Synthesis
The general procedure for the synthesis of 2-amino-3-bromo-5-fluoropyridine from 2-amino-5-fluoropyridine is as follows:
Method C: Bromination reaction using sulfuric acid (H2SO4). This was done as follows: a solution of 93% sulfuric acid (12.5 kg, 119 mol) in water (26 L) was added to a 50 L reactor, followed by 2-amino-5-fluoropyridine (6.5 kg, 58 mol). The reaction temperature was adjusted to 30 °C and then bromine (10 kg, 63 mol) was added in 10 portions over 3 hours. The reaction mixture was stirred at 45 °C for 18 hours, followed by continued stirring at 50 °C for 5 hours. Upon completion of the reaction, the mixture was cooled to 15 °C and transferred to a 400 L reactor for post-processing.
The products of the four reactions (4 x 6.5 kg) were combined and the reaction was quenched with a mixture of 50% sodium hydroxide (110 kg, 1375 mol) and sodium thiosulfate (1.8 kg, 11.4 mol) in water (100 L) at 50 °C, the quenching process lasted for 1-3 hours. The temperature was adjusted to 32 °C, the slurry was filtered and washed with water (80 L) to give a water-wet crude product (62 kg). The same operation was carried out for the second round of three reactions (3 x 6.5 kg of feedstock) to give a water-wet crude product (41 kg).
The crude product (103 kg) was dissolved (partially insoluble) in toluene (280 kg) at 25-30 °C. After addition of brine (20 kg), phase separation could not be achieved due to the presence of solids. The mixture was filtered through a diatomaceous earth pad, washed with toluene and layered. The organic phase was concentrated to 347 L to remove residual water by azeotropy and used in the subsequent preparation of compound 3a. The product concentration was determined by aliquoting to be 181 g/L in a yield of 62.8 kg. An additional 600 g of product was obtained by extraction of the water/brine layer by ethyl acetate (10 L) and separated, which was treated by filtration through a pad of magnesium salts, evaporation, and hexane grinding. The overall yield was 82%.
References
[1] Patent: WO2015/73481, 2015, A1. Location in patent: Paragraph 0259-0260
[2] Patent: WO2016/183116, 2016, A1. Location in patent: Paragraph 0251; 0252; 0253
[3] Patent: WO2017/97234, 2017, A1. Location in patent: Paragraph 00405
[4] Patent: WO2011/143366, 2011, A1. Location in patent: Page/Page column 75
[5] Patent: WO2011/143365, 2011, A1. Location in patent: Page/Page column 154
