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【结 构 式】 
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【药物名称】Ganstigmine hydrochloride, CHF-2819 【化学名称】N-(2-Ethylphenyl)carbamic acid (4aS,9aS)-2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro[1,2]oxazino[6,5-b]indol-6-yl ester hydrochloride 【CA登记号】223585-99-7 【 分 子 式 】C22H28ClN3O3 【 分 子 量 】417.93976 |
【开发单位】Chiesi (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Acetylcholinesterase Inhibitors |
合成路线1
The oxidation of eserine (I) by means of H2O2 and KHCO3 produced the geneseroline carbamate (II), which was hydrolyzed to geneseroline (III) employing 62% sulfuric acid at 85 C. The desired carbamate was then obtained by condensation of (III) with 2-ethylphenyl isocyanate (IV) either in the presence of K2CO3 in acetone or in the presence of t-BuOK under sonication, and the title compound was then isolated as the corresponding hydrochloride salt.
| 【1】 Ventura, P.; Pighi, R.; Servadio, V.; Pietra, C.; Amari, G.; Salsi, B.; Pivetti, F.; Delcanale, M.; Chiesi, P.; Villetti, G. (Chiesi Farmaceutici SpA); A process for the preparation of aminocarbonyl derivs. of geneseroline having selective brain anticholinesterase activity. WO 9919329 . |
| 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) | 40606 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methylcarbamate | 57-47-6 | C15H21N3O2 | 详情 | 详情 |
| (II) | 40607 | (4aS,9aS)-2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro[1,2]oxazino[6,5-b]indol-6-yl methylcarbamate | C15H21N3O3 | 详情 | 详情 | |
| (III) | 40608 | (4aS,9aS)-2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro[1,2]oxazino[6,5-b]indol-6-ol | C13H18N2O2 | 详情 | 详情 | |
| (IV) | 40609 | 2-ethylphenyl isocyanate; 1-ethyl-2-isocyanatobenzene | 40411-25-4 | C9H9NO | 详情 | 详情 |
合成路线2
An alternative procedure for the preparation of the intermediate geneseroline (III) consisted in the oxidation of eseretole (V) to geneseretole (VI), followed by ether cleavage by means of concentrated sulfuric acid.
| 【1】 Ventura, P.; Pighi, R.; Servadio, V.; Pietra, C.; Amari, G.; Salsi, B.; Pivetti, F.; Delcanale, M.; Chiesi, P.; Villetti, G. (Chiesi Farmaceutici SpA); A process for the preparation of aminocarbonyl derivs. of geneseroline having selective brain anticholinesterase activity. WO 9919329 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 40608 | (4aS,9aS)-2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro[1,2]oxazino[6,5-b]indol-6-ol | C13H18N2O2 | 详情 | 详情 | |
| (V) | 40610 | (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ethyl ether; (3aS,8aR)-5-ethoxy-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C15H22N2O | 详情 | 详情 | |
| (VI) | 40611 | (4aS,9aS)-6-ethoxy-2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro[1,2]oxazino[6,5-b]indole; (4aS,9aS)-2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro[1,2]oxazino[6,5-b]indol-6-yl ethyl ether | C15H22N2O2 | 详情 | 详情 |
合成路线3
The reaction of 2'-ethylphenserine (I) with MCPBA in chloroform gives the intermediate (II), which is treated in basic medium to yield the target geneserine derivative.
| 【1】 Yu, Q.-S.; et al.; Anticholinesterase activity of compounds related to geneserine tautomers. N-Oxides and 1,2-oxazines. J Med Chem 2002, 45, 17, 3684. |