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Synfacts 2018; 14(03): 0223
DOI: 10.1055/s-0037-1609112
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a PCSK9 Inhibitor

Contributor(s):
Philip Kocienski
Piotrowski DW. * Salan J. * et al. Pfizer, Inc., Groton and Nalas Engineering Services, Inc., Centerbrook, USA
A Scalable Route for the Regio- and Enantioselective Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale Synthesis of a PCSK9 Inhibitor.

Org. Process Res. Dev. 2017;
21: 1990-2000
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Further Information

Publication History

Publication Date:
15 February 2018 (online)

 
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Key words

PCSK9 inhibitor - tetrazole ring formation - organocatalysis - Negishi coupling - asymmetric hemiaminal ester formation

Significance

The target molecule I is a hemiaminal ester prodrug of an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) that is of interest for reducing serum LDL-cholesterol levels. A markworthy step in the synthesis depicted is the three-component dynamic kinetic resolution ­between tetrazole D, acetaldehyde, and isobutyric anhydride catalyzed by the enantiopure DMAP catalyst E to afford hemiaminal ester (S)-F (er = 97:3) in quantitative yield on a multikilogram scale.


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Comment

The tetrazole D was initially generated by reaction of nitrile C with hydrazoic acid generated in situ from sodium azide and ammonium chloride in DMF at >100 °C. This method generates toxic and explosive anhydrous hydrazoic acid (pK a = 4.6). A safer method shown here for the synthesis of D entails reaction of sodium azide (2 equiv) with nitrile C using zinc bromide (0.1 equiv) as a catalyst in isopropanol–water (1:1) at 75 °C. Under these conditions only trace amounts of hydrazoic acid are generated. The yield is 85%.


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