demethylgalanthamine (II), which is selectively monoesterified at the phenolic OH with N-methylcarbamic acid and CDI yielding the monoester (III). Finally this compound is esterified again at the remaining OH with isobutyric anhydride (IV) and TEA or DMAP affording the target diester. The selective monoesterification of (II) can also be performed with N-methylcarbamic anhydride and TEA or DMAP, with N-methylcarbamoyl chloride and DBU, or with N-methylisocyanate and K2CO3.
| 【1】 Bores, G.M.; Kosley, R.W. Jr.; Galanthamine derivatives for the treatment of Alzeimer's disease. Drugs Fut 1996, 21, 6, 621. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 39110 | Sodium 1-ethanethiolate; Sodium ethylmercaptide | 811-51-8 | C2H5NaS | 详情 | 详情 |
| (I) | 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 |
| (II) | 41227 | (4aS,6R,8aS)-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-3,6-diol | C16H19NO3 | 详情 | 详情 | |
| (III) | 41230 | (4aS,6R,8aS)-6-hydroxy-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-3-yl methylcarbamate | C18H22N2O4 | 详情 | 详情 | |
| (IV) | 22334 | 1-methylpropionic anhydride | 97-72-3 | C8H14O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The demethylation of galanthamine (I) with ethyl mercaptane sodium salt in hot DMF gives 6-demethylgalanthamine (II), which is selectively monoesterified at the phenolic OH with pivalic acid and CDI yielding the monoester (III). Finally this compound is esterified again at the remaining OH with isopropyl dicarbonate (IV) and TEA or DMAP affording the target diester. The selective monoesterification of (II) can also be performed with pivalic anhydride and TEA or DMAP, or with pivaloyl chloride and DBU.
| 【1】 Bores, G.M.; Kosley, R.W. Jr.; Galanthamine derivatives for the treatment of Alzeimer's disease. Drugs Fut 1996, 21, 6, 621. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 39110 | Sodium 1-ethanethiolate; Sodium ethylmercaptide | 811-51-8 | C2H5NaS | 详情 | 详情 |
| (I) | 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 |
| (II) | 41227 | (4aS,6R,8aS)-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-3,6-diol | C16H19NO3 | 详情 | 详情 | |
| (III) | 41228 | (4aS,6R,8aS)-6-hydroxy-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-3-yl pivalate | C21H27NO4 | 详情 | 详情 | |
| (IV) | 41229 | C8H14O5 | 详情 | 详情 |