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

N‑Nitroso N‑Didesmethyl Tiotropium is a proposed nitrosamine impurity related to tiotropium, a long‑acting muscarinic antagonist (LAMA) bronchodilator. The didesmethyl (dealkylated) impurity contains a nitrosatable amine that could undergo nitrosation in the presence of nitrosating agents (e.g., nitrite) under acidic conditions, forming the 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 N-Didesmethyl Tiotropium formation. Our findings revealed that N-Nitroso N-Didesmethyl Tiotropium 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 N-Didesmethyl Tiotropium Technical Information

• Molecular Weight: 392.45 g/mol
• Molecular Formula: C17H16N2O5S2
• IUPAC Name: (1R,2R,4S,5S,7s)-9-nitroso-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate
• CAS Number: N/A
• Synonyms: N/A

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