Synthesis
The general procedure for the synthesis of 4-fluorophenyl[d]isoxazol-3-one from 2-fluoro-N,6-dihydroxybenzamide is as follows:
1. Add tetrahydrofuran (2.23L) and 1,1'-carbonyl diimidazole (0.910Kg, 5.64mol) to a 20L jacketed reactor and mix with stirring at 20°C.
2. A solution of 2-fluoro-N,6-dihydroxybenzamide (744 g, 4.34 mol) in tetrahydrofuran (4.45 L) was slowly added to the reactor, the temperature was controlled to be lower than 30 °C, and stirring was continued at 25 °C for 30 h. The reaction was carried out at 25 °C with continuous stirring. Gas release was observed during the reaction.
3. The reaction mixture was warmed up to 60°C within 30 minutes and stirring was continued for 6 hours.
4. Upon completion of the reaction, the reactor was cooled to 20 °C and the pH was adjusted to 1 by adding 1N aqueous HCl (7.48 L) within 15 min.
5. set the jacket temperature to 35°C and concentrated the reaction mixture under vacuum to remove about 6.68 L of tetrahydrofuran.
6. The reactor was cooled to 15 °C and stirred for 1 h. A white slurry was obtained by filtration. The filter cake was washed with water (3.71 L) and dried in a vacuum oven at 40°C for 12 hours.
7. The target product 4-fluorobenzo[d]isoxazol-3-ol (597 g, 3.90 mol) was finally isolated in 90% yield.
Product characterization data: 1H NMR (400MHz, CD3OD) δ ppm 4.93 (b, 1H), 6.95 (dd, J = 10.1, 8.6, 1H), (d, J = 8.6, 1H), 7.52-7.57 (m, 1H); LRMS 154.029 (m + 1).
