Sodium Hydroxide → (R)-2-(tert-butylamino)-8-(6-ethyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-methylquinazolin-4(3H)-one

Participants

Reaction Conditions

Reaction Steps

A mixture of 2-(dicyclohexylphosphino)-2′,4′,6%-tri-isopropyl1,1′-biphenyl (Strem Chemicals, 16.02 mg, 0.034 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, 15.38 mg, 0.017 mmol), potassium phosphate tribasic (Sigma Aldrich, 267 mg, 1.260 mmol), (R)-6-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (505g, 232 mg, 0.840 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (Intermediate 701, 150 mg, 0.420 mmol) in 1,4-dioxane (4 mL), water (1.20 mL) in a sealed glass tube was heated at 80° C. for 1.5 h. The reaction mixture was treated with 1N NaOH and extracted with EtOAc (2×50 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude reaction mixture was chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column, using a gradient of 0-10% MeOH in DCM) affording a dark brown oil. It was suspended in Et2O with sonication and filtered and washed with Et2O and dried in the vacuum oven at 34° C. for 2 h affording (R)-2-(tert-butylamino)-8-(6-ethyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-methylquinazolin-4(3H)-one (505, 83.8 mg, 0.221 mmol, 52.6% yield) as a tan amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br. s.), 7.89 (2H, d, J=7.2 Hz), 7.65 (1H, br. s.), 7.18 (1H, br. s.), 6.71 (1H, br. s.), 5.94 (1H, br. s.), 4.45 (1H, br. s.), 3.48 (3H, br. s.), 1.84 (1H, br. s.), 1.61 (1H, br. s.), 1.50 (9H, br. s.), 0.85 (3H, br. s.). m/z (ESI, +ve) 380.0 (M+1)+.

Provenance & Evidence