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diethyl ({1-[(dibenzylamino)methyl]cyclopropoxy}methyl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.5%
With lithium tert-butoxide; In tetrahydrofuran; at 60℃;Inert atmosphere;
Under nitrogen protection,A solution of 1- (dibenzylamino) methylcyclopropanol (II-1) (1.15 g, 4.3 mmol) in tetrahydrofuran (10 ml)Lithium tert-butoxide (0.5 g, 6.2 mmol) and diethyl p-toluenesulfonyloxymethylphosphonate (III-1) (2.0 g, 6.2 mmol)The temperature was raised to 60 C.TLC monitoring reaction end,After cooling to room temperature, add saturated ammonium chloride solution (10ml)Solid precipitation.filter,The filter cake was washed with ethyl acetate (10 ml x 2)The combined organic layers were dried over anhydrous sodium sulfate,filter,Concentrated crude,Purification by flash column chromatography (petroleum ether: ethyl acetate = 2: 1)Get the oil,A total of 1.57g,The yield was 87.5%;
With sodium hydroxide; In dichloromethane; at 5 - 10℃; for 3h;
(2) 100 ml of dichloromethane and 78.7 g of p-toluenesulfonyl chloride were added to the above reaction solution.Cool down to 5 C, add 30% of liquid alkali 63.8 grams, the reaction is exothermic,Keep the dropping temperature between 5-10 C, and add 1 hour.After the addition is completed, the temperature is kept at 10 C for 2 hours, and the sample is tested.The reaction of 0.15% (less than 0.2%) of p-toluenesulfonyl chloride is completed.Still, layer, the aqueous layer was extracted once with 50 ml of dichloromethane.Combine the layers and add 100 ml of water to wash once.The water layer is separated; the layer is firstly distilled to recover dichloromethane.The residual dichloromethane was then dried under reduced pressure.Residue 115.1 g of diethyl p-toluenesulfonyloxymethylphosphonate,99.3% purity,The molar yield (calculated as p-toluenesulfonyl chloride) was 86.5%.
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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