Potassium Acetate → 4,2'-Difluoro-5'-(3-methyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4] triazin-7-yl)biphenyl-2-carbonitrile

HRID 895110Notes

Reaction equation

HRID 895110 reaction equation
[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[N:9][CH:10]=[CH:11][N:5]2[N:4]=[CH:3]1.Br[C:13]1[CH:14]=[CH:15][C:16]([F:28])=[C:17]([C:19]2[C:20]([C:26]#[N:27])=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:18]=1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:25][C:22]1[CH:21]=[C:20]([C:26]#[N:27])[C:19]([C:17]2[CH:18]=[C:13]([C:11]3[N:5]4[C:6]([C:7](=[O:8])[N:2]([CH3:1])[CH:3]=[N:4]4)=[N:9][CH:10]=3)[CH:14]=[CH:15][C:16]=2[F:28])=[CH:24][CH:23]=1

Participants

8

Reactant 3

HCID 517044Potassium AcetateHCID 114151595'-Bromo-2',4-difluoro-[1,1'-biphenyl]-2-carbonitrileHCID 116223593-methyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one

Product 1

HCID 98419394,2'-Difluoro-5'-(3-methyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4] triazin-7-yl)biphenyl-2-carbonitrileYield 77%

Reagents, catalysts & solvents 4

HCID 11776TriphenylphosphineCatalystHCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
120 °C

Procedure

3-Methyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one (75 mg, 0.5 mmol), 5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (prepared according to the procedure described in WO 02/38568) (220 mg, 0.75 mmol) and potassium acetate (74 mg, 0.75 mmol) were suspended in N,N-dimethylacetamide (2 ml) and degassed with nitrogen for 10 min. Palladium(II) acetate (5.6 mg, 0.025 mmol) and triphenylphosphine (6.6 mg, 0.025 mmol) were added and the mixture heated at 120° C. for 1 h. The mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (100 ml), washed with water (50 ml) and brine (30 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown solid. The solid was purified by flash column chromatography on silica, eluting with dichloromethane on a gradient of methanol (0-2%). The appropriate fractions were collected and concentrated, and the residue triturated with diethyl ether, which gave 4,2′-difluoro-5′-(3-methyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4] triazin-7-yl)biphenyl-2-carbonitrile (139 mg, 77%) as a white solid: δH (500 MHz, CDCl3) 3.55 (3H, s), 7.27 (1H, dd, J9 and 9), 7.35 (1H, ddd, J8, 8 and 3), 7.45 (1H, dd, J8 and 3), 7.47-7.49 (1H, m), 7.71 (1H, s), 7.73 (1H, s), 7.89-7.92 (2H, m); m/z (ES+) 364 (M++H).

Workup

  1. customdegassed with nitrogen for 10 min
  2. temperatureto cool to ambient temperature
  3. washwashed with water (50 ml) and brine (30 ml)
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. customevaporated
  7. customto give a brown solid
  8. customThe solid was purified by flash column chromatography on silica
  9. washeluting with dichloromethane on a gradient of methanol (0-2%)
  10. customThe appropriate fractions were collected
  11. concentrationconcentrated
  12. customthe residue triturated with diethyl ether, which

Sources & evidence

ORD record
ord-2af46ae4363048a08d6d883c4fe4c6bd
Source dataset
uspto-grants-2005_07
Patent number
US06914060B2

Reaction notes

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