Uses
2,6-Dimethyl-3-bromopyridine is an important organic synthesis intermediate with wide applications in pharmaceuticals and pesticides. For example, it can be used to synthesize a new generation of quinolone antibacterial drug—balofloxacin.
Synthesis
General procedure for the synthesis of 2,6-dimethyl-3-bromopyridine from 2,6-dimethylpyridine: 2,6-dimethylpyridine (115 kg, 1073.3 mol) was slowly added to pre-cooled fuming sulphuric acid (20-23%, 1015 kg, 2276.7 mol) over a period of 4.5 h at 0 °C, and the reaction temperature was maintained below 14 °C. The reaction temperature was kept below 14 °C. Subsequently, bromine (88.18 kg, 1103.6 mol) was added dropwise over 1 h at 5-10 °C. The reaction mixture was slowly warmed up to 150 °C over 12 hours. Analysis by TLC showed that about 40-50% of the feedstock was converted to the target product, while about 5% of the dimer by-product was generated. After cooling the reaction mixture to room temperature, bromine (88.18 kg, 1103.6 mol) was again added slowly. The reaction mixture was slowly heated to 65-75 °C over a period of 15 h. TLC analysis showed that the product conversion increased to 65-70% and the dimer by-product generation was maintained at 5%. The reaction mixture was quenched by the addition of water (500 L) and the reaction temperature was controlled below 20 °C during quenching. Subsequently, the reaction mixture was alkalized with 6.6 M NaOH solution (3800 L) and the temperature was controlled below 40 °C during alkalization. Ethyl acetate (220 L) was added and the mixture was stirred for 1 hour and then left to stand for 2 hours. The organic and aqueous layers were separated and the aqueous layer was treated with a solution of NaOH (10 kg) in water (10 L) and then extracted with ethyl acetate (160 L). The organic extracts were combined, washed with brine (100 L), dried with anhydrous sodium sulfate (50.0 kg), filtered and the solvent evaporated at atmospheric pressure. The residue was subjected to vacuum distillation and the fractions were collected at 58-60 °C and 2 mmHg to give 2,6-dimethyl-3-bromopyridine (98.45 kg, 49.2% yield) as a colorless liquid.
References
[1] Bioorganic Chemistry, 2004, vol. 32, # 1, p. 13 - 25
[2] Patent: WO2016/29216, 2016, A2. Location in patent: Page/Page column 83
[3] Patent: WO2018/81513, 2018, A1. Location in patent: Page/Page column 64
[4] Angewandte Chemie - International Edition, 2016, vol. 55, # 44, p. 13744 - 13748
[5] Angew. Chem., 2016, vol. 128, p. 13948 - 13952,5
