Novel Synthesis and Structural Characterization of Venetoclax Impurities via [2,3] Meisenheimer Rearrangement

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, we report 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 were confirmed using 1H NMR, HPLC, and mass spectrometry. This synthetic approach provides an efficient method for synthesising Venetoclax impurities VHA (3) and VHA (4).