Amines as leaving groups in nucleophilic aromatic substitution reactions. Part 5.1 Substitution vs. N-oxide formation in the reaction of N-n-butyl-2,6-dinitroaniline with hydroxide ions

Buján, Elba I.; Cañas, A. Irene; Rossi, Rita H. de

doi:10.1039/b103412j

Cited by 3 publications

(4 citation statements)

References 17 publications

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“…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.…”

Section: Degradation Pathways Of Venetoclaxsupporting

confidence: 67%

“…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].…”

Section: Degradation Pathways Of Venetoclaxmentioning

confidence: 99%

“…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.…”

Section: Degradation Pathways Of Venetoclaxmentioning

confidence: 99%

“…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).…”

Section: Degradation Pathways Of Venetoclaxmentioning

confidence: 99%

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On the Stability and Degradation Pathways of Venetoclax under Stress Conditions

Žigart

Črnugelj²,

Ilaš

et al. 2020

Pharmaceutics

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Venetoclax is an orally bioavailable, B-cell lymphoma-2 (BCL-2) selective inhibitor, used for the treatment of various types of blood cancers, such as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). In this study we investigated the degradation of venetoclax under various stress conditions including acidic, basic, oxidative, photolytic and thermolytic conditions. We isolated and identified six of its main degradation products produced in forced degradation studies. The structures of the isolated degradation products were determined by using nuclear magnetic resonance (NMR) spectroscopy, high resolution mass spectrometry (HRMS) and infrared (IR) spectroscopy. Additionally, one oxidation degradation product was identified with comparison to a commercially obtained venetoclax impurity. We proposed the key degradation pathways of venetoclax in solution. To the best of our knowledge, no structures of degradation products of venetoclax have been previously published. The study provides novel and primary knowledge of the stability characteristics of venetoclax under stress conditions. Venetoclax is currently the only BCL-2 protein inhibitor on the market. In addition to single agent treatment, it is effective in combinational therapy, so future drug development involving venetoclax can be expected. A better insight into the stability properties of the therapeutic can facilitate future studies involving venetoclax and aid in the search of new similar therapeutics.

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Section: Degradation Pathways Of Venetoclaxsupporting

confidence: 67%

Section: Degradation Pathways Of Venetoclaxmentioning

confidence: 99%

Section: Degradation Pathways Of Venetoclaxmentioning

confidence: 99%

Section: Degradation Pathways Of Venetoclaxmentioning

confidence: 99%

See 2 more Smart Citations

On the Stability and Degradation Pathways of Venetoclax under Stress Conditions

Žigart

Črnugelj²,

Ilaš

et al. 2020

Pharmaceutics

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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

2002

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One-Pot Two-Step Synthesis of 2-Aryl benzimidazole N-oxides Using Microwave Heating as a Tool

2019

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A methodology is reported for the preparation of 2-aryl-benzimidazole-3-oxide derivatives. By means of a one-pot two-step protocol, a library of 42 new compounds has been prepared. Reactions were performed in a total time of 40 min using microwave heating as a tool. A streamlined work-up process was also developed, allowing for facile isolation of the products. The methodology offers a more sustainable approach than previous routes, with only water and ethanol being used as solvents, and the products being isolated by means of a simple filtration without the need for any further purification.

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Amines as leaving groups in nucleophilic aromatic substitution reactions. Part 5.1 Substitution vs. N-oxide formation in the reaction of N-n-butyl-2,6-dinitroaniline with hydroxide ions

Cited by 3 publications

References 17 publications

On the Stability and Degradation Pathways of Venetoclax under Stress Conditions

On the Stability and Degradation Pathways of Venetoclax under Stress Conditions

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

One-Pot Two-Step Synthesis of 2-Aryl benzimidazole N-oxides Using Microwave Heating as a Tool

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