Acetic Acid → 3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxo-1-phenylpropyl acetate

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Reaction Steps

To a solution of 2-phenyloxirane (0.009 mL, 0.08 mmol) in THF (1.5 ml) was added LiOTf (12 mg, 0.08 mmol), (R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzene (30 mg, 0.07 mmol) and acetic acid (0.004 mL, 0.08 mmol) in succession. The reaction mixture was heated to reflux for 3 h. The reaction was allowed to cool to rt and diluted with EtOAc (15 mL). The organic layer was washed with sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude mixture was purified by preparative HPLC YMC ODS S5 30×100 mm column 30-100% MeOH (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm to yield 3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxo-1-phenylpropyl acetate (Example 265) as a white solid (26 mg, yield 62%, 1:1 RR:RS diastereomer mixture). LCMS: RT=2.19 min [M+H] 616.3 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.27 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.96 (d, J=4.95 Hz, 3H), 3.01 (ddd, J=14.30, 6.87, 3.02 Hz, 1H), 3.14 (td, J=8.94, 5.22 Hz, 1H), 3.523 (d, J=13.2 Hz, 0.5H), 3.62 (m, 0.5H), 3.72 (m, 0.5H), 3.82 (d, J=13.2 Hz, 0.5H), 5.30-5.34 (m, 1H), 5.74-5.97 (m, 1H), 6.46-6.53 (m, 2H), 6.60 (d, J=10.45 Hz, 1H), 6.67-6.72 (m, 1H), 6.80-7.31 (m, 13H).

Provenance & Evidence