Editing Fentanyl (section)

== Synthesis ==
Fentanyl is a 4-anilinopiperidine class synthetic opioid.<ref>{{cite journal | vauthors = Vardanyan RS, Hruby VJ | title = Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications | journal = Future Medicinal Chemistry | volume = 6 | issue = 4 | pages = 385–412 | date = March 2014 | pmid = 24635521 | pmc = 4137794 | doi = 10.4155/fmc.13.215 }}</ref> The synthesis of Fentanyl is accomplished by one of four main methods as reported in the scientific literature: the Janssen, Siegfried, Gupta, or Suh method.<ref>{{cite journal | vauthors = Valdez CA | title = Gas Chromatography-Mass Spectrometry Analysis of Synthetic Opioids Belonging to the Fentanyl Class: A Review | journal = Critical Reviews in Analytical Chemistry | volume = 52 | issue = 8 | pages = 1938–1968 | date = 17 November 2022 | pmid = 34053394 | doi = 10.1080/10408347.2021.1927668 | s2cid = 235255612 | doi-access = free | title-link = doi }}</ref><ref>{{cite web |title=News: April 2022 – UNODC: Three precursors of the most common synthesis routes used in illicit fentanyl manufacture now under international control |url=https://www.unodc.org/LSS/Announcement/Details/b152bda5-5d71-4f7e-9d68-1bdd9af04a83 |access-date=15 November 2023 |website=www.unodc.org |archive-date=15 November 2023 |archive-url=https://web.archive.org/web/20231115232130/https://www.unodc.org/LSS/Announcement/Details/b152bda5-5d71-4f7e-9d68-1bdd9af04a83 |url-status=live }}</ref>

=== Janssen ===
[[File:Benzoylbenzylfentanyl synth.png|class=skin-invert-image|thumb|upright|Portion of the Janssen method of synthesis, to synthesize a related opioid]]
The original synthesis as patented in 1964 by Paul Janssen involves the synthesis of [[benzylfentanyl]] from N-benzyl-[[4-Piperidone]]. The resulting benzylfentanyl is used as feedstock to [[norfentanyl]]. It is norfentanyl that forms fentanyl upon reaction with a phenethyl halide.<ref>{{Cite patent|number=US3141823A|title=Method for producing analgesia|gdate=1964-07-21|invent1=Janssen|invent2=Francis|inventor1-first=PA|inventor2-first=JG|url=https://patents.google.com/patent/US3141823A/en}}</ref><ref>{{cite web |date=18 June 2020 |title=Fentanyl Synthesis |url=https://gpatindia.com/fentanyl-synthesis-sar-mcqstructurechemical-properties-and-therapeutic-uses/ |url-status=live |archive-url=https://archive.today/20221228231415/https://gpatindia.com/wp-content/uploads/2020/06/fentanyl-synthesis.png |archive-date=28 December 2022 |website=GPTA India}}</ref>

