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

摘要

An improved process for the N-alkylation of tertiary morphinan alkaloid bases to form the corresponding quaternary morphinan alkaloid derivatives.

主权项

1. A process for the preparation of a quaternary derivative of a tertiary N-substituted morphinan alkaloid having a protected C(3) hydroxy substituent, the process comprising (i) generating a C(3)-O-protected tertiary morphinan alkaloid by reacting a C(3)-OH-morphinan alkaloid with a protecting agent, PG-L, (ii) combining the C(3)-O-protected tertiary N-substituted morphinan alkaloid substrate with an alkylating agent in an anhydrous solvent system, at a pressure less than about 2 atm., to form a reaction product mixture containing the quaternary derivative of the C(3)-O-protected 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 (iii) adding a non-solubilizing solvent to the reaction product mixture to precipitate the quaternary derivative, the quaternary derivative having less solubility in the non-solubilizing solvent than in the dipolar aprotic solvent, wherein the C(3)-OH-morphinan alkaloid has the structure of Formula 11, the C(3)-O-protected tertiary N-substituted morphinan alkaloid substrate has the structure of Formula 111 and the quaternary derivative has the structure of Formula 111A wherein
A is —C(O)—, —C(S)—, —C(═CH2)—, —CH(A1)- or —C(A1)=,A1 is hydroxy, alkoxy, or acyloxy,PG is a hydroxy protecting group;L is a counterion of the hydroxy protecting group,R1 is hydrocarbyl or substituted hydrocarbyl,R2 is hydrocarbyl or substituted hydrocarbyl,X− is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate, methylsulfate, ethylsulfate, trifluoromethanesulfonate, hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate;Y, if present, is hydrogen, hydroxy, alkoxy, or acyloxy, and the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14, respectively, represent (i) carbon-carbon single bonds, (ii) carbon-carbon single bonds between positions 6 and 7 and between positions 8 and 14, and a double bond between positions 7 and 8, or (iii) conjugated carbon-carbon double bonds between positions 6 and 7 and positions 8 and 14, with the proviso that Y is not present if there is a double bond between the carbons at positions 8 and 14.