Isopropyl Acetate → 3-Bromo-N-cyclopropyl-5-(3-methoxy-prop-1-ynyl)-4-methyl-benzamide

Participants

Reaction Conditions

Reaction Steps

To 3-bromo-5-(3-methoxy-prop-1-ynyl)-4-methyl-benzoic acid (0.38 M solution in THF) was added N,N-diisopropylethylamine (1.8 equiv.) and cyclopropylamine (1.35 equiv.) maintaining the internal temperature below 25° C. The mixture was cooled to 5° C. and 2-propanephosphoric acid anhydride (50 wt % in EtOAc, 1.5 equiv.) was added whilst maintaining the internal temperature below 25° C. The reaction mixture was aged for 1 h at ˜20° C. then cooled to 2° C. and 10 wt % aq. NH4Cl solution added, maintaining the internal temperature <30° C. Isopropyl acetate was added and the layers were allowed to settle. The lower aqueous layer removed. The organics were then washed with 1M HCl, followed by 10% NaHCO3 solution and finally 10% NaCl solution. The organic layer was concentrated to ˜1 M followed by the addition of toluene. The batch was then reconcentrated to ˜2 M and the resultant slurry aged for 18 h. Heptane was then added and the solids were filtered, washed with a mixture of 1:1 toluene/heptane and dried to give the title compound as an off-white solid. 1H NMR (500 MHz, Acetone-d6): δ 8.01 (s, 1 H), 7.92 (s, 1 H), 7.86 (s, 1 H), 4.37 (s, 2 H), 3.39 (s, 3 H), 2.95-2.89 (m, 1 H), 2.53 (s, 3 H), 0.76-0.67 (m, 2 H), 0.68-0.60 (m, 2 H). HRMS (ES, M+H) Calcd 322.0443. Found 322.0457.

Provenance & Evidence