Chemistry:Etonitazene

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Short description: Chemical compound
Etonitazene
Skeletal formula of etonitazene
Ball-and-stick model of the etonitazene molecule
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Chemical and physical data
FormulaC22H28N4O3
Molar mass396.491 g·mol−1
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Etonitazene, also known as EA-4941 or CS-4640,[1] is a benzimidazole opioid, first reported in 1957,[2] that has been shown to have approximately 1,000 to 1,500 times the potency of morphine in animals.[3][better source needed]

Because it is characterized by a strong dependency potential and a tendency to produce profound respiratory depression, it is not used in humans. It is, however, useful in animal models for addiction studies, particularly those requiring the animals to drink or ingest the agent, because it is not as bitter as opiate salts like morphine sulfate.[citation needed]

Synthesis

Etonitazene and its related opioid agonist benzimidazoles were discovered in the late 1950s,[4][5][6][7][8][9] by a team of Swiss researchers working at the pharmaceutical firm CIBA (now Novartis). One of the first compounds investigated by the Swiss team was 1-(β-diethylaminoethyl)-2-benzylbenzimidazole, which was found to possess 10% of the analgesic activity of morphine when tested in rodent bioassays. This finding encouraged the group to begin a comprehensive systematic study of 2-benzylbenzimidazoles and to establish the 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 o-phenylenediamine with para-ethoxy-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.[10]

Etonitazene 1960 unsubstituted simple synthesis

The most versatile synthesis[5] developed by the Swiss team first involved alkylation of 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 2,4-dinitroaniline compound is then selectively reduced to the corresponding primary amine by utilizing ammonium sulfide as the reducing agent. The ammonium sulfide can be formed in situ by the addition of concentrated aqueous ammonium hydroxide followed by saturation of the solution with hydrogen sulfide gas. The intermediate formed by the selective reduction of the 2-nitro substituent, 2-(β-Diethylaminoethylamino)-5-nitroaniline, is then reacted with the hydrochloride salt of the imino ethyl ether of 4-ethoxyphenylacetonitrile (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.[4]

Etonitazine syn.png

A particularly novel, high-yielding synthesis of etonitazene was developed by FI Carroll and MC Coleman in the mid-1970s[11] The authors were tasked with the preparation of large quantities of etonitazene, but found the conventional synthesis to be inadequate. The problem with the conventional synthesis was the lability of the imino ether reactant, 2-(4-Ethoxyphenyl)-acetimidic acid ethyl ester (prepared by reacting 4-ethoxyphenylacetonitrile with ethanolic HCl). The imino ether necessitated the use of anhydrous reaction conditions and was inconvenient to prepare in large quantities. This led the authors to experiment with the use of a coupling reagent, EEDQ (N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), in order to promote the condensation of 2-(2-diethylaminoethylamino)-5-nitroaniline with 4-ethoxyphenylacetic acid. The authors discovered that when this condensation was performed in the presence of 2 or more molar equivalents of EEDQ (added portionwise in 3 steps) in 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[12] [J. Org. Chem., 2011, 76(23), 9577-9583] from a South Korean team outlined a novel, one-pot synthesis for substituted and unsubstituted 2-benzyl-benzimidazoles that can be easily adapted to the preparation of etonitazene. The three component synthesis of the direct etonitazene precursor, 2-(4-Ethoxybenzyl)-5-nitro-1H-benzoimidazole, consists of a 2-Bromo- or 2-Iodo-5-nitro-phenylamine (1.0 molar equivalent), a 4-substituted benzaldehyde (1.2 equiv), and sodium azide (2 equiv). The 2-Halo-5-nitro-phenylamine requires a bromo or iodo group for optimal activity. 2-Chloro-phenylamines are completely unreactive. In addition to these three components, the reaction was optimized in the presence of 0.05 molar equivalents (5 mol%) of a catalyst, copper(I) chloride, and 5 mol% of ligand, TMEDA (tetramethylethylenediamine). After heating these components at 120 °C for 12 hours in DMSO, the direct etonitazene precursor, 2-(4-Ethoxybenzyl)-5-nitro-1H-benzoimidazole, was formed in an approx 80-90% yield. The secondary amine nitrogen of 2-(4-Ethoxybenzyl)-5-nitro-1H-benzoimidazole was then alkylated with (2-Chloroethyl)diethylamine to form etonitazene.[10] 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 clonitazene, which is much weaker than etonitazene (around 3x morphine). More recently since around late 2018 a number of designer analogues have started to appear on illicit markets around the world, with the most prominent compounds being metonitazene, isotonitazene and etazene, though others have continued to appear.[13][14]

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 Moscow illegal drug market in 1998, it was primarily smoked in laced cigarettes.[15] A chemist at Morton Thiokol synthesized the compound for his own use.[16] The drug was produced in Russia in 1996 and sold as 'Chinese Dwarf'. The drug resulted in an unconfirmed number of deaths due to its uncertain potency.[17] It appears to have a steep 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.[18]

See also

  • Etazen (desnitroetonitazene)

