Development and validation of a GC method for a key nemtabrutinib intermediate: Implementation of an in-situ free base sample preparation protocol

A novel synthetic approach to nemtabrutinib (MK-1026) was recently developed in our laboratories. The chemistry goes through a cyrene amine intermediate which does not contain any chromophore. As a result, analysis of this key chiral intermediate by HPLC-UV is not feasible. Initial attempts to devel...

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Published inJournal of pharmaceutical and biomedical analysis Vol. 241; p. 116002
Main Authors Rivera, Nelo R., Zewge, Daniel, Arvary, Rebecca, Lin, Mingxiang, Lohani, Sachin
Format Journal Article
LanguageEnglish
Published England Elsevier B.V 15.04.2024
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Abstract A novel synthetic approach to nemtabrutinib (MK-1026) was recently developed in our laboratories. The chemistry goes through a cyrene amine intermediate which does not contain any chromophore. As a result, analysis of this key chiral intermediate by HPLC-UV is not feasible. Initial attempts to develop a HPLC-CAD method were unfruitful; therefore, a gas chromatography method was developed and optimized to effectively monitor the cyrene amine free base and related impurities generated during the process. As the synthetic process continued to be optimized, the toluene sulfonic acid salt (p-TsOH) of the cyrene amine intermediate was later identified by our process chemistry group to be beneficial in terms of ease of isolation and purity upgrade. However, repeated injections of the cyrene amine p-TsOH intermediate resulted in rapid GC column deterioration. After identifying p-TsOH as the main cause of the issue, we developed a straightforward and practical procedure that involves using a resin to remove the p-TsOH counterion in-situ, which converts cyrene amine salt to its neutral form in sample solutions. This protocol was successfully demonstrated and proven to be an efficient solution. This methodology may find applications with other analytes containing counterions that need to be neutralized prior to analysis. •GC method development and validation for a key amine intermediate for the synthesis of nemtabrutinib.•The presence of p-toluenesulfonic acid (TsOH) counterion led to rapid decline in column performance and peak broadening.•A simple and practical in-situ free base method using a commercially available resin was developed to ensure column robustness.•Demonstrated the utility of this resin treatment protocol with other model amine-TsOH substrates.
AbstractList A novel synthetic approach to nemtabrutinib (MK-1026) was recently developed in our laboratories. The chemistry goes through a cyrene amine intermediate which does not contain any chromophore. As a result, analysis of this key chiral intermediate by HPLC-UV is not feasible. Initial attempts to develop a HPLC-CAD method were unfruitful; therefore, a gas chromatography method was developed and optimized to effectively monitor the cyrene amine free base and related impurities generated during the process. As the synthetic process continued to be optimized, the toluene sulfonic acid salt (p-TsOH) of the cyrene amine intermediate was later identified by our process chemistry group to be beneficial in terms of ease of isolation and purity upgrade. However, repeated injections of the cyrene amine p-TsOH intermediate resulted in rapid GC column deterioration. After identifying p-TsOH as the main cause of the issue, we developed a straightforward and practical procedure that involves using a resin to remove the p-TsOH counterion in-situ, which converts cyrene amine salt to its neutral form in sample solutions. This protocol was successfully demonstrated and proven to be an efficient solution. This methodology may find applications with other analytes containing counterions that need to be neutralized prior to analysis.
A novel synthetic approach to nemtabrutinib (MK-1026) was recently developed in our laboratories. The chemistry goes through a cyrene amine intermediate which does not contain any chromophore. As a result, analysis of this key chiral intermediate by HPLC-UV is not feasible. Initial attempts to develop a HPLC-CAD method were unfruitful; therefore, a gas chromatography method was developed and optimized to effectively monitor the cyrene amine free base and related impurities generated during the process. As the synthetic process continued to be optimized, the toluene sulfonic acid salt (p-TsOH) of the cyrene amine intermediate was later identified by our process chemistry group to be beneficial in terms of ease of isolation and purity upgrade. However, repeated injections of the cyrene amine p-TsOH intermediate resulted in rapid GC column deterioration. After identifying p-TsOH as the main cause of the issue, we developed a straightforward and practical procedure that involves using a resin to remove the p-TsOH counterion in-situ, which converts cyrene amine salt to its neutral form in sample solutions. This protocol was successfully demonstrated and proven to be an efficient solution. This methodology may find applications with other analytes containing counterions that need to be neutralized prior to analysis. •GC method development and validation for a key amine intermediate for the synthesis of nemtabrutinib.•The presence of p-toluenesulfonic acid (TsOH) counterion led to rapid decline in column performance and peak broadening.•A simple and practical in-situ free base method using a commercially available resin was developed to ensure column robustness.•Demonstrated the utility of this resin treatment protocol with other model amine-TsOH substrates.
ArticleNumber 116002
Author Rivera, Nelo R.
Lin, Mingxiang
Zewge, Daniel
Arvary, Rebecca
Lohani, Sachin
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Keywords Ambersep 900 hydroxide form resin
Toluenesulfonic acid salt
Cyrene amine
GC analysis
Nemtabrutinib intermediate
Language English
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  article-title: Charged aerosol detection in pharmaceutical analysis
  publication-title: J. Pharm. Biomed. Anal.
  doi: 10.1016/j.jpba.2012.03.019
  contributor:
    fullname: Almeling
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Snippet A novel synthetic approach to nemtabrutinib (MK-1026) was recently developed in our laboratories. The chemistry goes through a cyrene amine intermediate which...
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StartPage 116002
SubjectTerms Ambersep 900 hydroxide form resin
Cyrene amine
GC analysis
Nemtabrutinib intermediate
Toluenesulfonic acid salt
Title Development and validation of a GC method for a key nemtabrutinib intermediate: Implementation of an in-situ free base sample preparation protocol
URI https://dx.doi.org/10.1016/j.jpba.2024.116002
https://www.ncbi.nlm.nih.gov/pubmed/38309100
https://search.proquest.com/docview/2928853846
Volume 241
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