Green Chemistry Challenge: 2020 Greener Reaction Conditions Award
Merck & Co.
A Green Solution to the ProTide Synthesis Problem: Design of a Multifunctional Catalyst That Stereoselectively Assembles ProDrugs
Merck is being recognized for improving the process used to produce certain antiviral drugs used for the treatment of diseases including hepatitis C and HIV. The new process improved manufacturing efficiency and sustainability of one important antiviral by more than 85 percent. This reduces waste and hazards associated with the existing process and results in substantial cost savings.
Summary of Technology:
ProTide drugs were invented to increase cell permeability of nucleoside drugs, which are common antiviral and anticancer drugs. Nucleosides currently represent almost half of all antiviral and anticancer drugs on the market. Development of the ProTide strategy allowed breakthrough developments such as the discovery of sofosbuvir used to treat hepatitis C. However, ProTides are chiral molecules that require stereoselective and chemoselective installation of a 5’-aryloxyphosphoramidate moiety. Existing syntheses are inefficient due to poor chemoselectivity and require chiral reagents and many reaction steps, including the use of expensive, hazardous, and wasteful reagents.
Merck has developed a catalyst that can be used to synthesize uprifosbuvir with very high purity in just two reaction steps. The initial catalyst identification used high-throughput experimentation and optimization to identify an effective catalyst for stereoselective direct coupling of nucleosides to chlorophosphoramidates. Kinetics of the catalyzed reaction exhibited an unusual second-order dependence on catalyst, indicating involvement of two catalyst molecules and leading to the development of a dimeric catalyst. The dimeric catalyst itself can be synthesized with high yield and low PMI, contributing less than 15 percent of PMI to the overall synthetic process. Further, dichloromethane was able to be replaced in this process with 1,3-dioxolane. The catalyst was tested in syntheses of other ProTides including fluorouridine and azidothymidine and found to be effective in most cases with improved selectivity, demonstrating potential to green the syntheses of these and other ProTides.
Merck has used this new synthetic method to produce more than 150 kilograms of uprifosbuvir for clinical trials and anticipates that this method will be used in other ProTide syntheses. Merck’s life cycle analysis indicated that the new process resulted in greater than 75 percent improvements in PMI, energy use, water depletion, and other metrics compared to the first generation synthesis pathway.