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【结 构 式】 
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【药物名称】AD-5467 【化学名称】(±)-2,8-Diisopropyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazine-4-acetic acid 【CA登记号】112808-22-7, 112808-42-1 (R-isomer), 112808-43-2 (S-isomer) 【 分 子 式 】C16H21NO3S 【 分 子 量 】307.41467 |
【开发单位】Takeda (Originator), Senju (Licensee) 【药理作用】ENDOCRINE DRUGS, Symptomatic Antidiabetic Agents, Treatment of Diabetic Complications, Aldose Reductase Inhibitors |
合成路线1
The cyclization of 2-amino-6-isoproylphenol (I) with 2-bromo-3-methylbutyryl chloride (II) by means of NaHCO3 in ethyl acetate - water gives 2,8-diisopropyl-2H-1,4-benzoxazin-3(4H)-one (III), which is condensed with methyl bromoacetate (IV) by means of NaH in DMF yielding 2,8-diisopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-acetic acid methyl ester (V). The reaction of (V) with P2S5 in refluxing toluene affords the corresponding thioxo derivative (VI), which is finally hydrolyzed with NaOH in dioxane - methanol.
| 【1】 Meguro, K.; Ikeda, H.; Yamamoto, Y. (Senju Pharmaceuticals Co., Ltd.; Takeda Chemical Industries, Ltd.); Thiolactam-N-acetic acid derivs., their production and use. EP 0243018; JP 1988107970; US 4771050 . |
| 【2】 Prous, J.; Castaner, J.; AD-5467. Drugs Fut 1991, 16, 1, 13. |
| 【3】 Ikeda, H.; Meguro, K.; Yamamoto, Y.; Tawada, Sugiyama, Y.; Studies on antidiabetic agents. IX. A new aldose reductase inhibitor, AD-5467, and related 1,4-benzoxazine and 1,4-benzothiazine derivatives: Synthesis and biological activity. Chem Pharm Bull 1990, 38, 5, 1238-45. |
| 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) | 12306 | 2-Amino-6-isopropylphenol | C9H13NO | 详情 | 详情 | |
| (II) | 12307 | alpha-Bromoisovaleryl chloride; 2-Bromo-3-methylbutanoyl chloride | 52574-82-0 | C5H8BrClO | 详情 | 详情 |
| (III) | 12308 | 2,8-diisopropyl-2H-1,4-benzoxazin-3(4H)-one | C14H19NO2 | 详情 | 详情 | |
| (IV) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (V) | 12310 | methyl 2-(2,8-diisopropyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate | C17H23NO4 | 详情 | 详情 | |
| (VI) | 12311 | methyl 2-(2,8-diisopropyl-3-thioxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate | C17H23NO3S | 详情 | 详情 |