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【结 构 式】 
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【分子编号】32865 【品名】ethyl 3-[[(benzyloxy)carbonyl]amino]-2,5-dioxo-3-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C15H16N2O6 【 分 子 量 】320.30192 【元素组成】C 56.25% H 5.03% N 8.75% O 29.97% |
合成路线1
该中间体在本合成路线中的序号：(III)The alkylation of ethyl 2-(benzyloxycarbonylamino)cyanoacetate (I) with ethyl bromoacetate and anhydrous potassium carbonate in acetone gives diethyl 2-(benzyloxycarbonylamino)-2-cyanosuccinate (II), which is hydrolyzed by means of hydrogen peroxide and sodium carbonate in acetone/water, yielding 3-(benzyloxycarbonylamino)-3-(ethoxycarbonyl)pyrrolidine-2,5-dione (III). Racemic (III) is then resolved by means of crystallization with cinchonidine in ethanol to give the (-)-enantiomer (IV) (>99.5% e.e.). Hydrogenolysis of (IV) over Pd/C in ethanol, followed by treatment with 2,5-dimethoxytetrahydrofuran in acetic acid, affords (-)-3-(ethoxycarbonyl)-3-(pyrrol-1-yl)pyrrolidine-2,5-dione (VI). Treatment of (VI) with trichloroacetyl chloride in ethyl acetate, followed by condensation with 4-bromo-2-fluorobenzylamine in the presence of triethylamine, gives AS-3201 (>99.4% e.e.).
| 【1】 Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya, M.; Suzuki, M.; Matsumoto, J.; Novel, highly potent aldose reductase inhibitors: (R)-(-)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (AS-3201) and its congeners. J Med Chem 1998, 41, 21, 4118-29. |
| 【2】 Negoro, T.; Komiya, M.; Ono, Y.; AS-3201. Drugs Fut 2000, 25, 2, 131. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 | |
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| 19560 | (4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine | 112734-22-2 | C7H7BrFN | 详情 | 详情 | |
| (I) | 32863 | ethyl 2-[[(benzyloxy)carbonyl]amino]-2-cyanoacetate | C13H14N2O4 | 详情 | 详情 | |
| (II) | 32864 | diethyl 2-[[(benzyloxy)carbonyl]amino]-2-cyanosuccinate | C17H20N2O6 | 详情 | 详情 | |
| (III) | 32865 | ethyl 3-[[(benzyloxy)carbonyl]amino]-2,5-dioxo-3-pyrrolidinecarboxylate | C15H16N2O6 | 详情 | 详情 | |
| (IV) | 32866 | ethyl (3R)-3-[[(benzyloxy)carbonyl]amino]-2,5-dioxo-3-pyrrolidinecarboxylate | C15H16N2O6 | 详情 | 详情 | |
| (V) | 32867 | ethyl (3R)-3-amino-2,5-dioxo-3-pyrrolidinecarboxylate | C7H10N2O4 | 详情 | 详情 | |
| (VI) | 32868 | ethyl (3R)-2,5-dioxo-3-(1H-pyrrol-1-yl)-3-pyrrolidinecarboxylate | C11H12N2O4 | 详情 | 详情 | |
| (VII) | 32869 | ethyl (3R)-2,5-dioxo-3-[2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]-3-pyrrolidinecarboxylate | C13H11Cl3N2O5 | 详情 | 详情 |