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UBC Theses and Dissertations

Synthesis of N-phenethylnorhydromorphone : a hydromorphone analogue Lo, Karen


Since its clinical introduction in 1926, hydromorphone (7) has been used in the treatment of moderate to severe pain. Hydromorphone (7) is a semi-synthetic congener of morphine (1), and it has a relative analgesic potency of 5 to 1 compared to its parent compound 1. It has been shown from previous structure-activity relationships on opioid analgesics that when a peripheral group on the molecule is modified, the analgesic activity of the molecule is altered. Specifically, the substitution of a phenethyl moiety for the methyl group on the basic nitrogen of opioid analgesics produces an increase in analgesic activity. For example, fentanyl (27), which is part of the piperidine group of analgesics, is found in rats to be 300 times more potent than morphine (1), the gold standard for comparative effects between opioid analgesics. To date, the N-phenethyl derivative 20 of hydromorphone has not been synthesized. As such, the purpose of this study was to synthesize N-phenethylnorhydromorphone (20); and ultimately to test the analgesic activity of 20 in the rat model. We hypothesized that the direct alkylation of norhydromorphone (17) with an alkyl halide via an SN2 reaction mechanism would be an effective route for the synthesis of N-phenethylnorhydromorphone (20). Although the chemical method proved to be effective in producing the desired compound 20, it was not efficient, producing a low yield of 1.3%. The identity of compound 20 was confirmed by high-performance liquid chromatography-tandem mass spectrometry, infrared spectroscopy, and 1H NMR analysis, both one-dimensional and two-dimensional. In conclusion, an alternate approach towards the synthesis of compound 20 will need to be examined in order to improve the productive yield, such that more product will be available for further studies on the analgesic activity of N-phenethylnorhydromorphone (20). [Figures.]

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