Sodium Hydroxide → 6-tert-Butyl-2-{3-[5-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one

Participants

Reaction Conditions

Reaction Steps

In a 15 mL microwave reaction vial was added 6-chloro-4-(5-cyclobutylaminomethyl-pyrazin-2-ylamino)-2-methyl-2H-pyridazin-3-one (71 mg, 221 μmol, Eq: 1.00) in 7 mL n-butanol and 1.4 mL water. Argon was bubbled through the reaction mixture. To the reaction was added acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (218 mg, 309 μmol, Eq: 1.39), potassium phosphate tribasic (103 mg, 487 μmol then X-PHOS (15.8 mg, 33.2 μmol, Eq: 0.15). The mixture was purged with argon and (dibenzylideneacetone)palladium (9.55 mg, 16.6 μmol, Eq: 0.075) was added. The tube was sealed and heated at 110° C. (bath temp) for 3 hrs. The reaction mixture was allowed to cool to room temperature, a solution of NaOH (189 mg) in water (1.5 mL) was added and the mixture was stirred in an oil bath at 37° C. for 3 hrs. The crude reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The organic phase was concentrated and chromatographed on silica gel eluting with 5-10% (10% in NH4OH in MeOH) in (1/1) EtOAc/n-heptane to give a pure fraction (pale yellow) and mixed fractions (yellow). The pure fraction was concentrated and dissolved in DCM. Methanol was added to make a 10% solvent mixture of MeOH in DCM. Heptane was added which resulted in immediate precipitation of solid. The suspension was allowed to sit at room temperature overnight and the resultant solid was filtered, washed with n-heptane and dried to afford 35 mg (25%) of the title compound as an off-white solid. mp: 163-167° C.

Provenance & Evidence