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【结 构 式】 
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【药物名称】Zaldaride maleate, KW-5617, Zy-17617B, CGS-9343B 【化学名称】1-[1-(4-Methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-benzimidazol-2-one maleate (1:1) salt 【CA登记号】109826-27-9, 109826-26-8 (free base) 【 分 子 式 】C30H32N4O6 【 分 子 量 】544.61274 |
【开发单位】Gebro Pharma (Originator), Novartis (Originator), Kyowa Hakko (Licensee) 【药理作用】Antidiarrheal Agents, GASTROINTESTINAL DRUGS, Calmodulin Antagonists |
合成路线1
The cyclization of methyl 2-aminobenzoate (I) with 2,5-dimethoxytetrahydrofuran (II) in refluxing acetic acid gives methyl 2-(pyrrol-1-yl)benzoate (III), which by reduction with LiAlH4 in ether is converted into 2-(pyrrol-1-yl)benzyl alcohol (IV). The cyclization of (IV) with ethyl 2-oxopropionate (V) by means of butyllithium and tetramethylethylenediamine (TMEDA) in THF affords 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylic acid ethyl ester (VI), which is hydrolyzed with NaOH in refluxing ethanol to the corresponding free acid (VII). The condensation of (VII) with 1-(piperidin-4-yl)-2,3-dihydro-1H-benzimidazol-2-one (VIII) by means of carbonyldiimidazol (CDI) in THF gives 1-[1-(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-ylcarbonyl) piperidin-4-yl]-2,3-dihydro-1H-benzimidazol-2-one (IX), which is finally reduced with LiAlH4 in THF, and treated with maleic acid in acetone.
| 【1】 Robinson, C.; Robinson, K.; Castaner, J.; Zaldaride Maleate. Drugs Fut 1996, 21, 7, 719. |
| 【2】 Wasley, J.W.F.; Norman, J. (Novartis AG); Pyrrolo[1,2-a][4,1]benzoxazepins, process for their preparation, pharmaceutical compsns. containing them as well as therapeutic use. EP 0233483; JP 1987169791; JP 1995089966; US 4758559 . |
| 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) | 11161 | methyl 2-aminobenzoate; Methyl anthranilate | 134-20-3 | C8H9NO2 | 详情 | 详情 |
| (II) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (III) | 12133 | methyl 2-(1H-pyrrol-1-yl)benzoate | C12H11NO2 | 详情 | 详情 | |
| (IV) | 12134 | [2-(1H-Pyrrol-1-yl)phenyl]methanol | C11H11NO | 详情 | 详情 | |
| (V) | 12135 | ethyl 2-oxopropanoate; Ethyl pyruvate | 617-35-6 | C5H8O3 | 详情 | 详情 |
| (VI) | 12136 | ethyl 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylate | C16H17NO3 | 详情 | 详情 | |
| (VII) | 12137 | 4-Methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylic acid | C14H13NO3 | 详情 | 详情 | |
| (VIII) | 12138 | 1-(4-Piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one; 4-(2-Keto-1-benzimidazolinyl)piperidine | 20662-53-7 | C12H15N3O | 详情 | 详情 |
| (IX) | 12139 | 1-[1-[(4-Methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)carbonyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one | C26H26N4O3 | 详情 | 详情 |