Prediction and De-Risking of an Unusual API:Epimer Cocrystal in the Commercial Synthesis of Belzutifan

This article reports a rare example of the crystallization of a cocrystal of an organic molecule with its epimer. In this case, belzutifan, a novel treatment for von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC), crystallizes as a 1:1 cocrystal with one of its epimers (inversion of stereochemistry at the hydroxyl position). This observation is of particular importance to controlling the purity of the API in the commercial manufacturing process. After the discovery of this cocrystal, the crystalline structure was determined through a combination of crystal structure prediction (CSP) and powder X-ray diffraction followed by single-crystal X-ray diffraction structure determination. The only lattice interaction that exists between the two epimers is a π–π stacking arrangement created by the alternating fluorobenzonitrile aryl groups of each epimer. The formation of this complex, while unexpected, is a reminder that unexplored crystal forms can pose a significant risk to the robustness of chemical manufacturing processes. At present, the cost of leveraging CSP tools across the entirety of a synthetic process is significant. However, discoveries such as the belzutifan:hydroxy epimer cocrystal highlight why current investments in in silico tools are needed and justify expanding their use to de-risk commercial synthetic routes to expedite the development of life-saving medications.