A Scalable Route for the Regio- and Enantioselective Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale Synthesis of a PCSK9 Inhibitor

Abstract

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.

The Evolution of High-Throughput Experimentation in Pharmaceutical Development and Perspectives on the Future

“…A critical discovery by our Medicinal Chemistry group was the need to employ a very mild base in this coupling to avoid significant levels of prodrug cleavage byproduct 8 . CsF was identified as the preferred base to facilitate the Suzuki–Miyaura coupling while minimizing carbonate prodrug cleavage to the unprotected tetrazole, as has been previously disclosed in a Pfizer publication on a related compound in this series …”

Overcoming the Challenges of Making a Single Enantiomer N-1 Substituted Tetrazole Prodrug Using a Tin-Mediated Alkylation and Enzymatic Resolution

“…However, discovery of a small molecule PCSK9 inhibitor with the possibility to deliver it by the more convenient oral route has lagged behind the mAbs. Previous disclosures from the Pfizer laboratories have described small molecule protein translation inhibitors of PCSK9 such as PF-06446846 ( 1 ), , PF-07556769 ( 2 ), , and PF-06815345 ( 3 ; Figure ). Since PCSK9 is synthesized primarily in the liver, the mode-of-action of the aforementioned inhibitors makes them well-suited for application of a tissue-targeted delivery approach.…”

“…For target 3 , this required the bulk manufacture of prodrug modified tetrazole 6 . A safe process for the manufacture of iodopyrazole 7 has been developed, allowing access to multikilogram quanitites . This material, while highly energetic (DSC onset of 201 °C, 1020 J/g), is not friction or shock sensitive, allowing for safe handling and shipment under standard conditions.…”

“…For the previous PCSK9 lead compound ( 2 , Figure ), the key coupling between the requisite bromobenzamide 4 could be accomplished via a Negishi coupling of the corresponding iodopyrazole and bromobenzamide 4 . This same approach was evaluated using iodopyrazole 6 .…”

“…Since all attempts at a Negishi coupling had failed, the Suzuki conditions identified by medicinal chemistry for analog preparation were explored, requiring pinacol boronate 5 (Scheme ). Amination of 2-bromo-3-chloropyridine ( 21 ) with commercially available ( R )-1-Boc-3-aminopiperidine ( 22 ) via Buchwald–Hartwig amination followed by acylation with 5-fluoro-3-bromobenzoyl chloride ( 24 ) furnished the bromobenzamide 4 . This was converted to pinacol boronate 5 using standard conditions.…”