Dichloromethane → N-(6-(Difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide hydrochloride

Participants

Reaction Steps

A mixture of N-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-yl)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide (0.6 g, 1.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.242 g, 1.162 mmol), and PdCl2(dppf):CH2Cl2 (0.048 g, 0.058 mmol) in dioxane (10 mL)/2N Na2CO3 (5 mL) was heated in a microwave at 110° C. for 30 min. This reaction was repeated 4 times and reaction mixtures were combined. The reaction was diluted with CH2Cl2 (500 mL) and washed with H2O (3×200 mL). The organic phase was separated and concentrated to dryness via rotary evaporation. The resulting residue was suspended in EtOAc and sonicated. The resulting solid was collected by filtration and rinsed with EtOAc. The solid was the dissolved in MeOH/CH2Cl2 (5:95, 300 mL) and filtered through a silica plug and rinsed with MeOH/CH2Cl2 (5:95). Concentrated HCl (0.5 mL) was added to the collected eluent followed by active charcoal. The solution was stirred at ambient temperature for 1 hour and filtered through celite. The solvent was evaporated and the resulting residue was then triturated in EtOAc. The solid was collected by filtration, rinsed with EtOAc and dried in vacuum to provide the title compound, N-(6-(Difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide hydrochloride (0.92 g, 1.78 mmol, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (d, J=6.32 Hz, 4 H) 1.91-2.01 (m, 1 H) 3.87 (s, 3 H) 7.70 (d, J=9.35 Hz, 1 H) 7.90 (dd, J=9.60, 1.52 Hz, 1 H) 7.98-8.11 (m, 2 H) 8.19-8.32 (m, 2 H) 8.40 (s, 1 H) 8.70 (s, 1 H) 11.35 (s, 1 H). ESI-MS:m/z 516.1 (M+H)+. MP: 195° C. dec.

Provenance & Evidence