Background and overview[1]
Oseltamivir phosphate, whose English name is Oseltamivir phosphate, chemical substance registration number CAS RN is 196618-13-0, is a neuraminidase inhibitor jointly developed by Gilead of the United States and Roche of Switzerland. It is a commercial product Named Tamiflu, it is an effective drug for preventing and treating avian influenza. Oseltamivir phosphate was launched in Switzerland and the United States in 1999 and in my country in October 2001. Its main indications are: for the treatment of influenza A and B in adults and children 1 year old and above; For the prevention of influenza A and B in adults and adolescents 13 years of age and older. Oseltamivir phosphate is currently recognized as the most effective drug against avian influenza and is also a national strategic reserve drug.
Preparation[1]
1. Add 541.5g (1.116mol, HPLC99.989%) compound 2 into 700mL trifluoroacetic acid, stir, raise the temperature to 45~55℃, and keep the reaction for 3 hours; cool the reaction solution to 20~30℃. Add 250 mL of toluene, and concentrate the reaction solution under reduced pressure in a hot water bath at 45 to 55°C until no liquid flows out. Add 1000 mL of toluene to the concentrate, cool to 0 to 10°C, maintain 0 to 10°C, and add 300 mL of cold water; control the temperature to 0 to 10 ℃, slowly add 158.75g (3.969mol) sodium hydroxide in water (500mL) solution dropwise, adjust the pH to about 12 to 13, let it stand and separate the layers, extract the water layer with 500mL toluene, let it stand and separate the layers, combine the organic layers each time Wash three times with 250 mL of water and let stand to separate layers; the organic layer is dried with 50 g of anhydrous sodium sulfate and filtered. The combined filtrate is concentrated under reduced pressure in a hot water bath at 45-55°C until no liquid flows out. Add 2707.5 mL of n-heptane at 20-55°C. Stir for 2 hours at 30°C to precipitate solid, filter, and vacuum dry the filter cake at 45-55°C to obtain 413.5g of white solid compound 3, yield 94.38%, HPLC purity 99.54 antioxidant manufacturer 6%, single maximum impurity 0.112% .
2. Add 85.0g (0.217mol, HPLC purity 99.53%) compound 3 to 850mL ethanol, add 27.34g (0.260mmol) diethanolamine and 8.5g 10% palladium carbon (wet basis 50%), add black The suspension is heated to 68-78°C and reacted for 8 hours; the reaction solution is cooled to 20-30°C and filtered. Rinse the filter cake with 100 mL of ethanol. The combined filtrate is concentrated under reduced pressure in a hot water bath at 45-55°C until no liquid flows out. Dissolve with 450 mL of 2 mol/l HCl aqueous solution. The brown solution is concentrated under reduced pressure for 10 minutes. A large amount of gas is generated. The solution is Cool to 20~30℃; extract with 100mL methyl tert-butyl ether, and let stand to separate layers. When the temperature is lower than 20°C, use 25% ammonia solution to adjust the pH to 9-10 to form a brown emulsion. The emulsion was extracted 4 times with 200 mL of ethyl acetate each time, the organic layers were combined, washed with 200 mL of saturated brine, allowed to stand and separated, dried with 20 g of anhydrous sodium sulfate, and filtered. Rinse the filter cake with 50 mL of ethyl acetate. The combined filtrate is concentrated under reduced pressure in a hot water bath at 45-55°C until no liquid flows out. Dissolve the concentrate in 650 mL of ethanol to obtain a brown solution. Warm it up to 45-55°C and drip slowly. Add 14g (0.143mol) phosphoric acid in ethanol (250mL). After the dropwise addition, cool the resulting reaction solution to below -10°C, filter, and dry the filter cake under vacuum at 50-60°C to obtain 87.5g of white solid phosphoric acid. Crude oseltamivir, HPLC purity 99.895%, maximum single impurity 0.056%; add 87.5g crude oseltamivir phosphate to 3500mL of ethanol aqueous solution with a volume concentration of 99.2%, raise the temperature to reflux to dissolve, and cool to 65-70°C , add 4.4g activated carbon, raise the temperature to reflux, stir for 30 minutes, filter, cool the filtrate to 45~55℃, if solid precipitates, continue stirring to cool down to below -10℃, stir for 2 hours, filter, the filter cake will be at 50~60℃ After vacuum drying, 85.6g of crystal form A of oseltamivir phosphate was obtained, with a yield of 96.31%, an HPLC purity of 99.924%, and a single maximum impurity of 0.051%.
