【结 构 式】 |
【药物名称】Ondansetron hydrochloride, GG-032, SN-307, GR-C505/75, GR-38032F, Yatrox, Zofran Zydis, Zofran ODT, Zophren, Zofrene, Zofran 【化学名称】(±)-9-Methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3,4,9-tetrahydro-1H-carbazol-4-one monohydrochloride dihydrate 【CA登记号】103639-04-9, 116002-70-1 (free base), 99614-02-5 (free base;no stereoch.) 【 分 子 式 】C18H24ClN3O3 【 分 子 量 】365.86328 |
【开发单位】GlaxoSmithKline (Originator), Sankyo (Licensee), Vita (Licensee) 【药理作用】Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists |
合成路线1
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
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
Condensation of the lithium salt of indole derivative (I) with bromomethyl acrylic acid (II) in THF affords butyric acid derivative (III), which is then subjected to saponification with KOH in a refluxing mixture of MeOH /H2O to provide diacid compound (IV). Treatment of (IV) with 2-methylindole (V) at 160 C yields derivative (VI), which is finally converted into the desired product by first reaction with phosphoric acid and trifluoroacetic anhydride in acetonitrile, followed by hydrochloride dihydrate salt formation by treatment with HCl.
【1】 Caldero Ges, J.M.; Huguet Clotet, J. (Vita-Invest, SA); Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one. ES 2043535 . |
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) | 53894 | ethyl 1,2-dimethyl-1H-indole-3-carboxylate | n/a | C13H15NO2 | 详情 | 详情 |
(II) | 53895 | 2-(Bromomethyl)acrylic acid; alpha-(Bromomethyl)acrylic acid | 72707-66-5 | C4H5BrO2 | 详情 | 详情 |
(III) | 53896 | 2-{2-[3-(ethoxycarbonyl)-1-methyl-1H-indol-2-yl]ethyl}acrylic acid | n/a | C17H19NO4 | 详情 | 详情 |
(IV) | 53897 | 2-(3-carboxy-3-butenyl)-1-methyl-1H-indole-3-carboxylic acid | n/a | C15H15NO4 | 详情 | 详情 |
(V) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
(VI) | 53898 | 2-[(2-methyl-1H-imidazol-1-yl)methyl]-4-(1-methyl-1H-indol-2-yl)butanoic acid | n/a | C18H21N3O2 | 详情 | 详情 |
合成路线4
Condensation of 2-iodoaniline (I) with cyclohexane-1,3-dione (II) at 120 C yields secondary amine (III), which is then methylated with iodomethane by means of sodium hydride in refluxing benzene to provide tertiary amine (IV). Treatment of (IV) with lithium diisopropylamide (LDA) and dimethylaminomethylene iodide (Eschenmoser's salt) (V) in THF yields dimethylaminomethyl derivative (VI), which is then coupled with 2-methylindole (VII) in DMF to give compound (VIII). Cyclization of cyclohexenone derivative (VIII) by means of palladium (II) acetate and triethylamine in acetonitrile provides carbazolone derivative (IX), which is finally converted into the desired hydrochloride salt by treatment with HCl.
【1】 Bell, J.A.; Ewan, G.B.; Humber, D.C.; Costes, I.H.; Godfrey, N. (GlaxoSmithKline plc); Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones. EP 0221629 . |
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) | 27725 | 2-iodoaniline | 615-43-0 | C6H6IN | 详情 | 详情 |
(II) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
(III) | 53899 | 3-(2-iodoanilino)-2-cyclohexen-1-one | n/a | C12H12INO | 详情 | 详情 |
(IV) | 53900 | 3-[2-iodo(methyl)anilino]-2-cyclohexen-1-one | n/a | C13H14INO | 详情 | 详情 |
(V) | 48555 | Eschenmoser's salt; N,N-Dimethylmethyleneimmonium chloride; N,N-Dimethylmethyleneimmonium iodide | C3H8IN | 详情 | 详情 | |
(VI) | 53901 | 6-[(dimethylamino)methyl]-3-[2-iodo(methyl)anilino]-2-cyclohexen-1-one | n/a | C16H21IN2O | 详情 | 详情 |
(VII) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
(VIII) | 53902 | 3-[2-iodo(methyl)anilino]-6-[(2-methyl-1H-imidazol-1-yl)methyl]-2-cyclohexen-1-one | n/a | C18H20IN3O | 详情 | 详情 |
(IX) | 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 |
合成路线5
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 |
合成路线6
Treatment of 3-methoxy-2-cyclohexen-1-one (I) with n-butyllithium and diisopropylamine in THF, followed by addition of N,N-dimethylmethylene ammonium iodide (Eschenmoser's salt) (II) and precipitation with maleic acid, furnishes maleate (III). Methylation of (III) with iodomethane in DMF, followed by condensation with 2-methylimidazole (IV), affords compound (V), which is then converted into methylphenyl hydrazino derivative (VII) by first treatment with HCl in H2O followed by reaction with 1-methyl-1-phenylhydrazine (VI). Cyclization of (VII) is then performed by means of ZnCl2 in HOAc at 85 C to give carbazolone (VIII), and finally the target product is obtained by formation of the hydrochloride dihydrate salt.
【1】 Bell, J.A.; Ewan, G.B.; Oxford, A.W.; Humber, D.C.; Eldred, C.D.; Costes, I.H. (GlaxoSmithKline plc); Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones. EP 0219929 . |
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) | 53908 | 3-Methoxy-2-cyclohexen-1-one | 16807-60-6 | C7H10O2 | 详情 | 详情 |
(II) | 48555 | Eschenmoser's salt; N,N-Dimethylmethyleneimmonium chloride; N,N-Dimethylmethyleneimmonium iodide | C3H8IN | 详情 | 详情 | |
(III) | 55373 | C14H21NO6 | 详情 | 详情 | ||
(IV) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
(V) | 53910 | 3-methoxy-6-[(2-methyl-1H-imidazol-1-yl)methyl]-2-cyclohexen-1-one | C12H16N2O2 | 详情 | 详情 | |
(VI) | 53911 | 1-Methyl-1-phenylhydrazine; 1-Methylphenylhydrazine | 618-40-6 | C7H10N2 | 详情 | 详情 |
(VII) | 53912 | 6-[(2-methyl-1H-imidazol-1-yl)methyl]-3-(2-methyl-2-phenylhydrazino)-2-cyclohexen-1-one | n/a | C18H22N4O | 详情 | 详情 |
(VIII) | 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 |