Hydrochloric Acid → 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

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Reaction Steps

Further, 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 was prepared by suspending crude 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 (2.2 g; 4.9 mmol) in 333 ml of DCM. 50 ml of 0.2 M HCl in MeOH (10 mmol) was added. The mixture was stirred vigorously for 60 minutes and Sili-Thiourea (commercially available from Silicycle; 1.12 g) was added. The mixture was stirred at room temperature for 14 hours, filtered through Celite and washed with 10% MeOH in DCM (40 ml) to provide a total volume of filtrate of about 420 ml. 15 ml of a 2M HCl MeOH solution was added. The solution was concentrated by rotavap at 225 mbar, 22° C. bath temperature to remove about 325 ml of solvent. The solution was checked for clarity to ensure that solid formation was minimized. 10 ml of a 2M HCl MeOH solution was added. The solution was seeded with 25 mg of 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 salt. The solution was allowed to continue to concentrate at 130 mbar to remove 65 ml solvent in the presence of seed crystal. After the solution turned cloudy, the solution was maintained at room temperature for 40 minutes. The mixture was cooled to 0° C., stirred for 2 hours, and the solids collected by filtration. The solids were dried in vacuum at 60° C. overnight to afford 1.75 g of a pale-yellow solid.

Provenance & Evidence