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【结 构 式】 
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【药物名称】Nazasetron hydrochloride, Azasetron hydrochloride, Y-25130, Serotone 【化学名称】(±)-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 【CA登记号】141922-90-9, 123040-96-0 ((-)-enantiomer), 123040-95-9 ((-)-enantiomer, free base), 123040-94-8 ((+)-enantiomer), 123040-93-7 (( 【 分 子 式 】C17H21Cl2N3O3 【 分 子 量 】386.28122 |
【开发单位】Japan Tobacco (Originator), Mitsubishi Pharma (Originator), Taiho (Not Determined), Torii (Marketer), Temis-Lostalo (Licensee) 【药理作用】Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists |
合成路线1
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.
| 【1】 Tahara, T.; Kawakita, T.; Yasumoto, M.; Fukuda, T. (Welfide Corporation); Benzoxazine cpds. and pharmaceutical use thereof. EP 0313393; JP 1989207290; JP 1990005415; US 4892872 . |
| 【2】 Prous, J.; Castaner, J.; Azasetron Hydrochloride. Drugs Fut 1993, 18, 3, 206. |
| 【3】 Kawakita, T.; Tahara, T.; Kuroita, T.; Yasumoto, M.; Sano, M.; Fukuda, T.; Inaba, K.; 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. Chem Pharm Bull 1992, 40, 3, 624-30. |
| 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) | 13714 | Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate | 4068-78-4 | C8H7ClO3 | 详情 | 详情 |
| (II) | 13715 | Methyl 5-chloro-2-hydroxy-3-nitrobenzoate | C8H6ClNO5 | 详情 | 详情 | |
| (III) | 13716 | Methyl 3-amino-5-chloro-2-hydroxybenzoate | C8H8ClNO3 | 详情 | 详情 | |
| (IV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (V) | 13718 | Methyl 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate | C10H8ClNO4 | 详情 | 详情 | |
| (VI) | 13719 | Methyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate | C11H10ClNO4 | 详情 | 详情 | |
| (VII) | 13720 | 6-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid | C10H8ClNO4 | 详情 | 详情 | |
| (VIII) | 13721 | 6-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carbonyl chloride | C10H7Cl2NO3 | 详情 | 详情 | |
| (IX) | 13722 | 1-Azabicyclo[2.2.2]oct-3-ylamine; 3-Quinuclidinamine; 3-Aminoquinuclidin | 6238-14-8 | C7H14N2 | 详情 | 详情 |