General procedure for the synthesis of methyl 4,6-dihydroxynicotinate from dimethyl 1,3-acetone dicarboxylate and triethyl orthoformate: dimethyl 1,3-acetone dicarboxylate (2000 g, 11.5 mol), triethyl orthoformate (1947 mL, 11.5 mol), and acetic anhydride (2168 mL, 23.0 mol) were mixed and heated to react for 2 hr at 130°C. The reaction was carried out under vacuum. Upon completion of the reaction, the mixture was cooled to room temperature and subsequently concentrated under vacuum to a volume of about 1500 mL.The concentrated crude product was cooled in an ice bath and ammonia (2 L) was added slowly with continuous stirring. Thirty minutes after the addition of ammonia, the pH of the mixture was adjusted to acidic with concentrated hydrochloric acid (about 300 mL), followed by filtration to obtain a suspension. The resulting crude product was dried under vacuum to finally obtain methyl 4,6-dihydroxynicotinate (900 g, 46% yield), which can be directly used in the subsequent reaction steps.
