Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl
Abstract
The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (+/-)-cis and (+/-)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach.
Keywords:
heterocycles / rearrangement / acylation / protecting groups / diastereoselectivitySource:
Synthesis, 2017, 49, 14, 3126-3136Publisher:
- Georg Thieme Verlag Kg, Stuttgart
Funding / projects:
DOI: 10.1055/s-0036-1588985
ISSN: 0039-7881
WoS: 000406066800009
Scopus: 2-s2.0-85017147328
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Institution/Community
IHTMTY - JOUR AU - Jevtić, Ivana AU - Došen-Mićović, Ljiljana AU - Ivanović, Evica AU - Todorović, Nina AU - Ivanović, Milovan D. PY - 2017 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/2142 AB - The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (+/-)-cis and (+/-)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach. PB - Georg Thieme Verlag Kg, Stuttgart T2 - Synthesis T1 - Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl VL - 49 IS - 14 SP - 3126 EP - 3136 DO - 10.1055/s-0036-1588985 ER -
@article{ author = "Jevtić, Ivana and Došen-Mićović, Ljiljana and Ivanović, Evica and Todorović, Nina and Ivanović, Milovan D.", year = "2017", abstract = "The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (+/-)-cis and (+/-)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach.", publisher = "Georg Thieme Verlag Kg, Stuttgart", journal = "Synthesis", title = "Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl", volume = "49", number = "14", pages = "3126-3136", doi = "10.1055/s-0036-1588985" }
Jevtić, I., Došen-Mićović, L., Ivanović, E., Todorović, N.,& Ivanović, M. D.. (2017). Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl. in Synthesis Georg Thieme Verlag Kg, Stuttgart., 49(14), 3126-3136. https://doi.org/10.1055/s-0036-1588985
Jevtić I, Došen-Mićović L, Ivanović E, Todorović N, Ivanović MD. Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl. in Synthesis. 2017;49(14):3126-3136. doi:10.1055/s-0036-1588985 .
Jevtić, Ivana, Došen-Mićović, Ljiljana, Ivanović, Evica, Todorović, Nina, Ivanović, Milovan D., "Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl" in Synthesis, 49, no. 14 (2017):3126-3136, https://doi.org/10.1055/s-0036-1588985 . .