Reaction Steps
and 1-ethyl-3-(4-((S)-4-((S)-3-methylmorpholino)-5,6,8,9,10,10a-hexahydropyrimido[5,4-g]indolizin-2-yl)phenyl)urea (wq2): [4-Ethylureido)phenyl]boronic acid, pinacol ester (0.287 g, 0.000989 mol) (3S)-4-(2-chloro-5,6,8,9,10,10a-hexahydropyrimido[5,4-g]indolizin-4-yl)-3-methylmorpholine (0.251 g, 0.000813 mol), Tetrakis(triphenylphosphine)palladium(0) (0.04696 g, 4.064E-5 mol) Sodium carbonate (0.138 g, 0.00130 mol) and Potassium acetate (0.145 g, 0.00148 mol) were combined, nitrogen purged three times, added dry Acetonitrile (7.00 mL, 0.134 mol) followed by deoxygenated Water (4.00 mL, 0.222 mol), heated at 90° C. and stirred overnight. Added Tetrakis(triphenylphosphine)palladium(0) (0.062 g, 0.000054 mol) Sodium carbonate (0.059 g, 0.00056 mol) Potassium acetate (0.061 g, 0.00062 mol) Acetonitrile (3.50 mL, 0.0670 mol). The reaction mixture was heated at 120° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, and, chromatographed through silica gel (12 g, 0-10% MeOH in dichloromethane), purified by HPLC, and the diastereomers were separated by SFC. R-Diastereomer (wq1): 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.16 (t, J=9.2, 2H), 7.47 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.16-4.05 (m, 1H), 3.86 (d, J=11.2, 1H), 3.78-3.66 (m, 2H), 3.65-3.54 (m, 2H), 3.49-3.40 (m, 2H), 3.17-3.06 (m, 2H), 3.05-2.89 (m, 3H), 2.87-2.75 (m, 1H), 2.75-2.60 (m, 2H), 2.37 (dd, J=15.5, 7.5, 1H), 1.84-1.71 (m, 3H), 1.17 (d, J=6.6, 3H), 1.12 (t, J=7.2, 2H). LC/MS-m/z+437.2 (M+H)+; S-Diastereomer (wq2): 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.17 (d, J=8.7, 2H), 7.48 (d, J=8.7, 2H), 6.17 (t, J=5.3, 1H), 4.06 (s, 1H), 3.87 (d, J=11.2, 1H), 3.77 (d, J=7.7, 1H), 3.64 (dd, J=19.2, 10.4, 4H), 3.43-3.34 (m, 2H), 3.19-3.07 (m, 2H), 2.90 (dd, J=14.5, 8.1, 2H), 2.84-2.73 (m, 2H), 2.69 (d, J=10.8, 1H), 2.35 (d, J=8.5, 1H), 1.85-1.68 (m, 3H), 1.30 (d, J=6.6, 3H), 1.07 (t, J=7.2, 3H). LC/MS-m/z+437.2 (M+H)+.
