ES391890A1 - 2,6-methano-3-benzazocines and preparation thereof - Google Patents

Abstract

Procedure to prepare 2,6-methane-3-benzazocins having the formula I ** (See formula) ** where: Y1 is hydroxyl or acyloxy which is alkanoyloxy having 1 to 22 carbon atoms, alkenoyloxy having one or two double bonds and having 4 to 22 carbon atoms, Ar-Cm H2m-CO-O-, where m is an integer from 0 to 2 and Ar is phenyl, optionally substituted with from 1 to 3 alkyls having 1 to 4 carbon atoms, alkoxy having from 1 to 4 atoms, alkoxy having from 1 to 4 carbon atoms, halo, trifluoromethyl, dialkoxylamino having from 2 to 8 carbon atoms, and / or alkanoylamino having 1 to 6 carbon atoms; phenoxyacetoxy; naphthalenecarbonyloxy; pyridinocarbonyloxy; (cycloalcohyl-fluorocycloalcohil) -CmH2m-CO-O- having a total of 4 to 10 carbon atoms, of which 3 to 7 are ring carbon atoms in the cycloalcohyl, and where m is an integer from 0 to 2, alcoholcarbonate having from 2 to 7 carbon atoms, carbamyloxy, or (mono- or dialcohil) -carbamyloxy having from 2 to 9 carbon atoms; Y2 is hydrogen, an alcohol having 1 to 6 carbon atoms, or Ar1-CnH2n-, where n is an integer from 0 to 4 and Ar is phenyl or phenyl substituted with 1 to 3 members from the group consisting of an alcohol that it has 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, and dialkoxylamino having 2 to 8 carbon atoms; or Y1 and Y2, taken together, represent oxo; Q is alcoholic having 3 to 8 carbon atoms, alkenyl having 3 to 6 carbon atoms, haloalkenyl having 3 to 6 carbon atoms and having 1 to 3 chlorine, fluorine and / or bromine atoms bound to ethylenic carbon, cyanoalkyl having 2 to 6 carbon atoms, (mono- or dicyano) -alkenyl having 4 to 8 carbon atoms, 2,2-dialkoxyethyl having 4 to 8 carbon atoms, alkynyl having from 3 to 6 carbon atoms, (cycloalcohil or fluorocycloalcohil) -CnH2n-, where n is an integer from 0 to 4, and where the cycloalcohil has from 3 to 7 ring carbon atoms and has a total of 3 to 10 carbon atoms, 2- or 3-cycloalkenyl, where the cycloalkenyl has 5 or 6 ring carbon atoms and has a total of 5 to 8 carbon atoms, cycloalkenyl-Cp-H2p-, where p is an integer of 1 to 4 and where cycloalkenyl has 5 or 6 ring carbon atoms and has a total of 5 to 8 carbon atoms, and Ar2-CpH2p-, where p is an integer from 1 to 4 and Ar2 is phenyl or is phenyl substituted by nitro, alkanoylamino having 1 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms, alcohol having 1 to 4 carbon atoms, halo or trifluoromethyl, without the group Q having , in each case, carbon atom in any tertiary alpha; Z is hydrogen, hydroxyl or one of the acyloxy groups defined by Y1, or Z1 is alkoxy having 1 to 6 carbon atoms, difluoromethoxy, trifluoromethoxy, benzyloxy or alkenyloxy having 3 to 6 carbon atoms; R1 and R2 are hydrogen or alcoholic having 1 to 4 carbon atoms; R3 is an alcoholic having 1 to 4 carbon atoms; or an acid addition salt thereof, which method comprises N-alcoholyl a corresponding compound having formula VI (disclosed in the specification), to provide a compound with the desired Q or Q9 substituent; and, if desired, reduce the compound obtained, with effective reduction means to convert the 1-oxo group to a 1-hydroxyl group without affecting any cyano groups or ethylenic bonds that are present, and, if desired, react the 1,2,3,4,5,6-hexahydro-1-oxo-3- (Q6) -8- (Z3) -6- (r1) -11 (R2) -, 26-methane-3-benzazocine obtained with a Grignard reagent having the formula Y3-Mg-halogen, producing 1,2,3,4,5,6-hexahydro-1-hydroxy-1- (Y3) -3- (Q6) -8- ( Z3) -6- (R1) -11- (R2) -2,6-methane-3-benzazocine, where: Y3 is an alcohol having 1 to 6 carbon atoms, or Ar1-CnH2n-, where n is a integer from 0 to 4 and Ar1 is phenyl or phenyl substituted with from 1 to 3 members of the group consisting of alcoholic having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, and dialkoxylamino having from 2 to 8 carbon atoms; Q6 is hydrogen, alcoholic having 1 to 8 carbon atoms, alkenyl having 3 to 6 carbon atoms, haloalkenyl having 3 to 6 carbon atoms and having 1 to 3 members of the group consisting of chlorine , fluorine and bromine bound to ethylenic carbon, alkynyl having 3 to 6 carbon atoms, (cycloalcohyl or fluorocycloalcohyl) -CnH2n-, where n is an integer from 0 to 4 and where cycloalcohyl has from 3 to 7 carbon atoms ring and has a total of 3 to 10 carbon atoms, 2- or 3-cycloalkenyl, where the cycloalkenyl has 5 or 6 ring carbon atoms and has a total of 5 to 8 carbon atoms, cycloalkenyl-C2H2p-, where p is an integer from 1 to 4 and where cycloalkenyl has 5 or 6 ring carbon atoms and has a total of 5 to 8 carbon atoms, and Ar4-CpH2p-, where p is an integer from 1 to 4 and Ar4 is phenyl or alcohol-substituted phenyl having 1 to 4 carbon atoms, or alkoxy having 1 to 4 carbon atoms, without the member Q6 having, in each case , any tertiary alpha carbon atom; and Z3 is hydrogen, alkoxy having 1 to 6 carbon atoms, or alkenyloxy having 3 to 6 carbon atoms, and, if desired, esterifying the obtained compound, where Y1 and / or Z or Z2 is hydroxyl, with suitable blocking when necessary, to obtain a corresponding acyloxy group, and, if desired, to convert the free base obtained into an acid addition salt thereof. (Machine-translation by Google Translate, not legally binding)