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

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 ch...

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Published inOrganic 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
LanguageEnglish
Published American Chemical Society 17.02.2023
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Abstract 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.
AbstractList 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.
Author Zhang, Si-Wei
Dance, Zachary E. X.
Halsey, Holst M.
Song, Siqing
Lee, Alfred Y.
Ren, Hong
Cohen, Ryan D.
Rivera, Nelo R.
Bu, Xiaodong
Reibarkh, Mikhail
Lohani, Sachin
Chang, Darryl
AuthorAffiliation Chemical Engineering and Development
Small Molecule Analytical Research and Development
Analytical Enabling Capabilities
Process Research and Development
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Issue 2
Keywords gefapixant citrate
process understanding
solubility
sulfonamidation step
protonation
speciation
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Title Gefapixant Citrate (MK-7264) Sulfonamide Step Speciation Study: Investigation into Precipitation–Dissolution Events during Addition of Chlorosulfonic Acid
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