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Green Chemistry Challenge: 2017 Greener Synthetic Pathways Award

Merck & Co., Inc.


Letermovir: A Case Study in State-of-the-Art Approaches to Sustainable Commercial Manufacturing Processes in the Pharmaceutical Industry

Merck & Co., Inc., Rahway, New Jersey,  is being recognized for successfully applying green chemistry design principles to Letermovir, an antiviral drug candidate, that is currently in phase III clinical trials. The improvements to the way the drug is made, including use of a better chemical catalyst, increases the overall yield by more than 60%, reduces raw material costs by 93%, and reduces water usage by 90%.

Summary of Technology: 

Letermovir is an antiviral drug, currently at the end of phase III clinical trials, for the treatment of cytomegalovirus (CMV) infections. CMV is widely spread in the human population and can cause severe, life-threatening infections in immunocompromised patients. Letermovir has been granted Fast Track Status by the FDA and Orphan Product Designation by the European Medicines Agency for the prevention of CMV viremia in at-risk populations. The chemical process employed to supply most of the phase III clinical trials was based on a late-stage chiral resolution to obtain the desired steroisomer in the penultimate intermediate (QP-DTTA). An evaluation of this process revealed several areas for improvement, including a low overall yield of 10% due in part to a late stage resolution to access the sterogenic center, the use of nine different solvents, and high palladium loading in a C-H activated Heck reaction. There was also little opportunity to recycle solvents or reagents.

An early focus for improvement was to increase the efficiency of installing the single asymmetric quinazoline. Six novel asymmetric reactions were proposed to introduce the stereogenic center with minimal use of protecting groups, preventing waste on the molecular level. High-throughput reaction discovery tools facilitated a rapid investigation of these six asymmetric transformations with hundreds of potential catalysts and reaction conditions. High-throughput technology allowed for thousands of different reaction conditions to be screened and analyzed in a fraction of the time normally needed and were carried out at the sub-milligram scale, reducing the amount of solvent typically required for this type of investigation by at least a factor of 10. Three out of the four successful routes required the use of non-sustainable and costly transition metal catalysts (e.g. Pd, Ru, Rh) as well as expensive chiral ligands. As such, Merck focused its efforts on a novel aza-Michael approach with an aspirational goal to develop an economical, stable and fully recyclable organocatalyst to achieve this transformation in an asymmetric fashion. The new hydrogen bonding catalysts were easily recovered and re-used.

This new synthesis reduces the PMI by 73%, decreases raw material costs by 93%, and increases the overall yield by more than 60%. Merck estimates that this optimized process will result in the elimination of more than 15,000 MT of waste over the lifetime of Letermovir. Life-cycle assessment shows that the new process is expected to decrease the carbon footprint and water usage of the product by 89% and 90%, respectively.

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