Ondansetron hydrochloride, GG-032, SN-307, GR-C505/75, GR-38032F, Yatrox, Zofran Zydis, Zofran ODT, Zophren, Zofrene, Zofran

合成路线: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
文献作者:Coates,I.H.; Bell,J.A.; Ewan,G.B.; Humber,D.C.(GlaxoSmithKline plc)
参考来源:AU 8652614; EP 0191562; JP 1986210083; US 4695578


合成路线: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.

参考文献标题:Ketone derivs.
文献作者:Tyers,M.B.(GlaxoSmithKline plc)
参考来源:EP 0275668; JP 1988253083; US 4845115


合成路线: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
文献作者:Caldero Ges,J.M.; Huguet Clotet,J.(Vita-Invest,SA)
参考来源:ES 2043535


合成路线: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.

参考文献标题:Pharmaceutical product
文献作者:Kraus,W.; Weisert,A.; Spies,J.(GlaxoSmithKline plc)
参考来源:DE 3740351


合成路线: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.

参考文献标题:Pharmaceutical product
文献作者:Kraus,W.; Weisert,A.; Spies,J.(GlaxoSmithKline plc)
参考来源:DE 3906883


合成路线: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.

参考文献标题:Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones
文献作者:Bell,J.A.; Ewan,G.B.; Oxford,A.W.; Humber,D.C.; Eldred,C.D.; Costes,I.H.(GlaxoSmithKline plc)
参考来源:EP 0219929