The general procedure for the synthesis of ethyl 4,6-dihydroxynicotinate from ethanoic anhydride and diethyl 1,3-acetone dicarboxylate was as follows: diethyl 3-oxoglutarate (101 g, 0.5 mol), triethyl orthoformate (81.4 g, 0.55 mol), and acetic anhydride (102 g, 1 mol) were mixed and the reaction was maintained at a temperature of 120 °C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and dissolved in dichloromethane (1 L). Subsequently, the solution was cooled to 0 °C, 30% ammonia (80 mL) was slowly added, and then the reaction mixture was gradually warmed to room temperature and left overnight. The reaction mixture was extracted twice with water and the aqueous phase was adjusted to pH 5 with concentrated hydrochloric acid. after acidification, the precipitate was collected by filtration to afford ethyl 4,6-dihydroxynicotinate (60.0 g, 60% yield). The product was characterized by 1H NMR (400 MHz, DMSO-d6): δ 7.99 (s, 1H), 5.58 (s, 1H), 4.23 (q, J = 6.8, 14.0 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 184.1 [M + H]+.
