[Synthesis]
The general procedure for the synthesis of 2-chloromethyl-3-chloropyrazine from 2-chloro-3-methylpyrazine is as follows: 2-chloromethyl-3-chloropyrazine is prepared by chlorination as described in Jeromin, G.E. et al. (DE3519364, 1986) and Russell, M.G.N. et al. (J. Med. Chem. 2005, 48, 1367-1383) are described. 2-Methyl-3-chloropyrazine (24.3 g, 189 mmol) was dissolved in chloroform (100 mL), benzamide (100 mg, 0.8 mmol) was added and heated to reflux. Solid trichloroisocyanuric acid (17.6 g, 75.6 mmol) was slowly added under reflux conditions and the reaction was continued at reflux for 96 hours. After completion of the reaction, it was cooled to room temperature, the reaction mixture was filtered and initially purified using a 200 g silica gel column with dichloromethane as eluent. The product was further purified by silica gel chromatography using a gradient elution of 35% chloroform/hexane to 60% chloroform/hexane over 1 hour. The final 2-chloromethyl-3-chloropyrazine was obtained as a colorless oil in the yield of 5.39 g pure and 9.4 g crude with >70% yield. The products were confirmed by 1H-NMR (CDCl3): δ 8.50 (d, 1H, J = 2.2 Hz), 8.37 (d, 1H, J = 2.6 Hz), 4.80 (s, 2H), 2.50 (s, 3H); the GC/MS analysis showed the molecular weight M = 162 + 164. |