N-demethylation of morphinan alkaloids
Inventors
Roberge, Dominique • Elsner, Petteri • Kappe, Christian Oliver • Gutmann, Bernhard • Weigl, Ulrich • Cox, Douglas Phillip
Assignees
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Publication Number
US-10626120-B2
Publication Date
2020-04-21
Expiration Date
Abstract
The present disclosure relates to N-demethylation of a compound containing a tertiary N-methylamine, including for example a morphinan alkaloid, in a continuous flow system. In particular, the present disclosure relates to N-demethylation of oxymorphone-3,14-diacetate or 14-hydroxymorphinone-3,14-diacetate using highly active catalytic palladium (0) in a continuous flow system under elevated temperature and pressure condition. The methodology can be utilized towards the synthesis of noroxymorphone via aerobic palladium-catalyzed continuous flow N-demethylation.
Core Innovation
The invention describes a process for the N-demethylation of a compound containing a tertiary N-methylamine, wherein the compound is a compound of formula I. The process includes providing a liquid mixture containing the compound, a metal catalyst, and a solvent, then contacting the liquid mixture in a continuous flow system with a gaseous oxidant or an organic peroxide oxidant so that the compound and oxidant react to form a N-demethylated form of the compound.
The described approach applies an aerobic Pd(0)/Pd(II)-catalyzed oxidative N-demethylation in continuous flow, using molecular oxygen or organic peroxides as oxidants. The catalysis is described in terms of palladium species including Pd(0), Pd(II), and Pd(OAc)2, with examples also referencing Pd/C and Pd black. Solvent choices described include dimethylacetamide (DMA) and dimethylformamide (DMF), and acetic acid is described as a catalyst stabilizer.
The document further addresses performance and behavior in batch versus continuous flow, including reports that continuous-flow configurations can show substantially reduced conversions unless appropriate oxygen stoichiometry and catalyst stabilization are used. Formation or suppression of a N-formyl side product is described, along with Pd(0) deposition or loss such as Pd(0) agglomeration into Pd black on stainless-steel coil reactor surfaces. A downstream continuous-flow hydrogenation of the N-demethylation product is also described using Pd/Al2O3 cartridges, producing a hydrogenated N-demethylation product.
Claims Coverage
The independent claim covers a continuous-flow N-demethylation of tertiary N-methylamine-containing compounds of formula I by oxidative reaction with a gaseous oxidant or an organic peroxide oxidant using a metal catalyst and solvent. The set of dependent claims refines this inventive concept by specifying particular oxidants, catalysts/activation, solvent choices, and quantitative operating constraints, including an explicit yield threshold and a pressure range.
Continuous-flow oxidative N-demethylation of tertiary N-methylamine compound of formula I
A process comprising providing a liquid mixture containing the compound of formula I, a metal catalyst and a solvent; and contacting the liquid mixture with a gaseous oxidant or an organic peroxide oxidant in a continuous flow system to form a reaction mixture whereby the compound and oxidant react to form a N-demethylated form of the compound.
Overall claim coverage centers on continuous-flow oxidative N-demethylation of a tertiary N-methylamine-containing compound of formula I using a metal catalyst, solvent, and a gaseous or peroxide oxidant, with dependent claims further narrowing oxidant identity, catalyst form/activation, solvent selection, pressure operation, and an explicit yield threshold.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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