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【结 构 式】 
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【分子编号】19374 【品名】dimethyl 2-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzylidene]malonate 【CA登记号】 |
【 分 子 式 】C24H23NO6 【 分 子 量 】421.44976 【元素组成】C 68.4% H 5.5% N 3.32% O 22.78% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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 the title compound.
| 【1】 Shinkai, H.; et al.; Isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents. J Med Chem 1998, 41, 11, 1927. |
| 【2】 Shinkai, H.; The isoxazolidine-3,5-dione hypoglycemic agent JTT-501 and other nonthiazolidinedione insulin sensitizers. Drugs Fut 1999, 24, 8, 893. |
| 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) | 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 |