Proxorphan

Proxorphan, also known as proxorphan tartate, 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

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