Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 1─Process History and Development Strategy

Abstract

An improved synthesis has been developed for belzutifan, a novel HIF-2α inhibitor for the treatment of Von Hippel− Lindau (VHL) disease-associated renal cell carcinoma (RCC). The efficiency of previous supply and commercial routes was encumbered by a lengthy 5-step sequence, needed to install a chiral benzylic alcohol by traditional methods. Identification and directed evolution of FoPip4H, an iron/α-ketoglutarate dependent hydroxylase, enabled a direct enantioselective C−H hydroxylation of a simple indanone starting material. While this enabling transformation set the stage for a greatly improved synthesis, several other key innovations were made including the development of a base-metal-catalyzed sulfonylation, a KREDcatalyzed dynamic kinetic resolution, and a facile S N Ar reaction in water. Together, these improvements resulted in a significantly shorter synthesis (9 steps) versus the supply route (16 steps) and a 75% reduction in process mass intensity (PMI), while also removing the reliance on third-row transition metals and toxic solvents.

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 3─Development of a Scalable Enzymatic Oxidation Process

“…After the first commercial manufacturing process was developed, a more concise synthetic route was desired. The improved manufacturing process for belzutifan is outlined in Scheme . The key step in the synthesis is a stereoselective enzymatic oxidation of indanone 1 directly to hydroxyindanone 2 .…”

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

“…One of the key steps in the synthetic route is to convert indanone to hydroxyindanone (Scheme ). In the previous commercial route, − installing the hydroxyl group onto the indanone required five chemical steps, namely, ketalization, bromination, oxidation, reduction, and deprotection, all of which can be replaced by just one biocatalytic hydroxylation in a newly developed commercial route using engineered hydroxylase . The new reaction strategy streamlines the synthesis, reduces the raw material cost of goods, and offers a more sustainable manufacturing route.…”

Enantio- and Diastereoselective Total Synthesis of Belzutifan Enabled by Rh-Catalyzed Hydrogenation

“…In conclusion, we have demonstrated an enantio- and diastereoselective total synthesis of belzutifan in nine steps with 19% overall yield from 2-bromo-1,4-difluorobenzene. This route avoids a lengthy bromination–oxidation sequence and introduces the sulfone moiety under mild conditions in contrast to previous syntheses of belzutifan. , Furthermore, a novel Rh-catalyzed asymmetric hydrogenation was developed to afford the desired fluorinated product with high enantioselectivity, giving access to the final stereotriad in an efficient manner. To the best of our knowledge, this work showcases the first example of an asymmetric hydrogenation to directly access two contiguous fluorinated stereocenters, thereby highlighting the power of HTE, coupled with hydrogenation, as an enabling tool to access fluorinated molecules for drug discovery and beyond.…”

“…Belzutifan was previously synthesized in 16 steps and 4% overall yield . While the synthesis provided material to support clinical studies, the route suffered from some key drawbacks, including supply chain and cost risks associated with using 4-(methylthio)­phenol as the starting material.…”