General procedure for the synthesis of 5-chloro-2-hydroxy-3-cyano-4-methoxypyridine from 4-methoxy-2-oxo-1,2-dihydro-3-cyano-pyridine: 3-cyano-4-methoxy-2(1H)-pyridinone (6.0 g, 0.04 mol) was added to a 250 mL three-necked flask along with 45 mL of glacial acetic acid, and cooled down to below 15 °C. Subsequently, sulfonyl chloride (6.18 g, 0.045 mol) was added slowly, and the temperature of the reaction solution was controlled between 10 and 15 °C, and the titration rate was adjusted according to the temperature change. After the dropwise addition, stirring was continued for 30 min. Then, the reaction mixture was heated to 52 ± 2 °C and the reaction was held at 50-54 °C for 4 hours. The reaction process was monitored by thin layer chromatography (TLC, unfolding agent: ethyl acetate/methanol = 9:1). After confirming the complete reaction of the ingredients, the reaction solution was cooled to 20±2°C and stirred for 2 hours. The solid product was collected by filtration and the filter cake was washed with 58 mL of water. The wet product was dried at 80 °C under atmospheric pressure for 12 h to give 7.01 g of 3-cyano-4-methoxy-5-chloro-2(1H)-pyridinone as a white powder in 95.0% yield (theoretical yield 7.38 g).
