Sodium hydride → (6S)-6-(3,5-dimethylphenyl)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazinan-2-one

Participants

Reaction Conditions

Reaction Steps

To a stirred suspension of sodium hydride (60% in oil; 7.4 mg; 0.185 mmol) in THF (1.5 mL) at 0° C. under N2 was added a solution of (6S)-6-(3,5-dimethylphenyl)-1,3-oxazinan-2-one (Intermediate 21; 30 mg; 0.148 mmol) in THF (2 mL) dropwise. The reaction was stirred at 0° C. for 20 min prior to addition of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 13; 50 mg; 0.123 mmol) as a solution in THF (1.5 mL). The reaction was allowed to warm to room temperature and stirred for 72 h, then quenched with H2O and partitioned between EtOAc (25 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified first by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) and then by chiral HPLC (Chiralpak AD column; 15% IPA/heptane) to afford (6S)-6-(3,5-dimethylphenyl)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazinan-2-one as a clear oil. LCMS=530.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.66 (d, J=7.8 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 7.01-6.96 (m, 4H), 6.70 (d, J=12.1 Hz, 1H), 5.23-5.13 (m, 1H), 4.66-4.49 (m, 2H), 3.78 (s, 3H), 3.26-3.20 (m, 1H), 3.17-3.06 (m, 1H), 3.01-2.93 (m, 1H), 2.34 (s, 6H), 2.18-2.13 (m, 1H), 2.09-2.02 (m, 1H), 1.29-1.24 (m, 6H).

Provenance & Evidence