Ammonium Chloride → 6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-pyrazin-2-ylamino)-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one

Participants

Reaction Conditions

Reaction Steps

A solution of 6-chloro-2-methyl-4-(5-(trifluoromethyl)pyrazin-2-ylamino)pyridazin-3(2H)-one (109 mg, 0.36 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (264 mg, 0.54 mmol), potassium phosphate (189 mg, 0.89 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (17.0 mg, 0.04 mmol) in n-butanol (4 ml) and water (1 ml) was bubbled argon gas for 10 min. To this solution was added bis(dibenzylideneacetone)dipalladium(0) (10.3 mg, 0.02 mmol) was added and the resulting mixture heated to 100° C. for 2 hr. The mixture was cooled and then poured into a saturated ammonium chloride solution. The resulting mixture was extracted with methylene chloride (2×100 ml). The organic phases were combined and dried over MgSO4. The mixture was filtered and evaporated and the residue dissolved in dioxane (10 mL). To this solution was slowly added a 2 M lithium hydroxide solution (0.5 mL) and the resulting mixture stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution. The mixture was extracted with methylene chloride (2×150 ml). The organic phases were combined and dried over MgSO4. The mixture was filtered and evaporated and the residue purified via automated flash chromatography (Analogix, SF15-24 g column, 1%-10% methanol/dichloromethane gradient) to give a light yellow solid which was recrystallized from methanol/dichloromethane to give 6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-pyrazin-2-ylamino)-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one (65 mg, 31%) as a white solid: Mp 250-254° C.; LC/MS m/e calculated for C29H25F4N7O3 [M+H]+ 596.20, observed 596.3; 1H NMR (DMSO-d6) δ: 10.38 (s, 1H), 8.71-9.08 (m, 2H), 8.43-8.66 (m, 2H), 7.68-8.02 (m, 2H), 7.38-7.65 (m, 3H), 4.54-4.76 (m, 1H), 4.40 (br. s., 2H), 3.82 (s, 3H), 1.38 (s, 9H).

Provenance & Evidence