Reaction Steps
Piperidine (110 μL, 1.10 mmol) was added to a suspension of 4-(difluoromethoxy)-3,5-dimethoxybenzaldehyde (200 mg, 1.10 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (233 mg, 1.05 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 (4 mL) and water (2 mL) and the solution was acidified with 20% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water and filtered to afford (E)-2-[[4-(difluoromethoxy)-3,5-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (210 mg, 51%) as a pale yellow crystalline solid; mp 211-215° C.; δH (400 MHz, DMSO-d6) 3.87 (s, 6H, OCH3), 6.87 (t, J=75 Hz, 1H, OCHF2), 6.98 (d, J=15.6 Hz, 1H, CH═CHCO), 7.17 (s, 2H, H2′, H6′), 7.18 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 8.00 (d, J5,6=8.0 Hz, 1H, H6), 8.61 (d, J3,4=8.0 Hz, 1H, H3), 11.33 (s, 1H, NH), 13.60 (s, 1H, CO2H); δC (100 MHz, DMSO-d6) 56.4, 105.5, 116.8 117.2 (t, J=259 Hz), 120.4, 122.9, 123.1, 129.6, 131.1, 132.9, 134.0, 140.8, 141.1, 152.6, 163.7, 169.4; νmax 1153, 1113, 1224, 1506, 1593, 1694, 2602, 2946 cm−1.
