The general procedure for the synthesis of 4-chloro-5-fluoro-2-hydroxybenzaldehyde from hexamethylenetetetramine (210 g, 1.5 mol) and 3-chloro-4-fluorophenol (210 g, 1.43 mol) was as follows: hexamethylenetetetramine was added to trifluoroacetic acid (3.6 L) in small portions, and the resulting mixture was heated to reflux at 78 °C. Subsequently, a solution of 3-chloro-4-fluorophenol in trifluoroacetic acid (1.4 L) was slowly added dropwise, and stirring of the reaction mixture was continued for 1 hour after completion of the addition. After completion of the reaction, the mixture was cooled to room temperature and concentrated under vacuum. The concentrated residue was poured into ice water (2 L) and stirred overnight. The mixture was filtered, the filter cake was collected and dissolved in ethyl acetate (500 mL), dried with magnesium sulfate and concentrated again under vacuum. The crude product was washed with a solvent mixture of ethyl acetate/petroleum ether (10:1, v/v) to give the final 4-chloro-5-fluoro-2-hydroxybenzaldehyde as a white solid with a yield of 56.5 g in 23%. The product was characterized by 1H NMR (400 MHz, CDCl3) with chemical shifts of δ = 7.00-7.01 (m, 1H), 7.19-7.26 (m, 1H), 9.75 (s, 1H), 10.82 (s, 1H) ppm.
