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【结 构 式】 
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【药物名称】FLB-463 【化学名称】(S)-(-)-3-Bromo-N-(1-ethyl-2-pyrrolidinylmethyl)-2-hydroxy-5,6-dimethoxybenzamide 【CA登记号】101460-66-6, 125198-22-3 (mesylate salt) 【 分 子 式 】C16H23BrN2O4 【 分 子 量 】387.27671 |
【开发单位】AstraZeneca (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D2 Antagonists |
合成路线1
The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-bromo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.
| 【1】 Hogberg, M.; Novel substituted salicylamides and benzamides as selective dopamine D2-receptor antagonists. Drugs Fut 1991, 16, 4, 333. |
| 【2】 Ramsby, S.; Hogberg, T.; Strom, P.; Efficient stereoconservative syntheses of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines. Acta Chem Scand 1989, 43, 660-664. |
| 【3】 Hogberg, T.; Ramsby, S.; Strom, P.; Ebner, M.; Cyanide as an efficient and mild catalyst in the aminolysis of esters. J Org Chem 1987, 52, 2033-2036. |
| 【4】 Hogberg, T.; et al.; Potential antipsychotic agents. 5. Synthesis and antidopaminergic properties of substituted 5, 6-dimethoxysalicylamides and related compounds. J Med Chem 1990, 33, 1155-63. |
| 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) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (II) | 10925 | Iodoethane;ethyl iod | 75-03-6 | C2H5I | 详情 | 详情 |
| (III) | 42895 | ethyl (2S)-1-ethyl-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (IV) | 42896 | (2S)-1-ethyl-2-pyrrolidinecarboxamide | 55446-83-8 | C7H14N2O | 详情 | 详情 |
| (V) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 | |
| (VI) | 42897 | 3-bromo-2,5,6-trimethoxybenzoyl chloride | C10H10BrClO4 | 详情 | 详情 | |
| (VII) | 42898 | 3-bromo-N-[[(2S)-1-ethylpyrrolidinyl]methyl]-2,5,6-trimethoxybenzamide | C17H25BrN2O4 | 详情 | 详情 |