The original synthesis route reported by Pfizer is linear and comprises 11 steps with 28% overall yield. Whereas the new synthesis route has 6 steps that are convergent, which means some steps can be performed in parallel and therefore this is more time efficient. Not only is the overall yield for the new convergent route higher (46%), the method is also scalable!
Furthermore, the linear route uses more protecting groups, necessitating additional steps for their instalment and removal. Once removed, these protecting groups are often not recycled, and thus become waste. In addition, the linear route relies heavily on peptide coupling reactions, requiring stoichiometric coupling reagents and bases, leading to poor atom economy and considerable waste production. In the convergent route, most steps proceed with full conversion, thereby reducing the use of intermediate purifications. Additionally, the route also avoids using transition metals and peptide coupling reagents, resulting in an efficient and atom-economic process.
A more efficient synthesis route for Covid-19 Nirmatrelvir
6 February 2024
Pfizer’s covid drug nirmatrelvir inhibits SARS-CoV-2 main protease. To ensure global access to the drug, we need a more efficient synthetic route. Here, the research team at VU, led by Prof. Eelco Ruijter, have devised a more efficient route for the synthesis of nirmatrelvir.