Development of biocatalytic processes for islatravir

Abstract: Despite advances in green chemistry, pharmaceutical manufacturing remains resource and waste intensive due to complex syntheses and stringent quality requirements. Merck’s commitment to environmental sustainability drives Process Chemistry to develop more sustainable active pharmaceutical ingredient (API) manufacturing processes. This presentation will describe the development of a fully biocatalytic route to islatravir (MK8591), recipient of a 2025 Green Chemistry Challenge Award. This innovative biocatalytic process converts a simple five carbon glycerol derivative to islatravir via a linked enzyme cascade, reducing organic solvent usage, protecting group manipulations, step count, and waste generation while improving selectivity and overall efficiency relative to traditional chemocatalytic routes. By integrating multiple engineered enzymes to deliver islatravir with high selectivity and robustness, this work demonstrates that enzyme cascades can simultaneously meet quality and sustainability targets, establishing biocatalysis as a practical strategy for greener, lower waste API manufacturing.