3-Methylpyrrolidin-3-ol hydrochloride → 3-Bromo-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-benzamide

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A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 100 mg, 0.264 mmol), 3-methylpyrrolidine-3-ol hydrochloride (72.8 mg, 0.529 mmol), and TEA (147 μL, 1.058 mmol) in DMSO (199 μL) was stirred at 90° C. for 16 h. Additional TEA (73.7 μL, 0.529 mmol) was added to the mixture and stirring was continued for 72 h at 100° C. The cooled RM was diluted with TBME/EtOAc (1:1)(30 mL), sequentially washed 0.5 M HCl (3×5 mL), brine (5 mL) and then evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 20% to 60% EtOAc-EtOH+0.1% NH4OH (9:1)) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.98 min, m/z=459/461.0 [M+H]+, m/z=457/459 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 3H) 1.77-1.95 (m, 2H) 3.32-3.35 (m, 1H) 3.37-3.48 (m, 1H) 3.65 (d, J=10.03 Hz, 1H) 3.75 (td, J=9.41, 7.09 Hz, 1H) 4.79 (s, 1H) 6.90 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.81-7.91 (m, 3H) 8.13 (d, J=1.96 Hz, 1H) 10.17 (s, 1H).

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