Water → HCID 68981265, compound

Participants

Reaction Conditions

Reaction Steps

A 5 L three-neck round bottom flask was charged with (5-methyl-6-oxo-1,6-dihydro-pyridazin-3-3-yl)-acetic acid tert-butyl ester (10; 223 g, 0.996 mol) and THF (700 mL). The resulting solution was cooled to 0° C. and potassium tert-butoxide (1.2 L, 1.66 M in THF, 1.99 mol) was added dropwise over approximately 30 min. After cooling the reaction mixture to −55° C., a solution of 5-(2,3-difluoro-6-nitro-phenoxy)-isophthalonitrile (22; 150 g; 0.498 mol) in THF (1.0 L) was added dropwise over approximately 1 h. Following a THF rinse (500 mL), the cooling bath was removed, and the reaction mixture was stirred for 19 h with warming to ambient temperature. The reaction mixture was then quenched by the addition of 1N HCl (1.75 L). Following removal of the aqueous layer (2 L, pH of 3-4) the organic phase was washed with water (1.0 L) and brine (750 mL). The resulting THF solution was filtered through CELITE® and the filter aid washed with THF (500 mL). The solution was then concentrated in vacuo to afford a dark oil which was dissolved in NMP (850 mL) and warmed to approximately 50° C. Water (425 mL) was added dropwise. The cloudy solution was stirred slowly, seeded with a crystal and cooled to 0° C. After stirring at 0° C. for 30 min, the product was filtered. The filter cake was then washed with MeOH (100 mL, 200 mL) and dried in a vacuum oven (50° C., 25 Torr) to afford [3-(3,5-dicyano-phenoxy)-2-fluoro-4-nitro-phenyl]-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid tert-butyl ester (23; 157 g, 62% theory).

Provenance & Evidence