反应详情

温度

140 °C

DIPEA (77 μL, 0.44 mmol) was added to a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 33.1, 99 mg, 0.2 mmol) and (R)-pyrrolidin-3-ol, 20.9 mg, 0.24 mmol) in iPrOH (200 μL) in a vial, which was sealed and the RM mixture was stirred at 140° C. for 1.5 h. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was dissolved in DCM (1.1 mL), cooled to 0° C., treated with TFA (0.616 mL, 8 mmol) and stirred at RT for 3 h. The RM was poured in to 10% aq. Na2CO3 (10 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® silica gel column, DCM/MeOH from 2% to 10% MeOH) to afford the title compound as a beige powder. HPLC (Condition 4) tR=4.79 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=464 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.92 (m, 5H) 2.81-2.96 (m, 1H) 3.05-3.41 (m, 3H) 4.17 (br. s, 1H) 4.81 (br. s, 1H) 7.30 (d, J=8.60 Hz, 2H) 7.58 (s, 1H) 7.79-8.02 (m, 3H) 8.73 (s, 1H) 10.15 (s, 1H) 12.58-12.85 (m, 1H).

1. customwas sealed
2. temperatureAfter cooling at RT
3. washwashed with brine
4. dry with materialdried over Na2SO4
5. customthe solvent was evaporated off under reduced pressure
6. dissolutionThe residue was dissolved in DCM (1.1 mL)
7. temperaturecooled to 0° C.
8. stirringstirred at RT for 3 h
9. extractionextracted with EtOAc
10. dry with materialThe combined extracts were dried over Na2SO4
11. customthe solvent was evaporated off under reduced pressure
12. customto give a residue which
13. customwas purified by flash chromatography (RediSep® silica gel column, DCM/MeOH from 2% to 10% MeOH)