Nazasetron hydrochloride, Azasetron hydrochloride, Y-25130, Serotone
盐酸阿扎司琼 2H-1,4-苯甲氧嗪-8-羧酰胺,N-1-氮双环[2.2.2]辛-3-酰基-6-氯-3,4-二氢-4-甲基-3-氧-,一盐酸盐,(-)-(9CI) Chemical Name: (?-N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride; (?-6-Chloro-4-methyl-3-oxo-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride
CAS No. 141922-90-9, 123040-96-0 ((-)-enantiomer), 123040-95-9 ((-)-enantiomer, free base), 123040-94-8 ((+)-enantiomer), 123040-93-7 ((+)-enantiomer, free base), 123040-69-7 (free base), 123039-99-6 (free base, no stereoch.), 123040-16-4 (undefined stereoch.)
项目整合开发状态: Launched-1994
项目研究机构: Japan Tobacco (Originator), Mitsubishi Pharma (Originator), Taiho (Not Determined), Torii (Marketer), Temis-Lostalo (Licensee)
合成路线:The nitration of 5-chloro-2-hydroxybenzoic acid methyl ester (I) with nitric acid in sulfuric acid gives 5-chloro-2-hydroxy-3-nitrobenzoic acid methyl ester (II),which is reduced with Fe and NH4Cl in water yielding 3-amino-5-chloro-2-hydroxybenzoic acid methyl ester (III).The cyclization of (III) with chloroacetyl chloride (IV) by means of NaHCO3 in CHCl3 - water affords 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid methyl ester (V),which is methylated with methyl iodide and K2CO3 in DMF affording the corresponding 4-methyl derivative (VI).Hydrolysis of (VI) with ethanolic NaOH gives the corresponding acid (VII),which by treatment with refluxing SOCl2 is converted into its acyl chloride (VIII).Finally,this compound is condensed with 3-aminoquinuclidine (IX) by means of N-methylmorpholine (NMM) in CHCl3.
📌 参考资料/链接：
参考文献标题:Benzoxazine cpds.and pharmaceutical use thereof
文献作者:Tahara,T.; Kawakita,T.; Yasumoto,M.; Fukuda,T.(Welfide Corporation)
参考来源:EP 0313393; JP 1989207290; JP 1990005415; US 4892872
📄 详细内容
合成路线:The nitration of 5-chloro-2-hydroxybenzoic acid methyl ester (I) with nitric acid in sulfuric acid gives 5-chloro-2-hydroxy-3-nitrobenzoic acid methyl ester (II),which is reduced with Fe and NH4Cl in water yielding 3-amino-5-chloro-2-hydroxybenzoic acid methyl ester (III).The cyclization of (III) with chloroacetyl chloride (IV) by means of NaHCO3 in CHCl3 - water affords 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid methyl ester (V),which is methylated with methyl iodide and K2CO3 in DMF affording the corresponding 4-methyl derivative (VI).Hydrolysis of (VI) with ethanolic NaOH gives the corresponding acid (VII),which by treatment with refluxing SOCl2 is converted into its acyl chloride (VIII).Finally,this compound is condensed with 3-aminoquinuclidine (IX) by means of N-methylmorpholine (NMM) in CHCl3.
参考文献标题:Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives,a new class of potent serotonin-3 (5-HT3) receptor antagonists
文献作者:Kawakita,T.; Kuroita,T.; Yasumoto,M.; Sano,M.; Inaba,K.; Fukuda,T.; Tahara,T.
参考来源:Chem Pharm Bull 1992,40(3),624-30
合成路线:The nitration of 5-chloro-2-hydroxybenzoic acid methyl ester (I) with nitric acid in sulfuric acid gives 5-chloro-2-hydroxy-3-nitrobenzoic acid methyl ester (II),which is reduced with Fe and NH4Cl in water yielding 3-amino-5-chloro-2-hydroxybenzoic acid methyl ester (III).The cyclization of (III) with chloroacetyl chloride (IV) by means of NaHCO3 in CHCl3 - water affords 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid methyl ester (V),which is methylated with methyl iodide and K2CO3 in DMF affording the corresponding 4-methyl derivative (VI).Hydrolysis of (VI) with ethanolic NaOH gives the corresponding acid (VII),which by treatment with refluxing SOCl2 is converted into its acyl chloride (VIII).Finally,this compound is condensed with 3-aminoquinuclidine (IX) by means of N-methylmorpholine (NMM) in CHCl3.
参考文献标题:Azasetron Hydrochloride
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1993,18(3),206