The general procedure for the synthesis of 3-hydroxy-4-methyl-2-nitropyridine from 3-hydroxy-4-methylpyridine was as follows: 3-hydroxy-4-methylpyridine (59 g, 545 mmol) was added in batches to concentrated sulfuric acid (290 mL) under the cooling condition of an ice-water bath to ensure that the temperature of the reaction was maintained below 40°C. The reaction was carried out in the following manner. Subsequently, a mixture of pre-chilled fuming nitric acid (25.5 mL, 600 mmol) and concentrated sulfuric acid (58 mL) was slowly added dropwise to the reaction system over about 45 min at 0 °C, controlling the reaction temperature to not exceed 20 °C. After the dropwise addition, the reaction mixture was continued to be stirred at room temperature for 2 hours. After completion of the reaction, the mixture was slowly poured into an ice-water mixture (1.5 L). The pH of the mixture was carefully adjusted with ammonium hydroxide to 1-2. The resulting precipitate was collected by filtration and dried to afford the target product 3-hydroxy-4-methyl-2-nitropyridine (69.5 g, 83% yield). The product was confirmed by NMR hydrogen spectrum (300 MHz, DMSO-d6): δH 10.40 (s, 1H), 7.93 (d, J=4.5 Hz, 1H), 7.57 (d, J=4.5 Hz, 1H), 2.32 (s, 3H).
