Preparation of N-alkylated opiates by reductive amination
Inventors
Grote, Christopher W. • Orr, Brian • Jiang, Tao • Cantrell, Gary L.
Assignees
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Publication Number
US-8729266-B2
Publication Date
2014-05-20
Expiration Date
Abstract
The present invention is directed to the reduction of an N-imine moiety or a hemiaminal moiety of a morphinan in the presence of a ruthenium, rhodium, or iridium asymmetric catalyst and a hydrogen source.
Core Innovation
The invention relates to a process for the preparation of a N-alkylated morphinan (II) by reducing an N-imine morphinan or hemiaminal morphinan (I) in the presence of an asymmetric catalyst and a hydrogen source. The asymmetric catalyst comprises a dichloro(arene)Ru(II) dimer and a N-tosyl-diphenylethylenediamine ligand, and the N-imine morphinan or hemiaminal morphinan (I) is defined by morphinan structural features including Z1 as either >NCH(OH)(R9) or >N+−CH(R9), and Z2 as >NCH2(R9), with R9 defined as hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
The invention further encompasses the formation of N-imine/hemiaminal intermediates from nor-morphinans and aldehydes, leading to hemiaminal morphinans (I) where the corresponding imine/hemiaminal equilibrium is addressed conceptually in the description. In the described scope, the hemiaminal structure variables include Z1 being >NCH(OH)(R9) or >N+−CH(R9), and R9 covering hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, or heterocyclo substituents.
Specific N-alkylated morphinans are identified as products, including buprenorphine, 6-ketalnaltrexone, naltrexone, nalmefene, nalbuphine, and diprenorphine. The catalyst system is described in terms of ruthenium asymmetric catalyst embodiments that employ dichloro(arene)Ru(II) dimers together with the N-tosyl-diphenylethylenediamine ligand, and hydrogen sources are described as hydrogen sources suitable for the reduction step.
Claims Coverage
The partial content provides two independent claims (clm-00001 and clm-00005). Claim coverage centers on the same reductive amination concept using an asymmetric catalyst defined by a dichloro(arene)Ru(II) dimer and a N-tosyl-diphenylethylenediamine ligand, with additional independent limitations in claim clm-00005 focused on specific substituent constraints for R1, R2, R3, Z1, and R9.
Asymmetric reduction to N-alkylated morphinan using Ru(II) dimer and N-tosyl-diphenylethylenediamine
A process for the preparation of a N-alkylated morphinan (II) comprising reducing an N-imine morphinan or hemiaminal morphinan in the presence of an asymmetric catalyst and a hydrogen source, wherein the asymmetric catalyst comprises a dichloro(arene)Ru(II) dimer and a N-tosyl-diphenylethylenediamine ligand, and the N-imine morphinan or hemiaminal morphinan (I) has the formula with Z1 as >NCH(OH)(R9) or >N+−CH(R9), Z2 as >NCH2(R9), and R9 as hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
Restricted substituent pattern for forming N-alkylated morphinan products
The process wherein R1 is hydrogen; R2 is hydrogen; R3 is —OR311; R311 is hydrogen or C1-8 alkyl; Z1 is >NCH(OH)(R9) or >N+−CH(R9); and R9 is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, pentyl or cyclopentyl.
Across the two independent claims, the core coverage is the reduction of an N-imine morphinan or hemiaminal morphinan to obtain a N-alkylated morphinan using the specified ruthenium-based asymmetric catalyst system and hydrogen source, with claim clm-00005 further narrowing the substituent definitions for R1, R2, R3, Z1, R311, and R9.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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