Rapid nitrosamine formation from a tertiary amine: The nitrosation of 2-(N,N-Dimethylaminomethyl)pyrrole

Loeppky, Richard N.; Outram, Jerry R.; Tomasik, W.; FAULCONER, J. M.

doi:10.1016/s0040-4039(00)88318-5

Cited by 22 publications

(16 citation statements)

References 7 publications

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“…5.22 and 5.13 (two d, J = 9 Hz, 2H), 4.34 and 3.92 (two d,J = 9 Hz, 2H), 3.99 and 3.83 (two d, J = 11 Hz, 2H), 1.63 Synthesis of 4-Formyl-4-methyl-3-nitroso-l,3-oxazolidine (7). An adaptation of the Swern oxidation procedure was utilized (13).…”

Section: Methodsmentioning

confidence: 99%

An Aziridinium Ion Intermediate in the Nitrosation of a Hexetidine Model

Loeppky

Bae²

1994

Chem. Res. Toxicol.

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The nitrosation chemistry of 1,3,5-trimethyl-5-aminohexahydropyrimidine (2) has been investigated as a model for the behavior of the antimicrobial agent hexetidine (1) under similar conditions. The reaction of 2 with sodium nitrite in glacial acetic acid gives 4-methyl-4-[(methylnitrosamino)methyl]-3-nitroso-1,3-oxazolidine (4) as the major nitrosamine. This compound arises from a molecular rearrangement which proceeds through the diazotization of the primary amino group followed by intramolecular displacement of nitrogen to generate an aziridinium ion. The N-nitrosooxazolidine 4 forms from the nitrosation of an imidazolidine produced from the aziridinium ring hydrolytic opening. The N-nitrosooxazolidine 4, an isomer, 5-methyl-5-[(methylnitrosamino)methyl]-3-nitroso-1,3-oxazolidine (14), which is not formed in the nitrosation of 2, and an analog 4-methyl-4-[[(2-ethylhexyl)nitrosamino]methyl]-3-nitroso-1,3-oxazolidine (22) have been independently synthesized. The N-nitrosooxazolidine 22 which would be formed from hexetidine is not present in its nitrosation mixture, suggesting the absence of reactive aziridinium ions in that case. The dissimilar nitrosation chemistry of 2 and 1 are discussed.

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Section: Methodsmentioning

confidence: 99%

An Aziridinium Ion Intermediate in the Nitrosation of a Hexetidine Model

Loeppky

Bae²

1994

Chem. Res. Toxicol.

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“…A clear example of this behavior has been reported for aminopyrine 1 , , which rapidly liberates NDMA upon treatment with nitrous acid, and is believed to react through its enamine function to give an intermediate that directly eliminates NDMA (Scheme ). Gramine 2 , a component of barley malt, and related 2-dimethylaminomethylpyrrole 3 both exhibit rapid nitrosative dealkylation and give high yields of NDMA. In both cases, it is postulated that the electron-rich heterocycle participates in the elimination of NDMA from an initially formed N -nitroso ammonium ion (Scheme ).…”

Section: Nitrosation Of Amines In Watermentioning

confidence: 99%

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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“…It appears that tertiary amines possessing an electron-rich benzylic group as an alkyl group are quite prone to undergo nitrosative dealkylation. For example,2-(dimethylaminomethyl)pyrrole reacted in 3 min with 10 equiv of sodium nitrite in aqueous acetic acid at room temperature leading to dimethyl nitrosamine in 95% yield (Scheme , reaction (a)) . Gramine , and bromhexine, both containing an electron-rich N -benzylic substituent, have also been shown to undergo rapid nitrosamine formation (Scheme , reactions (b) and (c)).…”

Section: N–n Bond Formationmentioning

confidence: 99%

Pathways for N-Nitroso Compound Formation: Secondary Amines and Beyond

López‐Rodríguez

McManus

Murphy

et al. 2020

Org. Process Res. Dev.

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Recent drug recalls (e.g., valsartan and ranitidine) linked to the discovery of nitrosamine impurities have led to increased regulatory scrutiny in the manufacturing process of marketed medicines, notably for determining any sources of risk for nitrosamine (or related N-nitroso compound) formation within the manufacturing process. This review seeks to aid the risk assessment process through identifying known conditions and reactants through which N-nitroso compounds can be formed.

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Rapid nitrosamine formation from a tertiary amine: The nitrosation of 2-(N,N-Dimethylaminomethyl)pyrrole

Cited by 22 publications

References 7 publications

An Aziridinium Ion Intermediate in the Nitrosation of a Hexetidine Model

An Aziridinium Ion Intermediate in the Nitrosation of a Hexetidine Model

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

Pathways for N-Nitroso Compound Formation: Secondary Amines and Beyond

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