|
【结 构 式】 
|
【分子编号】45721 【品名】4-(1-bromoethyl)-6-chloro-5-fluoropyrimidine 【CA登记号】188416-28-6 |
【 分 子 式 】C6H5BrClFN2 【 分 子 量 】239.4742832 【元素组成】C 30.09% H 2.1% Br 33.37% Cl 14.8% F 7.93% N 11.7% |
合成路线1
该中间体在本合成路线中的序号：(VI)The fluorination of 3-oxopentanoic acid methyl ester with F2 gas gives 2-fluoro-3-oxopentanoic acid methyl ester (II), which is cyclized with formamidine (III) by means of NaOMe yielding 6-ethyl-5-fluoropyrimidin-4-ol (IV). Reaction of (IV) with POCl3 and TEA in dichloromethane affords 4-chloro-6-ethyl-5-fluoropyrimidine (V), which is brominated with NBS and AIBN in dichloromethane to provide 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (VI). Compound (VI) is condensed with 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone (VII) by means of I2 and Zn in THF furnishing a mixture of the diastereomeric racemates (2R*,3R*)- and (2R*,3S*)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (VIII) in a 1:10.3 molar ratio. The reductive dechlorination of (2R*,3S*)-(VIII) with H2 over Pd/C gives the (2R*,3S*)-racemate (IX), which is submitted to optical resolution by means of crystallization with (1R)-10-camphorsulfonic acid.
| 【1】 Butters, M.; et al.; Process development of voriconazole: A novel broad-spectrum triazole antifungal agent. Org Process Res Dev 2001, 5, 1, 28. |
| 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) | 15536 | methyl 3-oxopentanoate | 30414-53-0 | C6H10O3 | 详情 | 详情 |
| (II) | 45716 | (E)-3-amino-2-chloro-2-propenal | C3H4ClNO | 详情 | 详情 | |
| (III) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (IV) | 45720 | 6-ethyl-5-fluoro-4-pyrimidinol | C6H7FN2O | 详情 | 详情 | |
| (V) | 15371 | 4-chloro-6-ethyl-5-fluoropyrimidine | C6H6ClFN2 | 详情 | 详情 | |
| (VI) | 45721 | 4-(1-bromoethyl)-6-chloro-5-fluoropyrimidine | 188416-28-6 | C6H5BrClFN2 | 详情 | 详情 |
| (VII) | 15372 | 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone | 863867-75-6 | C10H7F2N3O | 详情 | 详情 |
| (VIII) | 15373 | (2R,3S)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H13ClF3N5O | 详情 | 详情 | |
| (IX) | 15375 | (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H14F3N5O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)
| 【1】 Huang WX, Ctu DD, Guo JH, 2006. Process for preparation of vorieonazole.发明专利申请公开说明书．CN 1814597 |
| 【2】 Zhou HM, Zhou Y-2007. Process for directional preparation of voriconazole and its pharmaceutical formulations，发明专利申请公开说明书．CN1919946 |
| 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) | 15375 | (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H14F3N5O | 详情 | 详情 | |
| (I) | 45721 | 4-(1-bromoethyl)-6-chloro-5-fluoropyrimidine | 188416-28-6 | C6H5BrClFN2 | 详情 | 详情 |
| (II) | 66963 | tris(1-(6-chloro-5-fluoropyrimidin-4-yl)ethyl)aluminum | C18H15AlCl3F3N6 | 详情 | 详情 | |
| (III) | 15372 | 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone | 863867-75-6 | C10H7F2N3O | 详情 | 详情 |