3-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone → 3-(1-Bromo-8-chloroimidazo[1,5-A]pyrazin-3-YL)-1-methylcyclobutanol

HRID 2402639Notes

Reaction equation

HRID 2402639 reaction equation
[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][C:14](=[O:16])[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[C:6]=12.[CH3:17][Mg]Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:13][C:14]([CH3:17])([OH:16])[CH2:15]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[C:6]=12

Participants

4

Reactant 2

HCID 161193273-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanoneHCID 178418332HCID 178418332, compound

Product 1

HCID 533286223-(1-Bromo-8-chloroimidazo[1,5-A]pyrazin-3-YL)-1-methylcyclobutanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

3-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (51.988 g, 0.17 mol) in anhydrous THF (550 g, 620 mL) under nitrogen at −78° C. was treated with a 3.0 M solution of methyl magnesium chloride in THF (130 mL, 0.38 mol) over 30 min. The mixture was stirred at −78° C. for 30 min and then the cooling bath was removed and the mixture quenched with 14% NH4Cl (132 g). EtOAc was added to the aqueous phase and the pH was adjusted to −5 with 20% HCl and the layers separated. The combined organic phases were concentrated in vacuo to a slurry and 0.5 L of toluene was added and the mixture concentrated in vacuo until the EtOAc was removed. The slurry was heated at reflux until homogeneous then allowed to cool to provide desired product, which was isolated by filtration and dried in vacuo. 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (s, 3H), 2.35-2.49 (m, 4H), 3.52 (dddd, 1H, J=9.6, 9.6, 9.6, 9.6 Hz), 5.18 (bs, 1H), 7.37 (d, 1H, J=5.2 Hz) and 8.26 (d, 1H, J=5.2 Hz).

Workup

  1. customthe cooling bath was removed
  2. customthe mixture quenched with 14% NH4Cl (132 g)
  3. additionEtOAc was added to the aqueous phase
  4. customthe layers separated
  5. concentrationThe combined organic phases were concentrated in vacuo to a slurry and 0.5 L of toluene
  6. additionwas added
  7. concentrationthe mixture concentrated in vacuo until the EtOAc
  8. customwas removed
  9. temperatureThe slurry was heated
  10. temperatureat reflux until homogeneous
  11. temperatureto cool

Sources & evidence

ORD record
ord-8f2eb7d7cd924e93984988fd72071697
Source dataset
uspto-grants-2014_08
Patent number
US08796455B2

Reaction notes

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