Proxorphan Explained

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.^[1] It acts preferentially as a κ-opioid receptor partial agonist and to a lesser extent as a μ-opioid receptor partial agonist.^{[2] [3] [4] [5] [6]}

Synthesis

Starting material for this preparation is ketoester 1, available by one of the classical benzomorphan syntheses.^[7] 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^[8] followed by reduction of the thus formed amide (7) with LiAlH₄. Cleaving off the O-methyl ether with sodium ethanethiol affords proxorphan (9).

See also

• Butorphanol
• Cyclorphan
• Ketorfanol
• Levallorphan
• Levomethorphan
• Levorphanol
• Moxazocine
• Nalbuphine
• Oxilorphan
• Xorphanol

Notes and References

1. Book: Elks J . The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 14 November 2014. Springer. 978-1-4757-2085-3. 1041–.
2. Leander JD . Further study of kappa opioids on increased urination . The Journal of Pharmacology and Experimental Therapeutics . 227 . 1 . 35–41 . October 1983 . 6137557 .
3. Hayes AG, Birch PJ . Reversal by beta-funaltrexamine and 16-methyl cyprenorphine of the antinociceptive effects of opioid agonists in the mouse and guinea-pig . Neuropharmacology . 27 . 8 . 813–816 . August 1988 . 3216959 . 10.1016/0028-3908(88)90096-2 . 54433737 .
4. Picker MJ, Dykstra LA . 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 . 249 . 2 . 557–566 . May 1989 . 2566680 .
5. Picker MJ, Craft RM, Negus SS, Powell KR, Mattox SR, Jones SR, Hargrove BK, Dykstra LA . 6 . 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 . 263 . 2 . 668–681 . November 1992 . 1331411 .
6. Book: Testa B . Advances in Drug Research. 22 October 2013. Elsevier. 978-1-4832-8798-0. 245–.
7. Barltrop JA . Syntheses in the morphine series; derivatives of bicyclo [3 : 3 : 1]-2-azanonane . Journal of the Chemical Society . 169 . 399–401 . March 1947 . 20240573 . 10.1039/JR9470000399 .
8. Synthesis of cyclopropanecarbonyl chloride. Zhang K, Lu M, Li Y . 18 October 2018. Chemical Industry Times. 17. 7. 36–38.