Skip to content
2000
Volume 22, Issue 11
  • ISSN: 1570-1786
  • E-ISSN: 1875-6255

Abstract

Novel simple approach was elaborated for the preparation of fentanyl and sufentanil starting from commercially available, cheap 1-methyl-4-piperidone. Compared to existing syntheses new route is shorter, easily scalable, and does not require the use of expensive palladium catalysts, high-pressure equipment, and chromatographic separations. Moreover, it allows for to avoidance of working with the unstable norsufentanil, which is prone to a facile acyl migration to the nitrogen atom of the piperidine core even at ambient temperature, resulting in contamination of the target product.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/loc/10.2174/0115701786366473250601080424
2025-11-01
2026-01-02

  • From This Site

    /content/journals/loc/10.2174/0115701786366473250601080424
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. StanleyT.H. EganT.D. Van AkenH. Anesth. Analg.2008106245146210.1213/ane.0b013e3181605add 18227300
     [Google Scholar]
  2. BirdH.E. HuhnA.S. DunnK.E. J. Addict. Med.202317550350810.1097/ADM.0000000000001185 37788600
     [Google Scholar]
  3. ThompsonJ.P. ThompsonD.F. Ann. Pharmacother.2016501088289110.1177/1060028016659077 27413071
     [Google Scholar]
  4. PrommerE. ThompsonL. Patient Prefer. Adherence2011515716410.2147/PPA.S7665 21573046
     [Google Scholar]
  5. EscobarY. MañasA. JuliáJ. GálvezR. ZaragozáF. MargaritC. LópezR. CasasA. AntónA. CruzJ.J. Clin. Transl. Oncol.201315752653410.1007/s12094‑012‑0981‑1 23263914
     [Google Scholar]
  6. KornickC.A. Santiago-PalmaJ. MorylN. PayneR. ObbensE.A.M.T. Drug Saf.2003261395197310.2165/00002018‑200326130‑00004 14583070
     [Google Scholar]
  7. JanssenP.A. NiemegeersC.J. DonyJ.G. Arzneimittelforschung196313502507 13957426
     [Google Scholar]
  8. JanssenP. AdriaanJ. JosephF. Patent US3141823A1964
     [Google Scholar]
  9. JanssenP. JageneauA.H.M. DemoenP.J.A. van De WesteringhC. De CanniereJ.H.M. RaeymaekersA.H.M. WoutersM. SanczukS. HermansB.K.F. J. Med. Pharm. Chem.19602327128010.1021/jm50010a003 14406756
     [Google Scholar]
  10. GuptaP.K. GanesanK. PandeA. MalhotraR.C. J. Chem. Res.20052005745245310.3184/030823405774309078
     [Google Scholar]
  11. MićovićI.V. IvanovićM.D. VuckovicS.M. ProstranM.Š. Došen-MićovićL. KiricojevićV.D. Bioorg. Med. Chem. Lett.200010172011201410.1016/S0960‑894X(00)00394‑2 10987438
     [Google Scholar]
  12. MurashovaU.A. SadchikovaN.P. SkalkinaL.V. SmirnovS.K. Pharm. Chem. J.200438633633810.1023/B:PHAC.0000048149.69824.4d
     [Google Scholar]
  13. JealW. BenfieldP. Drugs199753110913810.2165/00003495‑199753010‑00011 9010652
     [Google Scholar]
  14. ZhengL. WuL.J. Anhui Yiyao20162057657810.3969/j.issn.1009‑6469.2016.03.052
     [Google Scholar]
  15. MićovićI.V. RoglićG.M. IvanovićM.D. Došen-MićovićL. KiricojevićV.D. PopovićJ.B. J. Chem. Soc., Perkin Trans. 119961162041205010.1039/P19960002041
     [Google Scholar]
  16. Van DaeleP.G.H. De BruynM.F.L. BoeyJ.M. SanczukS. AgtenJ.T.M. JanssenP.A.J. Arzneimittelforschung19762681521153110.1002/chin.197646236 12769
     [Google Scholar]
  17. FujitaW. GomesI. DeviL.A. Br. J. Pharmacol.2015172237538710.1111/bph.12663 24571499
     [Google Scholar]
  18. ShangY. FilizolaM. Eur J. Pharmacol.2015763Pt B20621310.1016/j.ejphar.2015.05.01225981301
     [Google Scholar]
  19. MoresK.L. CassellR.J. van RijnR.M. Neuropharmacology2019152152110.1016/j.neuropharm.2018.11.010 30419245
     [Google Scholar]
  20. KabliN. NguyenT. BalboniG. O’DowdB.F. GeorgeS.R. Mol. Psychiatry201419998699410.1038/mp.2013.115 24061495
     [Google Scholar]
  21. FaouziA. UpretyR. GomesI. MassalyN. KeresztesA.I. Le RouzicV. GuptaA. ZhangT. YoonH.J. AnsonoffM. AllaoaA. PanY.X. PintarJ. MorónJ.A. StreicherJ.M. DeviL.A. MajumdarS. J. Med. Chem.20206322136181363710.1021/acs.jmedchem.0c00901 33170687
     [Google Scholar]
  22. GuptaA. MulderJ. GomesI. RozenfeldR. BushlinI. OngE. LimM. MailletE. JunekM. CahillC.M. HarkanyT. DeviL.A. Sci. Signal.20103131ra54ra6010.1126/scisignal.2000807 20647592
     [Google Scholar]
  23. PierreF. UgurM. FaivreF. DoridotS. VeinanteP. MassotteD. Neuropharmacology2019152304110.1016/j.neuropharm.2019.03.009 30858104
     [Google Scholar]
