Fentanyl 4- substituted analogs

Illegal use of fentanyl in the United States is linked to the availability of heroin. The majority of the users of the designer analogs of fentanyl prefer heroin and will use it instead when available. Due to the United States War on Drugs, the availability of fentanyl substitutes is being limited. 

This situation became particularly acute with respect to the development of illicit analogs of fentanyl to derive heroin substitutes. Fentanyl is a synthetic opioid, a p-receptor agonist, and is about 100-200 times more potent than morphine as an analgesic. As with other narcotic analgesics, respiratory depression is the most significant acute toxic effect of the fentanyl derivatives. Fentanyl analogs can be 80-1000... 

Fentanyl and its analogs are made from TV-substituted-4-piperidones [i.e., from the same intermediates of the reversed esters of pethidine (p. 266)]. These ketones condense with aniline under the influence of catalysts such as toluene-p-sulfonic acid(2) and zinc chloride(18) to give Schiff bases, which are reduced to diamines 4 by NaBH4 or LAH. Recently, the direct conversion of 4-piperidones to 4-anilino derivatives 4 has been achieved by reductive amination with aniline and sodium cyanoborohydride (NaBH3CN).(19) The diamines are acylated with propionic anhydride. 

In further papers from Janssen Pharmaceutica an extensive series of fentanyl analogs substituted at C-4 by carboalkoxy (C02R as in pethidine), alkoxymethyl (CH2OR) and acyl (COR as in ketobemidone) were reported.<37) When alkyl in these groups was methyl, all C-4 additions were advantageous and remarkable orders of potency were achieved in rats (similar, in fact, to those found for certain bridged thebaine analgesics, p. 69) as shown (13-15). 

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