PROBES FOR NARCOTIC RECEPTOR MEDIATED PHENOMENA. 38. AN EXPEDITIOUS SYNTHESIS OF RAC-CIS-4a-ETHYL-2-METHYL-1,2,3,4,4a,9a-HEXAHYDROBENZOFURO[2,3-c]PYRIDIN-6-OL AND RAC-CIS-2-METHYL-4a-PHENETHYL-1,2,3,4,4a,9a-HEXAHYDROBENZOFURO[2,3-c]PYRIDIN-6-OL.
A high-yielding five-step synthesis of cis-benzofuropyridin-6-ols provided an improved route to compounds with low to subnanomolar affinity at opioid receptors and high antinociceptive potency. This synthesis provided the known rac-cis-4a-ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1a) in high yield, and the novel rac-cis-2-methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1b). It was achieved using NBS to prepare the key intermediate 7. Di-demethylation followed by subsequent displacement of the bromine by the phenolic ion in hot Et(3)N gave the desired 1a. The structure of 1a was confirmed by X-ray crystallography.
Iyer
Malliga R
MR
Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Services, 5625 Fishers Lane, Room 4N03, Bethesda, MD 20892-9415.
Deschamps
Jeffrey R
JR
Jacobson
Arthur E
AE
Rice
Kenner C
KC