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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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May 10, 2006

A New Route to Tamiflu?

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Posted by Derek

There's been a lot of press coverage the last week or so about two new routes to Tamiflu (oseltamavir). Roche famously starts from shikimic acid, most of which they get from Chinese star anise, and the new syntheses are attempts to get around that bottleneck.

E. J. Corey's getting more attention than Masakatsu Shibasaki, partly because he's a Nobel winner and partly because he's made a point of placing his synthesis in the public domain. (Shibasaki's applied for a patent). It's nice to see organic synthesis make the headlines, but unfortunately, a lot of the coverage has been of the "Nobel Prize Winner Solves Tamiflu Problem" sort. I've also seen several stories that suggest that Corey's route opens the door (at last, right?) to mass production.

Not so fast. Roche has already been producing rather large amounts of oseltamavir, although they'd be glad to find a better route. And it's not like they haven't been trying themselves, as this PDF will make clear. And it's far from clear that Corey's route will be of commercial value, even though his overall yield, as given, is about 27%, which news articles are saying is roughly twice the yield from shikimic acid. (Note, though, that that Roche PDF claims a higher yield than Corey's - I'm not sure who's right).

Let's get technical and take a look at the chemistry. First off, the repeated claim that Corey's route starts from two of the cheapest feedstocks available - butadiene and acrylic acid - is only partly true. The key Diels-Alder reaction actually uses trifluoroethyl acrylate, which is substantially more expensive than acrylic acid, although admittedly ten times cheaper than the same amount of shikimic acid from the same source. Moving on, there are eleven steps, and according to the supplementary material for the paper (where the full experimentals are), steps 1, 3, 4, 5, 6, and 8 have chromatography in their workup. The others are run through a plug of silica or are taken on crude, which tells me that Corey's students probably tried to do the same with the remaining steps but took a hit on the yields. Every chromatographic purification adds a great deal to the cost of a process route, needless to say.

There are other wrinkles. Steps 1 and 2 start at -78 degrees before coming up to more process-friendly temperatures. Step 8 is a slow addition at -40, and step 9 is an inverse addition at -20. Low-temperature reactions are certainly doable on scale, but again, they'll add to the cost and complexity. Those last two steps involve an acylaziridine intermediate, whose thermal stability would need to be checked out, and could partially negate the advantage of not using azide in the route.

The scale of the reactions in this paper is in the ten-gram range, which is fine, until you get to steps 8 and 9. Those low-temperature reactions are shown on 300 and 160 milligrams, respectively. That tenfold drop in scale indicates another area that would need to be checked out; there can be a huge difference between something that works on a couple of hundred mgs and a useful process, especially in the cold.

All this isn't to say that Corey's route doesn't work, or that it can't work on scale. But it's important to keep in mind that the kind of chemistry done in his lab is about as far from industrial scale as you can get. It may be that the more interesting features of his route (the catalyzed Diels-Alder, for example) could be combined with some of Roche's own process ideas and turned into something feasible. But for now, this is an interesting route that's a long way from solving anyone's Tamiflu shortage.

To be fair, Corey himself isn't responsible for some of the hype, except I wish he wouldn't let himself be quoted as saying that the thinks that the Tamiflu production problems are "solved". Headline writers know nothing about organic chemistry or drug development, and they run with what's in the press releases. Of course, there's the larger question hanging over all of this: will Tamiflu even do anyone any good if there is a human outbreak of avian flu? And that, nobody knows.

Comments (19) + TrackBacks (1) | Category: Chemical News | Infectious Diseases


1. Epigenetics News on May 10, 2006 8:15 PM writes...

I think that this goes right back to the issue brought up here a couple of weeks ago about the difference between test tube and industrial scale, in vitro and in vivo, etc. It's important to keep perspective.

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2. Petros on May 11, 2006 2:32 AM writes...

Any bets on the reproducibility of that 27% yield even on a lab scale?

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3. freeradical on May 11, 2006 3:24 AM writes...

Three of the paragraphs in this post are duplicated.

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4. Ryan K. on May 11, 2006 6:20 AM writes...

Wow, ya. And I thought the post was just long winded and rambling. ;-)

I just had this conversation with my friend the other day, who worked at Gilead on the tamiflu team. Corey's route isn't remotely practical on any scale, let alone process scale. Try to reproduce that overall yield, I dare you! Go ahead... ;-)

In my opinion, the more practical, albeit maybe not beautiful is Shibasaki's, using azide to selectively open the chiral N-acylaziridine.

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5. Derek Lowe on May 11, 2006 7:52 AM writes...

Fixed the duplicate paragraphs - a cut-and-paste slip-up. Next time large sections of a post repeat, though, it'll be for literary effect, kind of like "Finnegan's Wake".

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6. organometallic on May 11, 2006 8:43 AM writes...

Roche gets 1/3rd of shikimic acid by fermentation of genetically modified Escherichia Coli bacteria, a techonology developed by John Frost at Michigan State University, East Lansing.

see science article.
Oseltamivir Becomes Plentiful--But Still Not Cheap
Martin Enserink
Science 21 April 2006: 382-383.

