Analgesics of the 6,14-ethenomorphinan type. 6-Deoxy-7.alpha.-orvinol and 6-deoxy-8.alpha.-orvinol

Abstract

6-Deoxythebaine was prepared as a precursor to C-6 alkyl substituted orvinols 15 [19(R)/(S)-butyl-6-deoxy-7.alpha.-orvinols] and 17 [19(R)/(S)-butyl-6-deoxy-8.alpha.-orvinols]. The C-6 methyl group was introduced by addition of methyllithium to codeinone. Transformation of 6-methylcodiene to its 6-methyl ether and 1,4-elimination of methanol with potassium tert-butoxide in Me2SO then gave 6-deoxythebaine in 49% overall yield. Diels-Alder addition of methyl vinyl ketone to this diene yielded 4 ketones i.e., 3 regio- and stereoisomeric 6,14-endo-ethenomorphinans and 1 exo adduct. The major ketone isomer provided the set of C-19 diastereomeric orvinols 15 in which the pendant carbon has the 7.alpha. configuration. Regioisomeric ketone, in which the acetyl group is at C-8, was formed in 3% yield and was similarly converted to the corresponding orvinols 17. Orvinol (R)-15 (R at C-19) is an analgesic of very high potency, 2200 times that of morphine; regioisomeric orvinols 17, in which the pendant tertiary alcohols are on C-8, are much less potent. The higher activity of the C-6 methyl and methoxyl analogs (R)-15 and [19(R)-butyl-7.alpha.-orvinal] indicates that C-6 alkyl substitution enhances analgesic potency in rats.