合成路线: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.
参考文献标题:Voriconazole
文献作者:Fromtling,R.A.; Castar,J.
参考来源:Drugs Fut 1996,21(3),266
合成路线: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.
合成路线:Alternatively,6-ethyl-5-fluoropyrimidin-4-ol (IV) can be obtained by reaction of 2,4-dichloro-5-fluoropyrimidine (X) with ethylmagnesium bromide in THF to give the dihydropyrimidine derivative (XI),which is aromatized by reaction with I2 and TEA in THF yielding 2,4-dichloro-6-ethyl-5-fluoropyrimidine (XII).The reaction of (XII) with NaOH and NH4Cl affords the aminooxy derivative (XIII) which is finally submitted to a reductive dechlorination and deamination with H2 over Pd/C in ethanol/water.
参考文献标题:Process development of voriconazole: A novel broad-spectrum triazole antifungal agent
文献作者:Butters,M.; et al.
参考来源:Org Process Res Dev 2001,5(1),28
产品链接: CAS No. 137234-62-9››