【结 构 式】 |
【分子编号】36836 【品名】(3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl 4-isopropylphenylcarbamate 【CA登记号】 |
【 分 子 式 】C35H37N3O2 【 分 子 量 】531.6978 【元素组成】C 79.06% H 7.01% N 7.9% O 6.02% |
合成路线1
该中间体在本合成路线中的序号:(XIV)6-Methoxytryptamine (I) was condensed with methyl chloroformate to give carbamate (II), and further alkylation with benzyl bromide yielded the N-benzyl indole (III). Oxidation of the indole ring of (III) with DMSO/HCl gave oxindole (IV). Phase-transfer methylation using iodomethane and benzyltrimethylammonium bromide afforded the racemic methyl derivative (Va-b). Subsequent reduction and cyclization of (Va-b) by means of Red-Al furnished the tricyclic compound (VIa-b), which was resolved with dibenzoyl D-tartaric acid to provide the (3aS)-enantiomer (VII). Conversion of (VII) to the N,N'-dibenzyl analogue (XI) was achieved via quaternization to the ammonium salt (VIII) with iodomethane in Et2O. Ring-opening of (VIII) under basic conditions produced the hydroxy tryptamine (IX), which was again quaternized to (X) with iodomethane and then cyclized with benzylamine to provide directly the dibenzyl compound (XI). Ether cleavage of (XI) with boron tribromide gave the phenolic derivative (XII). This was coupled with 4-isopropylphenyl isocyanate in the presence of a catalytic amount of Na to yield carbamate (XIV). Finally, hydrogenolytic cleavage of the benzyl groups of (XIV) over Pd(OH)2 furnished the title compound.
【1】 Yu, Q.-S.; et al.; Total syntheses and anticholinesterase activities of (3aS)-N(8)-norphysostigmine, (3aS)-N(8)-norphenserine, their antipodal isomers and other N(8)-substituted analogues. J Med Chem 1997, 40, 18, 2895-2901. |
【2】 Yu, Q.-S.; et al.; Syntheses and anticholinesterase activities of (3aS)-N1,N8-bisnorphenserine, (3aS)-N1,N8-bisnorphysostigmine. Their antipodal isomers and other potential metabolites of phenserine. J Med Chem 1998, 41, 13, 2371-79. |
【3】 Holloway, H.W.; Yu, Q.-S.; Greig, N.H.; Utsuki, T.; Brossi, A.; Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for Alzheimer's disease. J Med Chem 1999, 42, 10, 1855. |
【4】 Soncrant, T.T.; Brossi, A.; Greig, N.H.; Hausman, M.; Yu, Q.-S. (Axonyx Inc.; National Institutes of Health); Highly selective butyrylcholinesterase inhibitors for the treatment and diagnosis of Alzheimer's disease and dementias. CA 2264750; EP 0949920; WO 9902154 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester;[(chlorocarbonyl)oxy]methane;methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
(Va) | 36829 | methyl 2-[(3S)-1-benzyl-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]ethylcarbamate | C21H24N2O4 | 详情 | 详情 | |
(VIa),(VII) | 36830 | (3aS)-8-benzyl-5-methoxy-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole; (3aS)-8-benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether | C20H24N2O | 详情 | 详情 | |
(Vb) | 36837 | methyl 2-[(3R)-1-benzyl-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]ethylcarbamate | C21H24N2O4 | 详情 | 详情 | |
(VIb) | 36838 | (3aR)-8-benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aR)-8-benzyl-5-methoxy-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C20H24N2O | 详情 | 详情 | |
(I) | 36825 | O-Methylserotonin; 3-(2-Aminoethyl)-5-methoxyindole; 2-(5-Methoxy-1H-indol-3-yl)ethylamine; 2-(5-Methoxy-1H-indol-3-yl)-1-ethanamine; 5-Methoxytryptamine | 608-07-1 | C11H14N2O | 详情 | 详情 |
(II) | 36826 | methyl 2-(5-methoxy-1H-indol-3-yl)ethylcarbamate | C13H16N2O3 | 详情 | 详情 | |
(III) | 36827 | methyl 2-(1-benzyl-5-methoxy-1H-indol-3-yl)ethylcarbamate | C20H22N2O3 | 详情 | 详情 | |
(IV) | 36828 | methyl 2-(1-benzyl-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)ethylcarbamate | C20H22N2O4 | 详情 | 详情 | |
(VIII) | 36831 | (3aS)-8-benzyl-5-methoxy-1,1,3a-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-1-ium iodide | C21H27IN2O | 详情 | 详情 | |
(IX) | 36832 | (3S)-1-benzyl-3-[2-(dimethylamino)ethyl]-5-methoxy-3-methyl-2,3-dihydro-1H-indol-2-ol | C21H28N2O2 | 详情 | 详情 | |
(X) | 36833 | 2-[(3S)-1-benzyl-2-hydroxy-5-methoxy-3-methyl-2,3-dihydro-1H-indol-3-yl]-N,N,N-trimethyl-1-ethanaminium iodide | C22H31IN2O2 | 详情 | 详情 | |
(XI) | 36834 | (3aS,8aR)-1,8-dibenzyl-5-methoxy-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole; (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether | C26H28N2O | 详情 | 详情 | |
(XII) | 36835 | (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol | C25H26N2O | 详情 | 详情 | |
(XIII) | 34537 | 4-isopropylphenyl isocyanate; 1-isocyanato-4-isopropylbenzene | 31027-31-3 | C10H11NO | 详情 | 详情 |
(XIV) | 36836 | (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl 4-isopropylphenylcarbamate | C35H37N3O2 | 详情 | 详情 |