Hydrochloric Acid → N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride

Participants

Reaction Conditions

Reaction Steps

tert-Butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (423.9 g, 649.50 mmol) is dissolved in DCM (4.24 L). HCl in MeOH (5.74 N, 799.99 mL, 4.59 mol) is added and the solution is heated at 30° C. for 1 hour. Then the reaction mixture is heated to 45° C. and DCM (1.5 L) is added. After two hours, the solution is heated to 50° C. and DCM (2 L) is added. After 3 hours, DCM (2 L) is added followed by HCl in MeOH (4.5 N, 721.67 mL, 3.25 mol). After another 45 min, DCM (1 L), HCl in MeOH (4.5 N, 288.67 mL, 1.30 mol), and MeOH (1.5 L) are added. The reaction solution is then heated to 60° C. After 4 hours, MeOH (2 L) is added and 10 min later DCM (1 L) is added followed by HCl in MeOH (4.5 N, 200 mL). After 5 hours, the reaction is complete. The reaction mixture is concentrated to about ⅓ volume. MeOH (2 L) is added and the solution is concentrated to a thick slurry. Again, MeOH (2 L) is added and the mixture is concentrated to a thick slurry. The slurry is cooled to about 10-15° C. and then filtered. The solids are washed with MeOH. The solids are placed in a 55° C. vacuum oven for 2 days to give the desired product N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (377 g, 92.8%). MS (m/z): 551.0 (M−H).

Provenance & Evidence