The general procedure for the synthesis of 5-chloro-2-cyanopyridine-2-carboxylic acid from 5-chloro-2-cyanopyridine was as follows: in a 1000 mL four-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, 5-chloro-2-cyanopyridine (27.7 g, 0.2 mol) and 277 mg of ethanol were added, and the mixture was stirred until it was completely dissolved to form an aqueous solution. Subsequently, 277 mL of 10% NaOH solution was added and the mixture was heated to 90-100 °C and stirred under reflux conditions for 1.5 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) [unfolding reagent ratio of butanol-acetic acid-water = 5:2:2], and after confirming the completion of the reaction, the reaction solution was stirred and cooled to room temperature. The pH was adjusted to 2 with 2 N HCl solution and subsequently concentrated under reduced pressure to about 100 mL. Methanol was added to the concentrate to a total volume of 200 mL, and the solid product was collected by filtration after cooling to 0-5 °C. The filtrate was then filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was dissolved in a solvent mixture of 450 mL of dichloromethane and 50 mL of methanol, stirred for 1 hr and then filtered, and the resulting solid was washed with a 10% methanol-dichloromethane solvent mixture. Finally, the solid was dried in a vacuum oven at 60~65°C for 2 h. The white solid intermediate 5-chloropyridine-2-carboxylic acid was obtained as 25.5 g in 81.4% yield.
