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【结 构 式】 
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【分子编号】15372 【品名】1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone 【CA登记号】863867-75-6 |
【 分 子 式 】C10H7F2N3O 【 分 子 量 】223.1820064 【元素组成】C 53.82% H 3.16% F 17.03% N 18.83% O 7.17% |
合成路线1
该中间体在本合成路线中的序号：(V)The Friedel-Crafts' condensation of 1,3-difluorobenzene (I) with chloroacetyl chloride (II) by means of AlCl3 yields alpha-chloro-2,4-difluoroacetophenone (III), which is treated with 1,2,4-triazole (IV) and triethylamine in refluxing ethyl acetate giving alpha-(1H-12,4-triazol-1-yl)-2,4-diftuoroacetophenone (V). The reaction of (V) with trimethylsulfoxonium iodide (VI) by means of NaOH in toluene affords 1-[2-(2,4-di fluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole (VII), which is finally treated again with 1,2,4-triazole (IV) and K2CO3 in hot DMF.
| 【1】 Narayanaswami, S.; Richardson, K. (Pfizer Inc.); Triazole antifungal agents. EP 0096569; ES 523038 . |
| 【2】 Richardson, K. (Pfizer Inc.); Triazoles. GB 2099818; US 4404216 . |
| 【3】 Fromtling, R.A.; Castaner, J.; Serradell, M.N.; Fluconazole. Drugs Fut 1985, 10, 12, 982. |
| 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) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 16321 | 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone | 51336-94-8 | C8H5ClF2O | 详情 | 详情 |
| (IV) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 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) | 29693 | Trimethylsulfoxonium iodide | 1774-47-6 | C3H9IOS | 详情 | 详情 |
| (VII) | 29839 | 1-[[2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1H-1,2,4-triazole | 86386-76-7 | C11H9F2N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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 |
合成路线3
该中间体在本合成路线中的序号：(VII)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4
该中间体在本合成路线中的序号：(III)
| 【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 |
合成路线5
该中间体在本合成路线中的序号：(II)
| 【1】 Satyanarayana RM, Nagaraju C, Kodanda RA. 2007. Process for preparation of (2R,3S)-2-(2,4-difluorophenyl) -3-(5-fluoropyrimidur4-yl) -1-(1H-1,2.4-triazol-l-yl) butan-2-ol (voriconazole) from 4-chloro-6-ethyl-5-fluoropyrimidine and l-(2,4-difluorophenyl) -2-(1H-1,2,4-triazol-l-yl) ethanone. W0 2007013096 |
| 【2】 Sundaram V, Uppala VBR, Akundi SP, et aL. 2006. Process for preparation of voriconazole from l-(2,4-difluorophenyl) -2-(1H-1,2,4-triazol-l-yl) ethanone and 4-chloro-6-ethyl-5-fluoropyrimidine. WO 2006065726 |
| 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) | 15371 | 4-chloro-6-ethyl-5-fluoropyrimidine | C6H6ClFN2 | 详情 | 详情 | |
| (III) | 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 | |
| (II) | 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 |
合成路线6
该中间体在本合成路线中的序号：(II)
| 【1】 Zhang WX. 2004．Process for the preparation of voriconazole and its pharmaceutically acceptable salts.发明专利申请公开说明书，CN 1473825 |
| 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) | 15371 | 4-chloro-6-ethyl-5-fluoropyrimidine | C6H6ClFN2 | 详情 | 详情 | |
| (II) | 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 |
| (III) | 66964 | (2R,3S)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride | C16H13ClF3N5O.HCl | 详情 | 详情 | |
| (IV) | 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 |