Patent ID: 8669366

Claim:
A process for the preparation of a quaternary derivative of a tertiary N-substituted morphinan alkaloid, the process comprising: (i) combining a tertiary N-substituted morphinan alkaloid substrate with an alkylating agent solution and 0.1 equivalents of an anhydrous acid per equivalent of the substrate 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(s) with the aprotic dipolar solvent(s) constituting at least 25 wt. % of the solvent system, wherein the alkylating agent solution has a temperature below 0° C. and is combined with the tertiary N-substituted morphinan alkaloid substrate and the anhydrous solvent system at a temperature of between about 50° C. and about 85° C.; and (ii) adding a non-solubilizing solvent to the reaction product mixture to precipitate the quaternary derivative, wherein the tertiary N-substituted morphinan alkaloid substrate has the structure of Formula 1 and the quaternary derivative has the structure of Formula 1A: wherein A is —C(O)—, R 1 is cyclopropylmethyl, R 2 is hydrocarbyl or substituted hydrocarbyl, X 1 is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate, methylsulfate, ethylsulfate, trifluoromethanesulfonate, hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate; Y is hydroxy, Z is hydroxy, and the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14, respectively, represent carbon-carbon single bonds.