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, 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).