[Synthesis]
General procedure for the synthesis of 3-bromo-2,6-dimethylpyridin-4-amine from 2,6-dimethyl-4-aminopyridine: first, 4-nitro-2,6-dimethylpyridine-N-oxide (11.0 g, 65.4 mmol) was dissolved in 50 mL of acetic acid, followed by the addition of powdered iron (21.8 g, 390 mmol) in batches, while the mixture was stirred rapidly and gradually heated to 50 °C (note: the reaction becomes very exothermic at this temperature). After the exothermic reaction ceased, the mixture was continued to be heated at 80°C for 1 hour. Upon completion of the reaction, 50 mL of water was added to the solidified mixture and the suspension was filtered through a CELITE filter aid. The filtrate was adjusted to pH>12 with about 200 ml of 6N sodium hydroxide solution to form a green suspension. The suspension was extracted with three 300-mL portions of chloroform, the organic phases were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give pale yellow crystals (5.70 g, 71% yield). Next, 2,6-dimethylpyridin-4-ylamine (2.00 g, 16.4 mmol) was dissolved in 5 mL of acetic acid, and a 2N acetic acid solution of bromine (0.84 mL, 16.3 mmol) was added dropwise, and the reaction was carried out for 10 min in a water bath at room temperature. after 1 h, the resulting slurry was treated with 40 mL of a 20% sodium hydroxide solution, and extracted with triplicate 100 mL of methylene chloride. . The organic phases were combined, dried with magnesium sulfate, filtered and concentrated in vacuum. The solid obtained (containing starting material, target product and dibromo by-product in the ratio 1:3:1) was dissolved in 100 ml of hot hexane and the insoluble starting material was removed by hot filtration. The filtrate was cooled to room temperature and the title product was precipitated as fine white needle-like crystals (1.30 g, 40% yield). |