References

  1. ↑ "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.. November 1991. https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/ADA269546.xhtml. 
  2. ↑ Hoffmann K, Hunger A, Kebrle J, Rossi A, "Benzimidazoles", US patent 2935514, published 1957-09-19, issued 1960-05-03, assigned to Ciba Pharmaceutical Products Inc., Summit, NJ.
  3. ↑ "Factors Regulating Oral Consumption of an Opioid (Etonitazene) by Morphine-Addicted Rats". Psychopharmacologia 5 (1): 55–76. October 1963. doi:10.1007/BF00405575. PMID 14082382. 
  4. ↑ 4.0 4.1 "[Synthesis of analgesically active benzimidazole derivatives with basic substitutions]". Experientia 13 (10): 400–401. October 1957. doi:10.1007/BF02161116. PMID 13473817. 
  5. ↑ 5.0 5.1 "Benzimidazol-Derivate und verwandte Heterocyclen. IV. Die Kondensation von o-Phenylendiamin mit α-Aryl- und γ-Aryl-acetessigester" (in de). Helvetica Chimica Acta 43 (4): 1046–1056. 1960. doi:10.1002/hlca.19600430413. https://www.scribd.com/doc/78122927/Benzimidazole-Derivatives-and-Related-Hetero-Cycles-IV-the-Condensation-of-O-phenylenediamine-With-a-And-Gamma-Aryl-Acetoacetate-Helv-Chim-Acta-19. 
  6. ↑ "Benzimidazol-Derivate und verwandte Heterocyclen V. Die Kondensation von o-Phenylendiamin mit aliphatischen und alicyclischen β-Ketoestern" (in de). Helvetica Chimica Acta 43 (5): 1298–1313. 1960. doi:10.1002/hlca.19600430515. https://www.scribd.com/doc/78122989/Benzimidazole-derivatives-and-related-heterocycles-V-The-condensation-of-o-phenylenediamine-with-aliphatic-and-alicyclic-%C3%9F-keto-esters-Helv-Chim-Ac. 
  7. ↑ "Benzimidazol-Derivate und verwandte Heterocyclen VI. Synthese von Phenyl-[1-aminoalkyl-benzimidazolyl-(2)-essigsäure-estern und -amiden"] (in de). Helvetica Chimica Acta 43 (6): 1727–1733. 1960. doi:10.1002/hlca.19600430634. https://www.scribd.com/doc/78122995/Benzimidazole-Derivatives-and-Related-Hetero-Cycles-VI-Synthesis-of-Phenyl-1-Aminoalkyl-benzimidazolyl-2-Acetic-Acid-Esters-and-Amides-Helv-Ch. 
  8. ↑ "Benzimidazol-Derivate und verwandte Heterocyclen VII. Synthese neuer 2-Amino-benzimidazole" (in de). Helvetica Chimica Acta 44 (5): 1273–1282. 1961. doi:10.1002/hlca.19610440513. https://www.scribd.com/doc/78123010/Benzimidazole-Derivatives-and-Related-Hetero-Cycles-VII-Synthesis-of-New-2-Amino-benzimidazole-Helv-Chim-Acta-1961-44-5-1273-1282. 
  9. ↑ "[Benzimidazole derivatives with strong analgesic effects]". Experientia 13 (10): 401–403. October 1957. doi:10.1007/BF02161117. PMID 13473818. 
  10. ↑ 10.0 10.1 "Benzimidazol-Derivate und verwandte Heterocyclen. II. Synthese von 1-Aminoalkyl-2-benzyl-benzimidazolen" (in de). Helvetica Chimica Acta 43 (3): 800–809. 1960. doi:10.1002/hlca.19600430323. https://www.scribd.com/doc/78122975/Benzimidazole-Derivatives-and-Related-Hetero-Cycles-II-Synthesis-of-1-Aminoalkyl-2-Benzyl-benzimidazoles-Helv-Chim-Acta-1960-43-3-800-809. 
  11. ↑ "Etonitazene. An improved synthesis". Journal of Medicinal Chemistry 18 (3): 318–320. March 1975. doi:10.1021/jm00237a024. PMID 237125. 
  12. ↑ "Copper-catalyzed, one-pot, three-component synthesis of benzimidazoles by condensation and C-N bond formation". The Journal of Organic Chemistry 76 (23): 9577–9583. December 2011. doi:10.1021/jo2019416. PMID 22034860. 
  13. ↑ "Report on a novel emerging class of highly potent benzimidazole NPS opioids: Chemical and in vitro functional characterization of isotonitazene". Drug Testing and Analysis 12 (4): 422–430. April 2020. doi:10.1002/dta.2738. PMID 31743619. 
  14. ↑ "Synthesis, chemical characterization, and μ-opioid receptor activity assessment of the emerging group of nitazene new synthetic opioids.". Authorea. 12 November 2020. doi:10.22541/au.160520665.59016513/v1. https://en.authorea.com/doi/pdf/10.22541/au.160520665.59016513. 
  15. ↑ "Etonitazene Encountered in Moscow". Microgram 32 (9): 239–244. 1999. 
  16. ↑ Reavy, Pat (3 June 2003). "Chemist charged in drug case". Deseret News (Salt Lake City). http://www.deseretnews.com/article/987708/Chemist-charged-in-drug-case.html?pg=all. 
  17. ↑ "Этонитазен (etonitazene) - описание препарата" (in ru). Social Services LLC. http://lechenie-pri-narkomanii.ru/etonitazene.html. 
  18. ↑ "Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys". European Journal of Pharmacology 397 (1): 85–92. May 2000. doi:10.1016/s0014-2999(00)00248-x. PMID 10844102. 



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