The general procedure for the synthesis of 5-bromo-6-methylpyridine-2-carboxylic acid from 5-bromo-6-methyl-2-cyanopyridine is as follows:
1. 5-bromo-6-methyl-2-cyanopyridine (18 kg, 91.37 mol), sodium hydroxide (10 kg, 250 mol), water (26 kg) and methanol (59 kg) were added sequentially in a stainless steel reactor.
2. the mixture was stirred and heated to reflux temperature (66 °C) and the reaction was kept for 1.52 hours.
3. the progress of the reaction was monitored by high performance liquid chromatography (HPLC) and the reaction was stopped when the amount of raw material remaining was less than 1%.
4. the solvent was removed by distillation under reduced pressure at a temperature below 50 °C. The solvent was then concentrated into the residue.
5. after thickening, water (72 kg) was added to the residue and the mixture was cooled to 0 °C. the reaction was stopped when the remaining amount of the feedstock was less than 1%.
6. The pH is adjusted to 7 by slow addition of sulfuric acid (105 kg) to induce precipitation of the product.
7. The precipitate was separated by centrifugation and washed with an appropriate amount of water.
8. The resulting solid was dried in a vacuum drying oven to give the white solid product 5-bromo-6-methylpyridine-2-carboxylic acid (17.8 kg, 82.3 mol).
The purity of the product was greater than 98% and the yield was 90%.
