The general procedure for the synthesis of 5-bromo-3,6-dichloropyrazin-2-amine using 2-amino-6-chloropyrazine as starting material was as follows: N-bromosuccinimide (NBS, 34.3 g, 193.1 mmol) was added batchwise to a methanol (MeOH, 500 mL) solution of 2-amino-6-chloropyrazine (25 g, 193.1 mmol) over a period of 1 hour. Subsequently, the reaction mixture was stirred for 16 hours. The progress of the reaction was confirmed by thin layer chromatography (TLC) analysis, which showed that a small amount of raw material remained unreacted. NBS (1.4 g) was added and the reaction system was warmed to 50 °C with continuous stirring for 2 hours. Upon completion of the reaction, the mixture was cooled to 38 °C and N-chlorosuccinimide (NCS, 25.8 g, 193.1 mmol) was added. Next, the reaction mixture was heated to 50 °C again and kept for 16 hours. At the end of the reaction, the mixture was cooled to room temperature and quenched by adding water (500 mL). The precipitate was collected by filtration and dried in a vacuum dryer to afford the target product 2-amino-5-bromo-3,6-dichloropyrazine (45.4 g, 97% yield) as a white solid. The product was analyzed by 13C NMR (75 MHz, CDCl3) with chemical shifts of δ 149.9 (s), 145.6 (s), 129.6 (s), and 121.5 (s), respectively.LCMS analysis (using acetonitrile solution with 0.1% TFA, gradient of 15-95% over 10 min on a 30-mm column) showed a single peak with a retention time of 4.51 min, the (M + H)+ = 244, (M + H + ACN)+ = 285.
