Process for the reductive alkylation of normorphinans
Inventors
Hudson, Edmund C. • Woods, Sharon
Assignees
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Publication Number
US-8431701-B2
Publication Date
2013-04-30
Expiration Date
Abstract
The invention provides a process for the N-alkylation of normorphinan compounds to produce N-alkylated morphinan compounds. In particular, the process relates to the alkylation of a normorphinan compound by a carboxaldehyde in the presence of a reducing agent to form an N-alkylated morphinan.
Core Innovation
The patent discloses a process for the preparation of an N-alkylated morphinan having NR10 at position 17. The process contacts a normorphinan having a secondary amine at position 17 with an alkylating agent having R10, where R10 is chosen from hydrocarbyl and substituted hydrocarbyl, together with a proton acceptor and a reducing agent chosen from formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof.
The transformation proceeds to form the N-alkylated morphinan having NR10 at position 17 without the use of a transition metal catalyst. The process emphasizes one-pot operation without isolation of iminium intermediates while maintaining formation and use of an iminium-salt intermediate associated with the N-alkylation at position 17.
The disclosed process further specifies a carboxaldehyde alkylating agent, including cyclopropanecarboxaldehyde and cyclobutanecarboxaldehyde, together with a proton acceptor and a formic-acid-based reducing system. The examples target named N-alkylated morphinans derived from normorphinans and illustrate the conversion pathways using the labeled formula scheme.
Claims Coverage
The document contains one independent claim directed to a transition-metal-free reductive alkylation process to prepare an N-alkylated morphinan with NR10 at position 17. Dependent claims refine this process by specifying intermediate iminium-salt formation, formula-based two-step transformations, particular choices of alkylating agent and proton acceptor, and stereochemical and optical constraints for formula embodiments.
Transition-metal-free reductive N-alkylation at position 17
A process for the preparation of an N-alkylated morphinan having NR10 at position 17, comprising contacting a normorphinan having a secondary amine at position 17 with an alkylating agent having R10, chosen from hydrocarbyl and substituted hydrocarbyl, with a proton acceptor and a reducing agent chosen from formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof to form the N-alkylated morphinan having NR10 at position 17, wherein the process occurs without the use of a transition metal catalyst.
Iminium-salt intermediate formation
The process includes forming an intermediate iminium salt of the normorphinan before producing the N-alkylated morphinan.
Labeled formula two-step transformation to Formula (IIIa) / Formula (IIIb)
The process forms an N-alkylated morphinan of Formula (IIIa) by contacting a Formula (Ia) compound with an alkylating agent with R10 in the presence of a proton acceptor to make a Formula (IIa) compound, then contacting the Formula (IIa) compound with a reducing agent to produce Formula (IIIa), and similarly for the corresponding Formula (IIIb) path.
Proton acceptor and defined carboxaldehyde alkylating agent
The proton acceptor is triethylamine, and the alkylating agent is a carboxaldehyde with R10 selected as cyclopropylmethyl or cyclobutylmethyl.
Optical activity and stereochemical constraints by formula embodiments
Compounds of Formulas (Ia), (IIa), and (IIIa) have optical activity (−) or (+), and the configurations of carbons 5, 13, 14, and 9 are selected from RRRR, RRRS, RRSR, RSRR, SRRR, RRSS, RSSR, SSRR, SRRS, SRSR, RSRS, RSSS, SRSS, SSRS, SSSR, and SSSS, with carbons 15 and 16 both on either the alpha face or the beta face.
Overall, the claim set covers a reductive N-alkylation of a normorphinan at position 17 using an alkylating agent with R10, a proton acceptor, and a formic-acid-based reducing system, while explicitly avoiding any transition metal catalyst. Additional claimed refinements cover iminium-salt intermediate formation, conversion between labeled formula embodiments through alkylation and reduction steps, specified reagent selections, and stereochemical and optical constraints for particular formula representations.
Stated Advantages
Avoiding the use of a transition metal catalyst.
Enabling conversion to the N-alkylated morphinan without isolation of iminium intermediates.
Avoidance of hazardous hydrogen gas is emphasized in the disclosed process description.
Documented Applications
Preparation of N-alkylated morphinans at position 17, including conversions illustrated using named targets derived from normorphinans, such as conversion pathways leading to naltrexone and 6-ketonalbuphine.
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