Green Chemistry Challenge: 2022 Greener Synthetic Pathways Award
Merck & Company, Inc.
The Merck & Company, Inc., team is being recognized for developing a greener way to make LAGEVRIO™ (molnupiravir), an antiviral medicine for the treatment of COVID-19. This new production method has greatly reduced organic waste such as solvents and energy use. Merck reduced waste by improving the efficiency of the reaction and by improving the methods used to isolate and purify the product. Merck has also developed an additional production method that further reduces waste and hazards from the synthesis of molnupiravir.
Summary of Technology:
The ongoing COVID-19 public health emergency has led to the development of antiviral medications. Given the large number of antiviral doses required worldwide, creating medicines sustainably is important for human health and the environment. The Merck & Company, Inc., team created LAGEVRIO™ (molnupiravir), an antiviral medicine for the treatment of COVID-19. At first, molnupiravir was produced using a five-step sequence from uridine. However, this five-step synthesis had low overall yield and generated large quantities of solvent waste. The Merck team subsequently created a novel synthesis process that will reduce the creation of waste with a 1.6-fold improvement in overall yield and led to the invention of a process (aspirational biocatalytic cascade) that enables a three-step synthesis of molnupiravir from abundant chemicals while also providing a new and general platform for green nucleoside synthesis. These achievements came from several key breakthroughs:
- Dynamic crystallization – This innovation avoids an inefficient and wasteful crystallization step, with product selectively crystalizing as it is formed, improving recovery, reducing generation of waste and improving productivity.
- Direct isolation – The team changed the organic base and reaction solvent, which decreased byproduct formation and increased purity. This allowed for water to be added at the end of the reaction to crystalize the product, resulting in substantial reductions in organic solvent use and energy use.
- Development of a second-generation synthesis route utilizing a novel multi-enzyme cascade to directly use uracil and ribose as building blocks, avoiding the inefficient synthesis of uridine from those building blocks.
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