反应详情

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)+.

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