Combined experimental and quantum mechanical elucidation of the synthetically accessible stereoisomers of Hydroxyestradienone (HED), the starting material for vilaprisan synthesis.

Selective progesterone receptor modulators are promising therapeutic options for the treatment of uterine fibroids. Vilaprisan, a new chemical entity that was discovered at Bayer is currently in clinical development. In this study we provide a combined experimental and quantum chemical approach providing the data that allowed to present hydroxyestradienone as an acceptable starting material for drug substance synthesis. Hydroxyestradienone has four stereogenic centers leading to 8 diastereomers and 16 enantiomers of which only six diastereomers were synthetically accessible but two not. A computational multistep protocol resulting in density functional P2PLYP-D3(BJ)/dev2-TZVPP Gibbs free energies and SMD solvation free energies led to a clear separation between the existing and the synthetically not accessible enantiomers, whereas multiple geometry-based and cheminformatic descriptors were not able to explain experimental findings.