Hydrochloric Acid → 2,4-Difluorophenyl-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylbutyronitrile

HRID 1241929Notes

Reaction equation

HRID 1241929 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9](O)([CH2:15][N:16]1C=NC=N1)[C@@H:10](C)C(O)=O.[C:22]([N:29]1C=C[N:31]=[CH:30]1)([N:24]1[CH:28]=[CH:27]N=C1)=O.Cl.[O:35]1CCCC1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:10])([CH:27]([OH:35])[CH2:28][N:24]1[CH:22]=[N:29][CH:30]=[N:31]1)[C:15]#[N:16]

Participants

5

Reactant 4

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 682631,1'-CarbonyldiimidazoleHCID 10040259(Alphar,betar)-beta-(2,4-difluorophenyl)-beta-hydroxy-alpha-methyl-1H-1,2,4-triazole-1-butanoic acid

Product 1

HCID 865942462,4-Difluorophenyl-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylbutyronitrile

Conditions

Temperature
60 °C

Procedure

165 mg (0.55 mmol) of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyric acid were dissolved in 3.3 ml of tetrahydrofuran and, after the addition of 120 mg (0.72 mmol) of 1,1′-carbonyldiimidazole, stirred for 2 hours at 60° C. The reaction mixture was poured onto 10 ml of aqueous 0.5N HCl, extracted twice with each 25 ml of ethyl acetate, dried and evaporated to dryness. The crude residue was dissolved in 6 ml of aqueous 25% ammonium hydroxide and, after the addition of 2 mg of dimethylaminopyridine, stirred at room temperature for 1 hour. After evaporation of the reaction mixture the resulting residue was treated with 200 mg of POCl3 at 40° C. for 3 hours. After evaporation of the excess POCl3 under reduced pressure the crude product was poured onto water and extracted twice with 15 ml of ethyl acetate. The organic phase was dried with Na2SO4 and evaporated. Column chromatography on silica gel (eluent ethyl acetate/n-hexane=1:1) gave 95 mg (74%) of (2R,3R)-3-(2,4-difluorophenyl-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylbutyronitrile.

Workup

  1. extractionextracted twice with each 25 ml of ethyl acetate
  2. customdried
  3. customevaporated to dryness
  4. dissolutionThe crude residue was dissolved in 6 ml of aqueous 25% ammonium hydroxide
  5. additionafter the addition of 2 mg of dimethylaminopyridine
  6. stirringstirred at room temperature for 1 hour
  7. customAfter evaporation of the reaction mixture the resulting residue
  8. additionwas treated with 200 mg of POCl3 at 40° C. for 3 hours
  9. customAfter evaporation of the excess POCl3 under reduced pressure the crude product
  10. additionwas poured onto water
  11. extractionextracted twice with 15 ml of ethyl acetate
  12. dry with materialThe organic phase was dried with Na2SO4
  13. customevaporated

Sources & evidence

ORD record
ord-b9501891132249aea6a3406ba51feb78
Source dataset
uspto-grants-2006_10
Patent number
US07115643B2

Reaction notes

Loading…