Nitrosative dealkylation of some symmetrical tertiary amines

Gowenlock, B. G.; Hutchison, Roderick J.; Little, Janet; Pfab, Josef

doi:10.1039/p29790001110

Cited by 24 publications

(28 citation statements)

References 1 publication

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“…The limited kinetic data that is available for the nitrosation of tertiary amines gives a rate constant of 1.83 × 10 7 M −2 s −1 at 75 °C for the nitrosation of triethylamine in 60% aqueous acetic acid with an activation energy of 84.8 kJ/mol. 26 These experiments were conducted via an initial rate methodology at high concentrations of nitrous acid (0.1−0.5 M). Extrapolation using the Arrhenius equation (eq 11) with the reported rate constant as the reference estimates that the rate constant will be 1.34 × 10 5 M −2 s −1 at 25 °C.…”

Section: ■ Detailed Discussion and Resultsmentioning

confidence: 99%

“…66 The kinetics of the nitrosative dealkylation of triethylamine has been studied by an initial rate methodology in buffered aqueous acetic acid at 74.8 °C and pH > 3.1. 26 The kinetically determined rate law (eq 9) is consistent with a rapid reversible nitrosation of triethylamine followed by a slow rate-limiting elimination of nitroxyl to form an iminium ion intermediate (Scheme 8). In aqueous media, this rapidly hydrolyzes to give acetaldehyde and diethylamine, which rapidly undergoes nitrosation to form diethyl N-nitrosamine (NDEA)…”

Section: ■ Nitrosation Of Amines In Watermentioning

confidence: 99%

“…Additionally, given the reported reduced rate of nitrosamine formation from tertiary amines compared to that from secondary amines; basic tertiary amines with p K a s >9.5 are not expected to generate significant levels of nitrosamine by nitrosation, resulting from trace levels of nitrite in water.…”

Section: Risk Of Nitrosation By Trace Nitrite In Watermentioning

confidence: 99%

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Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

Ashworth

Dirat

Teasdale

et al. 2020

Org. Process Res. Dev.

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Regulatory requests that marketing authorization holders for chemically synthesized active substances risk assess their medicines for the potential presence of N-nitrosamines have led to a renewed interest in amine nitrosation. We have used published mechanistic and kinetic studies of amine nitrosation to assess the risk that traces of nitrite in the water used during active pharmaceutical ingredient (API) manufacturing could give rise to significant levels of N-nitrosamines. We conclude that the levels of nitrite typically found in water used for API manufacture are very low (<0.01 mg/L) and will not give rise to significant levels of N-nitrosamines through reaction with basic secondary amines (pK a > 9.5) in the majority of cases. The use of less basic amines, elevated processing temperatures, or low pH conditions in combination with elevated levels of nitrite have the potential to generate levels of N-nitrosamines that could lead to significant quantities being present in the isolated API if the downstream processing does not provide an adequate purge. The kinetic models described may be used to risk assess specific situations or processes. For example, the addition of traces of dimethylamine to a nitrosation reaction is predicted to lead to the rapid, quantitative formation of N-nitroso dimethylamine. Simple tertiary alkylamines can nitrosate via a dealkylative process, which is significantly slower than secondary amine nitrosation. Therefore, they do not represent a risk of N-nitrosamine formation under conditions where there is no significant risk of secondary amine nitrosation.

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Section: ■ Detailed Discussion and Resultsmentioning

confidence: 99%

Section: ■ Nitrosation Of Amines In Watermentioning

confidence: 99%

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Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

Ashworth

Dirat

Teasdale

et al. 2020

Org. Process Res. Dev.

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“…The most prominent mechanism of tertiary amine nitrosation, here designated as Mechanism A, is shown in Scheme 2. 8, 9 It involves the reversible N-nitrosation of the substrate (3→4) followed by the elimination of NOH to give an iminium ion 5. The hydrolysis of the latter and the nitrosation of the resultant secondary amine 6 lead to the nitrosamine 8.…”

Section: Introductionmentioning

confidence: 99%

The mechanistic origin of regiochemical changes in the nitrosative N-dealkylation of N,N-dialkyl aromatic amines

Teuten

Loeppky

2005

Org. Biomol. Chem.

