Gefapixant Citrate (MK-7264) Sulfonamide Step Speciation Study: Investigation into Precipitation–Dissolution Events during Addition of Chlorosulfonic Acid

• Published in: Organic process research & development Vol. 27; no. 2; pp. 286 - 294
• Main Authors: Rivera, Nelo R., Cohen, Ryan D., Zhang, Si-Wei, Dance, Zachary E. X., Halsey, Holst M., Song, Siqing, Bu, Xiaodong, Reibarkh, Mikhail, Ren, Hong, Lee, Alfred Y., Chang, Darryl, Lohani, Sachin
• Format: Journal Article
• Language: English
• Published: American Chemical Society 17.02.2023
• Subjects: gefapixant citrate; process understanding; solubility; sulfonamidation step; protonation; speciation
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.2c00313

Sulfonamidation is the pre-penultimate step in the commercial synthesis of gefapixant citrate. Several stress studies were performed during process characterization of this step to ensure process robustness and to mitigate potential upset scenarios. One parameter explored was the slow addition of chlorosulfonic acid (CSA) to form the sulfonic acid intermediate. During the extended addition, an unexpected series of precipitation–dissolution events were observed. To better understand these events and accommodate a CSA tank switch during the reaction, a detailed investigation using a variety of analytical techniques was performed, which revealed the formation of various protonated species of both the diaminopyrimidine starting material and sulfonic acid intermediate with stark differences in their solubility properties. This behavior explained the changes in solubility observed in the reaction system during CSA addition. This detailed speciation study supported the CSA addition procedure that was ultimately adopted for commercial process to ensure operation robustness.