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7. MolecularGeek on May 11, 2006 9:13 AM writes...

Finnegans Wake (note the use of the vocative) in chemical literature? It makes my head spin to consider it. That's even worse than J. Org. Chem 37:1, 184-6 and iambic pentameter. Will we have onomatopoeic verbs for laboratory operations and complex portamenteau words describing the source and structure of compounds in lieu of IUPAC? The mind spins. *boggle*

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8. Derek Lowe on May 11, 2006 9:33 AM writes...

Whoops, thanks MGeek, I messed up the title. If we were going to Joycify the chemical literature, I guess that JOC could be renamed "Hydrogen, Carbon, and Everything", for starters.

(Not having read all of FW - no one except James Joyce ever has, for my money, which is one of the things wrong with it - that's the best joke I can come up with).

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9. Mike W on May 11, 2006 9:41 AM writes...

Uh, guys, we're talking about a Corey paper and yields.

Perspective, gang.

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10. Jordan on May 11, 2006 10:10 AM writes...

There are groups that are producing natural products like lycopene in E. coli culture. I wonder if anyone has attempted to engineer bacteria to make shikimic acid?

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11. Ed on May 11, 2006 10:46 AM writes...

MolecularGeek, can you check your reference. I'm interested in seeing the article in iambic pentameter that you refer to but, but the reference doesn't seem to be accurate. Thanks.

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12. rhodium on May 11, 2006 11:27 AM writes...

I just got finished teaching the first semester of orgo and what I find interesing about EJ's route is that it summarizes the entire first semester of the course (except we did not do Diels-Alder). E2, electrophilic addition to double bonds, free radical bromination, issues of stereochemistry, inductive effects and conformational analysis, its all there. I can imagine, with a major's course, using it in a case study approach, although some of the regiochemistry would get a little complicated. Also a nice paper to go over if I ever do the third semester orgo course again. FInally, I'm reminded of the Bernoulli quote about Newton's anonymous solution to some math problems: I recognized the lion's paw. If you want a archetypal EJ synthesis, this is it.

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13. MolecularGeek on May 11, 2006 11:50 AM writes...

That was J.Org.Chem 36:1,184-6 (Bunnett and Kearly). Damn typos. Sorry all

Alternately, to bring the topic back around to your entry, you would have to change the title to "Here Comes EJ/Elias" or maybe "Harvard College & Environs" 8)

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14. Jim Hu on May 11, 2006 11:56 AM writes...


Comment #6 above. Given that, it's surprising that star anise is used for the other 2/3. Is star anise that cheap (Wikipedia says there's a shortage driven by tamiflu production)? I still use the same supply I bought years ago for cooking - it's a great seasoning for stewed meats like oxtails - but I have no idea what the market rate is.

Perhaps this is just a snapshot - it seems likely that the use of E. coli or another GMO will increase. It might be interesting to make shikimate in GM plants. One of the problems with large scale bacterial fermentations is that a phage infection can be very, very bad.

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15. Mark on May 11, 2006 2:17 PM writes...

Re the Corey procedure: has anyone validated the yields he reports? This group has been infamous in the past for inflating yields. I would be more worried about this than replacing the CC steps.

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16. Ryan K. on May 11, 2006 6:13 PM writes...

Umm... guys, do I need to remind everyone that this has no process applicibility? Have you seen the sheer volumes of solvent?

Carbon Tet? Methylene Chloride? C'mon, this route has almost zero scale up potential. They use 10mol% of the catalyst in the first step. When you're working on metric ton quantities, this is just not possible.

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17. ss on May 11, 2006 10:56 PM writes...

As a process development chemist, I must say that Corey's route looks eminently scalable after some finetuning.

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18. ross on May 12, 2006 4:51 PM writes...

most of the issues mentioned are relevant. i have a few of my own.
1) it seems that the journal policy for sample quality was not followed for the above mentioned paper. ("A. Sample Quality. For new substances, evidence of the homogeneity the purified sample should be included. Elemental analysis is sufficient. If no analysis was performed, then other evidence (for example, 1H NMR, 13C NMR, hplc, glpc, gel electrophoresis, etc.) should be included as figures in the Supporting Information.") 
2) Also no reaction conditions and yield is not provided for the final transformation ( compd 12 to tamiflu).  If the transformation is already known, then at least the reference where the conditions and the characterization data is reported needs to be cited in the text. 
3) Finally a reference where the characterization of compd. 12 is reported needs to be cited.

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19. Ed Vawter on May 13, 2006 3:03 PM writes...

I agree wih SS (comment 17). I briefly went over both routes on my blog. As a long time process chemist I'd much prefer tweaking the Corey proces to the Shibasaki one.

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A nice review in the May issue of Nature Reviews Microbiology on efforts to engineer phage resistance into industrial (esp. dairy) bacteria. Subscription is probably required; here's an excerpt from their conclusions: The plasticity of phage genom... [Read More]

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