General procedure for the synthesis of 2,5-dichloro-4,6-dimethylpyrimidine from 5-chloro-4,6-dimethylpyrimidin-2(1H)-one: Intermediate 14: Synthesis of 2,5-dichloro-4,6-dimethylpyrimidine. To 5-chloro-4,6-dimethylpyrimidin-2-ol (992 mg, 6.26 mmol) was added phosphorus oxychloride (POCl3, 2.22 mL, 23.77 mmol) followed by dropwise addition of diethylamino phosphate (Et2NP, 0.75 mL, 4.69 mmol). The reaction mixture was heated to reflux at 125 °C for 2 hours. After about 2 hours, the reaction mixture became homogeneous and complete consumption of the feedstock was confirmed by high performance liquid chromatography (HPLC) analysis. The reaction mixture was cooled to room temperature and slowly added dropwise to ice water. Upon melting of the ice, a white solid was observed to precipitate out of the pink liquid. The aqueous layer was extracted with dichloromethane (DCM), the organic layers were combined and dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure. Purification by column chromatography (eluent: n-hexane to 10% ethyl acetate/hexane) afforded the target product 2,5-dichloro-4,6-dimethylpyrimidine as a white solid (915 mg, 83% yield).1H NMR (500 MHz, CDCl3): δ 2.57 (s, 6H).
