A process for preparing octahydrobenzofuro (3,2-e) -isoquinoliner with analgesic and narcotic antagonistic activity as well as intermediates for use thereby

摘要

Process for preparing analgesic and narcotic antagonistic isoquinolines comprising: (a) contacting and reacting a lithiated anisole or alkyl phenyl ether, optionally substituted at the 3-position to the lithium atom, with a 4-piperidone to yield a 4-aryl-4-piperidinol; (b) dehydrating the piperidinol to a 4-aryl-1,2,3,6-tetrahydropyridine; (c) metalating and acylating the 1,2,3,6-tetrahydropyridine to yield a 1-(4-aryl- 1,2,3,4-tetrahydropyrid-4-yl)-4-hydroxy-1-butanone; (d) reducing the ketone moiety of the butanone to yield a 5-aryl-7-oxa-2-azabicyclo[3.2.1]-octane-6-propanol; (e) converting the alcohol moiety of the propanol to L to yield a 5-aryl-6-[3-(L)propyl]-7-oxa-2-azabicyclo [3.2.1]-octane in which L is a leaving group selected from the group consisting of -Cl, -Br, -I, p-MeC6H4SO3- and MeSO3-. (f) opening the amino furan ring of the bicyclooctane to yield a 4-(L)-1-(4-aryl-1,2,3,4-tetrahydropyrid-4-yl)-1-butanol derivative; (g) closing the 6-carbon ring of the butanol derivative by intramolecular reaction of the enamine and leaving group to yield a 4-a-aryl-2,3,4,4a,5,6,7, 8-octahydro-5-isoquinolinol or derivative thereof; and (h) reducing the enamine double bond of the octahydro-5-isoquinolinol or derivative thereof to yield a 4a-aryldecahydro-5-isoquinolinol or derivative thereof and (i) cyclizing the decahydro-5-isoquinolinol or derivative to yield a 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro-[3,2-e]isoquinoline, or, (h min ) cyclizing the octahydro-5-isoquinolinol or derivative thereof to yield a 2,3,5,6,7,7a-hexahydro-1H-benzofuro-[3,2-e]isoquinoline and (i min ) reducing the enamine double bond of the isoquinoline.