Process for the preparation of quaternary N-alkyl morphinan alkaloid salts
Inventors
Wang, Peter X. • Cantrell, Gary L. • Halvachs, Robert E. • Roesch, Kevin R. • Buehler, Henry J. • Haar, Jr., Joseph P.
Assignees
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Publication Number
US-8669366-B2
Publication Date
2014-03-11
Expiration Date
Abstract
An improved process for the N-alkylation of tertiary morphinan alkaloid bases to form the corresponding quaternary morphinan alkaloid derivatives.
Core Innovation
The disclosed invention provides a process for the preparation of a quaternary derivative of a tertiary N-substituted morphinan alkaloid. The process combines a tertiary N-substituted morphinan alkaloid substrate with an alkylating agent solution and anhydrous acid in an anhydrous solvent system, generating a reaction product mixture containing the quaternary derivative and any unreacted substrate. The solvent system comprises anhydrous aprotic dipolar solvent(s) in an amount of at least 25 wt.% of the solvent system, and the alkylating agent solution is at a temperature below 0°C prior to combination with the substrate and solvent system.
After forming the reaction product mixture, the process adds a non-solubilizing solvent to precipitate the quaternary derivative. The precipitation step is tied to the use of non-solubilizing solvents that limit solubility of the quaternary derivative in the non-solubilizing solvent, and the process is supported by disclosed refinements for selection of the non-solubilizing solvent and its solubility behavior. The described approach is directed to producing quaternary derivatives consistent with Formula 1A derived from a substrate defined by Formula 1.
The patent disclosure further emphasizes impurity and isoform control in producing quaternary morphinan derivatives such as naltrexone methobromide and methylnaltrexone-related variants. It reports high stereoselectivity for the desired R-isomer or S-isomer (relative to naltrexone methobromide), together with very low levels of C(3)-O-alkyl side derivatives, including C(3)-O-methyl impurities. The disclosure also includes composition claims directed to C(3)-hydroxy quaternary N-substituted morphinans (Formula 11A) having impurity limits for C(3)-alkoxy side derivatives (Formula 11C), as well as embodiments intended to improve yield/purity.
Claims Coverage
The independent claim covers a process for preparing a quaternary derivative of a tertiary N-substituted morphinan alkaloid using anhydrous aprotic dipolar solvent(s), sub-zero alkylating agent solution temperatures, and a precipitation step using a non-solubilizing solvent. Across the dependent claims, multiple inventive features refine the precipitation solvent behavior, specify example solvent/alkylating agent constituents, tighten pressure and temperature ranges, and constrain the addition rate of the alkylating agent solution; in total, the claim set includes one independent claim and several dependent refinements.
Quaternary morphinan formation in anhydrous aprotic dipolar solvent system with sub-zero alkylating agent solution
Combining a tertiary N-substituted morphinan alkaloid substrate with an alkylating agent solution and anhydrous acid in an anhydrous solvent system to form a reaction product mixture containing the quaternary derivative, wherein the solvent system comprises anhydrous aprotic dipolar solvent(s) constituting at least 25 wt.% of the solvent system, and wherein the alkylating agent solution has a temperature below 0°C prior to combination with the tertiary N-substituted morphinan alkaloid substrate and the anhydrous solvent system.
Precipitation of the quaternary derivative using a non-solubilizing solvent
Adding a non-solubilizing solvent to the reaction product mixture to precipitate the quaternary derivative.
Non-solubilizing solvent selection based on miscibility/solubility thresholds
Selecting the non-solubilizing solvent based on miscibility with 1-methyl-2-pyrrolidinone relative to water, with solubility of the non-solubilizing solvent in water below about 30 wt.% at 1 atm and 25°C, and with the quaternary derivative having solubility below about 5 wt.% at 1 atm and 25°C in the non-solubilizing solvent.
Specific non-solubilizing solvent and methyl bromide combination
Using the non-solubilizing solvent comprising chloroform, dichloromethane, ethyl acetate, propyl acetate, chlorobenzene, toluene, methyl ethyl ketone, or methyl butyl ketone, and using methyl bromide as the alkylating agent.
Tightened operating constraints for pressure, dipolar solvent fraction, and temperature
Carrying out the process at pressure below 1.25 atmospheres, with aprotic dipolar solvent(s) comprising at least 75 wt.% of the solvent system, and with the reaction temperature within 55°C to 85°C.
Constrained addition rate of alkylating agent solution
Having an average rate of addition of the alkylating agent solution less than 0.02 equivalents of alkylating agent per equivalent of substrate per minute.
Overall, the claims cover preparation of quaternary derivatives of tertiary N-substituted morphinan alkaloids via an anhydrous aprotic dipolar solvent system with alkylating agent solution maintained below 0°C, followed by precipitation using a non-solubilizing solvent. Dependent claim refinements add explicit miscibility/solubility thresholds, specify particular non-solubilizing solvent options and methyl bromide as the alkylating agent, and further constrain pressure, dipolar solvent fraction, temperature range, and alkylating agent solution addition rate.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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