A Novel Synthetic Approach Toward PT2977, a Selective Inhibitor of Hypoxia Inducible Factor-2α (HIF-2α)
Introduction
PT2977 (Belzutifan), now marketed by Merck as Welireg, is an orally bioavailable small-molecule (HIF-2α) inhibitor for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) that received FDA approval in 2021. Two different synthetic approaches toward PT2977 have been published. According to published methods, the synthesis of PT2977 can be effectively divided into two parts, initially involving generation of the diaryl ether indanone core bearing a methyl sulfone functionality, followed by elaboration of the all-cis stereotriad present at the indanol. Despite the formation of different intermediates, both routes proceed through a similar set of reactions that include AlCl3- catalyzed Friedel-Crafts cyclization, benzylic bromination, ketone protection-deprotection, and formation of the ether functionality through a SNAr reaction. A new synthetic approach to PT2977 is described herein. This novel route begins from commercially available 3-fluoro-5-hydroxybenzonitrile and 2-bromo-6-fluorobenzaldehyde, and proceeds through biaryl-methoxyindanone and biaryl-sulfone intermediates. Synthesis of the biaryl-sulfone intermediate has been achieved in overall high yield, and generation of the stereotriad to obtain PT2977 is underway. This process improves the overall synthesis by decreasing the number of synthetic steps and by removing protection-deprotection chemistry.
Methods
All the chemical reactions were performed in oven-dried glassware under an inert atmosphere using nitrogen gas. Key reactions employed to generate the desired intermediates included nucleophilic aromatic substitution (SNAr), Sonogashira cross-coupling, and alkyne carboalkoxylation. Thin-layer chromatography (TLC) plates were used to monitor reactions. Purification of intermediates and products was carried out with a Biotage Isolera flash purification system using silica gel (200−400 mesh, 60 Å) or manually in glass columns. Intermediates and products synthesized were characterized based on their 1H NMR, 13C NMR, and 19F NMR spectroscopic data using a Varian VNMRS 500 MHz or a Bruker DPX 300 MHz instrument. Mass spectrometry was carried out under positive or negative ESI (electrospray ionization) using a Thermo Scientific LTQ Orbitrap Discovery instrument. Purity of key intermediates and the final compound was determined by HPLC analysis using an Agilent 1200 HPLC system with a diode-array detector (λ = 190–400 nm), a Zorbax XDB-C18 HPLC column (150 mm, 5 μm), and a Zorbax reliance cartridge guard-column.
Results
The aromatic nucleophilic substitution reaction between 3-fluoro-5-hydroxybenzonitrile and 2-bromo-6-fluorobenzaldehyde produced the requisite biaryl-ether intermediate in high yield (86%). Sonogashira coupling of this biaryl-ether intermediate with TMS-acetylene afforded the desired biaryl-alkyne intermediate in excellent yield (92%), which subsequently underwent reaction with trimethylorthoformate catalyzed by p-toluenesulfonic acid (PTSA) to generate a masked-aldehyde intermediate (89% yield). An efficient desilylation reaction, carried out by exposure to K2CO3, generated the terminal-alkyne intermediate in quantitative yield. This Intermediate then underwent carboalkoxylation catalyzed by gold followed by PTSA-catalyzed hydrolysis to generate a methoxy-indanone intermediate in 73% yield. Selective iodination of this methoxy-indanone intermediate followed by sulfonylation established the key intermediate (biaryl-sulfone) with overall good yield.
Conclusion
A new approach toward the synthesis of PT2977 was established. The diaryl-ether linkage and methylsulfonyl group were successfully installed to generate key intermediate in seven steps. The second part of the synthesis to deliver the target PT2977 is underway. This novel procedure will reduce the number of synthetic steps making it a more economically viable and efficient process.