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【结 构 式】 
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【药物名称】FR-167356 【化学名称】2,6-Dichloro-N-[3-(1-hydroxy-1-methylethyl)-2-methyl-1-benzofuran-7-yl]benzamide 【CA登记号】174185-16-1 【 分 子 式 】C19H17Cl2NO3 【 分 子 量 】378.25824 |
【开发单位】Fujisawa (Originator) 【药理作用】Bone Diseases, Treatment of, Bone Resorption Inhibitors, METABOLIC DRUGS, Treatment of Osteoporosis, Vacuolar H+ ATPase (V-ATPase) Inhibitors |
合成路线1
The condensation of 2-fluoronitrobenzene (I) with acetone oxime (II) by means of NaH in DMF gives acetone O-(2-nitrophenyl)oxime (III), which is cyclized to 2-methyl-7-nitrobenzofuran (IV) by means of H2SO4. The Friedel Crafts acylation of (IV) with acetyl chloride and AlCl3 in dichloromethane affords 3-acetyl-2-methyl-7-nitrobenzofuran (V), which is reduced to the corresponding amino derivative (VI) with Fe and HCl in ethanol. The condensation of (VI) with 2,6-dichlorobenzoyl chloride (VII) by means of triethylamine in dichloroethane yields N-(3-acetyl-2-methylbenzofuran-7-yl)-2,6-dichlorobenzamide (VIII), which is finally submitted to a Grignard reaction with methylmagnesium bromide in THF.
| 【1】 Yamazaki, H.; et al.; Synthesis and pharmacological activities of novel benzofuran derivatives as vacuolar type H+-ATPase inhibitors. Symp Med Chem 1998, Abst 2-P-32. |
| 【2】 Kawai, Y.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K.; Yatabe, T.; Oku, T. (Fujisawa Pharmaceutical Co., Ltd.); Benzofuran derivs. useful as inhibitors of bone resorption. EP 0757682; JP 1997512795; US 5858995; WO 9529907 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 17791 | acetone oxime; Acetoxime | 127-06-0 | C3H7NO | 详情 | 详情 |
| (III) | 25083 | acetone O-(2-nitrophenyl)oxime | C9H10N2O3 | 详情 | 详情 | |
| (IV) | 25084 | 2-methyl-7-nitro-1-benzofuran | C9H7NO3 | 详情 | 详情 | |
| (V) | 25086 | 1-(7-amino-2-methyl-1-benzofuran-3-yl)-1-ethanone | C11H11NO2 | 详情 | 详情 | |
| (VI) | 24086 | benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetate | C25H25N3O6S | 详情 | 详情 | |
| (VII) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (VIII) | 25088 | N-(3-acetyl-2-methyl-1-benzofuran-7-yl)-2,6-dichlorobenzamide | C18H13Cl2NO3 | 详情 | 详情 |