Preparation of morphinan derivatives comprising N-demethylation, reductive amination and O-demethylation steps

摘要

A process for the preparation of a compound of formula (I) wherein R is a cyclopropyl, cyclobutyl or vinyl group, X is O or an optionally linked diC1-4alkoxy group comprises N-demethylating a compound of formula (II) by reaction with a -chloroethylchloroformate to form a compound of formula (III). The residue CH2-R shown in formula (I) is then introduced by reacting the compound of formula (III) with an aldehyde RCHO to form an intermediate with an iminium ion double which is reduced to form a compound of formula (IV), i.e. CH2-R is introduced by reductive amination.. The compound of formula (IV) is then reacted with BBr3 or other reagents capable of demethylating an aryl methyl ether to form a compound of formula (I). Preferably R is cyclopropyl and X is O, the compound of formula (I) then being naltrexone. N-Demethylation may be carried out in an aprotic solvent, e.g. 1,2-dichloroethane or acetonitrile and the reductive amination may be carried out in tetrahydrofuran, ethanol, isopropanol, dimethylformamide, dimethylsulfoxide, dichloromethane or 1,2-dichlorethane with reduction being carried out using a triacetoxyborohydride, a cyanoborohydride or hydrogen and a catalyst, e.g. palladium. The O-demethylation may be carried out in an aprotic solvent, e.g. toluene, tetrahydrofuran, chloroform, dichloromethane or 1,2-dichloroethane.