Aminopyrazine → 2-(Trifluoromethyl)imidazo[1,2-a]pyrazine

HRID 1893409Notes

Reaction equation

HRID 1893409 reaction equation
[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Br[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12]>C(O)(C)C.ClCCl>[F:12][C:11]([F:14])([F:13])[C:10]1[N:7]=[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]2[CH:9]=1

Participants

5

Reactant 2

HCID 78747AminopyrazineHCID 790083-Bromo-1,1,1-trifluoro-2-propanone

Product 1

HCID 32313062-(Trifluoromethyl)imidazo[1,2-a]pyrazine

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Procedure

2-Pyrazinamine (11.89 g, 125 mmol, commercially available from e.g. Sigma-Aldrich, Fluka or Acros) was dissolved in isopropanol (IPA) (200 mL) and 3-bromo-1,1,1-trifluoro-2-propanone (12.98 mL, 125 mmol) was added. The solution was stirred at room temperature for 2 hours and the heated at reflux for 18 h. The solution was concentrated in vacuo and the residue partitioned between saturated sodium bicarbonate solution (200 ml) and 20% IPA/DCM (300 ml). The aqueous phase was extracted with 20% IPA/DCM (5×200 ml) and the combined extracts were concentrated in vacuo. The residue was dissolved in ethyl acetate (500 ml) and washed with brine (2×100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid (17.69 g). The solid was dissolved in dichloromethane and initially purified by filtration through a plug of silica to afford product in 15.14 g. The solid was purified by flash chromatography (Biotage flash 65+, 0-100% [10% 2M NH3 in MeOH/DCM]/DCM) to afford the desired product in 5.61 g. LC/MS=408/410 (M+H)+, retention time=2.05 minutes (5 minute).

Workup

  1. temperaturethe heated
  2. temperatureat reflux for 18 h
  3. concentrationThe solution was concentrated in vacuo
  4. customthe residue partitioned between saturated sodium bicarbonate solution (200 ml) and 20% IPA/DCM (300 ml)
  5. extractionThe aqueous phase was extracted with 20% IPA/DCM (5×200 ml)
  6. concentrationthe combined extracts were concentrated in vacuo
  7. dissolutionThe residue was dissolved in ethyl acetate (500 ml)
  8. washwashed with brine (2×100 ml)
  9. dry with materialdried over anhydrous sodium sulfate
  10. concentrationconcentrated in vacuo
  11. customto afford a crude solid (17.69 g)
  12. filtrationinitially purified by filtration through a plug of silica
  13. customto afford product in 15.14 g
  14. customThe solid was purified by flash chromatography (Biotage flash 65+, 0-100% [10% 2M NH3 in MeOH/DCM]/DCM)

Sources & evidence

ORD record
ord-75e8e3fad00848979b7df302daa1785b
Source dataset
uspto-grants-2013_08
Patent number
US08513248B2

Reaction notes

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