丁香园AV

Belzutifan (MK-6482) is a first-in-class oral hypoxia-inducible factor 2伪 (HIF-2伪) inhibitor used for the treatment of patients with renal cell carcinoma associated von Hippel-Lindau (VHL) disease. The program achieved FDA breakthrough designation in 2020 and was approved in 2021 for VHL associated renal cell carcinoma. The molecule has a unique structure, including a highly substituted indanone with three contiguous chiral centers, two of which are secondary alkyl fluorides. A big challenge in the installation of this functionality is an oxidation of the indanone to install a chiral benzylic alcohol, which originally requires five consecutive chemical steps to achieve. This presentation details our extensive advances in synthetic methods and strategy develop a scalable process, including novel biocatalytic direct enantioselective hydroxylation that forges the desired C-O bond in a single step.