Process for the preparation of morphine analogs via metal catalyzed N-demethylation/functionalization and intramolecular group transfer

摘要

The present application is directed to an efficient conversion of C-14 hydroxylated morphine alkaloids to various morphine analogs, such as naltrexone, naloxone and nalbuphone. One feature of this process is an intramolecular functional group transfer from the C-14 hydroxyl to the N-17 nitrogen atom following a palladium-catalyzed N-demethylation.

主权项

1. A process for the preparation of a compound of Formula VI:wherein
X is selected from C(O)R2, S(O)R2, SO2R2, P(O)R2R2′, P(O)(OR2)R2′ and P(O)(OR2)(OR2′); R2 and R2′ are independently selected from C3-10cycloalkyl, C3-10heterocycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl and C5-10heteroaryl, each of the latter groups being unsubstituted or substituted with one or more substituents independently selected from C1-4alkyl, OC1-4alkyl, halo, CN, NO2, C6-10aryl and OC6-10aryl; represents a single or double bond, provided that two double bonds are not adjacent to each other; and R3 and R4 are independently selected from X, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when represents═O, then R4 is not present; the process comprising: (a) reacting a compound of Formula VII with a compound of Formula VIII(a) or VIII(b) under conditions to provide a compound of Formula IX:wherein LG1 is a leaving group;
X is selected from C(O)R2, S(O)R2, SO2R2, P(O)R2R2′, P(O)(OR2)R2′ and P(O)(OR2)(OR2′); R2 and R2′ are independently selected from C3-10cycloalkyl, C3-10heterocycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl and C5-10heteroaryl, each of the latter groups being unsubstituted or substituted with one or more substituents independently selected from C1-4alkyl, OC1-4alkyl, halo, CN, NO2, C6-10aryl and OC6-10aryl; represents a single or double bond, provided that two double bonds are not adjacent to each other; and R3 and R4 are independently selected from H, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when represents ═O, then R4 is not present; and (b) reacting the compound of Formula IX with a metal catalyst in the presence of an oxidant under conditions to provide the compound of Formula VI, wherein in the compounds of Formulae VI, VII, VIII and IX, one or more available hydrogens in R2, R2′, R3 and R4 is/are optionally replaced with F and/or one or more of available atoms in R2, R2′, R3 and R4 is/are optionally replaced with an isotopic label.