Cesium carbonate → 8-Cyclopropylmethyl-2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)imidazo[1,2-a]pyrazine

HRID 2233103Notes

Reaction equation

HRID 2233103 reaction equation
[CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.I[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([C:11]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=4)=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:2][CH2:3]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 11776TriphenylphosphineHCID 38589014-Iodo-2-(methylthio)pyrimidineHCID 574387698-Cyclopropylmethyl-2-(4-fluorophenyl)imidazo[1,2-a]pyrazine

Product 1

HCID 588695358-Cyclopropylmethyl-2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)imidazo[1,2-a]pyrazineYield 60.5%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

Into a flask were added 8-cyclopropylmethyl-2-(4-fluorophenyl)imidazo[1,2-a]pyrazine (5.84 g, 21.8 mmol), 4-iodo-2-(methylthio)pyrimidine (Frontier, 8.27 g, 32.8 mmol), Cs2CO3 (10.7 g, 32.8 mmol), PPh3 (2.29 g, 8.73 mmol), and DMF (50 mL). The mixture was degassed by bubbling Ar through it for about 5 min, before being charged with Pd(OAc)2 (0.981 g, 4.37 mmol) and heated at about 100° C. for about 18 h. The reaction was cooled to ambient temperature, the solvent was removed in vacuo, and the residue taken up in DCM and water. After filtration through a pad of Celite®, the organic layer was separated and the aqueous layer extracted about five more times with DCM, filtering through Celite® in every extraction step to break emulsions. The combined organic phase was dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography with heptane/EtOAc (gradient 20-80% EtOAc). After concentration, the residue was twice re-dissolved in DCM and re-concentrated to give 5.16 g (60%) of the title compound as a greenish solid: LC/MS (Table 1, Method g) Rt=3.43 min; MS m/z: 392.2 (M+H)+.

Workup

  1. customThe mixture was degassed
  2. customby bubbling Ar through it for about 5 min
  3. temperatureThe reaction was cooled to ambient temperature
  4. customthe solvent was removed in vacuo
  5. filtrationAfter filtration through a pad of Celite®
  6. customthe organic layer was separated
  7. extractionthe aqueous layer extracted about five more times with DCM
  8. filtrationfiltering through Celite® in every extraction step
  9. dry with materialThe combined organic phase was dried over Na2SO4
  10. concentrationconcentrated
  11. customThe crude material was purified by silica gel chromatography with heptane/EtOAc (gradient 20-80% EtOAc)
  12. concentrationAfter concentration
  13. dissolutionthe residue was twice re-dissolved in DCM
  14. concentrationre-concentrated

Sources & evidence

ORD record
ord-f3c1f7d7380841f58ee127c983b49352
Source dataset
uspto-grants-2010_05
Patent number
US07709468B2

Reaction notes

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