A Scalable Route for the Regio- and Enantioselective
Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale
Synthesis of a PCSK9 Inhibitor
posted on 2017-11-08, 00:00authored byAnne Akin, Mark T. Barrila, Thomas A. Brandt, Anne-Marie R. Dechert-Schmitt, Pascal Dube, David D. Ford, Adam S. Kamlet, Chris Limberakis, Andrew Pearsall, David W. Piotrowski, Brian Quinn, Sarah Rothstein, Jerry Salan, Liuqing Wei, Jun Xiao
The
synthesis of multigram quantities of small molecule PCSK9 inhibitor
(R,S)-3 is described.
The route features a safe, multikilogram method to prepare 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (10). A three-component dynamic kinetic resolution between tetrazole 10, acetaldehyde, and isobutyric anhydride was catalyzed by
a chiral DMAP catalyst to afford enantiomerically enriched hemiaminal
ester (S)-12 on multikilogram scale.
Magnesiation, transmetalation, and Negishi coupling provided access
to Boc-intermediate (R,S)-13, which was deprotected to provide (R,S)-3 in multigram quantities.