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【结 构 式】 
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【药物名称】Bemoradan, RWJ-22867, Orf-22867 【化学名称】(±)-5-Methyl-6-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2,3,4,5-tetrahydropyridazin-3-one 【CA登记号】123169-88-0, 112018-01-6 (undefined stereoch.) 【 分 子 式 】C13H13N3O3 【 分 子 量 】259.26686 |
【开发单位】Ortho-McNeil (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Phosphodiesterase III Inhibitors |
合成路线1
The acylation of benzoxazolin-2-one (I) with propionic anhydride (II) by means of P2O5 and MsOH gives 6-propionylbenzoxazolin-2-one (III), which is treated with chloroacetyl chloride to yield 7-propionyl-3,4-dihydro-2H-1,4-benzoxazin-3-one (IV). The Mannich condensation of (IV) with CH2O and NH3 followed by methylation with methyl iodide affords the trimethylammonium compound (V), which by reaction with KCN, followed by hydrolysis with HCl gives 3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-ylcarbonyl)butyric acid (VI). Finally this compound is cyclized with hydrazine to furnish the target pyridazinone.
| 【1】 Bonte, J.P.; Lesier, D.; Lespagnol, C.; et al.; 6-Acyl benzoxazolinones. I. Eur J Med Chem - Chim Ther 1974, 9, 491. |
| 【2】 Kryvenko, M.; Techer, H.; Lavergne, M.; et al.; Electrophilic substitutions of 2H-1,4-benzoxazine-3-one: Acylation and chlorosulfonation. CR Acad Sci Paris Ser C 1970, 270, 19, 1601. |
| 【3】 Lesier, D.; Lespagnol, C.; Bonte, J.P.; et al.; 6-Acyl benzoxazolinones. II. Preparation of some transformation products. Eur J Med Chem - Chim Ther 1974, 9, 497-500. |
| 【4】 Thyes, M.; Lehmann, H.D.; Gries, J.; et al.; 6-Aryl-4,5-dihydro-3(2H)-pyridazinones. A new class of compounds with platelet aggregation inhibiting and hypotensive activities. J Med Chem 1983, 26, 6, 800. |
| 【5】 Moussavi, Z.; Lesieur, D.; Depreux, P.; An aternative synthesis of cardiotonic 6-(3,4-dihydro-3-oxo-1,4[2H]benzoxazin-7-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-ones. Synth Commun 1991, 21, 2, 271. |
| 【6】 Combs, D.W.; Bemoradan and related pyridazinone cardiotonics. Drugs Fut 1993, 18, 2, 139. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (I) | 41299 | 2-Benzoxazolinone; 2(3H)-benzoxazolone; 1,3-benzoxazol-2(3H)-one | 59-49-4 | C7H5NO2 | 详情 | 详情 |
| (II) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (III) | 41300 | 6-propionyl-1,3-benzoxazol-2(3H)-one | C10H9NO3 | 详情 | 详情 | |
| (IV) | 41301 | 7-propionyl-2H-1,4-benzoxazin-3(4H)-one | C11H11NO3 | 详情 | 详情 | |
| (V) | 41302 | N,N,N,2-tetramethyl-3-oxo-3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-propanaminium | C15H21N2O3 | 详情 | 详情 | |
| (VI) | 41303 | 3-methyl-4-oxo-4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)butyric acid | C13H13NO5 | 详情 | 详情 |