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【结 构 式】

【分子编号】15375

【品名】(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

【CA登记号】

【 分 子 式 】C16H14F3N5O

【 分 子 量 】349.3154696

【元素组成】C 55.02% H 4.04% F 16.32% N 20.05% O 4.58%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

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2

该中间体在本合成路线中的序号:(IX)

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3

该中间体在本合成路线中的序号: (IV)

 

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
Extended Information