Water → 2-[2-Fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine

Participants

Reaction Conditions

Reaction Steps

A mixture of 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 161, Alternative synthesis, Step 4, 0.40 g, 1.69 mmol), crude (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.75 g, 2.29 mmol) and K2CO3 (0.48 g, 3.39 mmol) in DMF (16 mL) was stirred at 100° C. in a preheated oil bath overnight. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown oil, which was purified by chromatography on an ISCO silica gel column using 0 to 30% EtOAc/hexanes to give 0.335 g (43%) of 2-[2-fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.23 (d, 1H, J=1.0 Hz), 7.85 (t, 1H, J=8.2 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.7 Hz), 7.00 (dd, 1H, Ja=12.1 Hz, Jb=1.6 Hz), 5.20-5.05 (m, 1H), 4.25-4.15 (m, 2H), 3.10-2.95 (m, 2H), 2.87 (septet, 1H, J=6.9 Hz), 2.50 (s, 3H), 2.00-1.75 (m, 3H), 1.55-1.40 (m, 2H), 1.33 (d, 3H, J=6.4 Hz), 1.26 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 458 (M+H).

Provenance & Evidence