1H-1,2,4-Triazole → 5-Desfluoro voriconazole, (+/-)-

HRID 1196956Notes

Reaction equation

HRID 1196956 reaction equation
CS(Cl)(=O)=O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:25])([C@H:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[CH3:18])[CH2:15]O.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH:45]=[N:44][CH:43]=[N:42]1>O1CCCC1.CO.CN(C)C=O>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:25])([C@H:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[CH3:18])[CH2:15][N:41]1[CH:45]=[N:44][CH:43]=[N:42]1

Participants

9

Reactant 5

HCID 92571H-1,2,4-TriazoleHCID 11430Potassium Carbonate2×HCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 22844240HCID 22844240, compound

Product 1

HCID 228442395-Desfluoro voriconazole, (+/-)-

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Methanesulphonyl chloride (1.15 g) was added to a stirred solution of the product of part (iv) (2.35 g) and diisopropylethylamine (2.38 g) in dry tetrahydrofuran (30 ml) at -10° to -20° under an atmosphere of dry nitrogen. The solution was stirred at the same temperature for 1 hour and then anhydrous potassium carbonate (7.0 g) and dry N,N-dimethylformamide (25 ml) were added. The mixture was stirred at room temperature for 1.5 hours and then partitioned between water and ether. The organic layer was separated, washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was immediately dissolved in methanol (50 ml). 1H-1,2,4-Triazole (6.0 g) and anhydrous potassium carbonate (6.0 g) were added and the mixture was heated at 60° with stirring for 40 hours, then evaporated. The residue was partitioned between ethyl acetate/ether (1:1) and water, the organic layer was separated and washed with water, then dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. Initial elution with ethyl acetate gave impurity-containing fractions, and subsequent further elution with ethyl acetate/methanol (20:1) gave, after combination and evaporation of appropriate fractions, the title compound, (0.87 g), m.p. 55°-58°, [α]25/D -65.1° (0.55% in methanol).

Workup

  1. stirringThe mixture was stirred at room temperature for 1.5 hours
  2. custompartitioned between water and ether
  3. customThe organic layer was separated
  4. washwashed with water
  5. dry with materialdried (Na2SO4)
  6. customEvaporation of the solvent
  7. customgave an oil which
  8. temperaturethe mixture was heated at 60°
  9. stirringwith stirring for 40 hours
  10. customevaporated
  11. customThe residue was partitioned between ethyl acetate/ether (1:1) and water
  12. customthe organic layer was separated
  13. washwashed with water
  14. dry with materialdried (Na2SO4)
  15. customThe solvent was evaporated
  16. customthe residue was chromatographed on silica gel
  17. washInitial elution with ethyl acetate
  18. customgave
  19. additionimpurity-containing
  20. washfractions, and subsequent further elution with ethyl acetate/methanol (20:1)
  21. customgave
  22. customafter combination and evaporation of appropriate fractions
  23. customthe title compound, (0.87 g), m.p. 55°-58°, [α]25/D -65.1° (0.55% in methanol)

Sources & evidence

ORD record
ord-1916aaebdc824f5982bb8016071d4060
Source dataset
uspto-grants-1992_05
Patent number
US05116844

Reaction notes

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