1. 3-Fluorophenol (50 g, 446 mmol, 1 eq.) was dissolved in glacial acetic acid (250 mL) and 99% nitric acid (29.8 g, 468 mmol, 1.05 eq.) was slowly added dropwise over a period of about 1 hour at 20-25 °C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30-60 minutes and complete consumption of 3-fluorophenol was confirmed by HPLC monitoring.
2. Upon completion of the reaction, the reaction was quenched by the addition of water (500 mL). The mixture was extracted with cyclohexane (4 x 67 mL) to remove most of the regional isomers. The organic phases were combined and back-extracted with water (167 mL) to recover possible water-soluble regional isomers.
3. Combine the aqueous phases and extract with tert-butyl methyl ether (TBME, 3 x 167mL) to recover the target product. The TBME phases were combined and washed with 10% sodium carbonate solution (4 × 100 mL) to remove residual acetic acid.
4. Concentrate the TBME solution at atmospheric pressure, replacing it with toluene to yield approximately 100 mL of toluene solution. Slowly cool to room temperature to induce precipitation of the target product and filter to collect the solid.
5. The solid was dried overnight in an oven to afford 3-fluoro-4-nitrophenol in 29% yield and 97.9% HPLC purity.
6. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, 1H), 8.07 (m, 1H), 6.84-6.76 (m, 2H). 19F-NMR (376.209 MHz, DMSO) δ -114.28. LCMS (ESI-ve) m/z 156.00 (M-H).
Method B:
1. 3-Fluorophenol (1 eq.) was dissolved in glacial acetic acid (2.5 v/v) and 99% nitric acid (1.16 eq.) was added slowly dropwise at 20-25 °C for about 1 hour. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 h. Complete consumption of 3-fluorophenol was confirmed by HPLC monitoring.
2. Upon completion of the reaction, the reaction was quenched by the addition of water (2.5 v/v). Extraction with cyclohexane (1.675 v/v) was performed 7 times to remove most of the regional isomers. The organic phases were combined and back-extracted with water (1 volume) to recover possible water-soluble regional isomers.
3. Combine aqueous phases and extract twice with TBME (2.5 vol) to recover the target product. The TBME phases were combined and washed three times with 3% aqueous potassium carbonate (1.25 vol) to remove residual acetic acid.
4. The TBME solution was concentrated at atmospheric pressure, activated carbon (0.017 wt.) and toluene (4.0 v/v) were added, and the TBME was completely removed by distillation at atmospheric pressure. the warmed solution was filtered at 50-80° C. to remove insoluble particles, and then cooled to 0-50° C. to induce precipitation of the target product, which was filtered to collect the solid.
5. The crude product was washed with toluene (0.17 v/v) and petroleum ether (0.25 v/v), and the solid was dried in an oven overnight to afford 3-fluoro-4-nitrophenol in 27% yield and 97.4% HPLC purity.
6. 3-Fluoro-4-nitrophenol (1 equiv.) was heated in toluene (3.24 v/v) and kept at 110-115 °C for 30 min. Cooled to 80-100 °C filtered to remove insoluble particles, further cooled to 0-50 °C to induce precipitation of the target product and filtered to collect solids.
7. The crude product was washed with toluene (0.17 v/v) and the solid was dried in an oven overnight to afford 3-fluoro-4-nitrophenol in 77% yield (recrystallization only) and 99.2% HPLC purity.
8. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, 1H), 8.07 (m, 1H), 6.84-6.76 (m, 2H). 19F-NMR (376.209 MHz, DMSO) δ -114.28. LCMS (ESI-ve) m/z 156.00 (M-H).
