反应详情

温度

80 °C

3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (252 mg, 0.646 mmol), K3PO4 (206 mg, 0.968 mmol) and Pd(PPh3)4 (18.65 mg, 0.016 mmol) were added to N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)-5-iodonicotinamide (Stage 88.1, 160 mg, 0.323 mmol) was suspended in toluene (2 mL) in a. vial, which was sealed, purged with argon and stirred at 80° C. for 19 h. The RM was treated with EtOAc (60 mL), washed with an aq. sat. NaHCO3 solution (20 mL) and brine (2×20 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure. The residue was dissolved in MeOH (3 mL) and filtered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg, 1.5 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep®Silica gel column, 40 g, DCM/MeOH 95:5), dissolved in DCM (2 mL), treated with TFA (0.554 mL, 7.19 mmol) and stirred at RT for 2 h. The dark yellow RM was treated with EtOAc, washed with aq. sat. NaHCO3 solution and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH 9:1). The fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in MeCN (2 mL), sonicated and then stirred at RT for 1 h. The resulting suspension was filtered, washed with MeCN (3 mL) and dried to afford the title product as a white solid. HPLC (Condition 7) tR=5.648 min, UPLC-MS (Condition 8) tR=0.93 min, m/z=450.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3H) 3.52-3.60 (m, 2H) 3.92-4.01 (m, 2H) 4.34-4.44 (m, 1H) 5.51 (br. s, 1H) 6.16 (s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.84-7.90 (m, 2H) 8.04 (d, J=2.35 Hz, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.21 (s, 1H) 12.65 (br. s, 1H).

1. customvial, which was sealed
2. custompurged with argon
3. additionThe RM was treated with EtOAc (60 mL)
4. washwashed with an aq. sat. NaHCO3 solution (20 mL) and brine (2×20 mL)
5. dry with materialdried over Na2SO4
6. customthe solvent was evaporated off under reduced pressure
7. dissolutionThe residue was dissolved in MeOH (3 mL)
8. filtrationfiltered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg, 1.5 mmol),
9. filtrationfiltered
10. customthe filtrate was evaporated off under reduced pressure
11. customto give a residue which
12. customwas purified by flash chromatography (RediSep®Silica gel column, 40 g, DCM/MeOH 95:5)
13. dissolutiondissolved in DCM (2 mL)
14. stirringstirred at RT for 2 h
15. washwashed with aq. sat. NaHCO3 solution and brine
16. dry with materialdried over Na2SO4
17. customthe solvent was evaporated off under reduced pressure
18. customto give the crude product which
19. customwas purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH 9:1)
20. additionThe fractions containing pure product
21. customthe solvent was evaporated off under reduced pressure
22. customto give a residue which
23. customsonicated
24. stirringstirred at RT for 1 h
25. filtrationThe resulting suspension was filtered
26. washwashed with MeCN (3 mL)
27. customdried