[en] N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable organophotocatalytic procedure that accomplishes the N-demethylation step using molecular oxygen as the terminal oxidant and an organic dye (rose bengal) as an effective photocatalyst. Optimization of the reaction conditions under continuous flow conditions using visible-light irradiation led to an efficient, reliable, and scalable process, producing noroxycodone hydrochloride in high isolated yield and purity after a simple workup.
Disciplines :
Chemistry
Author, co-author :
Chen, Yuesu ; Université de Liège - ULiège > Molecular Systems (MolSys) ; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010, Graz, Austria ; Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010, Graz, Austria
Glotz, Gabriel; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010, Graz, Austria ; Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010, Graz, Austria
Cantillo, David ; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010, Graz, Austria ; Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010, Graz, Austria
Kappe, C Oliver; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010, Graz, Austria ; Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010, Graz, Austria
Language :
English
Title :
Organophotocatalytic N-Demethylation of Oxycodone Using Molecular Oxygen.
The CC FLOW Project (Austrian Research Promotion Agency FFG No. 862766) is funded through the Austrian COMET Program by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry of Science, Research and Economy (BMWFW), and by the State of Styria (Styrian Funding Agency SFG). The authors gratefully acknowledge Corning SAS for the generous loan of the Corning Advanced‐Flow Lab Photo Reactor used in this study. We are also thank Prof. Dr. Till Opatz for his informative suggestions during this research.The CC FLOW Project (Austrian Research Promotion Agency FFG No. 862766) is funded through the Austrian COMET Program by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry of Science, Research and Economy (BMWFW), and by the State of Styria (Styrian Funding Agency SFG). The authors gratefully acknowledge Corning SAS for the generous loan of the Corning Advanced-Flow Lab Photo Reactor used in this study. We are also thank Prof. Dr. Till Opatz for his informative suggestions during this research.
S. Berenyi, C. Csutoras, A. Sipos, Curr. Med. Chem. 2009, 16, 3215–3242;
A. F. Casy, R. T. Parfitt, Opioid Analgesics; Plenum Press: New York and London, 1986;
H. Nagase, Ed. Chemistry of Opioids; Springer: Heidelberg, 2011.
N. Sharghi, I. Lalezari, Nature 1967, 213, 1244;
J. W. Fairbairn, Planta Medica 1976, 29, 26–32;
L. E. Craker, J. E. Simon, Eds. Herbs, Spices, and Medicinal Plants: Recent Advances in Botany, Horticulture, and Pharmacology Vol. II,. Haworth Press Inc., Binghamton NY, 1991;
I. Schönfelder, P. Schönfelder, Der Kosmos Heilpflanzenführer: Über 600 Heil- und Giftpflanzen Europas, 4th Ed.; Franckh Kosmos Verlag: Stuttgart, 2019.
A. Ordóñez Gallego, M. G. Baron, E. E. Arranz, Clin. Transl. Oncol. 2007, 9, 298–307;
J. Riley, E. Eisenberg, G. Müller-Schwefe, A. M. Drewes, L. Arendt-Nielsen, Curr. Med. Res. Opin. 2008, 24, 175–192;
S. J. King, C. Reid, K. Forbes, G. Hanks, Palliat. Med. 2011, 25, 454–470.
United Nations Office on Drugs and Crime, World Health Organization, Opioid overdose: preventing and reducing opioid overdose mortality, United Nations, 2013;
G. Willyard, Nature 2019, 573, S17-S19.
M. S. Sadove, R. C. Balagot, S. Hatano, E. A. Jobgen, JAMA J. Am. Med. Assoc. 1963, 183, 666–668.
A. K. Clark, C. M. Wilder, E. L. Winstanley, J. Addict. Med. 2014, 8, 153–163;
J. M. Chamberlain, B. L. Klein, Am. J. Emerg. Med. 1994, 12, 650–660.
World Health Organization, World Health Organization Model List of Essential Medicines, 21st List, United Nations, 2019.
For the synthesis of Naloxone form oripavine, see:
R. J. Kupper, US7939543, 10 May, 2011;
J. R. Giguere, H. A. Reisch, S. Sandoval, J. L. Stymiest, US8921556, 30 December, 2014.
J. D. Phillipson, A. Scutt, A. Baytop, N. Özhatay, G. Sariyar, Planta Medica 1981, 43, 261–271;
A. Coop, J. W. Lewis, K. C. Rice, J. Org. Chem. 1996, 61, 6774.
For the synthesis of Naloxone from thebaine, see:
Z. Fang, J. Wang, W. Jiang, L. Zhang, R. Yu, D. Zhao, CN104230945 A, 24 December, 2014;
Y. Zheng, M. Lu, X. Wang, W. Sheng, Z. Qiu, Fudan Xuebao, Yixueban 2007, 34, 888–890;
J. Cardot, W.-C. Zhang, US9701687, 11 July, 2017;
M. Conza, V. Lellek, H. Zinser, US9701688, 11 July, 2017.
L. Werner, M. Wernerova, A. Machara, M. A. Endoma-Arias, J. Duchek, D. R. Adams, D. P. Cox, T. Hudlický, Adv. Synth. Catal. 2012, 354, 2706–2712.
