Hydrochloric Acid → 4-Fluoro-5-hydroxy-2-nitrobenzoic acid

Temperature

50 °C

To a 1 L reactor equipped with mechanical stirrer, addition funnel, thermocouple, reflux condenser and nitrogen inlet was charged 4,5-Difluoro-2-nitrobenzoic acid (82 g, 0.4 mol, 1 eq) and water (120 mL) to form a suspension. The suspension was heated to about 50° C. Solution of KOH in water (45 wt. %, 161 g, 1.3 mol, 3.25 eq) was slowly added over about 20 min so that the temperature of the exothermic reaction mixture was kept at 80-90° C. After addition, the mixture was stirred at about 80° C. for about half hour, until HPLC sample showed complete conversion. The mixture was cooled down to room temperature, acidified to pH 1 with concentrated HCl solution (105 ml, 1.26 mol, 3.2 eq), and extracted with 2-methyltetrahydrofuran (630 mL). The layers were separated. The upper organic layer was washed with water (150 mL), and distilled under vacuum to minimum volume. The dark brown residue was stirred in 200 mL of mixed solvent of toluene/methylcyclohexane (v/v, 2:1) to give a suspension. The slurry was filtered. The desired product, 4-fluoro-5-hydroxy-2-nitrobenzoic acid, was obtained as an off-white solid after drying under vacuum (68 g, 85% yield). 1H NMR (DMSO-d6, 400 MHz) δ 13.64 (br, 1H), 11.84 (br, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.25 (d, J=12.1 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz) δ 166.0, 151.6, 150.3, 150.2, 149.1, 138.4, 138.3, 127.0, 117.3, 113.7, 113.5.

1. customTo a 1 L reactor equipped with mechanical stirrer, addition funnel
2. temperaturethermocouple, reflux condenser and nitrogen inlet
3. customto form a suspension
4. customwas kept at 80-90° C
5. additionAfter addition
6. temperatureThe mixture was cooled down to room temperature
7. extractionextracted with 2-methyltetrahydrofuran (630 mL)
8. customThe layers were separated
9. washThe upper organic layer was washed with water (150 mL)
10. distillationdistilled under vacuum to minimum volume
11. stirringThe dark brown residue was stirred in 200 mL of mixed solvent of toluene/methylcyclohexane (v/v, 2:1)
12. customto give a suspension
13. filtrationThe slurry was filtered

ORD record

ord-1c5b39e348c04f6b8ed98f8b7ba8908c

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08519176B1