Method A. Step A. Synthesis of methyl 5-hydroxynicotinate. 5-Hydroxynicotinic acid (833 g, 5.99 mol) was dissolved in methanol (6.7 L), and concentrated sulfuric acid (292 mL) was slowly added dropwise, with the rate of dropwise acceleration controlled to maintain the temperature of the reaction mixture at 30°C. After the dropwise addition, the reaction mixture was stirred under reflux conditions for 7 days. Upon completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. Water (4 L) was added to the concentrate and the pH of the mixture was adjusted to 8 with sodium bicarbonate (NaHCO3), at which point a white solid precipitated. The mixture was stirred at room temperature for 1 h. The solid was collected by filtration and dried under vacuum at 60 °C for 3 days to afford the target product methyl 5-hydroxynicotinate (783 g, 85% yield) as a white solid. The product was characterized by 1H NMR (DMSO-d6, 400 MHz): δ 10.46 (s, 1H), 8.54 (s, 1H), 8.34-8.35 (d, J = 2.8 Hz, 1H), 7.59 (s, 1H), 3.85 (s, 3H).
