Synthetic Methods and SAR Data

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. 

Larger and smaller N-acyl functions provide less active analogs (potencies of fentanyl and NCOR analogs, pethidine = 1 NCOMe 50, NCOEt 700, 

In spite of the SAR discrepancies between the fentanyl and pethidine groups so far noted, the agonist (albeit weak) rather than antagonist activities of N-allyl and 3,3-dimethylallyl analogs (MHP potencies fentanyl, 470 N-allyl, 0.4 N-dimethylallyl, 0.5 pethidine l)(18)poiht to a closer relationship of the anilide group with the 4-phenylpiperidine than the morphine class of analgesic. 

1 Janssen (unpublished data) reports both ru and irans isomers, examined as oxalates, to have ED50 values near 0 04 mg/kg in the rat TW test 

R = CH2CH=CH2 throughout reagents a, KOH-isopropanol b, Ph(CH2)2Br-K2C03 c, (EtC0)20 

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