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

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. [Display omitted] •Significant side product identified during process development of GDC-0326.•Mass Spectrometry and NMR were not sufficient to determine the structure.•Raman analysis and eventually single crystal x-ray were necessary to definitively solve the structure and resolve the pathway to formation of the compound.