反应详情

温度

52.5 °C

A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250ml ) was vigously stirred. The color of iodine was disappeared and the inner temperature rose up to 65° C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55° C. over 45min. The resulting mixture was stirred at 55° C. for 30min. then at r.t. for 1 hr. The mixture was cooled down to −5° C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol ) in THF (150ml) dropwise over 40min. And the resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was cooled down to 5° C. and saturated NH4Cl aq. (100ml) was added carefully. The whole was diluted with H2O (600ml) and extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81% ) as pale yellow syrup.

1. customrose up to 65° C
2. stirringThe resulting mixture was stirred at 55° C. for 30min.
3. temperatureThe mixture was cooled down to −5° C
4. stirringAnd the resulting mixture was stirred at r.t. for 4hrs
5. temperatureThe reaction mixture was cooled down to 5° C.
6. extractionextracted with EtOAc (400 ml+200 ml×2)
7. dry with materialThe combined organic layer was dried over Na2SO4
8. concentrationconcentrated in vacuo
9. customThe residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1)