Hydrazide Nitrosamine Formation

N-nitrosamines Chemistry
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I have a hydrazide where R1, R2, and R3 are all carbonyls. So, there is a carbonyl immediately adjacent to each N. I cannot find any examples of similar molecules forming nitrosamines. Does anyone think this would be possible?

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To my understanding nitrosation of such compounds seems to be unlikely due to the electron withdrawing properties of the amide/carbonyl oxygen. Even if formed, such compounds shouldn’t be considered as cohort of concern since they essentially lack alpha-hydrogens necessary for CYP450 mediated metabolism and subsequent formation of alkyldiazonium, a feature characteristic of high potent N-nitrosamine impurities.

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@Muzaffar Nitroso mefenamic acid also does not have alpha-hydrogens. Still EMA has considered in Nitrosamine with AI of 78000 ng/day. Any thought on this case?

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N-Nitroso mefenamic acid, just like N-Nitroso-diphenylamine (TD50 167 mg/kg/day) is a diaryl N-nitrosamine lacking alpha-hydrogens. They are known to be mutagenic via a different mechanism i.e. trans-nitrosation potentially through Fischer−Hepp rearrangement. They are very weak carcinogens with AI much higher than 1.5 mcg/day and therefore non-cohort of concern compounds. For the diaryl N-nitrosamines you can consider an AI of 78000 ng/day in accordance with the EMA guidance.

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Thanks for the responses @Muzaffar and @hgajjar

This is very much appreciated. I should have thought of the alpha hydrogens. This information greatly changes our scope of work.

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Very well analyzed, Muzaffar,
the nitrosamines are not always activated by alpha hydroxylation, there are several other routes.

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If you have something like C=(O)NHNH-C=O group, this is not going to produce a nitrosamine anyway. Remember, we talked about nitrosamines vs nitrosamides. I think we need to contain ourselves to nitrosamine formation at this time. Also, four electron withdrawing bulky groups will make the formation of a N-nitroso compound quite challenging.

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I see what you mean. Thank you. This is greatly appreciated.

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@ASrinivasan Recently we received query from Health Canada mentioning “intermediates and impurities contain amide functional group with α-hydrogen” and asked to provide the results of a robust risk assessment for the presence of nitrosamine impurities in the proposed drug product.

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@Muzaffar provided an accurate analysis. Even if this species would get nitrosated (Which I doubt it would) it would not be a nitrosamine and would not be within the cohort-of-concern.

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