Reaction Steps
A stirred mixture of 3-bromo-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one (100 mg, 0.328 mmol, intermediate 2a), 2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (70 mg, 0.328 mmol, from example 114, step E), and triethylamine (0.137 mL, 0.985 mmol) in acetonitrile (2 mL) was heated at 120° C. in a CEM microwave for one hour. The reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine solution, dried over sodium sulfate, and evaporated under reduced pressure to give a crude residue. The crude residue was purified via preparative LC/MS (column: Waters Xbridge C18, 19×150 mm, 5 μm; guard column: Waters XBridge C18, 19×10 mm, 5 μm; mobile phase A: 5:95 methanol:water with 10 mM NH4OAc; mobile Phase B: 95:5 methanol:water with 10 mM NH4OAc; Gradient: 15-50% B over 25 min, followed by a 10 min hold at 50% B and 5 min hold at 100% B; flow: 15 ml/min) to afford 1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (68 mg, 46%). The diastereomeric mixture was separated by preparative chiral SFC (column=Chiralpak AD-H (250 mm×21 mm, 5 μm); isocratic solvent=40% methanol (w/0.25% DEA) in CO2, 100 bar; temp=25° C.; flow rate=75 g/min; injection volumn=1.1 mL (˜6 mg/mL in MeOH); λ=220 nM; Peak 1=3.2 min, Peak 2=5.0 min) to afford the titled compounds of example 117 (18 mg of peak-1, and 20 mg of peak-2). Data for example 117, P-1: LC-MS m/z 437 (M+H)+; 1H NMR (400 MHz, methanol-d4) δ ppm 7.55 (d, J=8.03 Hz, 2H) 7.42 (s, 2H) 6.97-7.04 (m, 1H) 6.62-6.95 (m, 3H) 4.48-4.68 (m, 3H) 3.76 (t, J=8.78 Hz, 1H) 3.50 (dt, J=3.31, 1.64 Hz, 0H) 3.25-3.31 (m, 0H) 3.11-3.18 (m, 0H) 2.99-3.05 (m, 0H) 2.41-2.71 (m, 3H) 2.16-2.26 (m, 1H) 2.08 (dq, J=12.91, 8.79 Hz, 1H) 1.78-1.91 (m, 2H). Data for example 117, P-2: LC-MS m/z 437 (M+H)+; 1H NMR (400 MHz, methanol-d4) δ ppm 7.55 (d, J=8.03 Hz, 2H) 7.41 (d, J=8.28 Hz, 2H) 7.00 (dd, J=12.39, 1.91 Hz, 1H) 6.62-6.93 (m, 3H) 4.47-4.70 (m, 3H) 3.69-3.77 (m, 1H) 3.38-3.55 (m, 1H) 3.24-3.30 (m, 1H) 3.15 (dt, J=3.31, 1.64 Hz, 1H) 2.74-2.83 (m, 2H) 2.52-2.72 (m, 2H) 2.44 (td, J=10.02, 4.80 Hz, 1H) 2.03-2.27 (m, 2H) 1.76-1.90 (m, 2H).
