Synthesis
Part B: Synthesis of 4,6-dichloro-5-fluoro-2-methylpyrimidine. 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine (60 g, 0.42 mol) was dissolved in 300 mL of phosphorus oxychloride (POCl3) and reacted at 120 °C for 3 hours. Upon completion of the reaction, the mixture was cooled to room temperature and subsequently concentrated under reduced pressure until the rate of evaporation of the solvent decreased to less than 1 drop/sec. Care was taken to avoid over-concentration to prevent loss of product due to volatilization. The concentrated crude product was slowly poured into crushed ice and the slurry was stirred for 1 hour and allowed to warm naturally to room temperature. The precipitated yellow solid was collected by filtration, washed with cold water and briefly air dried to a flow-through state. Finally, the solid was thoroughly dried in a desiccator filled with phosphorus pentoxide (P2O5) to give pure 4,6-dichloro-5-fluoro-2-methylpyrimidine (59 g, 79% yield). LCMS analysis showed (M + H)+ peaks located at 181/183.
References
[1] Patent: WO2009/61879, 2009, A1. Location in patent: Page/Page column 61
[2] Patent: WO2013/82388, 2013, A1. Location in patent: Page/Page column 67
[3] Patent: WO2007/75852, 2007, A2. Location in patent: Page/Page column 32
[4] Patent: US2007/197523, 2007, A1. Location in patent: Page/Page column 7
[5] Patent: US4617393, 1986, A
