Gefapixant Citrate (MK-7264): Development of a Green Manufacturing Process

A new eco-friendly manufacturing process for Gefapixant citrate, a P2X3 receptor antagonist under evaluation for chronic cough, has been established. This method features low process mass intensity (PMI), a concise synthetic sequence, high yields, minimal environmental impact, and reduced active pharmaceutical ingredient (API) costs. Key advancements include an efficient two-step methoxyphenol synthesis and an innovative flow-based pyrimidine synthesis, along with a simplified sulfonamide synthesis. Additionally, a novel salt metathesis technique is utilized to reliably produce the correct API salt form with high purity.