Potassium Acetate → 4,2'-Difluoro-5'-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile

HRID 1723675Notes

Reaction equation

HRID 1723675 reaction equation
Cl.[O:2]=[C:3]1[NH:8][CH2:7][CH2:6][N:5]2[CH:9]=[CH:10][N:11]=[C:4]12.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+]>CC(N(C)C)=O.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:9]3[N:5]4[CH:6]=[CH:7][NH:8][C:3](=[O:2])[C:4]4=[N:11][CH:10]=3)[CH:14]=[CH:15][C:16]=2[F:28])=[CH:24][CH:23]=1

Participants

7

Reactant 3

HCID 517044Potassium AcetateHCID 114151595'-Bromo-2',4-difluoro-[1,1'-biphenyl]-2-carbonitrileHCID 574341565H,6H,7H,8H-imidazo[1,2-a]pyrazin-8-one hydrochloride

Product 1

HCID 688704404,2'-Difluoro-5'-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrileYield 68.3%

Reagents, catalysts & solvents 3

HCID 11776TriphenylphosphineCatalystHCID 167845palladium(II) acetateCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
130 °C

Procedure

8-Oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (87 mg, 0.53 mmol), prepared as described in Example 25, was reacted with 5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (prepared as described in WO 02/074773, 204 mg, 1.3 mol eq) in DMA (2 ml) in the presence of potassium acetate (280 mg, 1.5 mol eq), palladium acetate (6 mg, 5 mol %) and triphenylphosphine (7 mg, 5 mol %). After bubbling nitrogen through the reaction mixture for 10 min, the temperature was raised to 130° C. and heating continued for 3 h. After cooling, the crude reaction mixture was poured onto a column of silica and purified using 0-5% methanol in dichloromethane as eluent. Recrystallization from ethyl acetate/dichloromethane gave 4,2′-difluoro-5′-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile (126 mg): δH (400 MHz, DMSO) 3.54-3.58 (2H, m), 4.28-4.32 (2H, m), 7.39 (1H, s), 7.54-7.59 (1H, m), 7.71-7.78 (4H, m), 8.05-8.08 (1H, m), 8.18 (1H, br s); m/z (ES+) 351 [M+H]+.

Workup

  1. customAfter bubbling nitrogen through the reaction mixture for 10 min
  2. temperatureheating
  3. temperatureAfter cooling
  4. customthe crude reaction mixture
  5. additionwas poured onto a column of silica
  6. custompurified
  7. customRecrystallization from ethyl acetate/dichloromethane

Sources & evidence

ORD record
ord-3e82acc4006442da9f980ae0b30bfe38
Source dataset
uspto-grants-2009_02
Patent number
US07485640B2

Reaction notes

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