反应详情

温度

110 °C

1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (29.6 g, 102 mmol), K3PO4 (51.6 g, 236 mmol) and Pd(PPh3)4 (4.55 g, 3.93 mmol) were added to a suspension of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 36.4 g, 79 mmol) in toluene (360 mL) under an argon atmosphere and the mixture was stirred at 110° C. for 4 h. The RM was poured into brine (500 mL) and extracted with EtOAc (2×1 L). The combined extracts were washed with brine (500 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give a residue which was purified by chromatography (Silica gel column, 1.5 kg, DCM/MeOH 95:5) to afford a dark yellow foam, that was dissolved in MeOH/DCM (1 L of 3:1) and treated with Si-Thiol (Biotage, 35 g, 45.5 mmol) for 17 h at 30° C. The resin was filtered off, and solvent was evaporated off under reduced pressure, until the desired compound crystallized. The product was filtered washed with MeOH and dried to afford the title compound.

1. extractionextracted with EtOAc (2×1 L)
2. washThe combined extracts were washed with brine (500 mL)
3. dry with materialdried over Na2SO4
4. customthe solvent was evaporated off under reduced pressure
5. customto give a residue which
6. customwas purified by chromatography (Silica gel column, 1.5 kg, DCM/MeOH 95:5)
7. customto afford a dark yellow foam, that
8. filtrationThe resin was filtered off
9. customsolvent was evaporated off under reduced pressure, until the desired compound
10. customcrystallized
11. filtrationThe product was filtered
12. washwashed with MeOH
13. customdried