反应详情

温度

45 °C

A solution of 8-bromo-3-ethyl-7-fluoro-2-(1-methylcyclopropyl)amino)quinazolin-4(3H)-one (513a, 181.1 mg, 0.53 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 (Example 705; 174 mg, 0.665 mmol), potassium phosphate (339 mg, 1.597 mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos precatalyst, 2nd generation; Aldrich; 20.97 mg, 0.027 mmol) in a mixture of 1,4-dioxane (2.2 mL) and water (0.55 mL) was stirred under argon at 45° C. for 1.5 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM). The isolated product was suspended in MeOH (2 mL), collected by vacuum filtration, washed with ethyl ether (5 mL), and dried in vacuo to provide (R)-3-ethyl-7-fluoro-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (148.2 mg, 0.375 mmol, 70% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.32 (1H, s), 7.90 (1H, s), 7.86 (1H, m, J=8.8, 6.3 Hz), 7.74 (1H, s), 7.11 (1H, dd, J=11.9, 8.8 Hz), 6.79 (1H, d, J=3.7 Hz), 4.66 (1H, q, J=6.3 Hz), 4.06 (2H, q, J=6.5 Hz), 1.54 (3H, s), 1.37 (3H, d, J=6.5 Hz), 1.15 (3H, t, J=6.9 Hz), 0.95-1.05 (2H, m), 0.86 (2H, d, J=2.0 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −102.43 (1F, s). m/z (ESI, +ve) 395.9 (M+H)+.

1. concentrationThe reaction mixture was then concentrated onto silica gel
2. customchromatographically purified (silica gel, 50-100% EtOAc/hexanes
3. filtrationcollected by vacuum filtration
4. washwashed with ethyl ether (5 mL)
5. customdried in vacuo