5-BROMO-2-CHLORO-4,6-DIMETHYLNICOTINONITRILE

23819-87-6

42951-71-3

General procedure for the synthesis of 2-chloro-4,6-dimethyl-5-bromonicotinonitrile from 2-hydroxy-3-cyano-4,6-dimethyl-5-bromopyridine: To a solution of 5-chloro-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (14 g, 61.7 mmol) in POCl3 (10 mL) was added phosphorus pentachloride (12.84 g, 61.7 mmol). The reaction mixture was heated to reflux and held for about 8 hours. Upon completion of the reaction, POCl3 was removed by distillation under reduced pressure. the residue was partitioned between dichloromethane (100 mL) and 5% aqueous sodium hydroxide solution (100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was again dissolved in POCl3 (20 mL) and phosphorus pentachloride (13 g, 62.4 mmol) was added. The reaction mixture was heated to reflux and held for about 12 hours. Upon completion of the reaction, POCl3 was removed by distillation under reduced pressure. the residue was partitioned between dichloromethane (100 mL) and 5% aqueous sodium hydroxide solution (100 mL). The organic phases were combined, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 5-bromo-2-chloro-4,6-dimethylnicotinonitrile (12 g, 79% yield). LCMS (Table 1, method d) retention time = 2.12 min; mass spectrum m/z = 246,248 (M + H).