88% |
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Under nitrogen protection, 1.25 kg of compound XIV,6.0 kg of DMF and 0.73 kg of magnesium isopropoxide.The temperature was raised to 65 C, and the reaction was stirred for 1 hour.The temperature was lowered to 45-55 C, and DEMP (Formula VI) was slowly added dropwise to the reactor in batches.After the addition was completed, the mixture was stirred at 45 to 55 C for 10 hours.The reaction was determined to be complete by HPLC, and DMF and isopropanol were concentrated under reduced pressure.6.25 kg of concentrated hydrochloric acid was added to the concentrate, the temperature was raised to 90 C, and the reaction was stirred for 10 hours.After the reaction was completed, the temperature was lowered to 10-15 C and stirred for 20-30 minutes.After filtration, the filter cake was washed with 1.0 kg of a dilute hydrochloric acid solution, and the filter cake was discarded.The filtrate was transferred to a reaction kettle, 2.0 kg of dichloromethane was added, and stirred for 15 minutes.Let stand for 30 minutes.The layers were separated, the aqueous phase was collected, and the hydrochloric acid was concentrated under reduced pressure.7.5 kg of water was added to the concentrate, the temperature was raised to 40 C, and the mixture was stirred until dissolved.Slowly add 40% NaOH aqueous solution to adjust the pH to 3.0.After the dropwise addition was completed, the mixture was stirred at 50 C for 3 hours.Cool naturally to room temperature and stir for 10-12 hours.Filter, filter cake was washed with 0.8kg of water,Get tenofovir crude.Purity 96.7%, containing 0.78% condensation impurities, genotoxic impurities 160ppm,The S-isomer impurity was 0.58%, and the isomer was 1.83%. |