63730-48-3

N-Alkyl allylic tertiary amines are dealkylated as illustrated by treatment of (-)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline in cold methylene chloride with m-chloroperbenzoic acid followed by the addition of aqueous ferrous chloride to provide a good yield of (+)-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline with substantial if not complete retention of optical activity. The product is an intermediate in a synthesis of the analgesic known as butorphanol.

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N-substituted-14-hydroxy-3-substituted-morphinan derivatives have been found to possess potent narcotic agonist or antagonist activity. In particular, the compound 3,14-dihydroxy-N-cyclobutylmethylmorphinan has been found to possess potent agonist/antagonist activity. A new and novel total synthesis for the preparation of these compounds is described herein.

N-substituted-14-hydroxy-3-substituted-morphinan derivatives have been found to possess potent narcotic agonist or antagonist activity. In particular, the compound 3,14-dihydroxy-N-cyclopropylmethylmorphinan has been found to possess potent agonist-antagonist activity. A new and more efficient total synthesis for the preparation of these compounds is described herein, which improvement comprises using a Schiff base of 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene to produce 3-methoxy-9-bromo-norhasubanan hydrobromide in substantially improved yields through the intermediate of the formula SPC1

A series of 3,14 dihydroxymorphinans 8 was synthesized via a method of (a) acylation of 3 methoxy Δ84 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 alkylated 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.