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【结 构 式】 
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【药物名称】Rufinamide, RUF-331, CGP-33101, Xilep, Inovelon 【化学名称】1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide 【CA登记号】106308-44-5 【 分 子 式 】C10H8F2N4O 【 分 子 量 】238.19826 |
【开发单位】Novartis (Originator), Eisai (Licensee) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiepileptic Drugs, NEUROLOGIC DRUGS, Neuropathic Pain, Treatment of, Sodium Channel Blockers |
合成路线1
Rufinamide has been obtained by several related ways: 1) Cyclization of 2,6-difluorobenzyl azide (I) with 2-propynoic acid (II) in hot toluene gives 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (III), which is treated with refluxing SOCl2 to yield the corresponding acyl chloride (IV). Finally, this compound is treated with aqueous concentrated NH4OH. 2) Cyclization of 2,6-difluorobenyzl azide (I) with 2-chloroacrylonitrile (V) in hot water or n-heptane gives 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carbonitrile (VI), which is treated with NaOH in hot toluene/water. 3) Esterification of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (III) with methanol/H2SO4 gives the corresponding methyl ester (VII), which is treated with NH3 in hot methanol.
| 【1】 Leeson, P.A.; Sorbera, L.A.; Rabasseda, X.; Castaner, J.; Rufinamide. Drugs Fut 2000, 25, 11, 1145. |
| 【2】 Meier, R. (Novartis AG); Fluorinated benzyltriazole derivs.. AU 8656319; EP 0199262; ES 8800176; ES 8802501; JP 1986243068 . |
| 【3】 Portmann, R. (Novartis AG); Process for preparing 1-substd. 4-cyano-1,2,3-triazoles. WO 9802423 . |
| 【4】 Burkhard, A.; Szelagiewicz, M.; Hofmeier, U.C.; Portmann, R.; Scherrer, W. (Novartis AG); Crystal modification of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and its use as antiepileptic. WO 9856772; WO 9856773 . |
| 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) | 41769 | 2,6-difluorobenzyl azide; 2-(azidomethyl)-1,3-difluorobenzene | C7H5F2N3 | 详情 | 详情 | |
| (II) | 41770 | propiolic acid | 471-25-0 | C3H2O2 | 详情 | 详情 |
| (III) | 41771 | 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid | C10H7F2N3O2 | 详情 | 详情 | |
| (IV) | 41772 | 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carbonyl chloride | C10H6ClF2N3O | 详情 | 详情 | |
| (V) | 12372 | 2-Chloroacrylonitrile | 920-37-6 | C3H2ClN | 详情 | 详情 |
| (VI) | 41773 | 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carbonitrile | C10H6F2N4 | 详情 | 详情 | |
| (VII) | 41774 | methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate | C11H9F2N3O2 | 详情 | 详情 |
合成路线2
| 【1】 Kankan RN, Rao DR, Birari DR.2010.Process for the preparation of Rufinamide. WO 2010/043849 A1. |
合成路线3
| 【1】 Mudd WH, Stevens EP.2010.An efficient synthesis of rufinamide, an antiepileptic drug. Tetrahedron Lett,51: 3229～3231. |