反应详情

温度

0 °C

To a solution of (R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (503b, 555 mg, 1.14 mmol) in DCM (30 mL) at 0° C. was added boron trichloride (1.0 M in DCM, 1.71 mL, 1.71 mmol) slowly dropwise. The resulting tan suspension was stirred at 0° C. for 5 min, then RT for 15 min. LC-MS indicated only unreacted starting material. The reaction mixture was treated with additional BCl3 solution (0.5 mL) at RT and stirred 10 min. LC-MS indicated product formation. The reaction was cooled to 0° C. in an ice bath and treated with MeOH (ca. 3 mL) and ca. 500 mg of powdered NaHCO3 and stirred for 5 min. The reaction mixture was then treated with silica gel and purified on an ISCO Combiflash RF (40 g Silicycle column, using a gradient of 0-20% MeOH in DCM) affording (R)-2-(tert-butylamino)-8-(6-(2-hydroxyethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrolo-2-yl)-3-methylquinazolin-4(3H)-one (503) (233 mg, 0.589 mmol, 51.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, s), 7.88 (2H, dd, J=7.6, 2.5 Hz), 7.66 (1H, br. s.), 7.18 (1H, t, J=7.7 Hz), 6.72 (1H, d, J=1.4 Hz), 5.93 (1H, s), 4.54 (1H, dd, J=8.8, 3.9 Hz), 3.52-3.83 (6H, m), 1.95-2.09 (1H, m), 1.55-1.67 (1H, m), 1.45-1.54 (9H, s). m/z (ESI, +ve) 396.0 (M+1)+.

1. waitRT for 15 min
2. stirringstirred 10 min
3. temperatureThe reaction was cooled to 0° C. in an ice bath
4. stirringstirred for 5 min
5. additionThe reaction mixture was then treated with silica gel
6. custompurified on an ISCO Combiflash RF (40 g Silicycle column