29/6/2021 Green Chemistry Challenge: 2021 Greener Synthetic Pathways Award | Green Chemistry | US EPA

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Green Chemistry Challenge: 2021 Greener Synthetic Pathways Award

Merck & Co., Inc.
Gefapixant Citrate
Merck’s Process Research and Development Team developed a green and sustainable commercial manufacturing process for gefapixant citrate,
an investigational medicine for refractory and unexplained chronic cough. This innovative process reduces costs and waste, potentially
facilitating worldwide access.

Summary of Technology:

Chronic cough is a serious and often underdiagnosed condition that has been estimated to affect as many as 5–10 percent of adults globally.
Gefapixant is an antagonist of the purinergic receptor P2X3. In Phase 3 trials, adult patients treated with gefapixant 45 milligrams twice daily
demonstrated a statistically significant reduction in 24-hour cough frequency versus placebo. The initial supply route to produce gefapixant
involved many steps and was characterized by a high process mass intensity (PMI). PMI provides a measure of process efficiency for
biopharmaceutical production. Although the initial PMI of 366 was suitable for commercial manufacturing – the Merck Team thought they
could do better.

Merck applied green chemistry techniques to synthesize gefapixant citrate, ultimately developing a green and sustainable commercial
manufacturing process with a PMI of 88 from commodity raw materials, a greater than four-fold improvement over the initial process. The key
innovations in this process are: (1) the implementation of a highly efficient two-step methoxyphenol synthesis; (2) an innovative
diaminopyrimidine synthesis using a hybrid flow-batch process; (3) a simplified direct sulfonamide synthesis; and (4) a novel and robust salt
metathesis approach to consistently deliver the correct salt form with high productivity. Merck also achieved a significantly higher yield and a
six-fold reduction in raw material costs. Furthermore, the alkylation step, that involved highly hazardous chemicals, has been replaced,
rendering this a safer and more robust commercial process. Merck also implemented energy-saving processes that reduced carbon dioxide and
carbon monoxide emissions.

Key to the sustainable process was the development of a SMART PMI tool which sets aspirational PMI targets to continuously spur innovation
in new synthetic methods. This tool helps Merck’s scientists find the most direct and sustainable route from commodity chemicals to active
pharmaceutical ingredients. The approach combining both green chemistry principles and SMART PMI demonstrated by Merck has potentially

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29/6/2021 Green Chemistry Challenge: 2021 Greener Synthetic Pathways Award | Green Chemistry | US EPA

wide-ranging application for the manufacture of pharmaceuticals.

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LAST UPDATED ON JUNE 8, 2021

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