Synthesis of Fluorinated Benzamide Derivative

Example 31

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To a solution of 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoic acid (80 mg, 1.0 eq) and (3-cyano-5-fluorophenyl)boronic acid (59 mg, 2.0 eq) in DMF (1.2 mL) 2M Cs2CO3 (0.27 mL, 3.0 eq) and Pd(dppf)Cl2·DCM (9 mg, 0.06 eq) under nitrogen atmosphere. After stirred at 110° C. for 20 h, the mixture was filtered through celite, rinsing with ethyl acetate (20 mL). The organic phase was washed with sat. aq. sodium bicarbonate (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Hexanes:ethyl acetate, 1:1) to obtain the acid IV-484-536 as white solid (22 mg, 25.2% yield).

¹H-NMR (400 MHz, DMSO-d⁶): δ=12.86 (s, 1H), 8.99 (t, 1H), 8.12 (s, 1H), 8.07 (d, 2H), 8.01 (dd, 1H), 7.89 (dd, 1H), 7.84 (d, 2H), 7.39 (d, 2H), 7.27 (m, 2H), 7.16 (m, 2H), 6.99 (d, 1H), 4.54 (d, 2H).

HPLC-MS: Rt 2.23 m/z 485.1 (MH⁺)