反应详情

温度

45 °C

A microwave tube was charged with 8-bromo-3-cyclopropyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (492a; 170 mg, 0.51 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; 167 mg, 0.64 mmol), X-Phos pre-catalyst II generation (Sigma-Aldrich; 20 mg, 0.025 mmol) and K3PO4 (Sigma-Aldrich; 324 mg, 1.53 mmol). The tube was sealed and purged with argon for 5 min. 1,4-Dioxane (1.4 mL) and water (0.35 mL) were added and Ar (g) was bubbled through the mixture for 5 min. The tube was sealed and heated in an oil bath at 45° C. for 90 min. The reaction was then cooled to RT and EtOAc and water were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-10% MeOH in CH2Cl2), to provide (R)-3-cyclopropyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(1H)-one (492) (117 mg, 0.30 mmol, 59% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.01 (s, 1H), 8.09 (dd, J=7.63, 1.37 Hz, 1H), 7.77 (dd, J=7.73, 1.27 Hz, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.13 (t, J=7.73 Hz, 1H), 6.93 (d, J=0.98 Hz, 1H), 4.63 (q, J=6.46 Hz, 1H), 2.67-2.74 (m, 1H), 1.55 (s, 3H), 1.36 (d, J=6.65 Hz, 3H), 1.19-1.27 (m, 2H), 0.99-1.04 (m, 2H), 0.83-0.88 (m, 2H), 0.73 (dd, J=3.91, 2.54 Hz, 2H). m/z (ES, +ve) 390.0 (M+H)+.

1. customThe tube was sealed
2. custompurged with argon for 5 min
3. addition1,4-Dioxane (1.4 mL) and water (0.35 mL) were added
4. customAr (g) was bubbled through the mixture for 5 min
5. customThe tube was sealed
6. temperatureThe reaction was then cooled to RT
7. additionEtOAc and water were added
8. customThe layers were separated
9. extractionthe aqueous layer was extracted with EtOAc (2×)
10. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
11. filtrationfiltered
12. concentrationconcentrated
13. customThe crude material was absorbed onto a plug of silica gel
14. custompurified by silica gel chromatography (0-10% MeOH in CH2Cl2)