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

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

In a 15 mL microwave reaction vial was added 6-chloro-4-(6-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridazin-3-ylamino)-2-methylpyridazin-3(2H)-one (75 mg, 213 μmol, Eq: 1.00), n-BuOH (6 ml) and water (1.5 ml). To the mixture was added potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (101 mg, 213 μmol, Eq: 1.00) under argon. X-PHOS (10.6 μA, 31.9 μmol, Eq: 0.15) and potassium phosphate tribasic (99.3 mg, 468 μmol, Eq: 2.2) was added followed by bis(dibenzylideneacetone)palladium (9.17 mg, 15.9 μmol, Eq: 0.075). The tube was sealed under argon and heated in an oil bath at 115° C. for 3 hrs then stirred at room temperature overnight. To this mixture was added 100 mg NaOH in 1 mL distilled water. The mixture was warmed in an oil bath at 50° C. for 3 hrs then stirred at room temperature overnight. The crude reaction mixture was diluted with water (20 mL) and extracted with DCM (2×30 mL). The combined organic extracts were concentrated and absorbed onto silica gel. The crude material was purified by LC chromatography eluting with 0-5% (10% NH4OH in MeOH) in 1/1 EtOAc/heptane to afford 67 mg (47%) of the title compound as a pale yellow solid. Mp: 140-145° C. 1H NMR (300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 1.67 (s, 6H), 2.37 (s, 6H), 2.80 (s, 2H), 3.80 (t, J=6.2 Hz, 1H), 3.92 (s, 3H), 4.45 (d, J=6.2 Hz, 2H), 6.90 (d, J=9 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 7.43-7.65 (m, 5H), 8.20 (s, 1H), 8.28 (d, J=2.5, 1H), 8.55 (s, 1H). LCMS (ES): 643(M+H), RT=1.942 min.

Herkunft & Nachweise