Background and overview[1,3]
Influenza, also known as influenza, is an acute respiratory infectious disease caused by influenza viruses, which seriously affects human health. Worldwide, 20% of children and 5% of adults are infected with influenza A (A) or B (B) every year. Influenza has a high mortality rate, seriously endangers human health and life, and causes huge economic losses and social panic. The highly pathogenic H5N1 avian influenza virus was first discovered to infect humans in 1997. Statistics from the World Health Organization show that the mortality rate of infected people can reach 60%. Various new H1N1 influenza virus variants continue to appear around the world, and the number of infected people continues to increase. Influenza has not only attracted widespread attention around the world, but has also become a viral infectious disease that my country focuses on prevention and control. Oseltamivir phosphate is currently recognized as the most effective drug against avian influenza and is also a national strategic reserve drug.
The chemical name of oseltamivir phosphate is: (3R, 4R, 5S)-4-acetamide-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid Ethyl ester, whose English name is Oseltamivirphosphate, is a neuraminidase inhibitor jointly developed by the American Gilead Company and the Swiss Roche Company. The trade name is Tamiflu. It is an effective drug for the prevention and treatment of 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.
Pharmacological effects[2]
Oseltamivir phosphate is the prodrug of its active metabolite, and its active metabolite (oseltamivir carboxylate) is a selective inhibitor of influenza virus neuraminidase. Neuraminidase is a glycoprotease on the surface of viruses whose activity is critical for the release of newly formed viral particles from infected cells and for further dissemination of infectious viruses in the human body. The active metabolite of this product can inhibit the neuraminidase activity of influenza A and B viruses. The half-inhibitory concentration of viral neuraminidase activity in vitro is as low as the nanogram (ng) level. Active metabolites have been observed to inhibit influenza virus growth in vitro and inhibit influenza virus replication and pathogenicity in vivo. This product reduces the spread of influenza A or B viruses by inhibiting the release of the virus from infected cells.
Indications[2]
Oseltamivir phosphate is used for the treatment of influenza A and B in adults and children 1 year old and above (this product can effectively treat influenza A and B, but the clinical application data of influenza B are not yet available. Many); used for the prevention of influenza A and B in adults and adolescents 13 years of age and older.
Dosage and usage[2]
The generally recommended oral dosage is 1 capsule (75mg) each time, 2 times a day for a total of 5 days. Medication should be started on the 1st or 2nd day after flu symptoms begin. This product can be taken with food or separately. For some patients, taking medication with food can increase their tolerance to the medication. Patients with renal insufficiency should adjust the dose appropriately according to their condition.
Notes[2]
Contraindicated for those allergic to any component of oseltamivir phosphate. Nausea, vomiting, bronchitis, insomnia, dizziness, abdominal pain, epistaxis, earache and conjunctivitis, redness (rash), dermatitis, bullous rash may occur after taking this product. Very few patients may experience hepatitis and elevated liver enzymes. Pancreatitis, angioedema, laryngeal edema, bronchospasm, facial edema, elevated eosinophils, decreased leukocytes, hematuria and other adverse reactions. Since the launch of this product, reports of self-injury and delirium incidents occurring during the treatment of this product have been received. Most of the reports are from Japan, mainly pediatric patients, but the correlation between this product and these events is unclear. Therefore, during treatment with this product, patients should be closely monitored for abnormal behaviors such as self-harm and delirium. It should not be used by patients with severe renal failure who require regular hemodialysis and continuous peritoneal dialysis. Children, pregnant women, and lactating women should not use this product.
Preparation specifications[2]
Capsules: 75mg.
Preparation[1] Waterproofing agent
A preparation method of oseltamivir phosphate that is suitable for commercial production and effectively improves product quality and yield:
Step 1): Add 541.5g (1.116mol, HPLC99.989%) compound 2 to 700mL trifluoroacetic acid, stir, raise the temperature to 45~55℃, and keep the reaction for 3 hours; the reaction solution is cooled to 20~30 ℃, add 250mL toluene, the reaction solution is concentrated under reduced pressure in a hot water bath of 45~55℃ until no liquid flows out, add 1000mL toluene to the concentrate, cool to 0~10℃, maintain 0~10℃, add 300mL cold water; control the temperature 0 ~10°C, slowly add 158.75g (3.969mol) sodium hydroxide in water (500mL) solution dropwise, adjust the pH to about 12~13, let stand and separate the layers, extract the water layer with 500mL toluene, let stand and separate the layers, combine the organic layers Wash three times with 250 mL of water each time, and let stand to separate layers; the organic layer is dried with 50 g of anhydrous sodium sulfate, filtered, and the combined filtrate is concentrated under reduced pressure in a hot water bath at 45 to 55°C until no liquid flows out, and 2707.5 mL of n-heptane is added. Stir for 2 hours at 20-30°C to precipitate solid, filter, and vacuum dry the filter cake at 45-55°C to obtain 413.5g of white solid compound 3, with a yield of 94.38%, an HPLC purity of 99.546%, and a single maximum impurity of 0.112%.
Step 2) Add 85.0g (0.217mol, HPLC purity 99.53%) of compound 3.Pour into 850mL ethanol, add 27.34g (0.260mmol) diethanolamine and 8.5g 10% palladium carbon (50% wet basis), heat the black suspension to 68~78°C and react for 8 hours; cool the reaction solution to 20~30 ℃, 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 2mol/l HCl aqueous solution. The brown solution is concentrated under reduced pressure for 10 minutes. A large amount of gas is generated. Cool the solution 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 four 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. The filter cake was rinsed with 50 mL of ethyl acetate, and the combined filtrate was concentrated under reduced pressure in a hot water bath at 45-55°C until no liquid flows out; the concentrate was dissolved in 650 mL of ethanol to obtain a brown solution, which was heated to 45-55°C and dripped slowly. Add 14g (0.14 3mol of cosmetic raw materials) phosphoric acid in ethanol (250mL). After the dropwise addition, cool the resulting reaction solution to below -10°C, filter, and vacuum dry the filter cake 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%.
Main reference materials
[1] CN201811023680.3 Preparation method of oseltamivir phosphate
[2] Physician’s Desk Medication Reference
[3] CN201610008498.5 Oseltamivir phosphate oral liquid and preparation method thereof
