Hydrogen Bromide → N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide

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A stirring suspension of N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-methoxy-5-methyl-benzamide (2.32 g, 6.51 mmol) in a 25% solution of HBr in acetic acid (60 mL, 0.11 M) was equipped with a refllux condenser and heated to 120° C. for 3.5 h. The mixture was allowed to cool and saturated aq NaCl (50 mL) and ethyl acetate (50 mL) were added. The layers were allowed to separate and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to provide an orange powder. Purification of the solid via silica gel flash chromatography (30% ethyl acetate in heptane) provided N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide (1.69, 73%) as a white powder: mp 149–150° C.; Rf 0.51 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 12.20 (d, J=1.5, 1 H), 7.30–7.29 (m, 2 H), 7.26 (s, 1 H), 7.14 (d, J=8.1 Hz, 1 H), 6.64 (d, J=10.8, 1 H), 6.48 (bd s, 1 H), 4.62 (d, J=5.7 Hz, 2 H), 2.19 (8, 3 H); ESI-LC/MS m/z calcd for C15H12BrF2NO2: 355.0. Found 354.0 (M−1)−. Anal. calcd for C15H12BrF2NO2: C, 50.58; H, 3.40; N, 3.93. Found C, 50.65; H, 3.47; N, 3.87.

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