Reductive amination of 6-keto normorphinans by catalytic hydrogen transfer
Inventors
Grote, Christopher W. • Cantrell, Gary L. • Mcclurg, Joseph P. • Thomasson, Catherine E. • Moser, Frank W.
Assignees
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Publication Number
US-8471023-B2
Publication Date
2013-06-25
Expiration Date
Abstract
The present invention provides processes for the stereoselective synthesis of 6-alpha-amino morphinans. In particular, the invention provides processes for the reductive amination of 6-keto normorphinans by catalytic transfer hydrogenation.
Core Innovation
The process provides a stereoselective reductive amination/transfer hydrogenation of a 6-keto normorphinan to form a 6-alpha-amino-N17-formyl morphinan epimer product. The process contacts a 6-keto normorphinan with an amine source, a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the 6-alpha-amino-N17-formyl morphinan.
The described core logic involves forming imine-related intermediates and converting them in situ to the 6-alpha epimer. An intermediate compound having a 6-imine moiety is produced, including a 6-imine bis-formate salt and a 6-imine-N17-formyl formate salt that are converted in situ to the 6-alpha-amino-N17-formyl morphinan.
The invention further emphasizes stereoselectivity and product composition control by limiting 6-beta-amino epimer formation. The process produces 6-alpha-amino-N17-formyl morphinan containing no more than about 2% of a 6-beta-amino epimer, and also defines a compound of Formula (IV) formed by reducing a compound of Formula (I) in the presence of the same combination of amine source (R6NH2), formate hydrogen donor, transition metal catalyst, and proton acceptor.
Claims Coverage
The document defines two independent processes. Across them, the inventive coverage centers on forming a 6-alpha-amino-N17-formyl morphinan from a 6-keto normorphinan using an amine source, a formate hydrogen donor, a transition metal catalyst, and a proton acceptor, and on forming a compound of Formula (IV) by reducing a compound of Formula (I) using the same key reagent/catalyst/proton-acceptor combination.
Contacting a 6-keto normorphinan with amine source, formate hydrogen donor, transition metal catalyst, and proton acceptor
A process for preparing a 6-alpha-amino-N17-formyl morphinan, comprising contacting a 6-keto normorphinan with an amine source, a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the 6-alpha-amino-N17-formyl morphinan.
Reducing a compound of Formula (I) to form a compound of Formula (IV)
A process for preparing a compound of Formula (IV), comprising reducing a compound of Formula (I) in the presence of an amine source (R6NH2), a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the compound of Formula (IV).
Overall, the claim coverage is anchored in a formate-ion hydrogen-donor reductive amination/transfer-hydrogenation framework that uses a transition metal catalyst and a proton acceptor to reach 6-alpha-amino-N17-formyl morphinans, with dependents covering intermediate formation, specific catalyst selections, and constraints on 6-beta-amino epimer content and stereochemical or optical configuration for products of Formulas (I) and (IV).
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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