Development of the Commercial Manufacturing Process for Xanomeline Tartrate, an Active Pharmaceutical Ingredient in KarXT

Abstract Development of the commercial manufacturing strategy and process employed for xanomeline tartrate (KTX-001), a key active pharmaceutical ingredient (API) in KarXT, is described. The development process involved identifying efficient processes for key bond-forming steps, including the conversion of regulatory starting material nicotinaldehyde (1) to stage 1 regulatory intermediate chlorothiadiazole 2, nucleophilic aromatic displacement of the chlorine atom within 2 with 1-hexanol followed by methylation to generate stage 2 regulatory intermediate pyridinium 4, and selective partial reduction of the pyridine ring to produce the API freebase, which after tartrate salt formation gave access to stage 3 regulatory intermediate crude xanomeline tartrate (crude KTX-001). A recrystallization process was developed to provide the drug substance xanomeline tartrate (KTX-001) in an overall yield of 35% from nicotinaldehyde (1) with HPLC purity of >99.0% on scales of 500+ kilograms per batch, suitable for reliable supply of this commercial drug substance.