The general procedure for the synthesis of methyl 3-bromo-6-chloropyrazine-2-carboxylate from methyl 3-amino-6-chloropyrazine-2-carboxylate was as follows: 100 mL of acetic acid was added to a 500 mL three-necked flask and cooled to 0 °C. Methyl 3-amino-6-chloropyrazine-2-carboxylate (20 g, 0.11 mol) was slowly added dropwise to 100 mL of aqueous hydrogen bromide solution at 0 °C. The dropwise addition process was continued for 30 min to ensure complete reaction. Subsequently, 50 mL of aqueous sodium nitrite (20.7 g, 0.33 mol) was slowly added dropwise while maintaining 0°C. After 30 minutes of reaction, the completion of the reaction was confirmed and 30 mL of 10% sodium bisulfite solution was added to terminate the reaction. The reaction mixture was extracted with ethyl acetate (200 mL x 2 times), the organic phases were combined and dried with 20 g of anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give methyl 3-bromo-6-chloropyrazine-2-carboxylate (23.3 g, 87% yield) as a white solid.
