Preparation of 6-alpha-amino N-substituted morphinans by catalytic hydrogen transfer

Inventors

Grote, Christopher W. • Cantrell, Gary L. • Mcclurg, Joseph P. • Thomasson, Catherine E. • Moser, Frank W.

Assignees

Mallinckrodt Inc • Specgx LLC

Abstract

The present invention provides processes for the stereoselective synthesis of 6-alpha-amino N-substituted morphinans. In particular, the invention provides processes for the reductive amination of 6-keto N-substituted morphinans by catalytic hydrogen transfer.

Core Innovation

The invention relates to a process for preparing a 6-alpha-amino N-substituted morphinan by contacting a 6-keto N-substituted morphinan with an amine source, a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor. The amine source comprises the formula R6NH2, wherein R6 is selected from hydrogen, hydrocarbyl, and substituted hydrocarbyl.

The process uses formate ion as a hydrogen donor in catalytic hydrogen transfer reductive amination to form 6-alpha-amino N-substituted morphinans. In further refinements, the contacting forms an intermediate as a formate salt of a 6-imine N-substituted morphinan, followed by conversion in situ to a formate salt of a 6-alpha-amino morphinan and then, upon contact with a proton acceptor, forming the 6-alpha-amino N-substituted morphinan.

The invention is also described for preparing a compound of Formula (IV) by reducing a compound of Formula (I) with the same components comprising an amine source, a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor. The product is defined by limits on the 6-beta amino epimer, including no more than about 5% and preferably no more than about 2% and/or less than about 1%.

Claims Coverage

The independent claims cover two process categories: preparing a 6-alpha-amino N-substituted morphinan from a 6-keto N-substituted morphinan, and reducing a compound of Formula (I) to form a compound of Formula (IV). Across the independent claims, the inventive features center on formate-ion hydrogen transfer reductive amination with a transition metal catalyst and proton acceptor, plus stereochemical purity control for the 6-alpha-amino products.

The independent-claim scope is anchored on catalytic hydrogen-transfer reductive amination using a formate-ion hydrogen donor and a proton acceptor to generate 6-alpha-amino N-substituted morphinans, including a stereochemical constraint on the 6-beta amino epimer content, and on an analogous reduction framework that converts Formula (I) into Formula (IV) using the same core reagent categories.

Stated Advantages

Documented Applications