Although some of the reagents used in this synthesis may be unfamiliar, organic chemistry students should be able to recognize what is going on in each step. In the first step shown, the Lewis acid boron trifluoride etherate promotes an internal SN2 reaction in which the carbonyl of the acetamide displaces the acetate ester to form the new ring. Notice the inversion of configuration at C4. This is then subjected to another SN2 reaction in which the nucleophile is the azide anion N3-. The reagent is trimethylsilyl azide, which also provides mildly Lewis acidic activation for the displacement. Azide groups are excellent precursors for amines, and the reduction of the azide is easily carried out. You can see that some care must be taken here, since if the reaction is left too long the hydrogenation of the alkene will also occur. Simple alkaline hydrolysis removes the methyl ester and the acetate ester protecting groups, and then the amino group is converted into the desired guanidino function using formamidine sulfonic acid. This provided the desired neuraminidase inhibitor 4-deoxy-4-guanidino-2,3-dehydro-N-acetyl neuraminic acid, which ultimately has become the anti-influenza drug (sold under the trade name Relenza by GlaxoSmithKline).
The multistep synthesis above shows that although the major bottleneck for Roche may be the availability of shikimic acid, production of oseltamivir is very involved. Increasing production volume (by Roche or others) would require construction of extensive new facilities (which may not be amenable to scaleup and, even if identical on paper, may not necessarily produce acceptable yields), and even if current facilities could handle a larger feedstock quantity, there would be a delay in production as the material makes it down the pipeline (~6 months or so). Producing large amounts of Tamiflu not only takes months to complete, but is also hazardous. Some of the steps in the synthesis require careful handling and relatively mild reaction conditions, as they involve the use of potentially explosive azide chemistry. Roche has explored ways to speed up production (Chimia 2004, 58, 621). It has developed an azide-free allylamine route from the epoxide to Tamiflu. It has also crafted routes that don’t rely on (–)-shikimic acid: a Diels-Alder-based one that uses furan and ethyl acrylate as starting materials and another that relies on catalytic hydrogenation of an isophthalic acid derivative followed by enzymatic desymmetrization. In addition, Frost and Guo at Michigan State University has developed a microbial synthesis of , which could reduce the need for azide chemistry if used as a starting material.
Neuraminidase Inhibitors for Influenza — NEJM
In early 2005, Roche announced a production shortage. (See , above). However, 2006, Roche said that production was about to reach 400-million treatment courses annually, that "capacity was well in excess of total government orders placed to date," and that "the supply shortage no longer exists." Total government orders between 2005 and 2007 were estimated to be around 200 million treatment doses. In fact, Roche CEO William Burns said that a shortage of orders could cause Roche to reduce production in the future. Roche attributes production increases in part to its agreements with 15 external contractors in 9 countries.
PPT – Tamiflu PowerPoint presentation | free to …
The development of resistance to commonly used antiviral drugs Relenza and Tamiflu has become a serious problem facing the world. It is reported that 98 percent of influenza A/H1N1 strains in North America are resistant to Tamiflu. The Withers group has designed a series of sialic acid analogs in which the C-2 OH group was replaced with fluoride to trap the virus by the formation of a covalent intermediate.
The Art of Drug Synthesis by Douglas S. Johnson | …
You can see how well zanamivir fits into the active site of influenza A neuraminidase from the X-ray crystal structure obtained by Zu et al. and indexed in the as . This is an interesting structure because the enzyme is the neuraminidase from the A/Brevig Mission/1/1918 H1N1 strain, one of the viruses that caused the 1918 Spanish Flu. The genome of this virus was obtained from the frozen body of a woman who died in the Alaskan village of in 1918. (and incidentally the Johan Hultin who found the virus is no relation to Dr. Hultin!). It is another variation of the H1N1 strain that is at the centre of the 2009/2010 concern about Swine Flu.
Chemical Synthesis; Chemical Analysis; Bioanalysis;
Numerous other synthetic routes to zanamivir have been published since the original synthesis shown here, and you can be very sure that the industrial synthesis is quite different. The problem with Zanamivir is that it cannot be administered orally. Because the guanidino group is strongly basic, if it were taken orally it would be protonated in the stomach. The resulting positively-charged structure could not be taken up from the gut. Zanamivir is usually administered by inhalation, but this is not as acceptable to many people as a pill would be, and does not give a particularly high level of bioavailability.