反应详情

温度

110 °C

6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 56, 100 mg, 0.253 mmol), tributyl(1-ethoxyvinyl)stannane (0.103 mL, 0.304 mmol), Pd(Ph3P)4 (29.3 mg, 0.025 mmol) and dioxane (1 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 110° C. for 2 h. The solvent was evaporated off under reduced the crude 6-(1-ethoxyvinyl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (100 mg, 0.232 mmol) was treated with 4 M HCl in dioxane (2 mL, 8.00 mmol), stirred at RT for 2 h and then treated with excess aq. Na2CO3 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 24 g, EtOAc/n-hexane from 50% to 70% EtOAc). The 6-acetyl-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (25 mg, 0.062 mmol) was dissolved in DCM (3 mL), cooled to −60° C. and treated dropwise with a solution of MeMgBr 1.4 M in THF/toluene (1:3) (0.089 mL, 0.124 mmol) at The RM was stirred for 1.5 h at −60° C., then treated with a sat. aq. NH4Cl solution and extracted with DCM. The combined extracts were dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative SFC (Column NH2; gradient 12% to 17% in 6 min.) and lyophilized in water/MeCN to afford the title compound. UPLC-MS (Condition 2) tR 0.79-0.94 min, m/z=419.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.49 (s, 6H) 5.02 (br. s, 1H) 7.39 (d, J=8.40 Hz, 2H) 7.87 (d, J=9.10 Hz, 2H) 8.11 (d, J=2.19 Hz, 1H) 8.77 (s, 2H) 9.09 (d, J=2.20 Hz, 1H) 9.13 (s, 1H) 10.55 (s, 1H).

1. customwas sealed
2. customevacuated/purged with argon
3. customThe solvent was evaporated off
4. stirringstirred at RT for 2 h
5. customthe solvent was evaporated off under reduced pressure
6. customto give a residue which
7. customwas purified by flash chromatography (RediSep® Silica gel column, 24 g, EtOAc/n-hexane from 50% to 70% EtOAc)
8. temperaturecooled to −60° C.
9. stirringwas stirred for 1.5 h at −60° C.
10. extractionextracted with DCM
11. dry with materialThe combined extracts were dried over MgSO4
12. customthe solvent was evaporated off under reduced pressure
13. customto give the crude product which
14. customwas purified by preparative SFC (Column NH2; gradient 12% to 17% in 6 min.)