Etonitazene

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Etonitazene
Skeletal formula of etonitazene
Ball-and-stick model of the etonitazene molecule
Clinical data
ATC code
  • none
Legal status
Legal status
Identifiers
  • 2-(p-Ethoxybenzyl)-1-diethylaminoethyl-5-nitrobenzimidazole
JSmol)
  • CCOC1=CC=C(CC2=NC3=C(N2CCN(CC)CC)C=CC(N(=O)=O)=C3)C=C1
  • InChI=1S/C22H28N4O3/c1-4-24(5-2)13-14-25-21-12-9-18(26(27)28)16-20(21)23-22(25)15-17-7-10-19(11-8-17)29-6-3/h7-12,16H,4-6,13-15H2,1-3H3 checkY
  • Key:PXDBZSCGSQSKST-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Etonitazene, also known as EA-4941 or CS-4640,

better source needed
]

Because it is characterized by a strong

morphine sulfate.[citation needed
]

Synthesis

Etonitazene and its related

structure-activity relationship
of this new family of analgesics. Two general synthetic methods were developed for the preparation of these compounds.

The first method involved the condensation of

phenylacetonitrile to form a 2-benzylbenzimidazole. The benzimidazole is then alkylated with the desired 1-chloro-2-dialkylaminoethane, forming the final product. This particular procedure was most useful for the preparation of benzimidazoles that lacked substituents on the benzene rings. A diagram of this method is displayed below.[11]

Etonitazene 1960 unsubstituted simple synthesis

The most versatile synthesis

2,4-dinitrochlorobenzene
with 1-amino-2-diethylaminoethane to form N-(β-Diethylaminoethyl)-2,4-dinitroaniline [aka: N'-(2,4-Dinitrophenyl)-N,N-diethyl-ethane-1,2-diamine]. The 2-nitro substituent o n the
phenylacetonitrile (aka: p-ethoxybenzyl cyanide). The imino ether, 2-(4-Ethoxyphenyl)-acetimidic acid ethyl ester hydrochloride, is prepared by dissolving the 4-substituted benzyl cyanide in a mixture of anhydrous ethanol and chloroform and then saturating this solution with dry hydrogen chloride gas. The reaction between the 2-(β-dialkylaminoalkylamine)-5-nitroaniline and the HCl salt of the imino ethyl ether results in the formation of etonitazene. This procedure is particularly useful in the preparation of the 4-, 5-, 6-, and 7-nitrobenzimidazoles. Varying the choice of the substituted phenylacetic acid imino ether affords compounds with a diversity of substituents on the benzene ring at the 2- position. A diagram of this particular synthesis as it applies to the preparation of etonitazene is shown below.[5]

A particularly novel, high-yielding synthesis of etonitazene was developed by FI Carroll and MC Coleman in the mid-1970s

THF at 50 °C for 192 hours (8 days), a near quantitative yield (100%) of etonitazene was obtained. In addition to the impressive improvement in yield over the conventional procedure, the work up procedure was greatly simplified since quinoline, carbon dioxide, and ethanol
were the only by-products formed. A diagram of this procedure is shown below.

Etonitazene 1975 synthesis

A 2011 publication

secondary amine nitrogen of 2-(4-Ethoxybenzyl)-5-nitro-1H-benzoimidazole was then alkylated with (2-Chloroethyl)diethylamine to form etonitazene.[11]
A diagram of this synthesis is shown below.

Etonitazene 2011 synthesis

Analogs

Further information: List of benzimidazole opioids

A number of analogues are known, with the only other well-known compound to come out of the original 1950s research being

etazene, though others have continued to appear.[14][15]

Of these analogues, only etonitazene and clonitazene are explicitly listed under UN conventions and so are controlled throughout the world. The rest would only be illegal in countries such as the US, Australia and New Zealand that have laws equivalent to the

Federal Analog Act. In the United States Etonitazene is a Schedule I narcotic controlled substance
with a DEA ACSCN of 9624 and a 25 gram (7⁄8 oz) manufacturing quota as of 2022.

Illicit production

Illicit production and sale of etonitazene has been limited. Identified on the

dose-response curve, and unpredictable pharmacokinetics especially when injected, in a similar manner to some other potent opioids such as dextromoramide, which may cause etonitazene to be especially hazardous when compared to opioids of similar potency such as fentanyl.[19]

See also

  • Etazen
    (desnitroetonitazene)

References

  1. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ^ King JW, Cleveland JP, Lennox WJ (November 1991). Williams JD, Reeves PJ (eds.). Synthesis and Bioactivity of 2-(Alpha-Hydroxy-Para-Alkoxybenzyl) and 2-Alkoxy Arylamino Analogs of Etonitazene (CS - 4640). Proceedings of the U.S. Army Chemical Research, Development and Engineering Center Scientific Conference on Chemical Defense Research. Aberdeen Proving Ground, Maryland: Edgewood Research, Development and Engineering Center, Aberdeen Proving Ground, MD.
  3. ^ US patent 2935514, Hoffmann K, Hunger A, Kebrle J, Rossi A, "Benzimidazoles", published 1957-09-19, issued 1960-05-03, assigned to Ciba Pharmaceutical Products Inc., Summit, NJ. 
  4. S2CID 38073529
    .
  5. ^
    S2CID 32179439
    .
  6. ^
    doi:10.1002/hlca.19600430413
    .
  7. doi:10.1002/hlca.19600430515
    .
  8. doi:10.1002/hlca.19600430634
    .
  9. doi:10.1002/hlca.19610440513
    .
  10. S2CID 6824038
    .
  11. ^
    doi:10.1002/hlca.19600430323
    .
  12. PMID 237125
    .
  13. PMID 22034860
    .
  14. S2CID 208187034
    .
  15. S2CID 234646245
    .
  16. ^ Sorokin VI, Ponkratov KV, Drozdov MA (1999). "Etonitazene Encountered in Moscow". Microgram. 32 (9): 239–244.
  17. ^ Reavy P (3 June 2003). "Chemist charged in drug case". Deseret News. Salt Lake City. Archived from the original on March 7, 2014.
  18. ^ "Этонитазен (etonitazene) - описание препарата" [Etonitazene (etonitazene) - a description of the drug] (in Russian). Social Services LLC. Archived from the original on 23 March 2019.
  19. PMID 10844102
    .
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