Challenges in the structure determination of a dimeric impurity found during development of GDC-0326

Autor:	Nathaniel L, Segraves, Stefan G, Koenig, Jeffrey, Stults, Shengli, Ma, Antonio G, DiPasquale, Sarah J, Robinson, David J, Russell
Rok vydání:	2022
Předmět:	Magnetic Resonance Spectroscopy Clinical Biochemistry Drug Discovery Imidazoles Benzoxepins Pharmaceutical Science Drug Contamination Mass Spectrometry Spectroscopy Analytical Chemistry
Zdroj:	Journal of Pharmaceutical and Biomedical Analysis. 213:114627
ISSN:	0731-7085
Popis:	While developing a synthetic route for GDC-0326, a PI3Kα selective inhibitor, a side product was identified which was adversely impacting process chemistry development. To aid in optimization of a viable synthetic pathway for the drug, it was decided to characterize this impurity. Initial efforts using typical high-resolution mass spectrometry data coupled with NMR analysis were unable to unambiguously identify the structure. The NMR analysis was hampered by a severe lack of protons in the core of the structure. While efforts were being made to produce suitable crystals for definitive x-ray analysis, Raman analysis was undertaken. The vibrational data were compared to DFT calculations for the two most likely structures. This data, along with chemical reasoning, eventually led to successful prediction of structure 2, which was ultimately confirmed by single crystal x-ray diffractometry data.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2ff1df6d23ebe38c4f30984d149abcbe https://doi.org/10.1016/j.jpba.2022.114627 Zobrazit plný text záznamu Full Text from ScienceDirect