4-Methyl fentanyl

In 1979-1980, some illegal fentanyl analogues appeared that were being sold as substitutes for heroin on the street. Suddenly, a series of more than a dozen mysterious deaths occurred in southern California. Upon autopsy, the victims strongly looked as if they had overdosed on heroin however, no traces of heroin could be found in their bodies. Later, forensic chemists identified a fentanyl analogue (alpha-methyl-fentanyl) that was present in all of the victims. As it turns out, alpha-methyl-fentanyl was being sold on the streets under the name China White (Figure 7.2), because it resembled (and contained) pure synthetic heroin that was produced in Southeast Asia. 

Figure 7.3 The chemical structure of fentanyl and its illegal analogues alpha-methyl-fentanyl and 3-methyl-fentanyl are shown here. Fentanyl was originally designed and marketed as an anesthetic, as it is 100 times stronger than morphine.

Figure 15.5. Structures of some "designer drugs" of abuse. Compare the structure of alpha-methyl fentanyl with that of fentanyl, MMP+ with that of pethidine, and ecstasy with that of methamphetamine.

Ayres, WA. et al. 1981. The bogus drug Three methyl and alpha methyl fentanyl sold as China "White of Psychoactive Drugs 13(1) 91-93. 

The enhancement of potency due to the presence of an equatorial methyl group noted in the meperidine series also applies to fentanyl analogues. The ring nitrogen of the starting material (27-1) for this particular derivative is protected by a benzyl group since it will be replaced later by a somewhat more complex side chain. 

The l-methyl-3-allyl congener of fentanyl was made by application of the routine synthesis to l-methyl-3-allyl-4-piperidone (p.267) while l-carbethoxy-3-allyl-4-piperidone served as intermediate for synthesis of the 3-allyl/propyl-N-phenethyl analogs (Scheme 8.1). Reduction of intermediate Schiff bases was highly stereoselective and the cis isomers were produced almost exclusively by both chemical and catalytic reduction procedures low yields of the 3-propyl... 

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). 

In contrast to these failures, several derivatives in which the anilido nitrogen of fentanyl is doubly linked to C-4 of the piperidine ring, forming a spirane (19), are highly potent, although unusual in requiring an a-methyl-benzyl rather than phenethyl substituent attached to the piperidine nitrogen. 

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