Hydrochloric Acid → Azd-8330

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (170 g, 0.35 mol), under nitrogen, in THF (850 mL) was added 2M HCl (318 mL), over 15 minutes at 17-22° C. After 1 hour the reaction was complete (as indicated by HPLC) and a solution of 2M sodium hydroxide (318 mL) was added, over 10 minutes, keeping the temperature at approximately 22° C. The pH of the mixture was approximately 8. The mixture was then partitioned with MIBK (1.02 L) and the lower aqueous layer was separated and discarded. The volume of the organic solution was then reduced by distillation, at ambient pressure and with a jacket temperature of 85-95° C. After the removal of 750 mL solvent the rate of distillation had slowed considerably and the mixture was cooled to approximately 22° C. Crystalline 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide Form 2 (1 g, seed, prepared as described in Example 16C) was added to the mixture followed by ethyl acetate (170 mL). After 5 minutes the mixture began to crystallize and iso-hexane (1.7 L) was added at 23-25° C. over 50 minutes. The slurry was held at 25° C. for 80 minutes and then filtered. The solid was washed with iso-hexane (680 mL) then dried in vacuum oven at 30° C. to provide the title material (147 g, 0.31 mol, 89% yield). 1H NMR (D6-DMSO): δ 7.63 (dd, 1H, J 11, 2 Hz, ArH), 7.55 (s, 1H, ArH), 7.38 (d, 1H, J 8.5 Hz, ArH), 6.52 (˜t, 1H, J 8.5 Hz, ArH), 4.91-4.35 (bs, 1H, OH), 3.74 (t, 2H, J 5 Hz, OCH2), 3.51 (˜t, 2H, J 5 Hz, OCH2), 3.25 (s, 3H, NCH3), 2.02 (s, 3H, ArCH3). MS (ESI) (+) m/z 484 (27%, [M+Na]+), 462 (100%, [M+H]+), 385 (8%), 100 (26%).

Provenance & Evidence