General procedure for the synthesis of 6-methoxypyridine-2-carboxylic acid from 6-hydroxypyridine-2-carboxylic acid and iodomethane: To a solution of 6-hydroxypyridine-2-carboxylic acid (1.39 g, 10.0 mmol) in toluene (35 mL) was added silver oxide (2.43 g, 10.5 mmol) and the mixture was stirred for 30 minutes. Subsequently, iodomethane (1.31 mL, 21.0 mmol) was added to the reaction system and the reaction mixture was heated to reflux and reacted overnight. Upon completion of the reaction, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated to give 1.45 g of methyl 6-methoxypyridine-2-carboxylate as a yellow solid. The solid was dissolved in tetrahydrofuran (50 mL) and then added to a mixture of 5N NaOH (20 mL, 100 mmol) and water (5 mL). After 1 hour of reaction, the reaction mixture was acidified to pH 3 with 5N HCl and then concentrated. To the resulting white solid, 20% MeOH/CHCl3 solvent mixture was added and the mixture was sonicated for 20 min. The mixture was filtered and the mother liquor was dried with anhydrous MgSO4 and concentrated to give 1.33 g of 6-methoxypyridine-2-carboxylic acid as a white solid in 87% yield. The product was confirmed to be structurally consistent by 1H NMR and MS (ion spray) showed m/z 152 (M-).
