Potassium Carbonate → N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Participants

Reaction Conditions

Reaction Steps

In a sealed tube, N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.124 g, 0.221 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.064 g, 0.332 mmol), potassium carbonate (0.092 g, 0.664 mmol), and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 85° C. overnight. Additional 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg) and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were added. The reaction mixture was degassed with Ar and heated at 85° C. for 2 days. The mixture was diluted with EtOAc and extracted with sat. NaHCO3 (aq). The organic extract was washed with brine, dried and evaporated. The crude product was purified by silica gel chromatography (25 g) eluting with CH2Cl2/MeOH to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (69 mg, 56.9% yield). The hydrochloride salt was formed by suspending N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.069 g, 0.126 mmol) in acetonitrile (2 ml) and adding 0.1N HCl (1.51 mL, 0.151 mmol). The mixture was sonicated for 10 min. The solution was diluted with water (2 mL), frozen and lyophilized. The crude lyophilate was dried at 80° C. for 4 h under vacuum to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (0.069 g, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.32 (s, 1H); 9.15 (s, 1H); 8.49 (d, J=6.5 Hz, 1H); 8.43 (dd, J=12.5, 7.0 Hz, 1H); 8.33 (s, 2H); 7.93 (d, J=7.8 Hz, 1H); 7.69 (dd, J=10.8, 7.3 Hz, 1H); 7.48 (dd, J=8.8, 4.9 Hz, 2H); 7.37 (t, J=8.8 Hz, 2H); 7.25 (d, J=6.5 Hz, 1H); 6.56 (d, J=7.9 Hz, 1H); 4.28 (q, J=7.0 Hz, 2H); 1.34 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 508.2 (M+H+).

Provenance & Evidence