HBTU Coupling Biproducts - Nitrosamines Risk?

[CMC-Consultant]

I’m working on a nitrosamines risk assessment for a synthetic API which uses Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU) as a coupling reagent. One of the bi-products of this reaction is 1-Hydroxybenzotriazole (HOBT). The API manufacturer has flagged HOBT as a molecule with amine functional groups in their risk assessment.

I have not found any information in the literature to suggest that HOBT can undergo nitrosation. Can anyone comment on the likelihood of a N-nitrosamine originating from HOBT (for example, 1-nitroso-1H-benzotriazole)?

Thanks in advance.

[chrischar]

Dear consultant,
i think that the below thread would be useful for your question

Formation of N-nitroso Fluconazole and Related Triazole-Imidazole APIs

Dear colleagues, I would like to pose a question regarding the use of Fluconazole. From what I have seen and researched about its structure, this compound contains two triazole groups that have the potential to react and form N-nitroso Fluconazole. My question is whether the formation of N-nitroso Fluconazole is a result of degradation of the molecule or a metabolic process to separate the triazole groups. [image] Fluconazole [image] N-nitroso Fluconazole I appreciate any insights or exper…

According to our experience, when we have asked for synthesis of a nitrosamine of a triazole type compound, several vendors have failed to synthesize it.
hope it helps
Christos

[1nsekt]

In general, nistrosated triazoles, indazoles or indoles should be concidered as genotoxic BUT NOT CoC as their mutagenicity is due to nitrosonium transfer rather than diazonium formation. Moreover they are reactive towards various nucleophiles and are prone towards hydrolysis/amonolysis making it easy to control during production process.

Eg: Efficient Nitroso Group Transfer fromN-Nitrosoindoles to Nucleotides and 2′-Deoxyguanosine at Physiological pH: A NEW PATHWAY FOR N-NITROSOCOMPOUNDS TO EXERT GENOTOXICITY - ScienceDirect

[ccdw]

@1nsekt

In general, nistrosated triazoles, indazoles or indoles should be concidered as genotoxic BUT NOT CoC as their mutagenicity is due to nitrosonium transfer rather than diazonium formation.

ICH M7 CoC is nitroso not nitrosamines, CoC definition is not mechanism specific for nitroso.