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Proxorphan

Chemical compound

Proxorphan
Summary

Chemical compound

or (1S,9R,10R)-17-(cyclopropylmethyl)-13-oxa-17-azatetracyclo[7.5.3.0~1,10~.0~2,7~]heptadeca-2,4,6-trien-4-ol

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Proxorphan (INN), also known as proxorphan tartate (USAN) (developmental code name BL-5572M), is an opioid analgesic and antitussive drug of the morphinan family that was never marketed. It acts preferentially as a κ-opioid receptor partial agonist and to a lesser extent as a μ-opioid receptor partial agonist.

Synthesis

4246413}}; Chem. Abstr. 95, 43442z (1981).

Starting material for this preparation is ketoester 1, available by one of the classical benzomorphan syntheses. Condensation with the ylide from Triethyl phosphonoacetate (HWE reaction) affords diester 2. Catalytic hydrogenation proceeds from the less hindered face to afford the corresponding saturated diester (3). The esters are then reduced by means of LiAlH4 to give the glycol (4); this undergoes internal ether formation on treatment with acid to form the pyran ring of 5. Von Braun reaction with BrCN (or ethyl chloroformate) followed by saponification of the intermediate leads to the 2° amine (6). This is converted to the cyclopropylmethyl derivative 8 by acylation with cyclopropylcarbonyl chloride followed by reduction of the thus formed amide (7) with LiAlH4. Cleaving off the O-methyl ether with sodium ethanethiol affords proxorphan (9).

References

References

  1. (14 November 2014). "The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies". Springer.
  2. (October 1983). "Further study of kappa opioids on increased urination". The Journal of Pharmacology and Experimental Therapeutics.
  3. (August 1988). "Reversal by beta-funaltrexamine and 16-methyl cyprenorphine of the antinociceptive effects of opioid agonists in the mouse and guinea-pig". Neuropharmacology.
  4. (May 1989). "Discriminative stimulus effects of mu and kappa opioids in the pigeon: analysis of the effects of full and partial mu and kappa agonists". The Journal of Pharmacology and Experimental Therapeutics.
  5. (November 1992). "Intermediate efficacy mu opioids: examination of their morphine-like stimulus effects and response rate-decreasing effects in morphine-tolerant rats". The Journal of Pharmacology and Experimental Therapeutics.
  6. (22 October 2013). "Advances in Drug Research". Elsevier.
  7. (March 1947). "Syntheses in the morphine series; derivatives of bicyclo [3 : 3 : 1]-2-azanonane". Journal of the Chemical Society.
  8. (18 October 2018). "Synthesis of cyclopropanecarbonyl chloride". Chemical Industry Times.
  9. {{US patent. 5504245
Wikipedia Source

This article was imported from Wikipedia and is available under the Creative Commons Attribution-ShareAlike 4.0 License. Content has been adapted to SurfDoc format. Original contributors can be found on the article history page.

antitussives benzomorphans kappa-opioid-receptor-agonists opioids hydroxyarenes cyclopropyl-compounds
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