PROCESS FOR THE PREPARATION OF QUATERNARY N-ALKYL MORPHINAN ALKALOID SALTS

摘要

Disclosed is a process for the preparation of a quaternary derivative of a tertiary N-substituted morphinan alkaloid having a C(3) hydroxy substituent, the process comprising (i) combining a tertiary N-substituted morphinan alkaloid substrate with an alkylating agent in an anhydrous solvent system to form a reaction product mixture containing the quaternary derivative of the tertiary N-substituted morphinan alkaloid substrate and any unreacted tertiary N-substituted morphinan alkaloid substrate, the solvent system comprising an anhydrous aprotic dipolar solvent with the aprotic dipolar solvent constituting at least 25 wt.% of the solvent system, and (ii) adding an anhydrous acid to the reaction product mixture to suppress ionization of the C(3) hydroxy substituent and production of C(3) alkoxy side products. Also disclosed is a process for the preparation of a quaternary derivative of a tertiary N-substituted morphinan alkaloid, the process comprising: (i) adding less than 3 equivalents of a solution of an alkylating agent dissolved in an anhydrous dipolar aprotic solvent to a tertiary N-substituted morphinan alkaloid substrate dissolved in an anhydrous solvent system, to form a reaction product mixture containing the quaternary derivative of the tertiary N-substituted morphinan alkaloid substrate and any unreacted tertiary N-substituted morphinan alkaloid substrate, the rate of addition of the alkylating agent being less than 0.02 equivalents of alkylating agent per equivalent of substrate per minute based upon the concentration of substrate in the reaction mixture; wherein the solution of the alkylating agent is maintained at a temperature below about 0 deg C and is added to the reaction mixture at a temperature of between about 50 deg C and about 85 deg C so as to inhibit O-alkylation at the C(3) hydroxide to less than 10% and inhibit evaporative loss of alkylating agent; and, (ii) adding an anhydrous acid to the reaction mixture to enhance product formation and inhibit side products when the substrate contains a C(3) hydroxy substituent.