N-Nitroso Dolutegravir; Synthesis Attempts and Failure Report (NAP Test)

N-Nitroso Dolutegravir is a proposed nitrosamine impurity related to dolutegravir, an integrase inhibitor used in HIV therapy. The impurity is considered a potential nitrosation product of a nitrosatable nitrogen-containing functionality that, in the presence of nitrosating agents (e.g., nitrite/nitrous acid) under acidic conditions, could form the corresponding N-nitroso derivative.

EMA Guidance on Nitrosamines

According to EMA guidelines, if repeated synthesis attempts fail to detect the formation of nitrosamine impurities, it is likely that the impurity either does not exist or poses an extremely low risk.

Nitrosation

We conducted multiple nitrosation assays under rigorous forced conditions (NAP tests), to evaluate the risk of N-Nitroso Dolutegravir formation. Our findings revealed that N-Nitroso Dolutegravir does not readily undergo nitrosation under the expected conditions, significantly reducing concerns about its potential formation.

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Our synthesis failure report provides a detailed account of the findings from our synthesis attempts and rigorous testing, demonstrating the non-formation of the nitroso impurity. It offers a comprehensive overview of the evaluated conditions and the resulting data.

N-Nitroso Dolutegravir Technical Information

• Molecular Weight: 448.38 g/mol
• Molecular Formula: C20H18F2N4O6
• IUPAC Name: (4R, 12aS)-N-(2, 4-difluorobenzyl)-7-hydroxy-4-methyl-N-nitroso-6, 8-dioxo-3, 4, 6, 8, 12, 12a-hexahydro-2H-pyrido[1′, 2′:4, 5]pyrazino[2, 1-b][1, 3]oxazine-9-carboxamide
• CAS Number: N/A
• Synonyms: N/A

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