Oxilorphan and Butorphanol. Potent Narcotic Antagonists and Nonaddicting Analgesics in the 3,14-Dihydroxymorphinan Series. Part V

A series of 3,14-dihydroxymorphinans 8 was synthesized via a method of (a) acylation of 3-methoxy-Δ8,14-morphinan 4a (b) stereospecific epoxidation of the resultant amides to β-epoxides 5 (c) simultaneous reduction of amide and epoxide functions and (d) demethylation of the resultant 3-methoxy-14-hydroxymorphinans 7. Alternatively deblocking of the amine function in 5b by hydrolysis followed by reduction of the resultant amino epoxide 5e afforded 14-hydroxy-3-methoxymorphinan 7e, which is readily alklyated and demethylated to give various 8. On a basis of interesting pharmacological profiles compounds l-8c (oxilorphan) and l-8d (butorphanol) were selected for clinical studies.