General procedure for the synthesis of 3-nitro-6-(trifluoromethyl)pyridine-2,4-diol from 4-hydroxy-6-(trifluoromethyl)pyridine-2(1H)pyridone: 3-trifluoromethyl-pyridine-2,4-diol (56 g, 310 mmol) was added in batches of 3-5 g at a time under stirring conditions to concentrated sulfuric acid (140 mL) to give a light brown solution. During the addition, the reaction temperature was raised to about 50°C. Subsequently, nitric acid (21.1 mL, 328 mmol, 70% HNO3, density = 1.4 g/mL) was added dropwise, with a controlled titration rate to maintain the reaction temperature between 45°C and 50°C. The titration process took about 90 minutes. After the addition of nitric acid, the reaction mixture was allowed to cool naturally to room temperature over a period of 3 hours. The reaction mixture was poured into an ice/water mixture (about 1.3 kg) with stirring and a light yellow precipitate precipitated after a few minutes. The precipitate was collected by filtration, dissolved in ethyl acetate, dried over sodium sulfate, filtered and the solvent evaporated. A second batch of product was obtained by extracting the aqueous filtrate with ethyl acetate. The two batches of product were combined and purified by crystallization from a mixed ethyl acetate/n-heptane solvent to give the final 3-nitro-6-trifluoromethyl-pyridine-2,4-diol as a white fluffy solid (49.5 g, 71% yield).
