Sodium Hydroxide → 6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(1-methyl-piperidin-4-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

참여 물질

반응 조건

반응 단계

In a 15 mL microwave reaction vial was added 6-chloro-2-methyl-4-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)pyridazin-3(2H)-one (160 mg, 478 μmol, Eq: 1.00), potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (272 mg, 573 μmol, Eq: 1.2) with n-BuOH (7.5 ml) and water (1.5 ml). Argon was bubbled through the solution for 5 min. To the mixture was added X-PHOS (34.2 mg, 71.7 μmol, Eq: 0.15) and potassium phosphate tribasic (304 mg, 1.43 mmol, Eq: 3). Argon was bubbled through the mixture for 5 min. To this mixture was added bis(dibenzylideneacetone)palladium (20.6 mg, 35.8 μmol, Eq: 0.075). The tube was sealed under argon and heated in oil bath at 110° C. for 3 hrs. The mixture was cooled to room temperature and treated with a solution of 220 mg NaOH in 1.5 mL water dropwise. The resultant mixture was heated in an oil bath at 50° C. for 3 hrs with strong stirring. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3×30 mL). The combined extracts were concentrated and purified by solid loading on a 40 g silica gel column and eluting with 5-10% (10% NH4OH in MeOH) in 1/1 EtOAc/hexane to afford 61 mg (20%) of the title compound as a yellow solid. mp: 260-265° C. 1H NMR (300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 1.80-2.20 (m, 6H), 2.37 (s, 3H), 2.90-3.07 (m, 3H), 3.85 (t, J=6.2 Hz, 1H), 3.92 (s, 3H), 4.45 (d, J=6.2 Hz, 2H), 7.15 (d, J=9 Hz, 1H), 7.35 (d, J=9 Hz, 1H), 7.43-7.65 (m, 5H), 8.28 (d, J=2.5, 1H), 8.32 (s, 1H), 8.78 (s, 1H). LCMS (ES): 625 (M+H), RT=2.21 min.

출처 및 근거