Potassium Phosphate, Tribasic → 5,2'-Difluoro-5'-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrile

HRID 2180035Notes

Reaction equation

HRID 2180035 reaction equation
Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:20][C:21]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([N:9]3[C:17]4[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=4[N:11]=[CH:10]3)[CH:5]=[CH:6][C:7]=2[F:8])[C:24]([C:25]#[N:26])=[CH:23][CH:22]=1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 221807884-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileHCID 224902931-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one

Product 1

HCID 224902925,2'-Difluoro-5'-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrileYield 60%

Reagents, catalysts & solvents 3

HCID 962WaterCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one (0.64 g, 2.0 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.99 g, 4.0 mmol) and potassium phosphate (0.68 g, 3.2 mmol) were placed in a flask with 1,4-dioxane (3 ml), and water (2 drops) was added. The mixture was degassed with nitrogen for 15 min before adding tris(dibenzylideneacetone)-dipalladium(0) (90 mg, 0.10 mmol) and tri-tert-butylphosphine (10% wt in hexanes, 0.20 ml, 0.10 mmol). The resulting mixture was heated at 70° C. for 16 h. The reaction mixture was allowed to cool, and then partitioned between dichloromethane (100 ml) and water (100 ml). The organic phase was washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel, eluting with dichloromethane on a gradient of ethanol (1-4%), gave a white solid. This solid was triturated with ethanol and filtered, yielding pure 5,2′-difluoro-5′-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrile as a white solid (423 mg, 60%): δH (400 MHz, d6-DMSO) 3.54 (3H, s), 6.69 (1H, d, J 7), 7.59-7.62 (2H, m), 7.71 (1H, t, J 9), 7.79 (1H, dd, J 9 and 7.84-7.90 (2H, m), 8.16 (1H, dd, J 9 and 6), 8.39 (1H, s); m/z (ES+) 363 [MH+].

Workup

  1. additionwas added
  2. customThe mixture was degassed with nitrogen for 15 min
  3. temperatureto cool
  4. custompartitioned between dichloromethane (100 ml) and water (100 ml)
  5. washThe organic phase was washed with water (100 ml) and brine (100 ml)
  6. dry with materialdried over anhydrous magnesium sulfate
  7. filtrationfiltered and pre-adsorbed onto silica
  8. customPurification by flash column chromatography on silica gel
  9. washeluting with dichloromethane on a gradient of ethanol (1-4%)
  10. customgave a white solid
  11. customThis solid was triturated with ethanol
  12. filtrationfiltered

Sources & evidence

ORD record
ord-9455c3275e9043059c028087e2bd5861
Source dataset
uspto-grants-2005_05
Patent number
US06887885B2

Reaction notes

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