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The regioselectivity of the nitrous acid mediated dealkylation of 4-substituted-N-ethyl-N-methylanilines is a function of the acidity of the reaction mixture. At high acidity deethylation predominates, whereas demethylation is the predominant reaction in nitrosamine formation at pH 2 and above. In some cases the regioselectivity of nitrosative dealkylation changes as the run proceeds. Through the use of the corresponding 4-nitroaniline as the primary substrate, CIDNP, kinetics, kinetic deuterium isotope effects and other transformations involving nitrosations with NO2 or NOBF4 in aprotic solvents, a new mechanism of tertiary amine nitrosation has been deduced and proposed to explain regioselective deethylation. The mechanism involves the oxidation of the substrate to the amine radical cation by NO+. This is followed by the abstraction of a hydrogen atom from the carbon adjacent to the amine nitrogen by NO2 to produce an iminium ion which reacts further to produce the corresponding aldehyde and the nitrosamine. Depending upon the acidity, this process competes with three other mechanistic pathways, two of which give the nitrosamine through the iminium ion, and one leads to the formation of C-nitro compounds. The competing pathways to nitrosamine formation involve NOH elimination from a nitrosammonium ion and deprotonation of the radical cation to give an alpha-amino radical which rapidly oxidized to the iminium ion. Predominant, but not highly regioselective demethylation occurs by these pathways. Nitro compound formation principally arises from the reaction of NO2 with the radical cation followed by deprotonation, but also occurs by para C-nitrosation followed by oxidation.

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“…The mechanism of tertiary amine nitrosation for normal aliphatic tertiary amines is given in Scheme 1. The process involves the reversible generation of a nitrosammonium ion (R3NNO+) followed by the rate limiting loss of NOH (17,18). More basic amines will form the nitrosammonium ion more slowly and decrease the overall rate of nitrosative dealkylation.…”

mentioning

confidence: 99%

Blocking Nitrosamine Formation

Loeppky

Bao

Bae

et al. 1994

ACS Symposium Series

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The fundamental chemical principles of blocking inadvertent nitrosamine formation and contamination through the recognition of structural features which predispose compounds toward rapid nitrosation as well as the development of new blocking agents are reviewed. Rapid nitrosamine formation from tertiary nitrogen compounds such as amines, amidines, and gem. diamines is shown to occur through an electron pair assisted nitrosative solvolysis type mechanism. The rapid production of nitrosamines from amdinocillin, an amidine containing antibiotic, and hexetidine, a widely used antimicrobial agent, are presented as examples of new findings. The development and assay of new monomeric and polymeric blocking agents is described. An advantage of the latter blocking agent is its ability to be removed from mixtures by physical means. This knowledge and these measures permit significant reductions in nitrosamine contamination to be realized.Nitrosamine formation in the human environment continues to be a significant problem despite the widespread recognition of the possible carcinogenic role of nitrosamines and other N-nitroso compounds. Many effective measures have been taken to eliminate or significantly reduce the level of nitrosamines in foods and other commercial products (7). In many instances, successful steps to block nitrosamine formation have been based upon an elucidation of the mechanisms by which they are formed and/or the use of specific blocking agents. These numerous individual successes, however, have not eliminated the problem of nitrosamine contamination. Moreover, there is now good evidence that nitrosamines form in vivo from several types of precursors, heightening concern that many tumors could have their origin in endogenous nitrosation (2).

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Nitrosative dealkylation of some symmetrical tertiary amines

Cited by 24 publications

References 1 publication

Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

The mechanistic origin of regiochemical changes in the nitrosative N-dealkylation of N,N-dialkyl aromatic amines

Blocking Nitrosamine Formation

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