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【结 构 式】 
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【药物名称】 【化学名称】3,5-Dichloro-N-[1(S)-[2-(2-chloropyridin-3-ylamino)-3,4-dioxo-1-cyclobuten-1-ylamino]-2,2-dimethylpropyl]benzamide 【CA登记号】 【 分 子 式 】C21H19Cl3N4O3 【 分 子 量 】481.76958 |
【开发单位】Abbott (Originator) 【药理作用】RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, K(ATP) Channel Activators |
合成路线1
Condensation between 3-amino-2-chloropyridine (I) and 3,4-diethoxycyclobut-3-ene-1,2-dione (II) in refluxing EtOH affords the (pyridylamino)cyclobutenedione (III). The remaining ethoxy group of (III) is then displaced with methanolic ammonia to furnish the diamino cyclobutenedione (IV).
| 【1】 Basha, F.Z.; Carroll, W.A.; Kort, M.E.; Gregg, R.J.; Dinges, J.; Perez Medrano, A. (Abbott Laboratories Inc.); Aminal diones as potassium channel openers. US 2002165264; US 6495576; WO 0262761 . |
| 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) | 11160 | 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine | 6298-19-7 | C5H5ClN2 | 详情 | 详情 |
| (II) | 30975 | 3,4-diethoxy-3-cyclobutene-1,2-dione | 5231-87-8 | C8H10O4 | 详情 | 详情 |
| (III) | 57596 | 3-[(2-chloro-3-pyridinyl)amino]-4-ethoxy-3-cyclobutene-1,2-dione | C11H9ClN2O3 | 详情 | 详情 | |
| (IV) | 57597 | 3-amino-4-[(2-chloro-3-pyridinyl)amino]-3-cyclobutene-1,2-dione | C9H6ClN3O2 | 详情 | 详情 |
合成路线2
Reaction of 3,5-dichlorobenzamide (V) with pivalaldehyde (VI) in the presence of benzotriazole (VII) gives rise to the benzotriazolyl benzamide (VIII). This is then condensed with the diamino cyclobutene (IV) to afford the racemic adduct (IX), which is finally resolved into the enantiomers employing chiral chromatography.
| 【1】 Kort, M.E.; Gregg, R.J.; Perez-Medrano, A.; et al.; Aminal-containing ATP-sensitive potassium channel openers for the treatment of bladder overactivity. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 351. |
| 【2】 Basha, F.Z.; Carroll, W.A.; Kort, M.E.; Gregg, R.J.; Dinges, J.; Perez Medrano, A. (Abbott Laboratories Inc.); Aminal diones as potassium channel openers. US 2002165264; US 6495576; WO 0262761 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 57597 | 3-amino-4-[(2-chloro-3-pyridinyl)amino]-3-cyclobutene-1,2-dione | C9H6ClN3O2 | 详情 | 详情 | |
| (V) | 57598 | 2-Amino-3,5-dichlorobenzoic acid; 3,5-Dichloroanthranilic acid | 5980-23-4 | C7H5Cl2NO | 详情 | 详情 |
| (VI) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VII) | 57599 | 1,2,3-Benzotriazole; 1H-Benzotriazole; Azimidobenzene; Benzotriazol | 95-14-7 | C6H5N3 | 详情 | 详情 |
| (VIII) | 57600 | N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-3,5-dichlorobenzamide | C18H18Cl2N4O | 详情 | 详情 | |
| (IX) | 57601 | 3,5-dichloro-N-[1-({2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide | C21H19Cl3N4O3 | 详情 | 详情 |