Stereochemical studies of narcotic analgesics related to pethidine and fentanyl.

  • Francis Omoseyin Ogungbamila

Student thesis: Doctoral ThesisPhD


A brief survey of synthetic narcotic analgesics, with particular attention to the C-methyl substituted reversed esters of pethidine and the 4-anilinopiperidine analgesics (fentanyl analogues), is given. The 2-and 3-monomethyl, and the 2,6-, 2,5-, and 3,5-dimethyl analogues of the reversed ester of pethidine have been tho-roughly investigated from both a stereochemical and structure-activity point of view, but this was not the case with the 2,3-dimethyl analogues, which was therefore a subject of the present thesis. The syntheses and characterisation of the isomeric 2,3-dimethyl analogues of the reversed ester of pethidine, including a novel route to the precursor 1,2,3-trimethyl-4-piperidone, are described. The relative stereochemistry of the precursor alcohols and their corresponding esters have been unambiguously established by spectroscopic techniques. The solute conformation of the isomeric alcohols and their corresponding esters were determined by 13 C-n.m.r spectroscopy, supplemented by 1H-nmr and infrared dilution studies, while the solid state confor-mation of the alcohols were determined by X-ray crystallography. Stereochemical structure-activity correlations in the 2,3-dimethyl analogues were in close agreement with established stereochemical structure-activity pattern in the reversed esters of pethidine, and they further highlight the significance of the enantiotopic C-methyl substitution on the activity of the 4-phenyl piperidine analgesics. The syntheses of the isomeric 3-allyl fentanyl and the N-methyl analogues, and the 3-propyl analogues, and their stereochemistry are also described. This aspect of the work was undertaken in order to establish the similarities or otherwise in the stereochemical structure-activity relationships of the 3-alkyl fentanyls and the corresponding 3-alkyl substituted reversed ester of pethidine. The pharmacological results, however, suggested there were no similarities in the relative modes of uptake of the two groups at the analgesic receptor site. The syntheses of the phenolic analogues of the reversed ester of pethidine, the 3-methyl analogue, and the N-phenethyl derivatives were also undertaken in order to further investigate the effects of phenolic substitu-tion on their opiate properties. The relative configuration and solute conformations of the derivatives were established by 13C-n.m.r spectroscopy. The results of the pharmacological tests confirmed the earlier report that a 4-(m-hydroxyphenyl) substitution in the reversed ester of pethidine led to abolition of activity, but it however failed to substantiate an earlier claim that the phenolic analogue of B-prodine, a potent narcotic agonist, was transformed into an antagonist devoid of any agonist activity. The chemistry and stereochemistry of the Prins product from a 4-substituted 1,2,3,5-tetrahydropyridine and excess of formaldehyde, a substituted bicyclic nonane, are also discussed in the appendix.
Date of Award1982
Original languageEnglish
Awarding Institution
  • University of Bath

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