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.
N-nitroso ticagrelor impurity is still defined in the EMA guideline, does anyone have any information about a development on this issue? Is this impurity standard still not available?
Dear Sedanur, the issue with ‘‘fake’’ nitroso compounds in the lists of EMA, FDA etc is getting worst…very recently, the N-nitroso ivacaftor was also added in the EMA list. We have asked several impurity manufacturers to synthesize this and and none of them succeeded (as it was expected).
I have also doubts about the synthesis of some of the new added nitroso-compounds in the EMA list.
I think that is time for the authorities, before to add in their list any new nitrosamine, for which the are doubts for its synthesis, to check deeply the validity of the reference standards.
Christos
Dear Christos thank you very much for your reply, yes you are right.
The EMA guideline also mentions the following statement:
‘‘During development of an analytical method, a reference standard of the relevant nitrosamine impurity is generally needed. If, despite extensive efforts, it becomes apparent that the relevant nitrosamine impurity cannot be synthesised, then this could be an indication that the nitrosamine either does not exist or that there is no risk of it being formed. In such cases, it may not be necessary to conduct confirmatory testing. This should be justified thoroughly on a case-by-case basis according to appropriate scientific principles. The justification could include relevant literature, information on structural/stereo-electronic features and reactivity of the parent amine, stability of the nitrosamine and experimental data to illustrate the efforts made to synthesise and to analyse the impurity. The justification should be included in the submitted risk assessment.’’
Maybe we can carry out our risk assessments in this way, but the authorities will still question the status of being on the EMA list. In this case, perhaps an application can be made to the EMA side.
i am in a position to know that at list one company has flagged the issue of the ‘‘fake’’ N-nitrosoticagrelor to EMA even one year ago, providing all the necessary data to prove its instability and transformation to isooxazoline derivative and nothing has happened…is still there, as you notice.
That’s why i propose that the authority itself should check for the validity of ‘‘suspicious’’ nitroso-compounds (nitrosamines and others)
thanks