【药物名称】Ondansetron hydrochloride, GG-032, SN-307, GR-C505/75, GR-38032F, Yatrox, Zofran Zydis, Zofran ODT, Zophren, Zofrene, Zofran
化学结构式(Chemical Structure):
参考文献No.2494
标题:Imidazolylmethyl substd. carbazoles
作者:Coates, I.H.; Bell, J.A.; Hunber, D.C.; Ewan, G.B. (GlaxoSmithKline plc)
来源:AU 8538097; BE 0901576; CH 664152; ES 8609309; ES 8708224; ES 8801247; FR 2561244; GB 2153821; JP 1985214784
合成路线图解说明:

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.

参考文献No.4982
标题: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
作者:Coates, I.H.; Bell, J.A.; Ewan, G.B.; Humber, D.C. (GlaxoSmithKline plc)
来源:AU 8652614; EP 0191562; JP 1986210083; US 4695578
合成路线图解说明:

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.

参考文献No.8700
标题:Ketone derivs.
作者:Tyers, M.B. (GlaxoSmithKline plc)
来源:EP 0275668; JP 1988253083; US 4845115
合成路线图解说明:

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.

参考文献No.53193
标题:Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one
作者:Caldero Ges, J.M.; Huguet Clotet, J. (Vita-Invest, SA)
来源:ES 2043535
合成路线图解说明:

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.

参考文献No.53989
标题:Pharmaceutical product
作者:Kraus, W.; Weisert, A.; Spies, J. (GlaxoSmithKline plc)
来源:DE 3740351
合成路线图解说明:

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.

参考文献No.53990
标题:Pharmaceutical product
作者:Kraus, W.; Weisert, A.; Spies, J. (GlaxoSmithKline plc)
来源:DE 3906883
合成路线图解说明:

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.

参考文献No.53991
标题:Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones
作者:Bell, J.A.; Ewan, G.B.; Oxford, A.W.; Humber, D.C.; Eldred, C.D.; Costes, I.H. (GlaxoSmithKline plc)
来源:EP 0219929
合成路线图解说明:

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抯 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.

参考文献No.53992
标题:Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones
作者:Bell, J.A.; Ewan, G.B.; Humber, D.C.; Costes, I.H.; Godfrey, N. (GlaxoSmithKline plc)
来源:EP 0221629
合成路线图解说明:

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抯 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.

参考文献No.53993
标题:Carbazolone derivs. and process for preparing the same
作者:Hars醤yi, K.; Bod, P.; Trischler, F.; Fekecs, E.; Horv醫h, E.; Csehl, A.; Hegedus, B.; Mersich, E.; Szabo, G. (Gedeon Richter Ltd.)
来源:EP 0595111
合成路线图解说明:

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.

参考文献No.53994
标题:An intermediate and process for its synthesis
作者:Dobay, L.; Czibula, L.; Sz醤tay, C.; Gazdag, M.; Greiner, I.; Werkn?Papp, E.; T醨k醤yi, G.; Zsoldosn?Babj醟, M.; Mih醠yfi, K. (Gedeon Richter Ltd.)
来源:WO 0172716
合成路线图解说明:

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.

参考文献No.659633
标题:Intramolecular cyclization of enaminones involving arylpalladium complexes. Synthesis of carbazoles
作者:Iida, H.; et al.
来源:J Org Chem 1980,45(15),2938
合成路线图解说明:

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.

参考文献No.659635
标题:An efficient process of ondansetron synthesis
作者:Kim, M.Y.; et al.
来源:Heterocycles 1997,45(10),2041
合成路线图解说明:

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.

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