General procedure for the synthesis of 2,6-dihydroxy-3-cyano-4-(trifluoromethyl)pyridine from ethyl trifluoroacetoacetate and cyanoacetamide: 29.8 g (0.53 mol) of potassium hydroxide was slowly added to a 250 mL four-necked flask fitted with a mechanical stirrer and a reflux condenser, followed by the addition of 100 mL of methanol, and stirred until dissolved and set aside. In another 500 mL four-necked flask equipped with a mechanical stirrer, a constant pressure dropping funnel, a drying tube and a reflux condenser, 43.4 g (0.52 mol) of cyanoacetamide and 150 mL of methanol were added and heated to reflux with mechanical stirring. After the reaction solution changed from turbid to light yellow and transparent, 100 g (0.54 mol) of ethyl trifluoroacetoacetate was added. Maintaining reflux, a preconfigured methanol solution of potassium hydroxide was added slowly and dropwise. The reaction was heated and refluxed for 24 h. The complete reaction of cyanoacetamide was confirmed by TLC monitoring. The reflux unit was changed to a distillation unit and about 3/4 of the methanol was recovered. Cold water was added to the residue and after cooling to room temperature, the pH was adjusted to 3-4 with dilute hydrochloric acid and stirring was continued for 0.5 hours. The reaction mixture was filtered and the filter cake was washed with water to give the white solid product 2,6-dihydroxy-3-cyano-4-(trifluoromethyl)pyridine. The product was dried at 80 °C to constant weight to give 84.5 g final in 80.1% yield and 98% HPLC purity.
