【结 构 式】 |
【分子编号】20308 【品名】4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene 【CA登记号】50824-05-0 |
【 分 子 式 】C8H6BrF3O 【 分 子 量 】255.0342496 【元素组成】C 37.68% H 2.37% Br 31.33% F 22.35% O 6.27% |
合成路线1
该中间体在本合成路线中的序号:(VII)Condensation of 2,4-dinitroimidazole (I) with the silyl-protected (S)-glycidol (II) gave the N-substituted imidazole (III). The free hydroxyl group of (III) was then protected as the tetrahydropyranyl ether (IV) by treatment with dihydropyran and pyridinium tosylate. Desilylation of (IV) by means of tetrabutylammonium fluoride proceeded with concomitant nitro group displacement to afford the pyranoimidazole derivative (V). The tetrahydropyranyl group of (V) was then removed by acidic hydrolysis to provide alcohol (VI). Finally, condensation of (VI) with 4-(trifluoromethoxy)benzyl bromide (VII) under Williamson's ether synthesis conditions provided the title compound.
【1】 Baker, W.R.; Shaopei, C.; Keeler, E.L. (PathoGenesis Corp.); Nitroimidazole antibacterial cpds. and methods of use thereof. EP 0866793; JP 1999508270; WO 9701562 . |
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) | 56023 | 2,4-dinitro-1H-imidazole | 5213-49-0 | C3H2N4O4 | 详情 | 详情 |
(II) | 42416 | tert-butyl(dimethyl)[(2S)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2S)oxiranylmethyl ether | 123237-62-7 | C9H20O2Si | 详情 | 详情 |
(III) | 56024 | (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(2,4-dinitro-1H-imidazol-1-yl)-2-propanol | C12H22N4O6Si | 详情 | 详情 | |
(IV) | 56025 | 1-[(2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-(tetrahydro-2H-pyran-2-yloxy)propyl]-2,4-dinitro-1H-imidazole; tert-butyl(dimethyl)silyl (2S)-3-(2,4-dinitro-1H-imidazol-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl ether | C17H30N4O7Si | 详情 | 详情 | |
(V) | 56026 | (6S)-2-nitro-6-(tetrahydro-2H-pyran-2-yloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine; (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl tetrahydro-2H-pyran-2-yl ether | C11H15N3O5 | 详情 | 详情 | |
(VI) | 56027 | (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol | C6H7N3O4 | 详情 | 详情 | |
(VII) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(X)1) The reaction of 1-(4-nitrophenyl)piperazine (I) with tert-butyl dicarbonate (II) and triethylamine in dichloromethane gives 4-(4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (III), which is reduced with H2 over Pd/C, yielding the corresponding 4-amino compound (IV). The reaction of (IV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (VI), which by reaction with hydrazine is converted into the semicarbazide (VII). The cyclization of (VII) with formamidine (VIII) and triethylamine in hot 2-methoxyethanol affords the triazolone (IX), which is condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF, giving the disubstituted triazolone (XI). The deprotection, elimination of the tert-butoxycarbonyl group, of (XI) with HCl yields the monosubstituted piperazine (XII), which is finally condensed with (2R,3S)-oxirane (XIII) by means of LiClO4 in refluxing acetonitrile.
【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148. |
【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30. |
【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 . |
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) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
(II) | 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 |
(III) | 20301 | tert-butyl 4-(4-nitrophenyl)-1-piperazinecarboxylate | C15H21N3O4 | 详情 | 详情 | |
(IV) | 20302 | tert-butyl 4-(4-aminophenyl)-1-piperazinecarboxylate | C15H23N3O2 | 详情 | 详情 | |
(V) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
(VI) | 20304 | tert-butyl 4-[4-[(phenoxycarbonyl)amino]phenyl]-1-piperazinecarboxylate | C22H27N3O4 | 详情 | 详情 | |
(VII) | 20305 | tert-butyl 4-[4-[(hydrazinocarbonyl)amino]phenyl]-1-piperazinecarboxylate | C16H25N5O3 | 详情 | 详情 | |
(VIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
(IX) | 20307 | tert-butyl 4-[4-(5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl]-1-piperazinecarboxylate | C17H23N5O3 | 详情 | 详情 | |
(X) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
(XI) | 20309 | tert-butyl 4-(4-[5-oxo-1-[4-(trifluoromethoxy)benzyl]-1,5-dihydro-4H-1,2,4-triazol-4-yl]phenyl)-1-piperazinecarboxylate | C25H28F3N5O4 | 详情 | 详情 | |
(XII) | 20310 | 4-[4-(1-piperazinyl)phenyl]-2-[4-(trifluoromethoxy)benzyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C20H20F3N5O2 | 详情 | 详情 | |
(XIII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(X)2) The addition of 1-(4-nitrophenyl)piperazine (I) to the chiral oxirane (XIII) as before gives the disubstituted piperazine (XIV), which is hydrogenated with H2 over Pd/C in ethyl acetate, yielding the anilino derivative (XV). The acylation of (XV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (XVI), which is treated with hydrazine to give the semicarbazide (XVII). The cyclization of (XVII) with formamidine (VIII) as before affords the triazolone (XVIII), which is finally condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF.
【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148. |
【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30. |
【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 . |
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) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
(V) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
(VIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
(X) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
(XIII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
(XIV) | 20312 | (2R,3R)-2-(2,4-difluorophenyl)-3-[4-(4-nitrophenyl)-1-piperazinyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C22H24F2N6O3 | 详情 | 详情 | |
(XV) | 20313 | (2R,3R)-3-[4-(4-aminophenyl)-1-piperazinyl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C22H26F2N6O | 详情 | 详情 | |
(XVI) | 20314 | phenyl 4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenylcarbamate | C29H30F2N6O3 | 详情 | 详情 | |
(XVII) | 20315 | N-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-1-hydrazinecarboxamide | C23H28F2N8O2 | 详情 | 详情 | |
(XVIII) | 20316 | 4-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C24H26F2N8O2 | 详情 | 详情 |