|
【结 构 式】 
|
【分子编号】41313 【品名】methyl 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetate 【CA登记号】 |
【 分 子 式 】C13H13NO3 【 分 子 量 】231.25116 【元素组成】C 67.52% H 5.67% N 6.06% O 20.76% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(III)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 |
合成路线3
该中间体在本合成路线中的序号：(III)The cyclization of methyl 4-bromo-3-oxopentanoate (I) with benzamide (II) and sodium hydrogen phosphate in refluxing ethanol gives methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (III), which is reduced with LiAlH4 in THF to yield the ethanol derivative (IV). The reaction of (IV) with methanesulfonyl chloride and TEA in dichloromethane affords the mesylate (V), which is condensed with N-(tert-butoxycarbonyl)-L-tyrosine (VI) by means of NaOH in hot DMSO/water to provide the 4-O-substituted tyrosine (VII), which is deprotected by means of HCl in dioxane to give intermediate (VIII) with a free amino group. Finally, this compound is condensed with benzoylacetone (IX) by means of trimethyl orthoformate in refluxing methanol to afford the target N-substituted tyrosine derivative.
| 【1】 Oplinger, J.A.; Dezube, M.; Willson, T.M.; Collins, J.L. (Glaxo Group Ltd.); Substd. oxazoles and thiazoles derivs. as hPPAR gamma and hPPAR alpha activators. EP 1102757; WO 0008002 . |
| 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) | 49397 | methyl 4-bromo-3-oxopentanoate | C6H9BrO3 | 详情 | 详情 | |
| (II) | 40592 | Benzamide | 55-21-0 | C7H7NO | 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) | 25395 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | 3978-80-1 | C14H19NO5 | 详情 | 详情 |
| (VII) | 49398 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propionic acid | C26H30N2O6 | 详情 | 详情 | |
| (VIII) | 49399 | (2S)-2-amino-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propionic acid | C21H22N2O4 | 详情 | 详情 | |
| (IX) | 23829 | 1-phenyl-1,3-butanedione | 93-91-4 | C10H10O2 | 详情 | 详情 |