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Plavix In A Single Step

Copper-catalyzed alpha-amination of carbonyls generates pharmaceutical agents in one step

by Bethany Halford
October 21, 2013 | A version of this story appeared in Volume 91, Issue 42

Several high-profile pharmaceuticals are carbonyl compounds with an amine group dangling at the carbon adjacent to C=O, or the α position. The blood thinners Plavix (clopidogrel bisulfate) and Effient (prasugrel), as well as the appetite suppressant amfepramone, all have this motif. Now, a team at Princeton University, led by David W. C. MacMillan, has come up with a general one-step method to attach amines to the α carbon in ketones, esters, and aldehydes (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja4096472). The trick, the team reports, is to use a copper(II) bromide catalyst. In the presence of oxygen, this catalyst adds a bromide to the α position in situ, and the resulting α-bromo carbonyl then undergoes nucelophilic attack by the amine. They used the reaction to synthesize racemic clopidogrel in one step from commercially available starting materials (shown). Previously patented syntheses of this compound require at least three steps. Because only one enantiomer of the compound is active as a blood thinner, the current asymmetric syntheses take five steps, including separation of isomeric intermediates. MacMillan’s group is trying to create an asymmetric version of the amination reaction.


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