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【结 构 式】 
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【分子编号】29063 【品名】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 【CA登记号】1076-38-6 |
【 分 子 式 】C9H6O3 【 分 子 量 】162.14484 【元素组成】C 66.67% H 3.73% O 29.6% |
合成路线1
该中间体在本合成路线中的序号：(I)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2
该中间体在本合成路线中的序号：(IV)Reaction of 4-methylthiobenzaldehyde (I) with acetone (A) affords in a 90% yield E-4-methylmercaptophenyl-3-buten-2-one (II), which is oxidized by sodium periodate to the sulfoxide (III) in a 55% yield without forming any sulfone as byproduct. The sulfoxide then reacts with 4-hydroxycumarin without solvent at 140 C to form methylsulfinylwarifarin. The compound is purified by extraction from ether with a 1% sodium hydroxide solution and then precipitated with 10% hydrochloric acid. The yield of the last step is 30% of theory.
| 【1】 Rehse, K.; Methylsulfinylwarfarin. Drugs Fut 1985, 10, 3, 205. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (I) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (II) | 29061 | (E)-4-[4-(methylsulfanyl)phenyl]-3-buten-2-one | C11H12OS | 详情 | 详情 | |
| (III) | 29062 | (E)-4-[4-(methylsulfinyl)phenyl]-3-buten-2-one | C11H12O2S | 详情 | 详情 | |
| (IV) | 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 |
合成路线3
该中间体在本合成路线中的序号：(I)
| 【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 |