During the N-Nitroso Ticagrelor synthesis, we encountered that no N-Nitrosation actually took place, and rather formation of some other NO-aduct (having the same Mass) has been isolated.
However, there are several companies that offers N-Nitroso Ticagrelor and what a surprise, N-Nitroso Ticagrelor have already its own CAS no. 2476859-55-7.
How exiting was, when I today came across online available document from MSN labs, where the MSN team experienced exactly the same issue; and describes proposed mechanism of Ticagrelor nitrosation, including cyclopropyl ring-opening, C-nitrosation followed by cyclization leading to 4,5-Dihydroisoxasole Derivate:
https://www.msnlabs.com/docs/scientific/TICAGRELOR_IMPURITY.pdf
Have you experienced the same?
We are working on synthesis of some ticagrelor nitrosamines derivatives…
will share our experience soon. thanks for the update
Interesting mechanism!
If synthesis proves impossible, this falls into the same bucket as the dipines - nitrosamines that would theoretically be category 5 but in practice do not form thus are not a concern at all. Anecdotally, something similar to your experience with contract manfacturers has also occured - a product is available claiming to provide nitroso-amlodipine, but upon delivery the compound proved to be something else…
See the current thread on the dipines for more discussion.
dipines do not form nitroso on the piperidine nitrogen , under nitrosation conditions they aromatize to form corresponding pyridine analogs… this is our practical experience…
Yes…our organization has also made several efforts over the year but resulted same results what you have described.
Hi nitroso-team,
recently we have been informed that some companies have in-stock the N-nitrosoticagrelor EP impurity B
O=NN(C1=C(N=NN2[C@H]3C@HC3)C2=NC(SCCC)=N1)[C@H]5C@HC@HC@@HC5
Does anyone has been purchase this impurity? Its formation looks difficult but no so ‘‘exotic’’ as the N-nitrosoticagrelor.
thank you in advance!!
PS. By the way to mention that the N-nitrosoticagrelor is still present in EMA list with AIs (appendix 1) although in this forum its formation has been proved as ‘‘non-possible’’ months ago. This is quite frustrating.
Ask NMR and MS spectra from these suppliers from this impurity. You are going to see, that these are the other impurity (4,5-Dihydroisoxasole derivate), not the required nitrosamine.
Bartaen, thank you very much for your suggestion.
The problem is that the NMR and MS spectra which usually are shared from the impurities manufacturers are veric ‘‘basic’’ and cannot distinguish such differences in the structure. I think that only 2-D NMR spectra and/or HRMS spectra could identify this in the case of the nitroso-derivatives of Ticagrelor.
Nevertheless, is good to know your feedback.
Fantastic discussion, all. This once again highlights the need to conduct a comprehensive risk assessment; it is not just about the presence of a secondary amine or nitrosating agent, as we continue to see from suppliers with their ‘checklist’; the chemistry of nitrosation and mechanism need to be an essential part of such an assessment.
It is even more critical that standard suppliers continue offering such materials that are impossible to produce!
Dear Bartaen,
we went back to the impurity producer asking to re-check its reagent. Finally they return back to us and answer that its reagent was not the right one, so we did not proceed further.
Thank you very much for one more time!!
best regards
Christos
Dear @romnaiffer ,
Do you think it would be a good idea to make a new dashboard, compiling amines which either fail to produce nitrosamines, or actually form other substances under nitrosating conditions?
I will be happy to make the dashboard; the question is: Are folk willing to share privately which nitrosamines have not been able to synthesize?? If so… we can build a database based on all the donated information.
Already justified that concerned NDSRI of Ticagrelor is less likely formed.