Reaktionsschritte
A stirred mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (4.29 g; 7.19 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78) (4.57 g; 21.57 mmol), tetrakis(triphenylphosphine)palladium (0) (1.0 g; 0.86 mmol), and sodium carbonate (6.35 g) in C6H6/EtOH/H2O (120 mL/17 mL/51 mL) was heated at reflux (100° C.) under N2 for 14 h. The reaction was partitioned between EtOAc (200 mL) and H2O (100 mL). The aqueous phase was extracted with EtOAc (3×200 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica-gel flash chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one as a yellow solid. To remove the yellow impurity, 2.7 g were dissolved in 165 mL EtOH and 275 mg decolorizing charcoal was added (activated carbon, Darco, G-60, 100 mesh powder, Aldrich). The mixture was stirred at room temperature for 40 min, filtered, and concentrated in vacuo. Trituration with ca. 25 mL hexanes afforded 2.46 g of the title compound as a white solid. 1H NMR indicated trace impurities which were removed by silica gel flash chromatography (0-15% EtOAc/hexanes gradient). Residual solvent was removed by lyophilization from acetonitrile. LCMS=638.3 (M+1)+. 1H NMR (benzene-d6, 500 MHz, 1:1 mixture of atropisomers): δ 7.82 (s, 0.5H), 7.60 (s, 0.5 H), 7.57 (s, 1 H), 7.33 (d, J=8 Hz, 1 H), 7.27 (d, J=9.9 Hz, 2 H), 7.02-6.98 (m, 1 H), 6.89 (d, J=8.5 Hz, 0.5 H), 6.82 (d, J=8.5 Hz, 0.5 H), 6.45 (d, J=12.1 Hz, 0.5 H), 6.35 (d, J=11.9 Hz, 0.5 H), 4.94 (d, J=16.0 Hz, 0.5 H), 4.87 (d, J=15.8 Hz, 0.5 H), 4.54 (d, J=8.0 Hz, 0.5 H), 4.50 (d, J=7.8 Hz, 0.5 H), 3.74-3.66 (m, 1 H), 3.23-3.15 (m, 1 H), 3.12 (s, 1.5 H), 2.99 (s, 1.5 H), 2.97-2.92 (m, 0.5H), 2.89-2.84 (m, 0.5 H), 1.21-1.09 (m, 6 H), −0.27 (d, J=6.7 Hz, 1.5 H), −0.40 (d, J=6.7 Hz, 1.5 H).
