The COVID-19 pandemic has underscored the urgent need for effective treatments. Paxlovid, a combination of nirmatrelvir and ritonavir, has proven highly effective in reducing severe COVID-19. However, the large-scale production of nirmatrelvir requires sustainable and cost-effective synthesis methods. Existing routes, while improved, still have opportunities for environmental and economic optimization. This research, in collaboration with the Bill and Melinda Gates Foundation, focuses on developing a scalable, environmentally friendly synthesis of nirmatrelvir, emphasizing cost-effectiveness and minimizing chiral center epimerization during peptide bond formation. The strategy employs a convergent route to leverage the benefits of scale and limit palladium residue in the final product.

The literature review section highlights the existing methods for nirmatrelvir synthesis, including Pfizer's original and improved routes. It points out limitations in these methods, such as the use of expensive and environmentally unfriendly reagents (e.g., HATU, EDC, Burgess reagent, chlorinated solvents) and low overall yields. The review emphasizes the need for a more sustainable and efficient alternative. Several other antiviral drugs developed to combat SARS-CoV-2 are mentioned, highlighting the importance and urgency of finding efficient synthetic routes for effective antiviral treatments.

The authors developed a 7-step synthesis of nirmatrelvir. Key innovations include: 1. **One-pot thioester/amide bond formation:** This utilizes di-2-pyridylthiocarbonate (DPTDC) as a coupling reagent, avoiding traditional reagents and facilitating easy removal of byproducts. 2. **Three-step, one-pot sequence to intermediate 6:** This involves thioesterification, amide bond formation, and hydrolysis, using EtOAc as a solvent and minimizing waste. 3. **Two-step, one-pot sequence to intermediate 9:** This utilizes a convergent approach to avoid the Burgess reagent and chlorinated solvents in amide dehydration. 4. **Two-step, one-pot sequence to nirmatrelvir:** This includes N-Boc deprotection with HCl (avoiding TFA due to epimerization concerns) and trifluoroacetylation. 5. **Synthesis of intermediate 8:** This involves a palladium-catalyzed amide exchange for dehydration, avoiding the Burgess reagent and chlorinated solvents. 6. **N-Boc deprotection of 13:** This carefully controls water content to minimize hydrolysis during the deprotection step. The methodology meticulously describes each step, including reaction conditions, yields, and purification methods. Detailed experimental procedures are provided in the Supplementary Information. The authors used techniques like in-flask extractions with minimal amounts of greener solvents, streamlining workup procedures and reducing waste.

The researchers successfully synthesized nirmatrelvir in seven steps with a 70% overall yield, significantly higher than Pfizer's reported 48%. The new route avoids traditional peptide coupling reagents and employs a recyclable solvent (EtOAc), reducing waste and cost. A novel amide dehydration method avoids the Burgess reagent and chlorinated solvents, further enhancing sustainability. DFT calculations revealed two rotamers of nirmatrelvir with an unexpectedly high rotational barrier. A comparison with Pfizer's improved route (data from a patent) showed a superior yield (70% vs 7.6%) and a dramatically reduced E-factor (120 vs 214, excluding aqueous waste; 54 vs 108, including aqueous waste), indicating a much smaller environmental footprint. The optimized synthesis provides a cost-effective and environmentally responsible pathway for large-scale nirmatrelvir production. The detailed characterization of intermediates and the final product confirmed the purity and structure of the synthesized nirmatrelvir.

The findings address the critical need for a sustainable and efficient synthesis of nirmatrelvir, a crucial component of Paxlovid. The superior yield and significantly reduced environmental impact (lower E-factor) of the new method compared to Pfizer's reported route demonstrates a significant advancement in the field. The avoidance of traditional coupling reagents and hazardous solvents contributes to a greener and more economical process, enhancing global access to this essential antiviral drug. The detailed mechanistic understanding gained through DFT calculations adds valuable insight into the properties of nirmatrelvir and guides future optimization efforts.

This study presents a highly efficient and sustainable 7-step synthesis of nirmatrelvir, achieving a 70% yield and significantly reducing the environmental impact compared to existing methods. The use of green chemistry principles and innovative reaction strategies makes this route suitable for large-scale production, improving global access to Paxlovid. Future research could explore further optimization of individual steps, investigation of alternative solvents, and scale-up studies to validate the economic viability of the method.

While the study demonstrates a significant improvement in the synthesis of nirmatrelvir, certain limitations exist. The study primarily focuses on the laboratory-scale synthesis, and further research is required to fully optimize and validate the process for industrial-scale production. The DFT calculations are performed in silico and may not perfectly represent the conditions in a real chemical reaction. The analysis of rotamers relies on NMR and DFT, and further experimental techniques could strengthen the characterization.