Preparation method of tapentadol intermediate methoxypropiophenone
A technology of methoxybenzene and tapentadol, applied in the field of medicine and biology, can solve the problems of unfavorable industrial application, low yield of m-methoxypropiophenone, etc., and achieves advantages of industrial production, low price and high yield Effect
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Embodiment 1
[0025] Add 75g of purified water, 30g of sodium hydroxide, and 50g of compound III to a 500L three-necked flask, heat the reaction mixture to an internal temperature of 80-90°C while stirring, and add 35g of dimethyl sulfate dropwise at this temperature. After the dropwise addition, Heat up to 95°C-102°C for reflux reaction. After 4 hours of reaction (the whole process maintains pH ≥ 10), continue to drop 15g of dimethyl sulfate. After the dropwise addition, keep 95°C-102°C for reflux reaction until compound III<5 %, lower the temperature to 30-35°C, then add 100g toluene and 30.4g sodium bicarbonate to keep the temperature at 30-35°C, add 36.5g dimethyl sulfate dropwise, after the dropwise addition, keep the temperature at 30-35°C for 4 hours (the whole process keeps pH ≥ 8), continue to drop 36.5g of dimethyl sulfate, after the dropwise addition, keep the temperature at 30-35°C for 4 hours (keep the whole process pH ≥ 8), continue to drop 18.3g of sulfuric acid Dimethyl este...
Embodiment 2
[0027] Add 20g of compound IV, 20g of DMF and 7.2g of sodium hydride into a 250mL reaction flask, under nitrogen protection, the system becomes gray and turbid, slowly add a mixed solution of 13.7g of methyl propionate and 5g of toluene to the system, and keep the temperature at 18 ~22°C, dropwise is completed in about 1 hour, keep the temperature at 18~22°C until compound IV<5%, slowly pour the reaction system into 40g concentrated hydrochloric acid pre-cooled to -5°C~0°C, control the temperature during the whole process less than 40°C. After the addition is complete, slowly add 20.3g of phosphorus oxychloride dropwise to the system. During the dropwise addition, the temperature is controlled to be less than 40°C. °C, filter, wash, separate layers, wash the organic layer with aqueous sodium chloride solution, discard the aqueous layer, and concentrate the organic layer to obtain 20.2 g of compound I with a purity of 90.2% and a yield of 95.8%.
Embodiment 3
[0029] Add 20g of compound IV, 20g of DMF and 7.2g of sodium hydride into a 250ml reaction bottle, under nitrogen protection, stir, slowly add 15.9g of methyl propionate dropwise into the system, the dropwise addition process is about 2hr, react for 1.5hr, sample GC to analyze compound IV After the reaction is complete, stop heating, cool to 20-25°C, add 250g of methyl tert-butyl ether and stir for later use to obtain reaction solution 1. Add 250g of methyl tert-butyl ether to 200g of ice water, and adjust the pH to 1-2 with HCl 2. Slowly add the reaction solution 1, adjust the pH to 1-2 with HCl while stirring, separate layers, wash, dry, filter, and concentrate to obtain 25.1 g of compound II with a yield of 90% and a purity of 90%.
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