The base catalyzed conjugate addition of 2-phenylbutyronitrile [769-68-6] (1) to ethyl acrylate (2) gives ethyl 4-cyano-4-phenylhexanoate, CID:139890735 (3). Alkaline hydrolysis of the nitrile group into an amide group, and subsequent acidic cyclization of the product affords the desired glutethimide (4).
Mechanism of action and uses
Glutethimide is a CYP2D6 enzyme inducer, enabling the body to convert higher amounts of codeine to morphine, frequently leading to ingestion of glutethimide alongside codeine-containing products, such as Tylenol No. 3 or No. 4, and widespread misuse, overdose, and fatalities. Colloquially called "hits," "pancakes and syrup," or "Dors and 4s", this combination is highly potent and often lethal due to extreme respiratory depression.[9][10]
In recreational quantities, any form of glutethimide was colloquially called a "Ciba" and all trade names of the medicine were manufactured as a white pill/tablet with a score line directed to be taken by mouth, and containing 500mg of the active ingredient.
During the 1980s, glutethimide became increasingly harder to access and subject to many restrictions as a CSA-classified Schedule II substance, but market demand for the product continued to exist among northeastern U.S. states and metropolitan centers, leading to the substance's clandestine "underground" manufacturing and sale, which only increased when methaqualone was fully withdrawn from the U.S. market and classified a Schedule I drug.[11]:203
Clinical research
Glutethimide's effect on quickening the conversion of codeine to morphine was studied clinically, including some research in the 1970s in various countries. In these studies, it was used under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, particularly as a Substitutionmittel[clarification needed] that may be a useful alternative to methadone.[12][13]
Glutethimide was available in the United States until 1993, when production ceased and it was withdrawn from the market. Since 2013, the U.S. DEA has limited annual production to three grams, equivalent to six Doriden tablets, suggesting that current use is limited to small-scale research.[citation needed]
Legal status
United States
Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances.[14] It was originally a Schedule III drug in the United States under the Controlled Substances Act, but in 1991 it was upgraded to Schedule II,[15] several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination.[10][16] It has a DEA ACSCN of 2550 and a 2013 production quota of 3g.
↑Barceloux DG (2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. Hoboken, N.J.: John Wiley & Sons, Inc. pp.492–493. ISBN978-0-471-72760-6. OCLC814224300.
12USpatent 2673205,Hoffmann K, Tagmann E,"3-Disubstituted Dioxopiperidines and the Manufacture thereof",issued 23 March 1954, assigned to CIBA
↑Salmon-Legagneur F, Neveu C (January 1952). "Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques". Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences. 234 (10): 1060–2.
↑Salmon-Legagneur F, Neveu C (1953). "Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques". Bull. Soc. Chim. France: 70.
↑DEpatent 950193,Hoffmann K Tagmann E,"Verfahren zur Herstellung neuer Dioxopiperidine",issued 4 October 1956, assigned to CIBA
↑Shamoian CA (1975). "Codeine and glutethimide. Euphoretic, addicting combination". New York State Journal of Medicine. 75 (1): 97–99. PMID1053824.
12Havier RG, Lin R (April 1985). "Deaths as a result of a combination of codeine and glutethimide". Journal of Forensic Sciences. 30 (2): 563–6. doi:10.1520/JFS11840J. PMID3998703. S2CID45780806.
↑Gahlinger P (2003). "Methaqualone and Glutethimide". Illegal Drugs: A Complete Guide to Their History, Chemistry, Use, and Abuse. Penguin. ISBN9780452285057. OCLC52269170.
↑Popa D, Loghin F, Imre S, Curea E (August 2003). "The study of codeine-gluthetimide pharmacokinetic interaction in rats". Journal of Pharmaceutical and Biomedical Analysis. 32 (4–5): 867–77. doi:10.1016/s0731-7085(03)00189-4. PMID12899973.
↑Feuer E, French J (February 1984). "Descriptive epidemiology of mortality in New Jersey due to combinations of codeine and glutethimide". American Journal of Epidemiology. 119 (2): 202–7. doi:10.1093/oxfordjournals.aje.a113738. PMID6695899.
