反应详情

Argon was bubbled into a mixture of 8-bromo-2-(tert-butylamino)quinazolin-4(3H)-one (408a, 62 mg, 0.21 mmol), K2CO3 (0.116 g, 0.84 mmol), dichlorobis(p-dimethylamino-phenylditbutylphosphine)palladium (ii) (Aldrich; 0.030 g, 0.042 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 (706; 0.110 g, 0.419 mmol) and 2 mL dioxane and 0.4 mL water for 1 min. The reaction was sealed and placed in a 100° C. oil bath for 30 min. The reaction was cooled and partitioned between sat'd aq. NH4Cl and DCM. The aqueous layer was extracted with 5% IPA/CHCl3 three times and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. This material was dissolved in DMSO, filtered, and purified by RPHPLC, Phenomenex Gemini 150×30 mm C18 column, 10-70% ACN/H2O with 0.1% TFA; product-containing fractions were treated with saturated aqueous NaHCO3 and DCM. The aqueous layer was extracted 3×DCM and combined organics dried over Na2SO4, filtered, and concentrated in vacuo to give 21 mg as a tan solid. The material was sonicated in 0.5 mL DCM for 2 min, then filtered, rinsing 2×DCM. The solid was collected and dried in vacuo to give (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (6 mg, 0.017 mmol, 8% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (1H, br. s.), 10.63 (1H, s), 7.95 (1H, dd, J=7.6, 1.6 Hz), 7.82 (1H, dd, J=7.8, 1.6 Hz), 7.62 (1H, s), 7.16 (1H, t, J=7.7 Hz), 6.79 (1H, d, J=1.4 Hz), 6.30 (1H, s), 4.54 (1H, d, J=6.7 Hz), 1.47 (9H, s), 1.36 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 352.1 (M+H)+.

1. customThe reaction was sealed
2. customplaced in a 100° C.
3. customfor 30 min
4. temperatureThe reaction was cooled
5. custompartitioned between sat'd aq. NH4Cl and DCM
6. extractionThe aqueous layer was extracted with 5% IPA/CHCl3 three times
7. dry with materialthe combined organics were dried over anhydrous Na2SO4
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. dissolutionThis material was dissolved in DMSO
11. filtrationfiltered
12. custompurified by RPHPLC, Phenomenex Gemini 150×30 mm C18 column, 10-70% ACN/H2O with 0.1% TFA
13. additionproduct-containing fractions were treated with saturated aqueous NaHCO3 and DCM
14. extractionThe aqueous layer was extracted 3×DCM
15. dry with materialcombined organics dried over Na2SO4
16. filtrationfiltered
17. concentrationconcentrated in vacuo
18. customto give 21 mg as a tan solid
19. filtrationfiltered
20. washrinsing 2×DCM
21. customThe solid was collected
22. customdried in vacuo