S. Thavaneswaran, K. McCamley, P. J. Scammells, Nat. Prod. Commun. 2006, 1, 885–897.
For the N-demethlyation using chloroformate, see:
A. Kimishima, C. J. Wenthur, B. Zhou, K. D. Janda, ACS Chem. Biol. 2017, 12, 36–0;
R. A. Olofson, J. T. Martz, J. P. Senet, M. Piteau, T. Malfroot, J. Org. Chem. 1984, 49, 2081–2082;
M. A. Schwartz, R. A. Wallace, J. Med. Chem. 1981, 24, 1525–1528.
For the N-demethlyation using BrCN, see:
A. Machara, M. A. A. Endoma-Arias, I. Císařova, D. P. Cox, T. Hudlický, Synthesis 2016, 48, 1803–1813;
B. R. Selfridge, X. Wang, Y. Zhang, H. Yin, P. M. Grace, L. R. Watkins, A. E. Jacobson, K. C. Rice, J. Med. Chem. 2015, 58, 5038–5052.
For the N-demethlyation using H2O2, see:
D. D. Do Pham, G. F. Kelso, Y. Yang, M. T. Hearn, Green Chem. 2014, 16, 1399–1409;
G. B. Kok, P. J. Scammells, Bioorg. Med. Chem. Lett. 2010, 20, 4499–4502;
Z. Dong, P. J. Scammells, J. Org. Chem. 2007, 72, 9881–9885;
K. McCamley, J. A. Ripper, R. D. Singer, P. J. Scammells, J. Org. Chem. 2003, 68, 9847–9850.
For the N-demethlyation using O2 and Pd, see:
R. J. Carroll, H. Leisch, E. Scocchera, T. Hudlicky, D. P. Cox, Adv. Synth. Catal. 2008, 350, 2984–2992;
A. Machara, L. Werner, M. A. Endoma-Arias, D. P. Cox, T. Hudlický, Adv. Synth. Catal. 2012, 354, 613–626.
A. Machara, D. P. Cox, T. Hudlicky, Adv. Synth. Catal. 2012, 354, 2713–2718.
B. Gutmann, U. Weigl, D. P. Cox, C. O. Kappe, Chem. Eur. J. 2016, 22, 10393–10398.
B. Gutmann, D. Cantillo, U. Weigl, D. P. Cox, C. O. Kappe, Eur. J. Org. Chem. 2017, 914–927.
B. Gutmann, P. Elsner, D. P. Cox, U. Weigl, D. M. Roberge, C. O. Kappe, ACS Sustainable Chem. Eng. 2016, 4, 6048–6061.
J. A. Ripper, E. R. Tiekink, P. J. Scammells, Bioorg. Med. Chem. Lett. 2001, 11, 443–445.
J. W. Beatty, C. R. Stephenson, Acc. Chem. Res. 2015, 48, 1474–1484;
G. Wu, Y. Li, X. Yu, Y. Gao, H. Chen, Adv. Synth. Catal. 2017, 359, 687–692.
P. Sobieszuk, J. Aubin, R. Pohorecki, Chem. Eng. Technol. 2012, 35, 1346–1358;
G. N. Doku, W. Verboom, D. N. Reinhoudt, A. van den Berg, Tetrahedron 2005, 61, 2733–2742.
D. Cambié, C. Bottecchia, N. J. Straathof, V. Hessel, T. Noël, Chem. Rev. 2016, 116, 10276–10341;
Y. Su, N. J. Straathof, V. Hessel, T. Noël, Chem. Eur. J. 2014, 20, 10562–10589;
K. Gilmore, P. H. Seeberger, Chem. Rec. 2014, 14, 410–418;
L. D. Elliott, J. P. Knowles, P. J. Koovits, K. G. Maskill, M. J. Ralph, G. Lejeune, L. J. Edwards, R. I. Robinson, I. R. Clemens, B. Cox, D. D. Pascoe, Chem. Eur. J. 2014, 20, 15226–15232;
E. M. Schuster, P. Wipf, Isr. J. Chem. 2014, 54, 361–370.
C. A. Hone, D. Roberge, C. O. Kappe, ChemSusChem 2017, 10, 32–41.
T. Y. Shang, L. H. Lu, Z. Cao, Y. Liu, W. M. He, B. Yu, Chem. Commun. 2019, 55, 5408–5419.
A. P. Darmanyan, Chem. Phys. Lett. 1984, 110, 89–94.
R. C. Kanner, C. S. Foote, J. Am. Chem. Soc. 1992, 114, 678–681.
N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075–10166;
M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem. 2016, 81, 6898–6926;
J. W. Tucker, C. R. J. Stephenson, J. Org. Chem. 2012, 77, 1617–1622.
C. J. Clarke, W.-C. Tu, O. Levers, A. Bröhl, J. P. Hallett, Chem. Rev. 2018, 118, 747–800.
Y. Chen, O. de Frutos, C. Mateos, J. A. Rincon, D. Cantillo, C. O. Kappe, ChemPhotoChem 2018, 2, 906–912.
This work was carried out with a 2.77 mL reactor. It should be noted that the commercial platform utilized can be readily scaled up even for gas liquid mixtures by simply using larger volume plates: N. Emmanuel, C. Mendoza, M. Winter, Horn, C. A. Vizza, L. Dreesen, B. Heinrichs, J.-C. M. Monbaliu, Org. Process Res. Dev. 2017, 21, 1435–1438.
