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【结 构 式】 
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【药物名称】Zonisamide, CI-912, AD-810, Zonegran, Excegran 【化学名称】3-(Sulfamoylmethyl)-1,2-benzisoxazole 【CA登记号】68291-97-4, 68291-98-5 (Na salt) 【 分 子 式 】C8H8N2O3S 【 分 子 量 】212.22856 |
【开发单位】Elan (Supplier), Eisai (Proprietary), Dainippon Pharmaceutical (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiepileptic Drugs, Antimigraine Drugs, Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, Migraine, Prophylactic Treatment of, NEUROLOGIC DRUGS, Neuropathic Pain, Treatment of, Sodium Channel Blockers, T-Type Calcium Channel Blockers |
合成路线1
The reaction of 3-bromomethyl-1,2-benzisoxazole (I) with sodium sulfite in hot methanol - water gives sodium 1,2-benzisoxazole-3-methanesulfonate (II), which by reaction with refluxing POCl3 is converted into 1,2-benzisoxazole-3-methanesufonyl chloride (III). Finally, this compound is treated with dry NH3 in ethyl acetate.
| 【1】 Uno, H.; et al. (Dainippon Pharmaceutical Co., Ltd.); Methane-sulfonamide derivatives, the preparation thereof and composition comprising the same. US 4172896 . |
| 【2】 Castaner, J.; Owen, R.T.; Blancafort, P.; Serradell, M.N.; AD-810. Drugs Fut 1980, 5, 8, 387. |
合成路线2
The reaction of 4-hydroxy-H-1-benzopyran-2-one (I) with hydroxylamine by means of NaOEt in ethanol gives 2-(1,2-benzisoxazol-3-yl)acetic acid (II), which is sulfonated by means of H2SO4 and Ac2O in refluxing ethyl acetate, or ClSO3H in refluxing dichloromethane, to yield 1,2-benzisoxazol-3-ylmethylsulfonic acid (III). The reaction of (III) with refluxing POCl3 affords the sulfonyl chloride (IV), which is finally treated with ammonia in ethyl acetate to provide the target Zonisamide
| 【1】 Schwartz, E.; Mendelovici, M.; Nidam, T.; Wizel, S. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Zonisamide intermediate and synthesis. WO 0320708 . |
| 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) | 29063 | 4-Hydroxycoumarine; 4-Hydroxy-2H-chromen-2-one; 4-hydroxy-2H-1-benzopyran-2-one; 4-oxocoumarin-3,4-dihydro-4-hydroxycoumarin; 4-hydroxy-2H-1-benzopyran-2-one | 1076-38-6 | C9H6O3 | 详情 | 详情 |
| (II) | 62503 | 2-(1,2-benzisoxazol-3-yl)acetic acid | C9H7NO3 | 详情 | 详情 | |
| (III) | 62504 | 1,2-benzisoxazol-3-ylmethanesulfonic acid | C8H7NO4S | 详情 | 详情 | |
| (IV) | 32734 | 1,2-benzisoxazol-3-ylmethanesulfonyl chloride | C8H6ClNO3S | 详情 | 详情 |
合成路线3
| 【1】 Naddaka V, Adin I .Klopfer E, et al. 2006. Two crystalline forms of sodium l,2-benzisoxazole-3-methanesulfonate, and processes for the preparation and use thereof in the synthesis of zonisarrude. US 20Q6009644 |
合成路线4
| 【1】 Jaweed Mukarram SM, Merwade AY, Shukla JD, et al. 2005. A process of the manufacture of zonisamide, useful as anticonvulsant agent. W0 2005044808 |
| 【2】 Nidam T, Mendelovici M, Schwartz E, et al. 2003. Process for the prepantion of l,2-benzisoxazole-3- methanesulforuc acid and its salts, intermediates in the synthesis of Zonisamide . W0 2003020708 |
| 【3】 Siva Kurnar BV, Bhirud SB, Chandnsekhar BK, et al. 2006. Process for the preparation of zonisamide. US 2006084814 |
| 【4】 Ueno Y, Ishikura T. 2005. One-pot process for the preparation of l,2-benziaoxazole-3-metbanesulforuunide from 4-hydroxycoumarin. US 2005215796 |
| 【5】 Uno H, Kurokawa M, Masuda Y, et al. 1979. Studies on 3-substituted l,2-benzisoxazole derivatives. 6. Syntheses of 3-(sulfamoylmethyl)-1,2-benzisonzole derivatives and their anticonvulsant activties. J Med Chem, 22 (2): 180～183 |
| 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) | 32734 | 1,2-benzisoxazol-3-ylmethanesulfonyl chloride | C8H6ClNO3S | 详情 | 详情 | |
| (I) | 29063 | 4-Hydroxycoumarine; 4-Hydroxy-2H-chromen-2-one; 4-hydroxy-2H-1-benzopyran-2-one; 4-oxocoumarin-3,4-dihydro-4-hydroxycoumarin; 4-hydroxy-2H-1-benzopyran-2-one | 1076-38-6 | C9H6O3 | 详情 | 详情 |
| (II) | 62503 | 2-(1,2-benzisoxazol-3-yl)acetic acid | C9H7NO3 | 详情 | 详情 | |
| (III) | 62504 | 1,2-benzisoxazol-3-ylmethanesulfonic acid | C8H7NO4S | 详情 | 详情 |
合成路线5
| 【1】 Mendelovici M, Gershon N, Nidam T, et al. 2003. Method for preparing l, 2-benzisoxazole-3-metbanesulfonyl chloride using thionyl chloride, and its amidation to form zonisamide. W0 2003072552 |