Background and Overview[1][2]
The full chemical name of Oseltamivir phosphate is 4-acetylamino-5-amino-3- (1-Ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate is an effective drug for preventing and treating avian influenza. A few years ago, when avian influenza brought disaster to human society, it was oseltamivir phosphate, trade name Tamiflu, jointly developed by Gilead of the United States and Roche of Switzerland, that was launched on the market and caused the disaster. The avian influenza caused by die-casting release agents to human society has been controlled. Afterwards, many countries listed oseltamivir phosphate as a national strategic reserve drug in case of emergency. Oseltamivir phosphate is a neuraminidase inhibitor, and its drug design can be found in the literature. However, so far, only Roche’s method has industrial value and can be produced. Judging from the production capacity of oseltamivir phosphate alone, it is not enough to deal with global problems. The method jointly developed by Gilead and Roche discloses a method using naturally occurring shikimic acid and quinic acid as starting materials, and introducing 1-ethylpropoxy functional energy through stereoselective reduction of ketals. Group, use azide reagent, allylamine, or tert-butylamine to introduce nitrogen-containing functional groups, stereoselective ring-opening reaction of aziridine and other steps to realize the industrial production of oseltamivir phosphate. Although this method has been industrialized, but There are many problems in its synthesis process.
Oseltamivir phosphate
Application[3]
Oseltamivir phosphate is a new type of neuraminidase (NA) inhibitor with extremely high selectivity. It can be used for influenza virus infections, bronchitis associated with infections, pneumonia, general pain, and severe fever. Treatment and prevention, especially effective against influenza A and B viruses. Oseltamivir was launched in Switzerland in 1999. A large amount of clinical practice has proved that it has the advantages of high efficiency, resistance to drug resistance, good patient tolerance and high safety. It is widely used in clinical practice to prevent and treat influenza.
Preparation[2]
Under nitrogen protection, put stearic acid 1801 into the reaction kettle and add ethyl (3R, 4R, 5S)-4 -N-acetylamino-5-N,N-bisallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid 12 g, 1,3-dimethylbar Add 5 g of bitaldehyde, 0.3 g of triphenylphosphine, 0.07 g of palladium acetate and 55 g of absolute ethanol. Stir and heat to 35°C and keep the reaction for 2 hours. Then, this hydrogenolysis reaction solution was added dropwise to another reaction kettle containing 3.5 grams of phosphoric acid and 36.5 grams of absolute ethanol at 50°C, stirred for 2 hours, cooled to -17°C ~ -18°C, and waited until the crystallization was complete. ,filter. Wash 20 grams x 3 with acetone and 20 grams x 3 with n-heptane in sequence, and dry to obtain crude oseltamivir phosphate.
Main references
[1] Hu Shanlian, Lin Jiangtao, Yu Xuezhong, Wang Aixia, Zhu Jihong, & Cui Dejian et al. (2004). Oseltamivir phosphate in the treatment of influenza Cost-effectiveness analysis. Chinese Medical Journal, 84(019), 1664-1667.
[2] Li Longyun, Cai Baiqiang, Wang Mengzhao, & Zhu Yuanjue. (2001). Oseltamivir phosphate in the treatment of influenza A multi-center clinical study. Chinese Journal of Internal Medicine (12), 838-842.
[3] Wei Pengyan, Jiang Yuying, & Qian Kun. (2020). Research progress on oseltamivir phosphate. Chemical Engineering and Technology, 10(6), 7.
