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【结 构 式】 
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【药物名称】Reglitazar, PNU-182716, JTT-501 【化学名称】4-[4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]isoxazolidine-3,5-dione 【CA登记号】170861-63-9 【 分 子 式 】C22H20N2O5 【 分 子 量 】392.4151 |
【开发单位】Japan Tobacco (Originator), Pfizer (Licensee) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARgamma Agonists |
合成路线1
Acetylation of N-benzoylaspartic acid beta-methyl ester (I) with acetic anhydride and subsequent decarboxylation gave the 3-benzoylamino-4-oxovalerate (II). The methyl oxazolylacetate (III) was prepared by cyclization of 4-oxovalerate (II) in the presence of Ac2O. Ester (III) was then reduced to alcohol (IV) with LiBH4 and further converted to mesylate (V) with methanesulfonyl chloride and Et3N. Coupling between mesylate (V) and 4-hydroxybenzaldehyde (VI) gave ether (VII). Knoevenagel condensation of (VII) with dimethyl malonate using piperidine acetate produced the benzylidene malonate (VIII). Finally, catalytic hydrogenation with Pd/C furnished JTP-20993. The title compound (JTT-501) is obtained by reaction of JTP-20993 with NH2OH.
| 【1】 Shinkai, H.; The isoxazolidine-3,5-dione hypoglycemic agent JTT-501 and other nonthiazolidinedione insulin sensitizers. Drugs Fut 1999, 24, 8, 893. |
| 【2】 Shinkai, H. (Japan Tobacco Inc.); Isoxazolidinedione deriv. and use thereof. EP 0684242; JP 1996517913; US 5728720; US 6057343; WO 9518125 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| JTP-20993 | 41516 | dimethyl 2-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl]malonate | C24H25NO6 | 详情 | 详情 | |
| (I) | 41311 | 2-(benzoylamino)-4-methoxy-4-oxobutyric acid | C12H13NO5 | 详情 | 详情 | |
| (II) | 41312 | methyl 3-(benzoylamino)-4-oxopentanoate | C13H15NO4 | 详情 | 详情 | |
| (III) | 41313 | methyl 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetate | C13H13NO3 | 详情 | 详情 | |
| (IV) | 19874 | 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol | C12H13NO2 | 详情 | 详情 | |
| (V) | 41315 | 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl methanesulfonate | C13H15NO4S | 详情 | 详情 | |
| (VI) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VII) | 19372 | 4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzaldehyde | C19H17NO3 | 详情 | 详情 | |
| (VIII) | 19374 | dimethyl 2-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzylidene]malonate | C24H23NO6 | 详情 | 详情 |