Quinone-related hexacyclic by-products in the production process of exemestane

•Quinone-related by-products were observed in the production process of exemestane.•The structure of the by-products was determined by NMR, MS and X-ray diffractometry.•The by-products are unprecedented hexacyclic compounds.•Hexacyclic products arise from an initial cycloaddition reaction.

Exemestane, a 3rd-generation aromatase inhibitor, is clinically used in the treatment of breast cancer in postmenopausal women. The key step of the industrial synthetic process, i.e., a dehydrogenation to introduce the Δ1-unsaturation, is normally performed with quinones such as p-chloranil or DDQ. We observed the formation of two different hexacyclic by-products, depending on the quinone used in the oxidation step. These compounds arise from an initial [4+2] cycloaddition between the precursor 6-methylenandrost-4-ene-3,17-dione and the quinone reagent, followed by a twofold dehydrohalogenation (with p-chloranil) or dehydrogenation (with DDQ). The structures of these unprecedented hexacyclic adducts were determined by a combination of mass spectrometry, NMR techniques and crystallographic analysis.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (136 K)Download as PowerPoint slide