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February 28, 2013
The Industrial Diels Alder, Revisited in Detail
Posted by Derek
Last year I mentioned the "good ol' Diels-Alder reaction", and talked about how it doesn't get used as much in drug discovery and industrial chemistry as one might think.
Now Stefan Abele from Actelion (in Switzerland) sends along this new paper, which will tell you pretty much all you need to know about the reaction's industrial side. The scarcity of D-A chemistry on scale that I'd noticed was no illusion (links below added by me):
According to a survey by Dugger et al. in 2005 of the type of reaction scaled in a research facility at Pfizer, and an analysis of the reactions used for the preparation of drug candidate molecules by Carey et al. in 2006, the DA reaction falls into the “miscellaneous” category that accounts for only 5 to 11 % of C-C bond-forming reactions performed under Good Manufacturing Practice. This observation mirrors the finding that C-C bond-forming reactions account for 11.5% of the entire reaction repertoire used by medicinal chemists in the pursuit of drug candidates. In this group, palladium-catalyzed reactions represent about 60% of the occurrences, while the “other” category, into which the DA reaction falls, represents only 1.8% of the total number of reactions. Careful examination of the top 200 pharmaceutical products by US retail sales in 2010 revealed that only one marketed drug, namely Buprenorphine, is produced industrially by using the DA reaction. Two other drugs were identified in the top 200 generic drugs of US retail sales in 2008: Calcitriol and its precursor Calciferol. Since 2002, Liu and co-workers have been compiling the new drugs introduced each year to the market. From 2002 to 2010, 174 new chemical entities were reported. Among them, two examples (Varenicline from Pfizer in 2006 and Peramivir by Shionogi in 2010) have been explicitly manufactured through a DA reaction. Similarly, and not surprisingly, our consultation with a large corpus of peers, colleagues, and experts in industry and academia worldwide revealed that the knowledge of such examples of the DA reaction run on a large scale is scarce, except perhaps in the field of fragrance chemistry.
But pretty much every reaction that has been run on large scale is in this review, so if you're leaning that way, this is the place to go. It doesn't shy away from the potential problems (chief among them being potential polymerization of one or both of the starting materials, which would really ruin your afternoon). But it's a powerful enough reaction that it really would seem to have more use than it gets.
Comments (11)
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1. David Formerly Known as a Chemist on February 28, 2013 10:25 AM writes...
It is indeed a powerful reaction, but pretty limited in the scope of what you can make with it. I'd guess that's why it's not used all that often on industrial scale
Permalink to Comment2. CMCguy on February 28, 2013 11:03 AM writes...
"chief among them being potential polymerization of one or both of the starting materials, which would really ruin your afternoon" hits the nail on the head as could lose a whole plant, storage tank or freight cars plus deal with environmental clean up issues. Many years ago I worked for an oil company that made petrochemical polymers and there were whispered rumors of a secret burial ground for truck and train tanker of styrene that polymerized prematurely. Maybe just a take off the Elephant Graveyards stories but I do recall a few closed door meetings and nervous people associated with the gossip.
Permalink to Comment3. Chemjobber on February 28, 2013 11:14 AM writes...
Doesn't Milkshake have a story about a reactor graveyard, with one of them being full of polymerized starting material? (Don't think it was Diels-Alder SM, though.)
Permalink to Comment4. Cosmo Kramer on February 28, 2013 11:30 AM writes...
Industrial use of the D-A reaction might be best exemplified--historically at least--by production of the now-banned insecticides Dieldrin and Aldrin.
Permalink to Comment5. Hap on February 28, 2013 1:02 PM writes...
No - I think Jose had a comment about a reaction mixture polymerized in a reactor (and dumped in the back with the connectors cut) in the "How Not To Do It: Ruining Stuff" (aka The Expensive Labware Destroyed Stupidly Edition).
Permalink to Comment6. Chemjobber on February 28, 2013 1:40 PM writes...
#5 -- that's the one!
Permalink to Comment7. a. nonymaus on February 28, 2013 1:48 PM writes...
One thing in favour of the D-A reaction is that it has a significant negative volume of activation. This means that there are reactions of unactivated dienes with weak dienophiles or other low-reactivity pairs (e.g. the cycloalkene / isopyrazole inverse electron-demand reaction) that will go at 10 kbar or so. I had wanted to run one of those in grad school, but my adviser balked at the experimental protocol that began with "To construct the press frame for the reactor, take a 5' x 3' x 1' plate of steel..." On the other hand, these pressures are in the range that industrial processes such as ethylene polymerization are done at.
Permalink to Comment8. Bruce Hamilton on February 28, 2013 2:36 PM writes...
A few decades ago I worked for a company that cargo skimmed styrene and VAM ( vinyl acetate monomer ) from passing chemical tankers into 50 tonne overhead mild steel tanks.
One of the tanks PCV ( positive closing and venting ) valves failed and routine dosing of inhibitor was insufficient due to the increasing volume of internal superficial fine rust.
The tanks started to warm, so the viscous products were quickly dumped into old 200 litre drums and those were buried in a new trench on site.
For the following years the burial site was clearly identified by the large number of seagulls roosting on the warm ground.
Permalink to Comment9. barry on February 28, 2013 2:45 PM writes...
in this context, mustn't forget E.J. Corey's heteroDielsAlder route to Tamiflu (which skewered Roche's whine that they were limited by starting materials).
Permalink to CommentI'd give you the link, but that seems to consign the post to the "spam" folder.
10. Hap on February 28, 2013 3:04 PM writes...
My first synthesis class spent a lot of time going through the various structures that can be generated through Diels-Alder reactions, in most cases through multi-reaction sequences (for example, DA/ozonolysis/aldol condensation to get acetylcyclopentenes). With the asymmetric versions and with access to dienes from enyne RCM, you should be able to access a lot of complexity reasonably quickly.
Having substrates polymerize would have to put a damper on the parade, though.
Permalink to Comment11. milkshake on February 28, 2013 4:49 PM writes...
the only bad polymerization story I had was from a Sokolovo acrylate plant built by Japanese in Czechoslovakia in 80s that suffered repeated shutdowns during the first few years due to problems with stabilizer addition, the acrylate ester polymerization inside the distillation columns was a major nuisance. Those multi-story high columns had to taken apart at the congealed sticky stinky goop removed by hand. There was also a shutdown-connected incident with missing used platinum mesh catalyst that some old groundkeeper guy mistook for scrap metal and took home to repair the rabbit hutches and fence around his vegetable garden
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