Saturday, May 13, 2006

New routes to make TAMIFLU

Unlike Roche's current commercial process for the active ingredient in TAMIFLU, two new synthetic routes avoid the use of (–)-shikimic or (–)-quinic acids, complex starting materials that are expensive and in limited supply. They also both depend on an asymmetric catalytic step early in the synthesis to create a key building block. They differ, however, in that the Corey route does not involve hazardous azide intermediates.

"Our synthetic pathway has several advantages over the current Roche production method," Elias J. 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.

Roche has been obtaining the shikimic acid starting material via extraction from Chinese star anise fruit and fermentation processes. It has recently signed up more than 15 external contractors to help it expand production of both intermediates and finished materials. With this help, Roche says it will be able to produce 400 million flu treatments annually by the end of 2006.

Whereas the Japanese researchers have applied for a patent, Corey and coworkers have put their process in the public domain. "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."

The C&E News story made no mention of Professor John W. Frost of Michigan State University. Of the allegations that limited supplies of star anise are a bottleneck to making Tamiflu, Professor John W. Frost stated: "I'm just completely astonished about the gnashing of teeth and the wringing of hands about the shikimic acid. The bottleneck should not be shikimic acid availability."


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