Reaction Steps
Piperidine (0.25 mL, 2.6 mmol) was added to a suspension of 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.52 g, 2.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.52 mg, 2.6 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5 mL) and water (2 mL) and the solution was acidified with 50% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water, filtered and washed with water to afford (E)-2-[[3-methoxy-4-(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (259 mg, 71%) as a colourless crystalline solid; mp 172-174° C.; δH (500 MHz, DMSO-d6) 3.90 (s, 3H, OCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.12 (t, J=75 Hz, 1H, OCHF2), 7.17 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.20 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.32 (dd, J5′,6′=8.0, J2′,6′=2.0 Hz, 1H, H6′), 7.56 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (dt, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.33 (s, 1H, NH), 13.60 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 56.1, 112.3, 114.5, 116.5 (t, J=256 Hz), 116.8, 120.4, 120.8, 121.4, 122.7, 122.9, 131.1, 132.9, 134.0, 140.6, 140.8, 150.7, 163.7, 169.4; HRMS (ESI−) calculated for C18H15F2NO5 [M-H ]− 362.0835, found 362.0839; νmax 1032, 1260, 1586, 1604, 1661, 2988, 3509 cm−1.
