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Example: 12 Preparation of 9-[2-(R)-(phosphonomethoxy)propyl] adenine (II) Method-B Magnesium di-tert-butoxide (1 .76 g) was added in four divided batches to a stirred suspension of 9-[2-(R)-(hydroxyl)propyl)adenine] (1 g) in N, N- dimethylformamide (3 ml) at 60-70C over a period of 1 h. The reaction mixture was heated to 90C and <strong>[3167-63-3]diethyl chloromethylphosphonate</strong> (1 .93 g) was added drop by drop to the reaction mixture over a period of 4 h. The reaction mixture was maintained at this temperature until the reaction was complete, as indicated by TLC. Nu, Nu-Dimethylformamide was distilled out under vacuum at 90-100C. To the residue thus obtained, aqueous hydrobromic acid (48% w/w, 10 ml) was added and the reaction mixture was heated to gentle reflux. After approximately 20 h at this condition, the reaction mixture was allowed to cool down to room temperature and filtered. The filtered solid was washed with dichloromethane (10 ml). The washing was concentrated to furnish a residue. The residue was combined with the filtrate and the combined filtrate was washed with dichloromethane (2 X 10 ml). To the aqueous layer, an aqueous solution of sodium hydroxide (50%) was added until the pH attained 2.1 -3. After several hours at room temperature, the aqueous layer was cooled to 0-5 C and stirred at this temperature for further hours to maximize precipitation of the desired product from the solution. The precipitated solid was filtered, washed with cold water (1 X 5 ml), acetone (2 X 5 ml) and dried to obtain 9-[2-(R)-(phosphonomethoxy)propyl]adenine; yield: 0.7 g.
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%.
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