Reaction Steps
To a stirred solution of the product of Example 4, Step 2, 5-{7-[(3S)-3-methylpyrrolidin-3-yl]-2-(morpholin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrimidin-2-amine hydrochloride (320 mg, 0.764 mmol) and TEA (232 mg, 2.29 mmol) in DCM (16 mL) was added 3-bromo-pyrrolidin-2-one (188 mg, 1.15 mmol) at 25° C. The mixture was stirred at 40° C. for 3 days, whereupon water (10 mL) was added. The mixture was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated to give a crude product (400 mg) as a yellow solid. The residue was purified by preparative TLC (silica gel, 10:1 DCM/MeOH) to give the racemic title compound (170 mg, 48%) as a yellow solid. This material was separated by preparative SFC column (AS, 250 mm×30 mm, 10 μm), mobile phase: 45% MeOH and NH3 in H2O, with a flowrate of 80 mL/min) to give the title compounds: Enantiomer 1 (Example 6), retention time 6.23 min (50 mg, 29%) as a yellow solid and enantiomer 2, retention time 6.21 min (19 mg) as a yellow solid. Enantiomer 1: SFC Retention time: 6.23 min; 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 2 H), 3.76-3.68 (m, 10 H), 3.43-3.33 (m, 5 H), 3.14-3.12 (m, 2 H), 3.05-3.00 (m, 1 H), 2.89-2.85 (m, 1 H), 2.56-2.53 (m, 1 H), 2.35-2.30 (m, 1 H), 2.14-2.10 (m, 1H), 2.00-1.95 (m, 1 H), 1.44 (s, 3 H). m/z (APCI+) for C23H31N9O2 466.2 (M+H)+. Enantiomer 2 (Example 7): SFC Retention time 6.21 min; 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 2 H), 3.82-3.68 (m, 12 H), 3.46-3.40 (m, 1 H), 3.36-3.33 (m, 1 H), 3.14-3.10 (m, 3 H), 3.03-3.00 (m, 1 H), 2.95-2.90 (m, 1 H), 2.54-2.51 (m, 1 H), 2.40-2.35 (m, 1 H), 2.14-2.11 (m, 1 H), 2.04-2.02 (m, 1 H), 1.44 (s, 3 H). m/z (APCI+) for C23H31N9O2 466.2 (M+H)+.
