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【结 构 式】 
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【药物名称】Oxiracetam, CT-848, CGP-21690E, ISF-2522, Neuractiv, Oriest, Neuromet 【化学名称】4-Hydroxy-2-oxo-1-pyrrolidineacetamide 【CA登记号】62613-82-5 【 分 子 式 】C6H10N2O3 【 分 子 量 】158.1582 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Cognition Disorders, Treatment of, NEUROLOGIC DRUGS |
合成路线1
The reaction of ethyl iminodiacetate (I) with 2-ethoxycarbonylacetyl chloride (II) by means ot triethylamine in refluxing methylene chloride gives ethyl N-(2-ethoxycarbonylacetyl)iminodiacetate (III), which is cyclized by means of sodium ethoxide in refluxing ethanol yielding ethyl 4-hydroxy-3-(ethoxycarbonyl)-DELTA3-pyrrolin-2-one-1-acetate (IV). The isomerization of (IV) with water in refluxing acetonitrile affords ethyl pyrrolidine-2,4-dione-1-acetate (V), which is reduced with NaBH4 in dimethoxyethane to ethyl 4-hydroxypyrrolidine-2-one-1-acetate (VI). Finally, this compound is treated with ammonia in methanol.
| 【1】 Pifferi, G.; Pinza, M.; Cyclic GABA [4-aminobutyric acid]-GABOB[4-amino-3-hydroxybutyric acid] analogs. I. Synthesis of new 4-hydroxy-2-pyrrolidinone derivatives. Farmaco 1977, 32, 8, 602-613. |
| 【2】 Pifferi, G.; Pinza, M. (ISF SpA); Pyrrolidine derivatives. DE 2635853; FR 2320741; GB 1550160; NL 7608946; US 4118396 . |
| 【3】 de Angelis, L.; Blancafort, P.; Serradell, M.N.; Castaner, J.; Oxiracetam. Drugs Fut 1980, 5, 8, 405. |
| 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) | 32712 | Ethyl 2-[(2-ethoxy-2-oxoethyl)amino]acetate; Ethyl iminodiacetate | 6290-05-7 | C8H15NO4 | 详情 | 详情 |
| (II) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| (III) | 32713 | Ethyl 3-[bis(2-ethoxy-2-oxoethyl)amino]-3-oxopropanoate; N-(2-Ethoxycarbonylacetyl)iminodiacetate | C13H21NO7 | 详情 | 详情 | |
| (IV) | 32714 | Ethyl 4-hydroxy-3-(ethoxycarbonyl)-delta3-pyrrolin-2-one-1-acetate; Ethyl 1-(2-ethoxy-2-oxoethyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate | C11H15NO6 | 详情 | 详情 | |
| (V) | 32715 | Ethyl 2-(2,4-dioxo-1-pyrrolidinyl)acetate; Ethyl pyrrolidine-2,4-dione-1-acetate | C8H11NO4 | 详情 | 详情 | |
| (VI) | 32716 | Ethyl 2-(4-hydroxy-2-oxo-1-pyrrolidinyl)acetate; Ethyl 4-hydroxypyrrolidine-2-one-1-acetate | C8H13NO4 | 详情 | 详情 |
合成路线2
The silylation of 3-hydroxy-4-aminobutyric acid (VII) with bistrimethylsilyl amine gives 3-(trimethylsilyloxy)-4-aminobutyric acid (VIII), which is cyclized to 4-(trimethylsilyloxy)-2-pyrrolidinone (IX) by heating. The treatment of (IX) with ethyl bromoacetate (A) affords ethyl 4-(trimethylsilyloxy)pyrrolidine-2-one-1-acetate (X), which by desilylation with HCl gives ethyl 4-hydroxypyrrolidine-2-one-1-acetate (VI). Finally, this compound is treated with ammonia in methanol.
| 【1】 Banfi, S.; et al. (ISF SpA); Preparation of pyrrolidine and pyrrolidin-2-one derivatives. DE 2758937; DE 2758939; ES 466856; FR 2380257; GB 1588075; JP 53101367; US 4173569 . |
| 【2】 de Angelis, L.; Blancafort, P.; Serradell, M.N.; Castaner, J.; Oxiracetam. Drugs Fut 1980, 5, 8, 405. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (VI) | 32716 | Ethyl 2-(4-hydroxy-2-oxo-1-pyrrolidinyl)acetate; Ethyl 4-hydroxypyrrolidine-2-one-1-acetate | C8H13NO4 | 详情 | 详情 | |
| (VII) | 32717 | 4-Amino-3-hydroxybutyric acid; 3-Hydroxy-4-aminobutyric acid | 352-21-6 | C4H9NO3 | 详情 | 详情 |
| (VIII) | 32718 | 4-Amino-3-[(trimethylsilyl)methyl]butyric acid; 3-(Trimethylsilyloxy)-4-aminobutyric acid | C8H19NO2Si | 详情 | 详情 | |
| (IX) | 32719 | 4-(Trimethylsilyloxy)-2-pyrroIidinone | C8H17NOSi | 详情 | 详情 | |
| (X) | 32720 | Ethyl 2-[2-oxo-4-[(trimethylsilyl)methyl]-1-pyrrolidinyl]acetate; ethyl 4-(Trimethylsilyloxy)pyrrolidine-2-one-1-acetate | C12H23NO3Si | 详情 | 详情 |