Novel synthesis and structural characterization of Venetoclax impurities via [2,3] Meisenheimer rearrangement

Abstract

Venetoclax 1, a BCL-2 inhibitor, is extensively used in the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia. In this study, is reported the synthesis of a novel Venetoclax impurity, VHA 3, via a [2,3] Meisenheimer rearrangement of VNO 2. Upon heating, VHA 3 undergoes further rearrangement, resulting in the formation of [1,2] Meisenheimer rearranged product VHA 4. The structures of these impurities have been confirmed using 1H and 13C NMR, HPLC, and mass spectrometry. This synthetic approach provides an efficient method for synthesising Venetoclax impurities VHA 3 and VHA 4.