=== Siegfried ===
[[File:NPP to fentanyl.svg|class=skin-invert-image|thumb|Siegfried method from NPP through 4-ANPP to fentanyl]]
The Siegfried method, initially described in 1978 and later published on [[The Hive (website)|The Hive]], involves the initial synthesis of [[N-phenethyl-4-piperidone|''N''-phenethyl-4-piperidone]] (NPP).<ref>{{cite journal | vauthors = Weedn VW, Elizabeth Zaney M, McCord B, Lurie I, Baker A | title = Fentanyl-related substance scheduling as an effective drug control strategy | journal = Journal of Forensic Sciences | volume = 66 | issue = 4 | pages = 1186–1200 | date = July 2021 | pmid = 33951192 | pmc = 8360110 | doi = 10.1111/1556-4029.14712 }}</ref> This intermediate is [[Reductive amination|reductively aminated]] to [[4-anilino-N-phenethylpiperidine|4-anilino-''N''-phenethylpiperidine]] (4-ANPP). Fentanyl is produced following the reaction of 4-ANPP with an acyl chloride.<ref>{{cite web |title=Synthesis of Fentanyl |url=https://erowid.org/archive/rhodium/chemistry/fentanyl.html |website=Rhodium |publisher=Siegfried |access-date=24 January 2023 |archive-date=5 August 2022 |archive-url=https://web.archive.org/web/20220805104925/https://www.erowid.org/archive/rhodium/chemistry/fentanyl.html |url-status=live }}</ref> The Siegfried method was used in the early 2000s to manufacture fentanyl in both domestic and foreign clandestine laboratories.<ref>{{cite web |title=Designation of Benzylfentanyl and 4-Anilinopiperidine, Precursor Chemicals Used in the Illicit Manufacture of Fentanyl, as List I Chemicals |url=https://www.federalregister.gov/documents/2020/04/15/2020-07064/designation-of-benzylfentanyl-and-4-anilinopiperidine-precursor-chemicals-used-in-the-illicit |website=Federal Register |access-date=28 January 2023 |date=15 April 2020 |archive-date=5 November 2021 |archive-url=https://web.archive.org/web/20211105125231/https://www.federalregister.gov/documents/2020/04/15/2020-07064/designation-of-benzylfentanyl-and-4-anilinopiperidine-precursor-chemicals-used-in-the-illicit |url-status=live }}</ref>

=== Gupta ===
[[File:GuptaFent2.jpg|class=skin-invert-image|thumb|Gupta method from [[4-Piperidone]] to fentanyl]]
The Gupta (or 'one-pot') method starts from [[4-Piperidone]] and skips the direct use of 4-ANPP/NPP; rather, the compounds are formed only as impurities or temporary intermediates.<ref>{{cite journal |vauthors=Gupta P |date=9 November 2005 |title=A Convenient One-Pot Synthesis of Fentanyl |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/chin.200549130 |access-date=24 January 2023 |journal=ChemInform |volume=36 |issue=49 |doi=10.1002/chin.200549130 |archive-date=24 January 2023 |archive-url=https://web.archive.org/web/20230124235847/https://onlinelibrary.wiley.com/doi/abs/10.1002/chin.200549130 |url-status=live }}</ref> For the first half of 2021, the [[Drug Enforcement Administration|U.S. Drug Enforcement Administration]] found the Gupta method was the predominant synthesis route in their samples of seized fentanyl.<ref>{{cite web |title=Fentanyl Profiling Program Report |url=https://www.dea.gov/sites/default/files/2022-05/FPP%20Report%20January%202022.pdf |publisher=Drug Enforcement Administration |access-date=25 January 2023 |pages=1–2 |archive-date=25 January 2023 |archive-url=https://web.archive.org/web/20230125211947/https://www.dea.gov/sites/default/files/2022-05/FPP%20Report%20January%202022.pdf |url-status=live }}</ref> In 2022, Braga and coworkers described a synthesis of fentanyl involving continuous flow that uses reagents similar to the ones described for the Gupta procedure.<ref name = "Braga_2022">{{cite journal | vauthors = Braga FC, Ramos TO, Brocksom TJ, de Oliveira KT | title = Synthesis of Fentanyl under Continuous Photoflow Conditions | journal = Organic Letters | volume = 24 | issue = 45 | pages = 8331–8336 | date = November 2022 | pmid = 36346151 | doi = 10.1021/acs.orglett.2c03338 | s2cid = 253396263 }}</ref>

=== Suh ===
The Suh (or 'total synthesis') method skips the direct use of piperidine precursors in favor of creating the ring system in situ.<ref name="pmid9875518">{{cite journal | vauthors = Suh YG, Cho KH, Shin DY | title = Total synthesis of fentanyl | journal = Archives of Pharmacal Research | volume = 21 | issue = 1 | pages = 70–72 | date = February 1998 | pmid = 9875518 | doi = 10.1007/BF03216756 | s2cid = 31408546 }}</ref>