Shorter road to Tamiflu synthesis

Kudos to the Elias J. Corey laboratory at Harvard University for a chemistry tour de force and for their position on intellectual property rights. Both are important. First, the chemistry.

A serious obstacle to ramping up oseltamivir (Tamiflu) production in anticipation of a possible pandemic of influenza/A has been its long production cycle. Pharma giant Roche initially claimed the drug could not be made in less than 12 months and required more than a dozen steps, some of them involving very hazardous materials. It also required the use of expensive and scarce ingredients, (-)-shikimic or (-)-quinic acids. Shikimic acid is derived from fermentation of Chinese star anise fruit, in limited supply.

Now Corey has devised a way to make oseltamivir without these complex starting materials and without hazardous intermediates. A second alternative route by Japanese researcher, Masakatsu Shibasaki, is also said to have inexpensive starting materials and no hazardous steps, but smaller yield:

"Our synthetic pathway has several advantages over the current Roche production method," Corey says. "It is shorter, doesn't involve any hazardous substances, begins with very cheap starting materials that are pennies per pound, and has excellent overall yield." Corey's overall yield is about 30%—about twice that of the commercial route and significantly higher than the approximately 1% that can be calculated for Shibasaki's.

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Although Roche researchers declined to comment on the new synthetic routes, a spokeswoman says the company is in contact with the authors of both papers. Both the technical potential and regulatory impact of any new route still have to be explored, she comments. In his group's paper, Corey, who serves as an adviser to Palo Alto-based Roche Biosciences, thanks Roche researchers in Switzerland for their encouragement. (Chemical and Engineering News)

There is some way to go before either method is in production, but the more important part of the announcement is that Corey has placed his method in the public domain. Shibasaki, by contrast, has applied for a patent, although this wouldn't prevent him from allowing no cost licensing if he wished. However, given the situation, Corey's move is highly significant and should be considered a model for others.

"I hope the work will stimulate others to work on different ways of synthesizing Tamiflu," Corey says. "Although our route is already very efficient, it's conceivable that when you put new developments together, you'll have an even better and cheaper process. I think the Tamiflu supply problem is solved."

Solved, that is, if someone will make the drug with this process. Roche has invested much in production facilities using a process for which they have the license. On the other hand, many independent companies may now use this new process, with or without Roche's permission (Roche still has the license for the drug itself).

In 1990 Corey won the Nobel Prize in Chemistry for his achievements in chemical synthesis. He hasn't lost the touch.

Nor the commitment to the common good.