Process for the preparation of quaternary N-alkyl morphinan alkaloid salts

1. 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.

2. The process of claim 1 , wherein the non-solubilizing solvent is more miscible with 1-methyl-2-pyrrolidinone than with water and has a solubility of less than about 30 wt. % in water at 1 atmosphere and 25° C.; and wherein the quaternary derivative has a solubility of less than about 5 wt. % at 1 atmosphere and 25° C. in the non-solubilizing solvent.

3. The process of claim 1 , wherein the non-solubilizing solvent comprises chloroform, dichloromethane, ethyl acetate, propyl acetate, chlorobenzene, toluene, methyl ethyl ketone, or methyl butyl ketone; and the alkylating agent is methyl bromide.

4. The process of claim 1 , wherein said process is carried out at a pressure of less than 1.25 atmospheres; the aprotic dipolar solvent(s) constitute(s) at least 75 wt. % of the solvent system; and the reaction is carried out within a temperature range of 55-85° C.

5. The process of claim 1 wherein the average rate of addition of the alkylating agent solution is less than 0.02 equivalents of alkylating agent per equivalent of substrate per minute.