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【结 构 式】 
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【分子编号】53889 【品名】9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one 【CA登记号】27387-31-1 |
【 分 子 式 】C13H13NO 【 分 子 量 】199.25236 【元素组成】C 78.36% H 6.58% N 7.03% O 8.03% |
合成路线1
该中间体在本合成路线中的序号：(V)Condensation of 2-bromo-p-toluidine (I) with cyclohexane-1,3-dione (II) gives bromo enaminone (III), which is N-methylated with iodomethane and NaH, affording tertiary enaminone (IV). Treatment of (IV) with triphenylphosphine-palladium acetate complex/NHCO3 or palladium acetate in acetonitrile provides carbazolone (V). Treatment of carbazolone (V) with sodium metal in EtOH/dioxane (or sodium methoxide in 1,2-dimethoxyethane) and diethyl oxalate (VI) provides ethoxallyl derivative (VII), which is then converted into glyoxylic acid lactone (VIII). Coupling of (VIII) with 2-methylimidazol (IX) by means of benzyltriethylammonium chloride in CHCl3/H2O furnishes glyoxylate (X), which is converted into the target product by reaction again with 2-methylimidazol (IX) in dioxane and final treatment with HCl. Alternatively, glyoxylate (X) can be directly obtained from (VIII) by reaction with formaldehyde and 2-methylimidazol (IX) in dioxane.
| 【1】 Iida, H.; et al.; Intramolecular cyclization of enaminones involving arylpalladium complexes. Synthesis of carbazoles. J Org Chem 1980, 45, 15, 2938. |
| 【2】 Harsanyi, K.; Bod, P.; Trischler, F.; Fekecs, E.; Horvath, E.; Csehl, A.; Hegedus, B.; Mersich, E.; Szabo, G. (Gedeon Richter Ltd.); Carbazolone derivs. and process for preparing the same. EP 0595111 . |
| 【3】 Dobay, L.; Czibula, L.; Szantay, C.; Gazdag, M.; Greiner, I.; Werkne Papp, E.; Tarkanyi, G.; Zsoldosne Babjak, M.; Mihalyfi, K. (Gedeon Richter Ltd.); An intermediate and process for its synthesis. WO 0172716 . |
| 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) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
| (II) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
| (III) | 53887 | 3-(2-bromoanilino)-2-cyclohexen-1-one | n/a | C12H12BrNO | 详情 | 详情 |
| (IV) | 53888 | 3-[2-bromo(methyl)anilino]-2-cyclohexen-1-one | n/a | C13H14BrNO | 详情 | 详情 |
| (V) | 53889 | 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one | 27387-31-1 | C13H13NO | 详情 | 详情 |
| (VI) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (VII) | 53890 | ethyl 2-hydroxy-2-(9-methyl-4-oxo-1,2,4,9-tetrahydro-3H-carbazol-3-ylidene)acetate | n/a | C17H17NO4 | 详情 | 详情 |
| (VIII) | 53891 | n/a | C16H13NO4 | 详情 | 详情 | |
| (IX) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
| (X) | 53892 | 2-methyl-1H-imidazol-3-ium 2-[3-(hydroxymethyl)-9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-2-oxoacetate | n/a | C20H21N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Mannich alpha-methylenation of N-methyltetrahydrocarbazolone (I) with morpholine in refluxing acetic and acid formaldehyde provides methylenecarbazolone derivative (II), which is then subjected to Michael addition with 2-methylimidazole (III) by means of alumina in refluxing toluene. Finally, formation of the desired hydrochloride dihydrate salt is obtained by treatment with HCl.
| 【1】 Kim, M.Y.; et al.; An efficient process of ondansetron synthesis. Heterocycles 1997, 45, 10, 2041. |
合成路线3
该中间体在本合成路线中的序号：(I)Treatment of tetrahydrocarbazolone (I) with formaldehyde and dimethylamine in EtOH provides tertiary amine (II), which is then methylated with refluxing iodomethane to furnish methanaminium iodide (III). Condensation of (III) with 2-methylimidazole (IV) in DMF affords free base (V), which is converted into the desired product, the hydrochloride dihydrate, by treatment with HCl in isopropanol/water. Alternatively, free base (V) can be obtained by other related procedures: (a) treatment of methanaminium iodide (III) with sodium carbonate in water to furnish methylene derivative (VI) followed by condensation with 2-methylimidazole (IV) in refluxing water; (b) conversion of (VI) into chloromethyl derivative (VII) by treatment with ethereal HCl in CHCl3, followed by reaction of (VII) with 2-methylimidazole (IV) in DMF; (c) treatment of dimethylamino derivative (VIII) with 2-methylimidazole (IV) in refluxing water; or (d) methylation of carbazolone (IX) with dimethylsulfate and sodium hydride in DMF.
| 【1】 Tyers, M.B. (GlaxoSmithKline plc); Ketone derivs.. EP 0275668; JP 1988253083; US 4845115 . |
| 【2】 Coates, I.H.; Bell, J.A.; Ewan, G.B.; Humber, D.C. (GlaxoSmithKline plc); 1,2,3,9-Tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, compsn. containing them, and method of using them to treat neuronal 5HT function disturbances. AU 8652614; EP 0191562; JP 1986210083; US 4695578 . |
| 【3】 Coates, I.H.; Bell, J.A.; Hunber, D.C.; Ewan, G.B. (GlaxoSmithKline plc); Imidazolylmethyl substd. carbazoles. AU 8538097; BE 0901576; CH 664152; ES 8609309; ES 8708224; ES 8801247; FR 2561244; GB 2153821; JP 1985214784 . |
| 【4】 Kraus, W.; Weisert, A.; Spies, J. (GlaxoSmithKline plc); Pharmaceutical product. DE 3740351 . |
| 【5】 Kraus, W.; Weisert, A.; Spies, J. (GlaxoSmithKline plc); Pharmaceutical product. DE 3906883 . |
| 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),(VIII) | 53904 | 3-[(dimethylamino)methyl]-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one | n/a | C16H20N2O | 详情 | 详情 |
| (I) | 53889 | 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one | 27387-31-1 | C13H13NO | 详情 | 详情 |
| (III) | 53905 | N,N,N-trimethyl(9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methanaminium iodide | n/a | C17H23IN2O | 详情 | 详情 |
| (IV) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
| (V) | 53903 | 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one | n/a | C18H19N3O | 详情 | 详情 |
| (VI) | 53893 | 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one | n/a | C14H13NO | 详情 | 详情 |
| (VII) | 53906 | 3-(chloromethyl)-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one | n/a | C14H14ClNO | 详情 | 详情 |
| (IX) | 53907 | 3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one | n/a | C17H17N3O | 详情 | 详情 |