The general procedure for the synthesis of 2-fluoro-N,4-dihydroxybenzamide from 2-fluoro-4-hydroxybenzonitrile is as follows:
1. 139 g (2.1 mol) of 50% aqueous hydroxylamine solution was slowly added dropwise to 144.0 g (1.05 mol) of methanol solution of 2-fluoro-4-cyanophenol at room temperature. Subsequently, the temperature of the reaction system was gradually increased to reflux and stirred under these conditions for 3 hours. Upon completion of the reaction, the reaction mixture was cooled in an ice bath and cold water was added to induce crystallization. The crystallized product was collected by filtration and dried to give 139.5 g of intermediate (1-A) in 82% yield.
2. 8.1 ml (0.1 mol) of pyridine was added to 300 ml of N,N-dimethylacetamide at room temperature. Subsequently 17 g (0.1 mol) of intermediate (1-A) and 6.7 g (33 mmol) of phthaloyl dichloride were added in batches. After the addition was completed, the reaction was stirred at room temperature for 30 minutes, then the reaction temperature was raised to 100 °C and stirring was continued for 3 hours. After completion of the reaction, the reaction system was allowed to cool naturally to room temperature. Methanol was added to the reaction mixture to induce precipitation of crystals, which were collected by filtration. After drying, 36 g of intermediate (1-B) was obtained in 83% yield.
3. 8.7 ml (50 mmol) of N,N-diisopropylethylamine was added to 300 ml of N,N-dimethylacetamide at room temperature. To this solution 8.7 g (20 mmol) of intermediate (1-B) and 9.6 g (50 mmol) of octyl chloroformate were added dropwise. Subsequently 14 g of potassium carbonate was added and stirred for 3 hours at room temperature. After completion of the reaction, tetrahydrofuran was added and the solid was separated by filtration. Methanol was added to the filtrate to induce crystallization. The crystals were collected by filtration, dried and dispersed in methanol, heated and filtered again to give 13.4 g of the target compound (1) in 90% yield.
The phase transition temperature of the target compound (1) was determined by DSC and the texture was observed under polarized microscope with the following results: from crystal to SmC phase at 133 °C, from SmC phase to SmB phase at 159 °C, from SmB phase to nematic phase (Nb) at 194 °C, and finally to isotropic liquid (Iso) at a higher temperature.
