General procedure for the synthesis of dimethyl (2-oxo-3,3-difluoroheptyl) phosphonate from ethyl 2,2-difluorohexanoate and dimethyl methylphosphonate: Dimethyl methylphosphonate (215 mL) was dissolved in tetrahydrofuran (THF, 1450 mL), stirred and the reaction solution was cooled to -78 °C. Slowly n-butyllithium (N-BuLi, 804 mL) was added dropwise and stirring was continued for 2 hours. Subsequently, ethyl 2,2-difluorohexanoate (145 g) was added dropwise. The reaction mixture was stirred at -78 °C for some time, then slowly warmed to 0 °C and continued stirring for 1 hour. The progress of the reaction was monitored by thin layer chromatography (TLC, unfolding agent ratio hexane: ethyl acetate = 1:1). Upon completion of the reaction, the reaction was diluted with the addition of pentane (1000 mL) and the pH was adjusted to 6 with 2 M sulfuric acid solution.The aqueous layer was separated and the organic layer was re-extracted with pentane. The organic layer was combined and dried with anhydrous sodium sulfate. After filtration to remove the desiccant, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluent ratio hexane:ethyl acetate=1:1) to afford pure dimethyl (2-oxo-3,3-difluoroheptyl)phosphonate (161 g, 78% yield).
