Synthesis
General procedure for the synthesis of 4,6-dichloro-5-fluoropyrimidine from 5-fluoro-4,6-dihydroxypyrimidine (Method B): phosphoryl chloride (0.593 L, 6.376 mol) was slowly added to a 2 L three-necked round-bottomed flask containing 5-fluoropyrimidine-4,6-diol (276.459 g, 2.125 mol) to form a slurry at room temperature. N,N-dimethylaniline (81 mL, 0.638 mol) was slowly added to this slurry through the addition funnel and the reaction was exothermic. The reaction mixture was continued to be stirred at 110°C for 6 hours. Upon completion of the reaction, the mixture was cooled to room temperature and slowly poured into a 2 L mixture consisting of brine and ice under stirring. The aqueous layer (showing red color) was extracted with dichloromethane (2 x 2 L). The organic layers were combined and washed sequentially with cold 6 N hydrochloric acid (2 × 1 L, showing honey brown color) and saturated sodium bicarbonate solution (1 L). The organic layer was dried with anhydrous sodium sulfate, filtered through glass fiber paper under vacuum, and concentrated under reduced pressure (without heating) to afford 4,6-dichloro-5-fluoropyrimidine (CAS No. 213265-83-9, 347.9 g, 2.084 mol, 98% yield) as an amber colored oil. Nuclear magnetic resonance (NMR) analysis showed traces of dichloromethane in the product. 4,6-Dichloro-5-fluoropyrimidine (420 g, 2.515 mol) was subjected to vacuum distillation, and the fraction with a boiling point of 35°C (pressure 1 torr) was collected to give a colorless oily substance (332.574 g, 1.992 mol, 79% yield). The product solidified at -78°C and remelted to liquid at room temperature. Distillation conditions: oil bath temperature 100°C; product boiling point 35°C; pressure 1 Torr. 1H NMR (400 MHz, DMSO-d6) δ 8.8 (s, 1H).
References
[1] Patent: WO2012/40279, 2012, A1. Location in patent: Page/Page column 86
[2] Patent: WO2003/106432, 2003, A1. Location in patent: Page column 11
[3] Patent: WO2003/106432, 2003, A1. Location in patent: Page column 12
[4] Patent: WO2003/106432, 2003, A1. Location in patent: Page column 10
