Synthesis and pharmacology of metabolically stable tert-butyl ethers of morphine and levorphanol.

3-O-tert-Butylmorphine (5) was prepared from 6-O-acetylmorphine (3) via alkylation with N,N-dimethylformamide di-tert-butyl acetal, followed by hydrolytic removal of the 3-(dimethylamino)-2-propenoate group. The same process was used to prepare the tert-butyl ether of levorphanol (6), (-)-3-tert-butoxy-N-methylmorphinan (8). Both 5 and 8 exhibited in vitro affinity for the opiate receptor comparable to codeine and had analgesic properties in the writhing test. Only 5 exhibited activity in the tail-flick procedure and neither compound showed significant antitussive activity.