SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 18,19-DEHYDROBUPRENORPHINE

18,19-Dehydrobuprenorphine (2) was prepared in five steps starting from thevinone (3) which is readily available from thebaine by Diels-Alder reaction. Grignard reaction with tert-BuMgBr afforded tert-butylthevinol (4) which was N-demethylated via N-cyano-tert-butylthevinol (5) using BrCN. Alkali treatment gave N-nor-tert-butylthevinol (6) which was alkylated with cyclopropylmethyl bromide to give N-cyclopropylmethyl-tert-butylthevinol (7), followed by ether cleavage with thiolate to yield 2. 18,19-Dehydrobuprenorphine displayed in opioid receptor binding studies very high affinity for mu receptors, while the affinity for kappa and delta receptors was lower. In the tail-flick test in mice, compound (2) was 25 times more potent than morphine and ca. 2.5 times as potent as buprenorphine.