Dimethylformamide → 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-1H,3H-imidazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone

HRID 279179Notes

Reaction equation

HRID 279179 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[O:19]=[C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])=[CH:27][CH:26]=2)[CH:23]=[CH:22][N:21]1[C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH:49]=[N:48][NH:47][C:46]2=[O:50])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:47]1[C:46](=[O:50])[N:45]([C:42]2[CH:41]=[CH:40][C:39]([N:21]3[CH:22]=[CH:23][N:24]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])=[CH:29][CH:30]=4)[C:20]3=[O:19])=[CH:44][CH:43]=2)[CH:49]=[N:48]1)[CH3:12]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 101311911-((2-(2,4-Difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole, (2R-cis)-HCID 154546524-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1H,3H-imidazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone

Product 1

HCID 154546442-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-1H,3H-imidazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazoloneYield 7.8%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.2 g), 4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1H,3H-imidazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (2.2 g) and potassium carbonate (powder: 3.5 g) were added to N,N-dimethylformamide (50 ml), and the mixture was heated with stirring at 90° C. for 42 hours. After cooling, the resultant was diluted with ethyl acetate (150 ml) and tetrahydrofuran (50 ml). Ice water (150 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (elute:ethyl acetate/acetone=10/1) and crystallized from tetrahydrofuran-diisopropyl ether to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-1H,3H-imidazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 2; 0.26 g) as a colorless crystalline powder.

Workup

  1. temperaturethe mixture was heated
  2. temperatureAfter cooling
  3. customto separate the ethyl acetate layer
  4. extractionThe aqueous layer was extracted with ethyl acetate (100 ml)
  5. washwashed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml)
  6. dry with materialThe ethyl acetate layer was dried over anhydrous magnesium sulfate
  7. distillationdistilled under reduced pressure
  8. customto remove the solvent
  9. customThe residue was purified by silica gel chromatography (elute:ethyl acetate/acetone=10/1)
  10. customcrystallized from tetrahydrofuran-diisopropyl ether

Sources & evidence

ORD record
ord-eaeb7746033e435f933740f758e081ac
Source dataset
uspto-grants-2002_03
Patent number
US06362206B1

Reaction notes

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