Process Development of Key α‐Hydroxyamide Intermediate WUT‐8 (Multikilogram Scale) for the Synthesis of Anti‐COVID‐19 Drug “Leritrelvir”

ABSTRACT Leritrelvir is a groundbreaking oral antiviral for COVID‐19, distinguished as the first ritonavir‐free, covalent inhibitor targeting the SARS‐CoV‐2 3CL protease. To enable its scalable and economical manufacture, we developed a robust, multikilogram‐scale synthesis of the key chiral α‐hydroxyamide intermediate WUT‐8. Starting from commercially available methyl ( S )‐2‐(Boc‐amino)‐3‐[( S )‐2‐oxopyrrolidin‐3‐yl]propanoate (WUT‐1), an optimized four‐step sequence delivers α‐hydroxyamide intermediate ( WUT‐8 ) in 85.2% overall yield and >99% HPLC purity without a single column chromatographic purification. Key innovations include (1) a solvent‐controlled NaBH 4 reduction that preserves stereochemical integrity, (2) a one‐pot oxidation–isonitrile addition protocol to avoid the isolation of a sensitive aldehyde intermediate, and (3) a recrystallization‐based purification (ethyl acetate/ n ‐heptane) that replaces column chromatography. The process has been successfully scaled to produce WUT‐8 in 82.5 kg batches under cGMP‐ready conditions, demonstrating excellent stability and reproducibility. This work establishes a practical, high‐yielding, and column chromatography‐free route to WUT‐8, providing a reliable industrial supply for the production of leritrelvir.