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1. Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 4─Applications of Process Analytical Technology in Heterogeneous Biocatalytic Hydroxylation

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   Contributor(s):: Qin, Yangzhong, Mattern, Keith A., Zhang, Victoria, Abe, Kotoe, Kim, Jungchul, Zheng, Michelle, Gangam, Rekha, Kalinin, Alexei, Kolev, Joshua N., Axnanda, Stephanus, Dance, Zachary E. X., Ayesa, Umme, Ji, Yining, Grosser, Shane T., Appiah-Amponsah, Emmanuel, McMullen, Jonathan P.

   Belzutifan has been approved recently by the U.S. Food and Drug Administration (FDA) for treating patients with certain types of Von Hippel-Lindau (VHL) disease-associated tumors. Although a commercial synthetic process has been established to make belzutifan, a further optimized process with...

2. Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination

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   Contributor(s):: Bottecchia, Cecilia, Lévesque, François, McMullen, Jonathan P., Ji, Yining, Reibarkh, Mikhail, Peng, Feng, Tan, Lushi, Spencer, Glenn, Nappi, Jarod, Lehnherr, Dan, Narsimhan, Karthik, Wismer, Michael K., Chen, Like, Lin, Yipeng, Dalby, Stephen M.

   We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel–Lindau syndrome. Compared with the clinical supply route, the photochemical...

3. Manufacturing Process Development for Belzutifan, Part 4: Nitrogen Flow Criticality for Transfer Hydrogenation Control

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   Contributor(s):: Marzijarani, Nastaran Salehi, Fine, Adam J., Dalby, Stephen M., Gangam, Rekha, Poudyal, Samiksha, Behre, Taylor, Ekkati, Anil R., Armstrong, Brittany M., Shultz, C. Scott, Dance, Zachary E. X., Stone, Kevin

   A scalable and efficient synthesis of hydroxyindanone 3, a key intermediate for belzutifan (MK-6482), is described. Mechanistic studies revealed the sensitivity of the reduction reaction toward the CO2 byproduct. Special effort was required to design a scale-insensitive process for the removal of...