Reaction Steps
To a solution of (9H-fluoren-9-yl)methyl (S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate (10 mg, 0.01 mmol) in DCM (0.5 mL) was added piperidine (20 mg, 0.1 mmol). The reaction mixture was stirred at rt for 1.5 h and concentrated. The residue was purified by preparative HPLC (Axia column, 30×100 mm, 30-100% MeOH/H2O with 0.1% TFA over 12 min, flow rate 40 mL/min, monitoring at 220 nm) to yield (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1H, s), 7.17-7.22 (1H, m), 7.12 (2H, t, J=7.33 Hz), 7.03-7.08 (2H, m), 6.96-7.02 (2H, m), 6.88 (3H, s), 6.59 (2H, d, J=7.07 Hz), 5.85 (1H, t, J=2.53 Hz), 4.09 (1H, s), 3.91 (1H, d, J=13.14 Hz), 3.71 (1 H, d, J=13.39 Hz), 2.66 (2H, m). (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323B) was prepared in the same method here and isolated as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (1H, s), 7.19 (1H, t, J=7.33 Hz), 7.08-7.15 (4H, m), 6.93-7.00 (2H, m), 6.84-6.92 (2H, m), 6.81 (1H, s), 6.58 (2H, d, J=7.07 Hz), 5.84 (1H, t, J=2.65 Hz), 4.26 (1H, d, J=5.56 Hz), 3.76-3.86 (2H, m), 2.53 (1H, d, J=10.61 Hz), 2.43-2.49 (1H, m). The stereochemistry of (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) and (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323B) was assigned arbitrarily.
