反应详情

温度

140 °C

A mixture of 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1, 150 mg, 0.321 mmol), 2-hydroxymethylmorpholine (75 mg, 0.643 mmol) and DIPEA (0.224 mL, 1.285 mmol) in iPrOH (0.6 mL) in a sealed vial was stirred at 140° C. for 4 h. The RM was dissolved in EtOAc, washed with water (3×20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in DCM (2.5 mL), treated with TFA (0.912 mL, 11.84 mmol) and stirred at RT for 2 h. The RM was diluted with EtOAc, washed with aq. sat. NaHCO3 solution (2×40 mL) and with water (2×40 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH 9:1) followed by preparative HPLC (Condition 10). Fractions containing product were combined and the solvent was evaporated off under reduced pressure to give an aqueous residue which was treated with Na2CO3 (100 mg) and extracted with EtOAc. The combined extracts were washed with water (2×20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column 4-EP, from 20% to 25% in 6 min) to give the title compound as a white solid. HPLC (Condition 7) tR=5.738 min, UPLC-MS (Condition 3) tR=0.90 min, m/z=464.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.67 (m, 1H) 2.73-2.86 (m, 1H) 3.22-3.30 (m, 1H) 3.35-3.45 (m, 2H) 3.47-3.68 (m, 3H) 3.70-3.84 (m, 1H) 4.52-4.77 (m, 1H) 6.60/6.69 (s, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.79-7.96 (m, 3H) 8.20/8.35 (br. s, 1H) 8.74 (br. s, 1H) 10.36/10.41 (s, 1H) 13.03/13.19 (s, 1H).

1. washwashed with water (3×20 mL)
2. dry with materialdried over Na2SO4
3. customthe solvent was evaporated off under reduced pressure
4. customto give a residue which
5. stirringstirred at RT for 2 h
6. washwashed with aq. sat. NaHCO3 solution (2×40 mL) and with water (2×40 mL)
7. dry with materialdried over Na2SO4
8. customthe solvent was evaporated off under reduced pressure
9. customto give a crude product which
10. customwas purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH 9:1)
11. additionFractions containing product
12. customthe solvent was evaporated off under reduced pressure
13. customto give an aqueous residue which
14. extractionextracted with EtOAc
15. washThe combined extracts were washed with water (2×20 mL)
16. dry with materialdried over Na2SO4
17. customthe solvent was evaporated off under reduced pressure
18. customto give a crude product which
19. customwas purified by preparative SFC (Column 4-EP, from 20% to 25% in 6 min)