[Synthesis]
The mixture was heated to 120 °C with 2-fluorophenyl acetate (3,1.070 kg, 6.94 mol) and monochlorobenzene (5.34 L). Aluminum trichloride (1.39 kg, 10.42 mol) was added in batches over a period of 70-75 min at 120 °C, increasing the temperature by about 5 °C by controlling the rate of addition. The reaction was continued at the same temperature for 3 hours. Subsequently, the reaction mixture was cooled to 0-5 °C. Water (1.07 L) and 3.5% hydrochloric acid (2.14 L) were added sequentially under vigorous stirring using an ice bath to keep the internal temperature below 30 °C. The mixture was stirred vigorously at 5-10 °C for 1 h and then filtered, the solid filter cake was washed with water (1 L) and dried to give a beige solid, i.e., para-isomer 4 (416 g, 38.8% yield, HPLC purity >98%). The organic layer was separated from the filtrate and the organic layer was washed with water (2 L) and concentrated at atmospheric pressure to give the crude product (530 g), which was subsequently purified by steam distillation. The first part of the steam distillation was a liquid rich in 2-fluorophenol (45.2 g, LC analysis showed 70% 2-fluorophenol, 4% 4, 21% 5), and the second part was a light yellow solid, i.e., the neighboring isomer 5. The product 5 was separated by filtration, washed with water (80 mL), and then dried under vacuum to give the title compound (257.6 g, yield 24%, HPLC purity > 98.2%) as a light yellow solid. Steam distillation of the residue (HPLC analysis showed 92.7% 4, 3.63% 5) was crystallized by MTBE:hexane to give compound 4 (205.4 g, 19.2% yield, HPLC purity >98%).1H NMR (CDCl3, 400 MHz) data for 3-fluoro-4-hydroxyacetophenone (4): δ 7.75-7.67 (m, 2H, ArH), 7.06 (t, 1H, J = 8.4 Hz, ArH), 5.98 (d, 1H, J = 4 Hz, Ar-OH), 2.56 (s, 3H, Ac). m/z 153.00 was observed by LCMS. 1H NMR (CDCl3, 400 MHz) data of 3-fluoro-2-hydroxyacetophenone (5): δ 12.29 (s, 1H OH), 7.56-7.51 (m, 1H, ArH), 7.32-7.25 (m, 1H, ArH), 6.88-6.81 (m, 1H, ArH), 2.66 (s, 3H, CH3). m/z 153.00 observed by LCMS. |