  24. KreegerT.J. ArnemoJ.M. Handbook of Wildlife Chemical Immobilization.WyomingInternational Wildlife Veterinary Services Laramie1996
     [Google Scholar]
  25. NakhaeeS. SaeediF. MehrpourO. Heliyon2023912e2308310.1016/j.heliyon.2023.e23083 38144320
     [Google Scholar]
  26. FerrareziW.P.P. BragaA.F.A. FerreiraV.B. MendesS.Q. BrandãoM.J.N. BragaF.S.S. CarvalhoV.H. Braz. J. Anesthesiol.202171664264810.1016/j.bjane.2021.03.030 34411627
     [Google Scholar]
  27. PalamarJ.J. CottlerL.B. GoldbergerB.A. SevertsonS.G. GrundyD.J. IwanickiJ.L. CiccaroneD. Am. J. Drug Alcohol Abuse202248447148010.1080/00952990.2022.2081923 35704785
     [Google Scholar]
  28. PasternakG.W. PanY.X. Pharmacol. Rev.20136541257131710.1124/pr.112.007138 24076545
     [Google Scholar]
  29. MonkJ.P. BeresfordR. WardA. Drugs198836328631310.2165/00003495‑198836030‑00003 2903821
     [Google Scholar]
  30. Porela-TiihonenS. KokkiH. KokkiM. Expert Opin. Pharmacother.202021121407141810.1080/14656566.2020.1766025 32486875
     [Google Scholar]
  31. ZhiM. DiaoY. LiuS. HuangZ. SuX. GengS. ShenL. SunJ. LiuY. Eur. J. Clin. Pharmacol.202076450150610.1007/s00228‑019‑02806‑x 31912188
     [Google Scholar]
  32. Waara-WolleatK.L. HildebrandK.R. StewartG.R. Pain Med.20067325125910.1111/j.1526‑4637.2006.00155.x 16712626
     [Google Scholar]
  33. AlnemariA.M. KrafcikB.M. MansourT.R. GaudinD. World Neurosurg.201710650952810.1016/j.wneu.2017.07.009 28712906
     [Google Scholar]
  34. JanssenP.A. Van DaeleG.H.N Patent US4179569A1976
     [Google Scholar]
  35. PuthuparampilP.K. EturiS.R. CarrollR. 2008.Patent WO2008005423A1,2008
     [Google Scholar]
  36. WalzA.J. HsuF.L. Tetrahedron Lett.201455250150210.1016/j.tetlet.2013.11.058
     [Google Scholar]
  37. SrimuruganS. MuruganK. ChenC. Chem. Pharm. Bull. (Tokyo)200957121421142410.1248/cpb.57.1421 19952457
     [Google Scholar]
  38. KillgoreK. MattewJ. Patent US7208604B22007
     [Google Scholar]
  39. ShinD.Y. RyuJ.S. HyunS.S. ParkH.J. JeonR.O. SuhY.G. Arch. Pharm. Res.199922439840010.1007/BF02979064 10489880
     [Google Scholar]
  40. KudzmaL.V. SevernakS.A. BenvengaM.J. EzellE.F. OssipovM.H. KnightV.V. RudoF.G. SpencerH.K. SpauldingT.C. J. Med. Chem.198932122534254210.1021/jm00132a007 2585442
     [Google Scholar]
  41. EsipovaT.V. BorisenkoA.A. Terent’evP.B. GrishinaG.V. HerzshuhR. Russ. J. Org. Chem.200642574274710.1134/S1070428006050162
     [Google Scholar]
  42. NakatsuboF. CocuzzaA.J. KeeleyD.E. KishiY. J. Am. Chem. Soc.197799144835483610.1021/ja00456a056 874235
     [Google Scholar]
  43. VateleJ.M. Tetrahedron Lett.198425525997600010.1016/S0040‑4039(01)81742‑1
     [Google Scholar]
  44. ManoharanT.S. MadyasthaK.M. SinghB.B. BhatnagarS.P. WeissU. Synthesis198319831080981210.1055/s‑1983‑30523
     [Google Scholar]
  45. KoldobskiiA.B. MorozovaS.M. ShilovaO.S. DankovY.V. MoiseevS.K. J. Fluor. Chem.202427311023610.1016/j.jfluchem.2023.110236
     [Google Scholar]
  46. BragaF.C. RamosT.O. BrocksomT.J. de OliveiraK.T. Org. Lett.202224458331833610.1021/acs.orglett.2c03338 36346151
     [Google Scholar]
  47. GhaffarzadehM. JoghanS.S. FarajiF. Tetrahedron Lett.201253220320610.1016/j.tetlet.2011.11.018
     [Google Scholar]
  48. BrandsmaL. VasilevskyS.F. VerkuijsseH.D. Application of transition metal catalysts in organic synthesis.New YorkSpringer-Verlag2012
     [Google Scholar]
  49. StokesB.J. OpraS.M. SigmanM.S. J. Am. Chem. Soc.201213428114081141110.1021/ja305403s 22742056
     [Google Scholar]
  50. VardanyanR. VijayG. NicholG.S. LiuL. KumarasingheI. DavisP. VanderahT. PorrecaF. LaiJ. HrubyV.J. Bioorg. Med. Chem.200917145044505310.1016/j.bmc.2009.05.065 19540763
     [Google Scholar]
/content/journals/loc/10.2174/0115701786366473250601080424
Loading
Simple Practical Preparations of Sufentanil from Cheap and Commercially Available 1-methyl-4-piperidone
Lett. Org. Chem. 22, 861 (2025); https://doi.org/10.2174/0115701786366473250601080424
/content/journals/loc/10.2174/0115701786366473250601080424
/content/journals/loc/10.2174/0115701786366473250601080424
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): 1-methylpiperid-4-one; analgesics; demethylation; fentanyl; nucleophilic substitution; Sufentanil; synthetic opioids

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test