Diisopropylamine → rac 5-Desfluoro Voriconazole

HRID 2380040Notes

Reaction equation

HRID 2380040 reaction equation
C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1)[CH3:14].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29](=[O:36])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1>CCCCCC.O1CCCC1.O.C(O)(=O)C>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29]([OH:36])([CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1)[CH3:14])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1

Participants

9

Reactant 4

HCID 7912DiisopropylamineHCID 5880801-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanoneHCID 110078414-EthylpyrimidineHCID 178418339Butyllithium

Product 1

HCID 22323347rac 5-Desfluoro Voriconazole

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Procedure

n-Butyllithium (4.0 ml of a 2.5M solution in hexane) was added to a stirred solution of diisopropylamine (1.01 g) in dry tetrahydrofuran (30 ml) at -70° under an atmosphere of dry nitrogen. The solution was stirred at -70° for 0.17 hour, followed by 0.17 hour at 0° and then re-cooled to -70°. 4-Ethylpyrimidine (1.08 g) was added and the solution was stirred at -70° for 0.75 hour. A solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.23 g) in dry tetrahydrofuran (30 ml) was added over 0.17 hour. The solution was stirred at -70° for 1 hour and then acetic acid (1 ml) was added. The solution was allowed to reach room temperature and was then diluted with water. The mixture was extracted three times with ethyl acetate and the combined extracts were washed with water then dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. Initial alution with ethyl acetate/hexane (3:2) gave recovered ketone starting material. Further elution with ethyl acetate gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.305 g), m.p. 114°-115.5° (from ether/hexane).

Workup

  1. waitfollowed by 0.17 hour at 0°
  2. temperaturere-cooled to -70°
  3. stirringthe solution was stirred at -70° for 0.75 hour
  4. stirringThe solution was stirred at -70° for 1 hour
  5. customto reach room temperature
  6. extractionThe mixture was extracted three times with ethyl acetate
  7. washthe combined extracts were washed with water
  8. dry with materialthen dried (Na2SO4)
  9. customThe solvent was evaporated
  10. customthe residue was chromatographed on silica gel
  11. customInitial alution with ethyl acetate/hexane (3:2) gave
  12. customrecovered ketone starting material
  13. washFurther elution with ethyl acetate
  14. customgave
  15. customafter combination and evaporation of appropriate fractions

Sources & evidence

ORD record
ord-7735da2e2eff44f3984550dd27b8ac1a
Source dataset
uspto-grants-1994_11
Patent number
US05364938

Reaction notes

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