Acetic Acid → (S)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide

Participants

Reaction Conditions

Reaction Steps

To a solution of (S)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene prepared as described in Procedure 149, 150, 151 and 152 (23 mg, 0.060 mmol) in THF (0.25 mL) was added 3,3,3-trifluoropropanal (0.006 mL, 0.071 mmol) and acetic acid (0.004 mL, 0.071 mmol) followed by a 0.5M solution of zinc chloride in THF (0.142 mL, 0.071 mmol). The reaction mixture was heated at 55° C. for 16 h. The reaction mixture was allowed to cool to room temperature then a solution of 25% NaOMe in MeOH (25 uL) was added and the reaction mixture was heated at 40° C. for 18 h. The reaction mixture was allowed to cool to room temperature then a drop of acetic acid was added and the solvent was removed under a stream of nitrogen. The residue was purified by prep TLC plate, eluting with 25% EtOAc/hexanes, to yield (S)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 332A, 7 mg, 22% yield) and (R)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 332B, 6 mg, 18% yield) as clear colorless oils. (S)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 332A): 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=8.57, 4.17 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). (R)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 332B): 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 2.23-2.34 (m, 1H) 2.77-2.88 (m, 2H) 3.73 (d, J=12.75 Hz, 1H) 3.99 (d, J=12.74 Hz, 1H) 4.44-4.47 (m, 1H) 6.61 (d, J=7.47 Hz, 2H) 6.98-7.07 (m, 4H) 7.14-7.28 (m, 6H) 7.69 (s, 1H). The stereochemistry of (S)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 332A) and (R)-4,4,4-trifluoro-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-hydroxybutanamide (Example 332B) was assigned arbitrarily.

Provenance & Evidence