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【结 构 式】 
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【药物名称】 【化学名称】4-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole 【CA登记号】177754-60-8 【 分 子 式 】C17H13F3N2O2S 【 分 子 量 】366.36456 |
【开发单位】Pfizer (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Cyclooxygenase-2 Inhibitors |
合成路线1
Reaction of benzaldehyde (I) with trimethylsilyl cyanide and ZnI2 gave O-trimethylsilyl cyanohydrin (II). Subsequent condensation of (II) with 4-(methylthio)benzaldehyde (III) in the presence of lithium hexamethyldisilazide, followed by quenching of the intermediate (IV) with KHF2 and HCl, provided benzoin (V). This was oxidized either under Swern conditions, or with Bi2O3 in acetic to afford the corresponding benzil (VI). Condensation of (VI) with trifluoroacetaldehyde ethyl hemiacetal (VII) produced imidazole (VIII). Finally, oxidation of the sulfide group of (VIII) with hydrogen peroxide in AcOH provided the target sulfone.
| 【1】 Barta, T.E.; Collins, P.W.; Weier, R.M.; Stealey, M.A.; Antiinflammatory 4,5-diarylimidazoles as selective cyclooxygenase inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3443. |
| 【2】 Weier, R.M.; Collins, P.W.; Stealey, M.A.; Barta, T.E.; Huff, R.M. (Pharmacia Corp.); 4,5-Substd. imidazolyl cpds. for the treatment of inflammation. EP 0772601; US 5620999; WO 9603387 . |
| 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) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (II) | 26578 | 2-phenyl-3-(trimethylsilyl)propanenitrile | C12H17NSi | 详情 | 详情 | |
| (III) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (IV) | 26579 | 3-hydroxy-3-[4-(methylsulfanyl)phenyl]-2-phenyl-2-[(trimethylsilyl)methyl]propanenitrile | C20H25NOSSi | 详情 | 详情 | |
| (V) | 26580 | 2-hydroxy-2-[4-(methylsulfanyl)phenyl]-1-phenyl-1-ethanone | C15H14O2S | 详情 | 详情 | |
| (VI) | 26581 | 1-[4-(methylsulfanyl)phenyl]-2-phenyl-1,2-ethanedione | C15H12O2S | 详情 | 详情 | |
| (VII) | 26582 | 1-ethoxy-2,2,2-trifluoro-1-ethanol | 433-27-2 | C4H7F3O2 | 详情 | 详情 |
| (VIII) | 26583 | methyl 4-[5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl]phenyl sulfide | C17H13F3N2S | 详情 | 详情 |
合成路线2
An related procedure was based on the formation of the intermediate stilbene sulfone (XII) by Wittig reaction. Thus, condensation of phosphonium salt (IX) with aldehyde (X) in the presence of LiOEt gave stilbene (XI) as a mixture of geometric isomers. Then, oxidation of the sulfide group of (XI) with Oxone provided stilbene sulfone (XII). Alternatively, phosphonium salt (XIV), prepared from benzyl chloride (XIII) and triphenyl phosphine, was condensed with benzaldehyde to yield (XII). The oxidation of stilbene (XII) with KMnO4 produced benzil (XV). Finally, cyclization of (XV) with hemiacetal (VII) furnished the title imidazole.
| 【1】 Barta, T.E.; Collins, P.W.; Weier, R.M.; Stealey, M.A.; Antiinflammatory 4,5-diarylimidazoles as selective cyclooxygenase inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3443. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 | |
| (VII) | 26582 | 1-ethoxy-2,2,2-trifluoro-1-ethanol | 433-27-2 | C4H7F3O2 | 详情 | 详情 |
| (IX) | 26584 | benzyl(triphenyl)phosphonium iodide | 15853-35-7 | C25H22IP | 详情 | 详情 |
| (X) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (XI) | 26585 | methyl 4-[(Z)-2-phenylethenyl]phenyl sulfide | C15H14S | 详情 | 详情 | |
| (XII) | 26586 | methyl 4-[(Z)-2-phenylethenyl]phenyl sulfone | C15H14O2S | 详情 | 详情 | |
| (XIII) | 26587 | 4-(chloromethyl)phenyl methyl sulfone | C8H9ClO2S | 详情 | 详情 | |
| (XIV) | 26588 | [4-(methylsulfonyl)benzyl](triphenyl)phosphonium chloride | C26H24ClO2PS | 详情 | 详情 | |
| (XV) | 26589 | 1-[4-(methylsulfonyl)phenyl]-2-phenyl-1,2-ethanedione | C15H12O4S | 详情 | 详情 |