Veeramani et al.
Nirmatrelvir is the active main protease inhibitor of PAXLOVID, an oral antiviral candidate manufactured by Pfizer. Oral administration of Nirmatrelvir tablets, in combination with Ritonavir tablets, has been shown to irreversibly inhibit SARS-CoV-2 viral protease. It has been used in the treatment of mild to moderate cases of COVID-19 and shows promising in vitro activity against the SARS-CoV-2 Omicron variant. However, Nirmatrelvir could potentially be commercially unviable due to challenges in scalability.
Veeramani et al. have demonstrated an improved process for the final step in the synthesis of Nirmatrelvir using continuous flow chemistry. The conventional synthesis of the molecule is limited by the boiling points of the required solvents and prolonged reaction times. Furthermore, high levels of impurities are formed due to epimerization, and expensive reagents such as the Burgess reagent are necessary. However, flow chemistry techniques can circumvent some of these challenges. The pressure induced by pumping reagents through channels overcomes the limitation of the boiling points of the solvents. Formation of by-products is also minimised by controlled mixing. Furthermore, flow reactors can facilitate enhanced heat and mass transfer while maintaining inert conditions due to the absence of headspace. Combined, these factors result in a scalable and highly time-efficient technique.
Experiments were performed on an R-Series flow chemistry platform with small reactor volumes (2 and 10 ml tubular reactors) and using one V-3 Peristaltic pumps as variable BPR. Tetrahydrofuran was used as a solvent throughout all experimental trials. The authors optimized the temperature, residence time and concentration of reagents to maximise product purity and yield. The intermediate formed during the synthesis was optionally purified by column chromatography before being subjected to flow. The isolated yields of product obtained were typically 60 – 70 %, with an isolated peak purity of >90 %, as determined by HPLC.
This improved flow chemistry process for the final step of Nirmatrelvir synthesis using Vapourtec technology is shown to be scalable, time-efficient and clean. The protocol does not require reagents that are commercially scarce, or any reagents that require special handling or storage conditions. Veeramani et al. demonstrate a commercially viable continuous flow strategy to manufacture a potentially life-saving anti-COVID-19 molecule.
Further developments of the flow chemistry strategy are in progress. A telescoped multi-step continuous flow synthesis for the formation of the amide intermediate from its individual components, followed by conversion to the nitrile compound, is underway. Furthermore, the high-throughput nature of the protocol will be demonstrated by translating the synthesis through higher versions of pilot-plant and production-level scalable reactors.
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