Process Research and Scale-up of the κ-Opioid Receptor Agonist CJ-15,161 Drug Candidate

Authors

  • Brian M. Andresen
  • Brian C. Vanderplas
  • John L. Tucker
  • Janice E. Sieser
  • Maxime Riou
  • Teresa M. Makowski
  • Joel M. Hawkins
  • Melina Girardin
  • Arun Ghosh
  • Kristina Dupont-Gaudet
  • Nga M. Do
  • Keith M. DeVries
  • Michel Couturier
  • Stéphane Caron
  • Timothy J.N. Watson

DOI:

https://doi.org/10.2533/chimia.2006.554

Keywords:

N-arylation, Aziridinium, Copper, Oxazolidinone, Palladium, Process chemistry

Abstract

This account depicts strategies adopted during the development of the κ-opioid receptor agonist CJ-15,161. While the original discovery synthesis was enabled for scale-up, concomitant process research aimed at identifying a novel and more efficient route was undertaken. In the former case, an efficient four-step sequence has been developed, where the process features four consecutive regioselective and stereospecific inversions at a single aziridinium stereogenic center, which leads to overall retention of stereochemistry in a single operation. The search for novel routes has also resulted in two converging methods involving efficient intermolecular N-arylation strategies. The first approach involves Pd-catalyzed intermolecular N-arylation of an appropriately functionalized diamine, obtained from the precursor α-amino acids or, more conveniently, from the corresponding 1,2-amino alcohols. The second approach exploits efficient intermolecular N-arylation of oxazolidinones using catalytic copper in the presence of a bidentate ligand leading to a straightforward and practical synthesis of CJ-15,161.

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Published

2006-09-27

Issue

Section

Scientific Articles

How to Cite

[1]
B. M. Andresen, B. C. Vanderplas, J. L. Tucker, J. E. Sieser, M. Riou, T. M. Makowski, J. M. Hawkins, M. Girardin, A. Ghosh, K. Dupont-Gaudet, N. M. Do, K. M. DeVries, M. Couturier, S. Caron, T. J. Watson, Chimia 2006, 60, 554, DOI: 10.2533/chimia.2006.554.