Isolation and structure elucidation of unexpected in-process impurities during tetrazole ring formation of an investigational drug substance
Copyright © 2016 John Wiley & Sons, Ltd.
| Veröffentlicht in: | Magnetic resonance in chemistry : MRC. - 1985. - 55(2017), 4 vom: 04. Apr., Seite 253-262 |
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| 1. Verfasser: | |
| Weitere Verfasser: | , , , , , , , |
| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2017
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| Zugriff auf das übergeordnete Werk: | Magnetic resonance in chemistry : MRC |
| Schlagworte: | Journal Article 13C NMR 15N NMR 1H NMR HRMS NMR Schmidt-like reaction mechanism drug development in-process impurities investigational drug mehr... |
| Zusammenfassung: | Copyright © 2016 John Wiley & Sons, Ltd. During the formation of a tetrazole ring on an investigational drug, two in-process impurities were detected and analyzed by LC-MS, which suggested that both impurities were drug-related with the same mass-to-charge ratio. To understand and control their formation, both impurities were isolated from the mother liquor of the reaction using a multi-step isolation procedure to obtain a sufficient amount for high-resolution mass spectrometry (HRMS) and NMR structural analysis. HRMS suggested a protonated mass of 577.32 Da for both impurities; however, MS fragmentation patterns provided limited information on their structures. NMR analysis indicated the presence on an additional NH functional group in both isolates with similar spatial and bond correlations to one of the dimethylcarbamoyl moieties and the corresponding aromatic ring. A phenyldimethylcarbamoylamino moiety was supported by the NMR and HRMS data and could be explained based on the 'Schmidt-like' reaction mechanism, which was an unexpected reaction pathway. Because the reaction conditions were fixed because of safety concerns, the crystallization protocol was redesigned to reduce the levels of these impurities significantly. Copyright © 2016 John Wiley & Sons, Ltd |
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| Beschreibung: | Date Completed 05.04.2018 Date Revised 05.04.2018 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1097-458X |
| DOI: | 10.1002/mrc.4413 |