Synthesis
General procedure for the synthesis of 2-bromo-4,6-dimethylpyridine from 2-amino-4,6-dimethylpyridine: A 48% aqueous hydrobromic acid solution (Aldrich, 65 mL, 1.2 mol, 10 eq.) was cooled to -5 °C and 4,6-dimethylpyridin-2-amine (Aldrich, 15.0 g, 0.12 mol, 1.0 eq.) was added. Bromine (Aldrich, 19.7 mL, 0.38 mol, 3.1 eq.) was added slowly and dropwise with mechanical stirring to the thick white salt mixture formed. The resulting red mixture was treated with aqueous sodium nitrite (32 mL water, Aldrich, 22.1 g, 0.32 mol, 2.6 eq.) for 1 hr below 5 °C. The temperature was maintained below 5°C during the nitrite addition process, followed by a gradual warming to 20°C over 2 hr. The reaction mixture was adjusted to pH 14 with aqueous sodium hydroxide and extracted with methyl tert-butyl ether (MTBE). The organic phase was washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product (29 g of red oily material) was purified by fast chromatography (silica gel, 350 g) using 2-7% ethyl acetate-cyclohexane as eluent to give an orange oily product (11.0 g, 48% yield). The product was purified by 1H NMR (DMSO-d6, 300 MHz) δ 7.30 (1H, s), 7.13 (1H, s), 2.39 (3H, s), 2.26 (3H, s); 13C NMR (DMSO-d6, 75 MHz) δ 159.4, 151.3, 140.9, 125.7, 123.4, 23.7, 20.3 ; ESI-MS m/z 186/188 ([M+H]+).
References
[1] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 7945 - 7952
[2] Helvetica Chimica Acta, 1992, vol. 75, # 5, p. 1578 - 1592
[3] Patent: WO2004/56806, 2004, A1. Location in patent: Page 50
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 16, p. 7126 - 7135
[5] Patent: EP3124482, 2017, A1. Location in patent: Paragraph 0512; 0513
