Chemistry Blog

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Feb 16

Has Tamiflu got a cold?

by Quintus | Categories: science news, synthetic chemistry | (37062 Views)

Tamiflu, made by Roche and licensed by them from Gilead and stockpiled in many countries has proved to be a big money maker for Roche. It is one of two neuramidase inhibitors currently available for the treatment of influenza, the other being Zanamivir from Glaxo. Tamiflu is sold as its mono-phosphate salt. During the recent outbreak of avian flu due to the H5N1 virus Tamiflu was the drug treatment of choice for many physicians.

 

Now questions are being asked again about it’s effectiveness and it’s actual performance in clinical trials, the data of which has not been fully published by Roche in spite of promises to release this information. A new web site has been established to achieve the aim of providing doctors and patients’ access to this information. In a hard hitting editorial the editor of the British Medical Journal gives big Pharma a well deserved tongue (or in this case pencil) lashing, criticising the lack of information as to the clinical trial results of not just these two compounds but a number of others. Which she says must be made available to independent scrutiny.

It turns out that an review of the data on the available neuramidase inhibitors, commissioned by the British Government, discovered that around 60% of the data of the phase III trials collected by Roche has never been made available for examination.

Why does Big Pharma have a level of secrecy that would make the CIA look proud? Well I suppose in the first instance it’s about big money. One Tamiflu pill costs about $10, and that’s expensive. The recommended dosing regimen is 75 mg twice a day for 5 days, $100. Multiply that by the huge number of people contracting influenza and it comes to a lot of money. This year the sales are expected to DOUBLE from $350 million to around $750 million. So, I suppose that alone justifies the most of the secrecy concerning the reluctance to produce the complete trial results. Combined with a supply problem keeping the demand high also pushes the price up. I would hope that the deficit in supply is due to capacity problems and nothing else. Secondly; publishing the results of clinical trials give an insight into the companies working practices, which they most certainly don’t want made public. In the third instance if any minor complications turn up in the trials this may lead the company to tone down their significance, if there is any. Fourthly; could there be any bad publicity arising from any side effects of the compounds. No doubt there are perhaps other reasons that I am unaware of.

Moving back to chemistry the optimisation of the synthesis of Tamiflu makes a very interesting read and I recommend it as an excellent source of solutions to scale-up difficulties. It can be found here unfortunately behind a paywall. The synthesis starts off with shikimic acid and delivers Tamiflu in 17-22% yield after 15 steps. It has two azide reactions; the first one opens an epoxide to give a mixture of hydroxy azides 1 & 2 in a 9:1 mixture:

Both isomers form the same aziridine in the next step. The hydroxy azides are thermally labile, the stability being better in solution.

The next crucial step is the one pot sequence consisting of aziridine formation, via a Staudinger type process, using triphenylphosphine, followed by ring opening with sodium azide/sulphuric acid and finally acylation.

This series of reactions circumvents the unfavourable thermal properties of both the aziridine and the amino azide and allows for faster reactions and higher yields while maintaining process safety and quality of the product.

For this superb piece of process chemistry the Roche group received the Sandmeyer prize of the Swiss Chemical Society in 2006.

2 comments

  1. synthesizing ideas

    Several labs have already reported new methods in making Tamiflu without shikimic acid.

    1. Quintus

      Yes, I’m aware of that but didn’t really want to include them in this post. And, as far as I know none of them have been carried out on a production scale, yet.

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