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Zanamivir influenza medicine from axit sialic

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Zanamivir is an enzyme neuraminidase inhibitor medicine, used to treat and prevent influenza on human’s body. Now, scientists from the Institute of Chemistry under Vietnam Academy of Science and Technology have conducted a research project on this active element.


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Influenza is an infectious disease affecting human, mammals and birds, and is caused by type A, B and C viruses, which have the RNA structure of the Orthomyxoviridae family. In heavy cases, influenza causes pneumonia and respiratory difficulties, and can cause death, especially for children, pregnant women, old people and the chronically ill. To cope with influenza epidemics, researchers mainly develop specific vaccines and reserve anti-virus medicines, including enzyme neuraminidase (oseltamivir and zanamivir) inhibitor medicine of the influenza virus. Together with vaccine innoculation, oseltamivir and zanamivir are anti-virus medicines which are recommended to be given priority use by WHO.

In 2005, facing the urgent demand of medicines to prevent an influenza epidemic, the Prime Minister permitted the Institute of Chemistry under Vietnam Academy of Science and Technology to successfully conduct the oseltamivir active element from anise materials in water. As a result, the achieved productivity was 70% of public productivity in the world. The product met pharmaceutical standards. Continuing research, scientists from the Institute of Chemistry made a survey on the synthetic possibility zanamivir influence prevention medicine from acid sialic in Vietnam.

Zanamivir and Acid sialic (Acid N-axetylneuraminic)

Together with oseltamivir, zanamivir is the only medicine which can prevent influenza on humans caused by H5N1 and H1N1 virus. Vietnam prepared oseltamivir (Tamiflu) medicine. But there was no zanamivir – the first influenza medicine belonging N1 kind, discovered and commercialized before oseltamivir. The scientific name of zanamivir is acid 5-acetamido-4-guanidino-6-(1,2,3-trihydroxy-propyl)-5,6-dihydro-4H-pyran-2-carboxylic. The discovery of zanamivir opens research possibilities for new medicines which have the same effect on enzyme neuraminidase inhibitor to prevent and treat influenza.

Acid sialic is an input to synthetize zanamivir. The name acid sialic (Neu5Ac2en) is used to indicate derivation at O- and N- positions of acid neuraminic, just for acid N-axetylneuraminic. Acid sialic of carbohydrate groups is on animal cells and microorganism, especially in glycoprotein and gangliosid. The commercial acid sialic is extracted from whey of the cheese and milk process as well as egg yolk, and costs about 5,000 USD per kilo.

Zanamivir synthetic process in the world

In 1994, zanamivir was first synthesized and made public by Von Itzstein and other scientists from the Department of Pharmaceutical Chemistry under Monash University (Australia). Then, Chandler and co-workers of Glaxo company (GSK, Britain) acquired results, improved reaction steps and made them public in 1995. Accordingly, this method produced 8.3% of general output. The synthetic process is described in Figure 1.


Figure 1: Zanamivir synthetic process according to Chandler

Up to now, the research of Chandler has been the only publication about zanamivir synthetic method, the output of which is greater than milligrams, and it reproduces details about reaction conditions and physiochemical properties of the requisite substances.

Recently, a research group of Yao (China) proposed a new approach to synthetize into intermediate compound 5. Researchers started from another material - D-glucono-δ-lactone, which is cheaper than acid sialic. However, the synthetic process is longer and much complicated, including 24 steps, with lower productivity (0.2%).

Researching on synthesizing Zanamivir from Acid sialic by Institute of Chemistry

Synthetizing methyl N-acetylneuraminate (2) and O-pentaacetoxy (3) from acid sialic

Scientists from the Institute of Chemistry used acid sialic (axit N-acetylneuraminic) 98% from China as the input for the zanamivir synthetic process. They decided to use the method of Warner, using ion exchange resin Dowex-H, with the role of catalyst. Reaction was performed in the room in 10 hours. The output was metyl (2) este product of acid N-acetylneuraminic with a productivity of 99%.

Then, to synthetize O-pentaacetoxy (3), scientists applied axetyl effective chemistry method recently published, using BF3.OEt2 catalysis at 00C. Productivity in this case exceeded 95%.


Figure 2: The diagram of O-pentaacetoxy 3 derivative making

The use of catalysts which were ion exchange resin Dowex-H (for este chemical reaction) and BF3.OEt2 (for axetyl chemical reaction) had more advantages than the method by scientists from Glaxo.

Synthesizing intermediate compound – oxazoline (4) key from O-pentaacetoxy (3)


Figure 3: Diagram to synthesize oxazoline (4) from O-pentaacetoxy (3) according to a and b methods

Firstly, scientists conducted a survey on oxazoline (4) synthetic process according to Chandler’s process. O-pentaacetoxy (3) compound was separated from two types of OAc and formed oxazoline round thanks to the effect of strong acid Lewis, which was TMSOTf at 520C in 2.5 hour. The productivity of this reaction achieved 40%. The pilot instead of TMSOTf by BF3.OEt2 catalysis in dichloromethane at room temperature at night, the productivity of the reaction to form oxazoline round from penta-acetoxy (5) was similar to the method using TMSOTf (42%). To increase productivity, scientists made a survey on one-pot method, directly from metyl este (2) to oxazoline (4), without passing O-pentaacetoxy (3), gave the highest productivity (73,3%) and was the most economic effectiveness.

Synthesizing zanamivir from oxazoline (4) intermediate compound

The next, scientists successfully conducted reactions from oxazoline (4) intermediate compound to Zanamivir (9) final product (Figure 1). Zanamivir product had IR and NMR data which were compatible with their structure.

Therefore, scientists from the Institute of Chemistry under Vietnam Academy of Science and Technology built a stable process, including seven major steps, synthesizing from acid sialic with the general productivity of 6.6% (the productivity made public in the world was 8.3%). Especially, in the first period, from acid sialic to oxazolin (4) was optimized and gave a general productivity of 74%, higher than the productivity made public by (61.7%). However, the productivity gained in the later period is still low. Now, synthesizing zanamivir influenza medicine still continues to be researched.

Translated by Tuyet Nhung
Link to Vietnamese Version

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