Reaction Steps
3-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-(trifluoromethylsulfonyloxy)-benzyl)-N-(3-fluorophenyl)-N-methylbenzamide (from Example 5, 0.70 g, 1.2 mmol) was combined with anhydrous sodium carbonate powder (0.65 g, 6.1 mmol), 10 mL anhydrous acetonitrile, sodium iodide (0.03 g, 0.2 mmol), and 1-bromo-3-fluoropropane (0.12 mL, 1.3 mmol). The reaction was stirred for three days at room temperature under nitrogen, and then concentrated under reduced pressure. The residue was suspended in 15 mL ethanol, 10 mL of 10% w/v aqueous NaOH solution was added, and the reaction was stirred 2 hours at room temperature. The ethanol was removed under vacuum and the residue was partitioned between water and dichloromethane. The solution was adjusted to pH 8.5 using 3 N HCl, separated and extracted again with dichloromethane (2×15 mL). The solution was dried (Na2SO4/MgSO4) and concentrated under reduced pressure. The residual oil was purified by chromatography on silica gel (EtOAc+2% NH4OH/CH2Cl2) to give 0.39 g (0.77 mmol) of the desired product as an off-white foam. 1H NMR (600 MHz, d6-DMSO): δ 9.28 (s, 1H), 7.17-7.24 (m, 5H), 7.04-7.07 (m, 2H), 6.97 (dt, J=2.2, 8.4 Hz, 1H), 6.88 (dd, J=1.2, 8.0 Hz, 1H), 6.61 (dd, J=1.8, 8.0 Hz, 1H), 6.55 (s, 1H), 6.41 (d, J=7.4 Hz, 1H), 4.74 (br s, 1H), 4.42 (dt, J=47.5, 6.0 Hz, 2H), 3.30 (s, 3H), 2.70 (dd, J=2.9, 11.0 Hz, 1H), 2.55-2.61 (m, 1H), 2.48-2.52 (m, 1H—partially obscured by DMSO peak), 2.38-2.42 (m, 1H), 2.26 (br d, J˜9.2 Hz, 1H), 2.19-2.24 (m, 1H), 2.00 (dd, J=7.3, 10.8 Hz, 1H), 1.70-1.75 (m, 1H), 1.64-1.70 (m, 2H), 0.95 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.2, Hz, 3H). Calculated for C30H35F2N3O2: C, 70.98; H, 6.95; N, 8.28; F, 7.48%. Found: C, 70.78; H, 7.23; N, 8.19; F, 7.24%.
