Reaction Steps
To a solution of (R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene (22 mg, 0.057 mmol) in CH2Cl2 (0.10 mL) was added 3,3,3-trifluoropropanal (0.010 mL, 0.11 mmol) and pyridine (0.018 mL, 0.23 mmol) followed by trifluoroacetic acid (0.009 mL, 0.11 mmol). The reaction mixture was heated at 40° C. for 4 h. Additional 3,3,3-trifluoropropanal (0.010 mL, 0.11 mmol) was added and heating at 40° C. for was continued for 2 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed under a stream of nitrogen. The residue was purified by prep TLC plate, eluting with 40% Et2O/hexane, to yield (S)-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 329A, 11 mg, 36% yield) and (R)-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 329B, 11 mg, 36% yield) as clear colorless oils. (S)-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 329A): LCMS: RT=1.81 min [M+H] 518.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 2.24-2.36 (m, 1H) 2.81-2.91 (m, 2H), 3.74 (d, J=13.18 Hz, 1H), 3.99 (d, J=13.18 Hz, 1H), 4.43 (dd, J=10.11, 3.52 Hz, 1H), 6.60 (d, J=7.47 Hz, 2H), 6.99-7.07 (m, 4H), 7.12-7.28 (m, 6H), 7.70 (s, 1H). (R)-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 329B): LCMS: RT=1.82 min [M+H] 518.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 2.23-2.35 (m, 1H), 2.77-2.88 (m, 2H), 3.73 (d, J=12.75 Hz, 1H), 3.99 (d, J=12.74 Hz, 1H), 4.45 (dd, J=8.35, 3.95 Hz, 1H), 6.61 (d, J=7.47 Hz, 2H), 6.98-7.04 (m, 4H), 7.16-7.28 (m, 6H), 7.69 (s, 1H). The stereochemistry of (S)-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 329A) and (R)-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 329B) was assigned arbitrarily.
