Continuous flow Aza-Michael reaction for preparing the fast-acting synthetic opioid drug Remifentanil

Artur Vaz; João Luis Callegari Lopes; Giuliano Cesar Clososki

doi:10.1590/s2175-97902023e22764

Authors

Artur Vaz Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto https://orcid.org/0000-0002-6231-5003
João Luis Callegari Lopes Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto
Giuliano Cesar Clososki Universidade de São Paulo. Faculdade de Ciências Farmacêuticas de Ribeirão Preto Ribeirão Preto https://orcid.org/0000-0001-7605-4150

DOI:

https://doi.org/10.1590/s2175-97902023e22764%20%20

Keywords:

Remifentanil, Opioids, Organic synthesis, Continuous flow synthesis

Abstract

Remifentanil is a modern fentanyl analogue with ultrashort-action granted by an esterase-labile methyl propanoate chain. Here, we present the development of a continuous flow methodology for the key N-alkylation step of remifentanil preparation in a biphasic, “slug-flow” regime. We screened parameters under microwave-assisted reactions, translated conditions to flow settings, and obtained remifentanil under 15-min residence time in a 1-mL microreactor, with a space-time yield of 89 mg/mL·h and 94% yield.

Downloads

Download data is not yet available.

References

Adamo A, Beingessner RL, Behnam M, Chen J, Jamison TF, Jensen KF, et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science (80-). 2016;352(6281):61-7. Doi: 10.1126/science. aaf1337.

» https://doi.org/10.1126/science. aaf1337

Aguillon A, Leão R, Oliveira KT, Brocksom T, Miranda L, de Souza ROMA. Process intensification for obtaining a cannabidiol intermediate by Photo-oxygenation of limonene under continuous-glow conditions. Org Process Res Dev. 2020;24(10):2017-24. Doi: 10.1021/acs.oprd.0c00131.

» https://doi.org/10.1021/acs.oprd.0c00131

Bloemendal VRLJ, Janssen MACH, van Hest JCM, Rutjes FPJT. Continuous one-flow multi-step synthesis of active pharmaceutical ingredients. React Chem Eng. 2020;5(7):1186-97. Doi: 10.1039/d0re00087f.

» https://doi.org/10.1039/d0re00087f

Bürkle H, Dunbar S, van Aken H. Remifentanil: A novel, short-acting, μ-opioid. Anesth Analg. 1996;83(3):646-51. Doi: 10.1097/00000539-199609000-00038.

» https://doi.org/10.1097/00000539-199609000-00038

Dallinger D, Kappe CO. Why flow means green-Evaluating the merits of continuous processing in the context of sustainability. Curr Opin Green Sustain Chem. 2017;7:6-12. Doi: 10.1016/j.cogsc.2017.06.003.

» https://doi.org/10.1016/j.cogsc.2017.06.003

Feldman PL. Insights into the chemical discovery of remifentanil. Anesthesiology. 2020;(5):1229-34. Doi: 10.1097/ALN.0000000000003170.

» https://doi.org/10.1097/ALN.0000000000003170

Glasnov TN, Kappe CO. The microwave-to-flow paradigm: Translating high-temperature batch microwave chemistry to scalable continuous-flow processes. Chem-A Eur J. 2011;17(43):11956-68. Doi: 10.1002/chem.201102065.

» https://doi.org/10.1002/chem.201102065

Janssen PA, Gardocki JF. Method for producing analgesia. US 3141823 A, Dr. C. Janssen N.V., 1964.

Kockmann N, Gottsponer M, Zimmermann B, Roberge DM. Enabling continuous-flow chemistry in microstructured devices for pharmaceutical and fine-chemical production. Chem-A Eur J. 2008;14(25):7470-7. Doi: 10.1002/chem.200800707.

» https://doi.org/10.1002/chem.200800707

Malet-Sanz L, Susanne F. Continuous flow synthesis. a pharma perspective. J Med Chem. 2012;55(9):4062-98. Doi: 10.1021/jm2006029.

» https://doi.org/10.1021/jm2006029

Mandrelli F, Buco A, Piccioni L, Renner F, Guelat B, Martin B, et al. The scale-up of continuous biphasic liquid/liquid reactions under super-heating conditions: Methodology and reactor design. Green Chem. 2017;19(6):1425-30. Doi: 10.1039/c6gc02840c.

» https://doi.org/10.1039/c6gc02840c

Murie VE, Nicolino PV, dos Santos T, Gambacorta G, Nishimura RHV, Perovani IS, et al. Synthesis of 7-Chloroquinoline derivatives using mixed lithium-magnesium reagents. J Org Chem. 2021;86(19):13402-19. Doi: 10.1021/acs.joc.1c01521.

» https://doi.org/10.1021/acs.joc.1c01521

Pastre JC, Browne DL, Ley SV. Flow chemistry syntheses of natural products. Chem Soc Rev. 2013;42(23):8849-69. Doi: 10.1039/c3cs60246j.

» https://doi.org/10.1039/c3cs60246j

Pieber B, Gilmore K, Seeberger PH. Integrated flowprocessing-challenges in continuous multistep synthesis. J Flow Chem. 2017;7(October):1-8. Doi: 10.1556/1846.2017.00016.

» https://doi.org/10.1556/1846.2017.00016

Porta R, Benaglia M, Puglisi A. Flow chemistry: recent developments in the synthesis of pharmaceutical products. Org Process Res Dev. 2016;20(1):2-25. Doi: 10.1021/acs.oprd.5b00325.

» https://doi.org/10.1021/acs.oprd.5b00325

Raffa RB, Pergolizzi JV, LeQuang JA, Taylor R, Colucci S, Annabi MH. The fentanyl family: A distinguished medical history tainted by abuse. J Clin Pharm Ther. 2018;43(1):154-8. Doi: 10.1111/jcpt.12640.

» https://doi.org/10.1111/jcpt.12640

Sheldon RA. The: E factor 25 years on: The rise of green chemistry and sustainability. Green Chem. 2017;19(1):18-43. Doi: 10.1039/c6gc02157c.

» https://doi.org/10.1039/c6gc02157c

de Souza JM, Galaverna R, de Souza ANN, Brocksom TJ, Pastre JC, de Souza ROMA, et al. Impact of continuous flow chemistry in the synthesis of natural products and active pharmaceutical ingredients. An Acad Bras Cienc. 2018;90(1):1131-74. Doi: 10.1590/0001-3765201820170778.

» https://doi.org/10.1590/0001-3765201820170778

Continuous flow Aza-Michael reaction for preparing the fast-acting synthetic opioid drug Remifentanil

Authors

DOI:

Keywords:

Abstract

Downloads

References

Downloads

Published

Issue

Section

License

How to Cite

Funding data