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【结 构 式】 
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【分子编号】58088 【品名】(3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aS,8aR)-5-methoxy-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole 【CA登记号】 |
【 分 子 式 】C14H20N2O 【 分 子 量 】232.32568 【元素组成】C 72.38% H 8.68% N 12.06% O 6.89% |
合成路线1
该中间体在本合成路线中的序号：(X)Condensation of 5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (IV) with 2-chloro-N,N-dimethylethyl-amine (V) by means of NaNH2 in toluene gives 3-[2-(di-methylamino)ethyl]-5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (VI), which is reduced with Vitride (sodium bis(2-methoxyethoxy)aluminum dihydride) in toluene to yield the secondary alcohol (VII). Optical resolution of (VII) by means of (+)-2,3-di-O-(p-toluoyl)tartaric acid provides the (2S,3S)-diastereomer (VIII), which by reaction with methyl iodide in ethyl ether affords the ammonium salt (IX). Cyclization of compound (IX) by means of methylamine in acetonitrile provides esermethole (X), the methyl ether of eseroline, which is demethylated by means of BBr3 in dichloromethane to give eseroline (II). Finally, eseroline is condensed with phenyl isocyanate (VIII) by means of Na in ethyl ether.
| 【1】 Castañer, J.; Sorbera, L.A.; Phenserine Tartrate. Drugs Fut 2003, 28, 1, 18. |
| 【2】 Brossi, A.; Bi, S.; Greig, N.H.; Pei, X.-F.; 125. Total synthesis of racemic and optically active compounds related to physostigmine and ring-C heteroanalogues from 3-[2'-(dimethylamino)ethyl]-2,3-dihydro-5-methoxy-1,3-dimethyl-1H-indol-2-ol. Helv Chim Acta 1994, 77, 5, 1412. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 20365 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol | C13H18N2O | 详情 | 详情 | |
| (III) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (IV) | 58084 | 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one | C11H13NO2 | 详情 | 详情 | |
| (V) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
| (VI) | 58085 | 3-[2-(dimethylamino)ethyl]-5-methoxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one | C15H22N2O2 | 详情 | 详情 | |
| (VII) | 58086 | 3-[2-(dimethylamino)ethyl]-5-methoxy-1,3-dimethyl-2-indolinol | C15H24N2O2 | 详情 | 详情 | |
| (VIII) | 58087 | (2S,3S)-3-[2-(dimethylamino)ethyl]-5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-ol | C15H24N2O2 | 详情 | 详情 | |
| (IX) | 36822 | 2-[(2S,3S)-2-hydroxy-5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-3-yl]-N,N,N-trimethyl-1-ethanaminium iodide | C16H27IN2O2 | 详情 | 详情 | |
| (X) | 58088 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aS,8aR)-5-methoxy-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C14H20N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Condensation of 5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (IV) with 2-chloroacetonitrile (XI) by means of a chiral phase transfer catalyst gives 2-(5-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-y)-acetonitrile, which is separated into enantiomers by chromatography. Reductocyclization of the (S)-enantiomer (XII) by means of Vitride affords (3aS)-N1-noresermethole (XIII), which is submitted to a reductive methylation to provide esermethole (X). O-demethylation of (X) by means of BBr3 or AlCl3 gives eseroline (II), which is finally condensed with phenyl isocyanate.
| 【1】 Castañer, J.; Sorbera, L.A.; Phenserine Tartrate. Drugs Fut 2003, 28, 1, 18. |
| 【2】 Greig, N.H.; Pei, X.-F.; Brossi, A.; Phenserine, a novel anticholinesterase related to physostigmine: Total synthesis and biological properties. Aust J Chem 1996, 49, 2, 171. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 20365 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol | C13H18N2O | 详情 | 详情 | |
| (III) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (IV) | 58084 | 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one | C11H13NO2 | 详情 | 详情 | |
| (X) | 58088 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aS,8aR)-5-methoxy-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C14H20N2O | 详情 | 详情 | |
| (XI) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (XII) | 58089 | 2-[(3S)-5-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]acetonitrile | C13H14N2O2 | 详情 | 详情 | |
| (XIII) | 58090 | (3aS,8aR)-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aS,8aR)-5-methoxy-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C13H18N2O | 详情 | 详情 |