反应详情

Piperidine (100 μL, 1.01 mmol) was added to a suspension of 3,4-bis(difluoromethoxy)benzaldehyde (240 mg, 1.01 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (204 mg, 0.92 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-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (259 mg, 71%) as a colourless crystalline solid; mp 190-193° C.; δH (400 MHz, DMSO-d6) 6.96 (d, J=15.6 Hz, 1H, CH═CHCO), 7.18 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.38 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.78 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.68 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.69 (d, J5,6=8.0 Hz, 1H, H6), 11.35 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 116.3 (t, J=258 Hz), 116.5 (t, J=258 Hz), 117.0, 120.1, 120.5, 120.8, 123.0, 123.8, 126.7, 131.1, 132.8, 133.9, 139.3, 140.7, 141.9, 142.7, 163.5, 169.4; HRMS (ESI−) calculated for C18H13F4NO5 [M-H ]− 398.0646, found 398.0652; νmax 1034, 1217, 1513, 1604, 1683, 2892, 3466 cm−1.

1. customThe reaction flask was fitted with a Dean-Stark apparatus
2. temperatureheated
3. temperatureto reflux for 30 min
4. filtrationthe resulting suspension was filtered
5. washwashed with toluene
6. dissolutionThe piperidinium salt was dissolved in MeOH (5 mL)
7. filtrationThe crude product was collected by filtration
8. customrecrystallised from EtOH/water
9. filtrationfiltered
10. washwashed with water