Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 1: Introduction and Process Overview

Abstract

A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. The newly developed commercial process features low process mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, and significantly reduced API costs. The key innovations are the implementation of a highly efficient two-step methoxyphenol synthesis, an innovative pyrimidine synthesis in flow, a simplified sulfonamide synthesis, and a novel salt metathesis approach to consistently deliver the correct active pharmaceutical ingredient (API) salt form in high purity.

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 3: Development of a One-Pot Formylation–Cyclization Sequence to the Diaminopyrimidine Core

“…The 5:1 NMP/toluene conditions provided end of reaction (EOR) stability for >72 h and could be safely scaled up to deliver hundreds of kilograms of compound 2 without experiencing any safety-related issues. This discovery allowed us to telescope the methoxyphenol stream isolated from the upstream methoxylation reaction directly into the alkylation reaction without the need for extensive solvent switching. An aqueous workup provided compound 2 as a solution in toluene that could be distilled to the appropriate volume for use in the pyrimidine-forming reaction.…”

Understanding flow chemistry for the production of active pharmaceutical ingredients

“…Recent developments in API syntheses also include the flow synthesis of gefapixant citrate (MK-7264) ( Ren et al., 2020 ), ticagrelor ( Hugentobler et al., 2017 ), darunavir ( Leão et al., 2015 ), ciprofloxacin ( Armstrong et al., 2021 ), rufinamide ( Borukhova et al., 2016a ), among others.…”

A Holistic Strategy for Cyanide Control and Safety for Pharmaceutical Manufacturing

“…The active pharmaceutical ingredient takes the form of a citrate salt synthesized via a green, sustainable process. 1 The manufacturing route employs the reagent chloroacetonitrile (ClCH 2 CN), excess of which is prone to cyanide formation upon hydrolysis. In order to best mitigate any cyanide risk, we developed a manufacturing route with a demonstrated ability to control the cyanide levels in the process and waste streams.…”

“…Gefapixant citrate is a small-molecule pharmaceutical that acts as a P2X3 receptor antagonist for treatment of chronic cough. The active pharmaceutical ingredient takes the form of a citrate salt synthesized via a green, sustainable process . The manufacturing route employs the reagent chloroacetonitrile (ClCH 2 CN), excess of which is prone to cyanide formation upon hydrolysis.…”