A mixture of 2-[2-fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine (0.33 g, 0.72 mmol) in acetone (25 mL) and water (10 mL) was treated with Oxone® (1.33 g, 2.17 mmol). The reaction mixture was stirred at ambient temperature overnight. Water (60 mL) was added, the mixture was extracted with EtOAc. The combined organic extract was washed with water, brine, and dried over Na2SO4, filtered, and the filtrate was concentrated to a light beige solid, which was purified by chromatography on an ISCO silica gel column using 0 to 55% EtOAc/hexanes to give 2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-[((1S)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine (0.255 g, 70% ee, 72%) as a white solid. The solid was subjected to chiral separation [column: OJ-H, column mobile phase: 75% CO2: 25% of a 9/1 mixture of MeOH/CHCl3 (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] to give two (R and S) enantiomers, with the (S)-isomer eluting first. The material was triturated with 9% EtOAc/hexanes to afford the title compound (0.15 g) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 8.28 (d, 1H, J=1.2 Hz), 8.22 (t, 1H, J=7.7 Hz), 7.82 (dd, 1H, Ja=8.2 Hz, Jb=1.7 Hz), 7.75 (dd, 1H, Ja=10.3 Hz, Jb=1.7 Hz), 5.25-5.10 (m, 1H), 4.30-4.15 (m, 2H), 3.10-3.00 (m, 5H), 2.87 (septet, 1H, J=6.9 Hz), 2.00-1.80 (m, 3H), 1.55-1.40 (m, 2H), 1.34 (d, 3H, J=6.1 Hz), 1.26 (d, 6H, J=6.8 Hz); LRMS (ESI), m/z 490 (M+H).
