Step 2: Preparation of 5-methoxypyrazine-2-carboxylic acid
To a solution of 5-chloropyrazine-2-carboxylic acid (7 g, 44.15 mmol) in methanol (55 mL) was added concentrated sulfuric acid (0.4 mL) and heated to reflux for 4 hours at 65 °C. Upon completion of the reaction, the reaction mixture was cooled to room temperature and diluted with methanol (15 mL). Subsequently, a methanolic solution of sodium methanolate (8.58 g, 158.94 mmol, 35 mL) was slowly added and the reaction mixture was stirred for 30 min at room temperature. Next, a 30 mL aqueous solution of sodium hydroxide (2.825 g, 70.643 mmol) was added to the reaction mixture, followed by 40 mL of water. The reaction mixture was heated at 40 °C for 1 h, followed by concentration under reduced pressure to remove methanol. The residue was diluted with water and the pH was adjusted to 2-3 with 38% aqueous hydrochloric acid and then extracted with ethyl acetate (600 mL x 3). The organic layers were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-methoxypyrazine-2-carboxylic acid (6.43 g, 94% yield) as an orange solid. Mass spectrometry analysis: calculated value [M + H]+: 155.04; measured value [M + H]+: 155.1.
