Reaction Steps
and 1-(4-((S)-8-(cyanomethyl)-7-ethyl-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (xs2): 1-(4-(7-acetyl-8-(cyanomethyl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (0.051 g, 0.00011 mol) in dry Tetrahydrofuran (1.00 mL, 0.0123 mol) at 0° C. was added 1.0 M of Borane-THF complex in Tetrahydrofuran (0.320 mL) dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was cooled at 0° C. then about 1 mL 1M HCl dropwise then added 1M NaOH until pH10. The reaction mixture was extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, purified by HPLC, and the diastereomers were separated by SFC. R Diastereomer (xs1): 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.19 (t, J=11.3, 2H), 7.48 (d, J=8.7, 2H), 6.15 (t, J=5.3, 1H), 4.19 (d, J=6.6, 1H), 3.90 (d, J=11.6, 1H), 3.75 (d, J=12.2, 2H), 3.60 (dd, J=25.9, 11.5, 3H), 3.51-3.38 (m, 1H), 3.23-3.17 (m, 1H), 3.10 (ddd, J=24.6, 15.3, 9.3, 3H), 2.86 (dt, J=14.5, 7.2, 1H), 2.67 (s, 1H), 2.59 (dd, J=13.2, 6.9, 2H), 2.55-2.39 (m, 2H), 1.18 (d, J=6.6, 3H), 1.08 (dt, J=14.3, 7.1, 6H). LC/MS-m/z+464.2 (M+H)+; S Diastereomer (xs2) 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.20 (d, J=8.7, 2H), 7.48 (d, J=8.7, 2H), 6.15 (t, J=5.5, 1H), 4.14 (d, J=6.8, 1H), 3.88 (d, J=10.3, 1H), 3.81-3.70 (m, 2H), 3.70-3.57 (m, 3H), 3.39 (t, J=11.0, 1H), 3.14 (ddd, J=19.9, 12.1, 6.1, 4H), 3.07-2.98 (m, 1H), 2.84 (dq, J=13.9, 7.0, 1H), 2.59 (ddd, J=21.5, 15.3, 8.2, 4H), 1.34 (d, J=6.6, 3H), 1.08 (dt, J=14.3, 7.1, 6H). LC/MS-m/z+464.2 (M+H)+.
