Hydrochloric Acid → ent-Voriconazole

HRID 2384514Notes

Reaction equation

HRID 2384514 reaction equation
Cl.ClC1C=CC(S[C:10]2[N:15]=[CH:14][N:13]=[C:12]([C@@H:16]([CH3:33])[C@@:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])([OH:24])[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[C:11]=2[F:34])=CC=1.C([O-])=O.[NH4+]>O1CCCC1.O.[Zn]>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C@@:17]([OH:24])([C@@H:16]([C:12]1[C:11]([F:34])=[CH:10][N:15]=[CH:14][N:13]=1)[CH3:33])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1

Participants

7

Reactant 3

HCID 313Hydrochloric AcidHCID 2723923Ammonium formateHCID 86643731HCID 86643731, compound

Product 1

HCID 15230631ent-VoriconazoleYield 90%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

13.3 g of zinc powder treated with 1N HCl was dissolved in 300 ml of tetrahydrofuran and refluxed for 1 hour. The resulting solution was cooled to 50° C., and 20 g of (2R,3S)/(2S,3R)-3-[6-(4-chloro-phenylsulfanyl)-5-fluoro-pyrimidine-4-yl]-2-(2,4-difluoro-phenyl)-1-[1,2,4]triazol-1-yl-butane-2-ol obtained in Example 1 or 2 was added thereto. 7.71 g of ammonium formate dissolved in 200 ml of water was slowly added to the resulting mixture for 30 min, and refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered and washed with 200 ml of ethyl acetate. The resulting residue was washed with 200 ml of saturated ammonium chloride aqueous solution, and the water layer was removed therefrom. The organic layer was washed with 200 ml of sodium bicarbonate and 200 ml of brine, and dried over magnesium sulfate. 200 ml of ethyl acetate and 100 ml of hexane were added to the resulting residue, and 9 ml of concentrated HCl was added thereto for crystallization. 200 ml of ethyl acetate and 200 ml of sodium bicarbonate were added to the obtained solid mixture and stirred for 10 min, and the resulting solid was filtered out by using celite. The resulting organic layer was washed with 200 ml of a 5% sodium hydroxide aqueous solution and concentrated under a reduced pressure to obtain the crystallized title compound (12.7 g, yield: 90%).

Workup

  1. temperaturerefluxed for 1 hour
  2. additionwas slowly added to the resulting mixture for 30 min
  3. temperaturerefluxed for 4 hours
  4. temperatureThe reaction solution was cooled to room temperature
  5. filtrationfiltered
  6. washwashed with 200 ml of ethyl acetate
  7. washThe resulting residue was washed with 200 ml of saturated ammonium chloride aqueous solution
  8. customthe water layer was removed
  9. washThe organic layer was washed with 200 ml of sodium bicarbonate and 200 ml of brine
  10. dry with materialdried over magnesium sulfate
  11. addition200 ml of ethyl acetate and 100 ml of hexane were added to the resulting residue, and 9 ml of concentrated HCl
  12. additionwas added
  13. customfor crystallization
  14. addition200 ml of ethyl acetate and 200 ml of sodium bicarbonate were added to the obtained solid mixture
  15. filtrationthe resulting solid was filtered out
  16. washThe resulting organic layer was washed with 200 ml of a 5% sodium hydroxide aqueous solution
  17. concentrationconcentrated under a reduced pressure
  18. customto obtain the

Sources & evidence

ORD record
ord-6d967083ab0f431dafe6d5092bf6738d
Source dataset
uspto-grants-2012_09
Patent number
US08263769B2

Reaction notes

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