Sodium Carbonate → 8-Cyclopropylmethyl-2-(2,4-difluorophenyl)imidazo[1,2-a]pyrazine

HRID 2233080Notes

Reaction equation

HRID 2233080 reaction equation
[Br-].[CH:2]1([CH2:5][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4][CH2:3]1.C([Li])CCC.Cl[C:31]1[C:32]2[N:33]([CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[F:47])[N:39]=2)[CH:34]=[CH:35][N:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH:2]1([CH2:5][C:31]2[C:32]3[N:33]([CH:37]=[C:38]([C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=4[F:47])[N:39]=3)[CH:34]=[CH:35][N:36]=2)[CH2:4][CH2:3]1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 3084208(Cyclopropylmethyl)triphenylphosphonium bromideHCID 574387428-Chloro-2-(2,4-difluorophenyl)imidazo[1,2-a]pyrazineHCID 178418339Butyllithium

Product 1

HCID 592950848-Cyclopropylmethyl-2-(2,4-difluorophenyl)imidazo[1,2-a]pyrazineYield 22%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

To a suspension of (cyclopropylmethyl)triphenylphosphonium bromide (Alfa Aesar, 10.2 g, 25.7 mmol) in dry DME (60 mL) kept between about −30° C. and 40° C. was added a 2.5M solution of n-butyllithium in hexanes (10.2 mL, 25.7 mmol) over about 5 min. After stirring between about −30° C. and −40° C. for about 45 min, 8-chloro-2-(2,4-difluorophenyl)imidazo[1,2-a]pyrazine (Example #13, Step A, 5.74 g, 23.2 mmol) was added. The mixture was warmed to ambient temperature, then stirred at about 85° C. for about 3.5 h, at which point a solution of Na2CO3 (1.364 g, 12.9 mmol) in water (50 mL) was added and heating was continued overnight. After cooling to ambient temperature, the mixture was partitioned between 1 N HCl and CHCl3 and the organic phase extracted five more times with 1 N HCl. The combined aqueous phase was rendered alkaline with NaOH and extracted with Et2O. After drying over Na2SO4 and concentration, the crude material was purified by silica gel chromatography with heptane/EtOAc (gradient 10-100% EtOAc). After concentration, the residue was three times re-dissolved in DCM and re-concentrated to give 0.728 g (22%) of the title compound as an orange solid: LC/MS (Table 1, Method g) Rt=3.08 min; MS m/z: 286.1 (M+H)+.

Workup

  1. customkept between about −30° C. and 40° C.
  2. additionwas added
  3. temperatureheating
  4. waitwas continued overnight
  5. temperatureAfter cooling to ambient temperature
  6. customthe mixture was partitioned between 1 N HCl and CHCl3
  7. extractionthe organic phase extracted five more times with 1 N HCl
  8. extractionextracted with Et2O
  9. dry with materialAfter drying over Na2SO4 and concentration
  10. customthe crude material was purified by silica gel chromatography with heptane/EtOAc (gradient 10-100% EtOAc)
  11. concentrationAfter concentration
  12. dissolutionre-dissolved in DCM
  13. concentrationre-concentrated

Sources & evidence

ORD record
ord-38afd9f0b93b4217b30e39499802bc43
Source dataset
uspto-grants-2010_05
Patent number
US07709468B2

Reaction notes

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