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【结 构 式】 
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【药物名称】VP-343 【化学名称】(S,S)-N-[4-(2-Hydroxy-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxalin-5-ylcarbonyl)phenyl]-4'-methylbiphenyl-2-carboxmide 【CA登记号】 【 分 子 式 】C32H29N3O3 【 分 子 量 】503.60623 |
【开发单位】Wakamoto (Originator) 【药理作用】Diuretics, RENAL-UROLOGIC DRUGS, Vasopressin V2 Antagonists |
合成路线1
Condensation of 1-fluoro-2-nitrobenzene (I) with cis-4-hydroxy-D-proline methyl ester (II) in hot acetonitrile provided the N-(2-nitrophenyl)proline derivative (III). The stereochemical inversion of the hydroxyl group of (III) was achieved by Mitsunobu coupling with acetic acid, followed by basic hydrolysis of the resulting acetate ester (IV) to acid (V). The nitro acid (V) obtained was then hydrogenated over Pd/C to form the tricyclic lactam (VI). Further reduction of the lactam carbonyl group by means of NaBH4 in refluxing THF gave pyrroloquinoxaline (VII). This was finally coupled with 4-(4'-methyl-2-biphenylcarboxamido)benzoyl chloride (VIII) to furnish the target amide.
| 【1】 Naito, A.; Ohtake, Y.; Hasegawa, H.; et al.; Novel vasopressin V2 receptor-selective antagonists, pyrrolo[2,1-a]quinoxaline and pyrrolo[2,1-c][1,4]benzodiazepine derivatives. Bioorg Med Chem 1999, 7, 6, 1247. |
| 【2】 Matsukawa, H.; Toyofuku, H.; Naito, A.; Ohtake, Y.; Saito, Y.; Naito, K. (Wakamoto Pharmaceutical Co., Ltd.); Biphenyl derivs. and medicinal compsns.. EP 0987266; WO 9843976 . |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 36815 | methyl (2R,4R)-4-hydroxy-2-pyrrolidinecarboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 36816 | methyl (2R,4R)-4-hydroxy-1-(2-nitrophenyl)-2-pyrrolidinecarboxylate | C12H14N2O5 | 详情 | 详情 | |
| (IV) | 36817 | methyl (2R,4S)-4-(acetoxy)-1-(2-nitrophenyl)-2-pyrrolidinecarboxylate | C14H16N2O6 | 详情 | 详情 | |
| (V) | 36818 | (2R,4S)-4-hydroxy-1-(2-nitrophenyl)-2-pyrrolidinecarboxylic acid | C11H12N2O5 | 详情 | 详情 | |
| (VI) | 36819 | (2S,3aR)-2-hydroxy-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxalin-4(5H)-one | C11H12N2O2 | 详情 | 详情 | |
| (VII) | 36820 | (2S,3aR)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxalin-2-ol | C11H14N2O | 详情 | 详情 | |
| (VIII) | 36821 | 4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl chloride | C21H16ClNO2 | 详情 | 详情 |