反应详情

温度

40 °C

A mixture of 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (510a, 88 mg, 0.270 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 109 mg, 0.324 mmol), X-Phos precatalyst II (10.61 mg, 0.013 mmol), and potassium phosphate (172 mg, 0.809 mmol) in 1,4-dioxane (2.2 mL)/water (0.54 mL) was sparged with nitrogen for 3 min at RT; the red solution was then heated to 40° C. for 1 h when starting bromide and product were observed via LCMS. More (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (120 mg) was added, and the red solution was stirred for another 1 h at 40° C. when more product was observed via LCMS. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous sodium bicarbonate (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 0-6% 2 M ammonia in MeOH/DCM to give (R)-7-fluoro-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (510, 15 mg, 0.039 mmol, 14% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83-0.89 (m, 2H) 0.96-1.05 (m, 2H) 1.38 (d, J=6.65 Hz, 3H) 1.54 (s, 3H) 3.38 (s, 3H) 4.66 (q, J=6.39 Hz, 1H) 6.80 (d, J=3.91 Hz, 1H) 7.11 (dd, J=11.93, 8.80 Hz, 1H) 7.75 (s, 1H) 7.84 (s, 1H) 7.85-7.90 (m, 1H) 13.39 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −102.44 (s, 1F). MS (ESI, pos. ion) m/z: 382.1 (M+1).

1. customwas sparged with nitrogen for 3 min at RT
2. additionMore (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (120 mg) was added
3. additionThe reaction mixture was diluted with EtOAc (100 mL)
4. additionadded to a separatory funnel
5. washwashed with saturated aqueous sodium bicarbonate (2×75 mL)
6. customthe organic layer was separated
7. dry with materialdried over Na2SO4
8. concentrationconcentrated
9. customwas purified