ChemInform Abstract: Amines as Leaving Groups in Nucleophilic Aromatic Substitution Reactions. Part 5. Substitution vs. N‐Oxide Formation in the Reaction of N‐n‐Butyl‐2,6‐dinitroaniline with Hydroxide Ions

Abstract

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On the Stability and Degradation Pathways of Venetoclax under Stress Conditions

“…In addition to dimerization, two more key degradation pathways were discovered in basic conditions. The first key degradation pathway in basic conditions is the cyclization of a o -nitroaniline moiety, which produces benzoimidazole N -oxide, degradation product B1 ( 6 ) [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. The proposed mechanism for cyclization can be seen in Scheme 5 .…”

“…First, the nitrogen atom from the amino group is deprotonated by a hydroxide anion and water is eliminated. Lastly, cyclization involving the nitroso group and azomethine moiety occurs [ 51 , 54 , 56 ]. The product can form a tautomer ( Scheme 6 ) [ 49 , 54 ].…”

“…The reaction is likely solvent-dependent. The reaction mechanism was previously observed with the addition of various organic solvents such as 1,4-dioxane [ 51 , 52 , 53 ], alcohols [ 53 , 54 ], DMF or DMSO [ 53 , 54 ]. Similar cyclization was observed under photolytic conditions on other molecules [ 47 ], therefore, in the case of venetoclax, this product could also form when exposed to photolytic conditions.…”

“…The second key degradation pathway in basic conditions is a nucleophilic aromatic substitution (S N Ar) of the 2-nitro-substituted benzene with the hydroxyl group from NaOH [ 50 , 54 , 58 , 59 , 60 ], resulting in degradation product B2 ( 7 ).…”