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【结 构 式】 
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【分子编号】15374 【品名】(2R,3R)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol 【CA登记号】 |
【 分 子 式 】C16H13ClF3N5O 【 分 子 量 】383.7602296 【元素组成】C 50.08% H 3.41% Cl 9.24% F 14.85% N 18.25% O 4.17% |
合成路线1
该中间体在本合成路线中的序号：(VII)The cyclization of 2-fluoro-3-oxopentanoic acid ethyl ester (I) with formamidine (II) by means of sodium methoxide in refluxing methanol gives 6-ethyl-5-fluoropyrimidin-4(3H)-one (III), which by reaction with refluxing POCl3 is converted into 4-chloro-6-ethyl-5-fluoropyrimidine (IV). The condensation of (IV) with 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone (V) by means of lithium diisopropylamide in THF yields two pairs of diastereomers (R*,S*)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)-2-butanol (VI) (racemic pair A) and the (R*,R*)-racemic pair B (VII). The reductive dechlorination of (VI) with H2 over Pd/C in ethanol affords the racemic pair (VIII), which is submitted to optical resolution with 1(S)-(+)-10-camphorsulfonic acid.
| 【1】 Fromtling, R.A.; Castaner, J.; Voriconazole. Drugs Fut 1996, 21, 3, 266. |
| 【2】 Ray, S.J.; Richardson, K. (Pfizer Inc.); Triazole antifungal agents. EP 0440372; JP 1992211078; JP 1997208583; US 5278175; US 5773443 . |
| 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) | 15368 | ethyl 2-fluoro-3-oxopentanoate | C7H11FO3 | 详情 | 详情 | |
| (II) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (III) | 15370 | 6-ethyl-5-fluoro-4(3H)-pyrimidinone | C6H7FN2O | 详情 | 详情 | |
| (IV) | 15371 | 4-chloro-6-ethyl-5-fluoropyrimidine | C6H6ClFN2 | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 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 | |
| (VII) | 15374 | (2R,3R)-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 | |
| (VIII) | 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 |