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【结 构 式】 
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【药物名称】 【化学名称】2-(5-Chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,2,4-triazol-3-one 【CA登记号】202822-21-7 【 分 子 式 】C15H9ClF3N3O2 【 分 子 量 】355.70608 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, Large Conductance BK(Ca) Channel Activators |
合成路线1
4-Bromobenzotrifluoride (I) is converted to the corresponding Grignard reagent (II), which undergoes addition to diethyl oxalate, yielding keto ester (III). Subsequent saponification of ester (III) gives the phenylglyoxylic acid derivative (IV). Condensation of (IV) with 5-chloro-2-methoxyphenylhydrazine (V) affords the aryl hydrazone (VI). Curtius rearrangement of the carboxyl moiety of (VI) by means of diphenylphosphoryl azide generates the corresponding isocyanate, which spontaneously cyclizes to the triazolone (VII). Methyl ether cleavage in (VII) with boron tribromide gives rise to the title phenol derivative.
| 【1】 Hewawasan, P.; et al.; The synthesis and structure-activity relationships of 1,3-diaryl 1,2,4-(4H)-triazol-5-ones: A new class of calcium-dependent, large conductance, potassium (maxi-K) channel opener targeted for urge urinary incontinence. Bioorg Med Chem Lett 2002, 12, 7, 1117. |
| 【2】 Meanwell, N.A.; Starrett, J.E. Jr.; Hewawasam, P.; Romine, J.L.; Martin, S.W.; Gribkoff, V.K. (Bristol-Myers Squibb Co.); Diphenyl oxadiazolones as potassium channel modulators. JP 2000516925; US 5869509; WO 9804135 . |
| 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) | 34473 | 1-bromo-4-(trifluoromethyl)benzene | 402-43-7 | C7H4BrF3 | 详情 | 详情 |
| (II) | 39311 | bromo[4-(trifluoromethyl)phenyl]magnesium | C7H4BrF3Mg | 详情 | 详情 | |
| (III) | 57631 | ethyl 2-oxo-2-[4-(trifluoromethyl)phenyl]acetate | C11H9F3O3 | 详情 | 详情 | |
| (IV) | 57632 | 2-oxo-2-[4-(trifluoromethyl)phenyl]acetic acid | C9H5F3O3 | 详情 | 详情 | |
| (V) | 57633 | 1-(5-chloro-2-methoxyphenyl)hydrazine; 4-chloro-2-hydrazinophenyl methyl ether | C7H9ClN2O | 详情 | 详情 | |
| (VI) | 57634 | 2-[(Z)-2-(5-chloro-2-methoxyphenyl)hydrazono]-2-[4-(trifluoromethyl)phenyl]acetic acid | C16H12ClF3N2O3 | 详情 | 详情 | |
| (VII) | 57635 | 2-(5-chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C16H11ClF3N3O2 | 详情 | 详情 |