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February 28, 2013
The Industrial Diels Alder, Revisited in Detail
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.
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