反应详情

温度

105 °C

A mixture of 1-(3-(tert-butylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-yl)ethanol (310b; 960 mg, 1.732 mmol), 2-bromo-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (608) (596 mg, 2.77 mmol), K2PO4 (1177 mg, 5.54 mmol), X-Phos (Strem Chemicals, Inc., 83 mg, 0.173 mmol), and Pd2dba3 (Aldrich) (79 mg, 0.087 mmol) in a mixture of 1,4-dioxane (15 mL) and water (3.00 mL) was heated under argon at 105° C. for 1.5 h. The reaction mixture was then cooled to RT, diluted with water (100 mL), and extracted with 5% MeOH/DCM (3×100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) followed by trituration of the collected solid with Et2O (10 mL) furnished 2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (310) (172 mg, 0.45 mmol, 26% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br. s.), 7.85 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=8.0, 1.2 Hz), 7.47 (1H, s), 7.34 (1H, t, J=7.8 Hz), 7.04 (1H, d, J=2.2 Hz), 6.93 (1H, s), 6.43 (1H, br. s.), 4.96 (1H, q, J=6.8 Hz), 3.43 (2H, td, J=6.8, 2.5 Hz), 2.86 (2H, t, J=6.8 Hz), 1.54 (9H, s), 1.50 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 380.1 (M+H)+. Separation of this material (310c) by supercritical-fluid chromatography (Chiralpak IC (150×30 mm, 10 μm), 70% liquid CO2/30% MeOH (+20 mM NH4OH), 70 mL/min) separately afforded: first-eluting peak, (S)-2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, (310; 35.0 mg, 0.092 mmol, m/z (ESI, +ve) 380.1 (M+H)+); and second-eluting peak, (R)-2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (311; 39.0 mg, 0.103 mmol, m/z (ESI, +ve) 380.1 (M+H)+).

1. temperatureThe reaction mixture was then cooled to RT
2. extractionextracted with 5% MeOH/DCM (3×100 mL)
3. dry with materialThe combined extracts were dried over Na2SO4
4. filtrationfiltered
5. concentrationconcentrated onto silica gel
6. customChromatographic purification (silica gel, 0-100% EtOAc/hexanes