One-pot preparation of hexahydroisoquinolines from amides
Inventors
Grote, Christopher W. • Moser, Frank W. • Wang, Peter X. • Cantrell, Gary L. • Berberich, David W.
Assignees
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Publication Number
US-8431705-B2
Publication Date
2013-04-30
Expiration Date
Abstract
The present invention provides an efficient process for the preparation of hexahydroisoquinolines from amides. In particular, the invention provides a good yielding, one-pot process for the synthesis of hexahydroisoquinolines.
Core Innovation
The patent describes a one-pot process for the preparation of a compound comprising Formula (IV). The process converts a compound comprising Formula (I) by contacting the Formula (I) compound with POCl3 to form a compound comprising Formula (II), and the compound comprising Formula (II) is not isolated as a solid prior to the next step.
Next, the compound comprising Formula (II) is contacted with an asymmetric catalyst and a hydrogen donor comprising a formate ion to form a compound comprising Formula (III). The compound comprising Formula (III) is not isolated as a solid prior to the subsequent step.
Finally, the compound comprising Formula (III) is contacted with an alkali metal and an electron source to form the compound comprising Formula (IV). The disclosure presents the approach as an efficient, one-pot sequential conversion leading to optically active hexahydroisoquinolines comprising Formula (IV).
Claims Coverage
The document provides one independent claim defining a one-pot, three-step process with non-isolation of Formula (II) and Formula (III) as solids before the next steps. Dependent claims refine the asymmetric catalyst selection, hydrogen donor definition, and quantitative constraints and performance criteria.
Three-step one-pot synthesis without solid isolation
A one-pot process for preparing a compound comprising Formula (IV) comprising: contacting a compound comprising Formula (I) with POCl3 to form a compound comprising Formula (II); contacting the compound comprising Formula (II) with an asymmetric catalyst and a hydrogen donor comprising a formate ion to form a compound comprising Formula (III); and contacting the compound comprising Formula (III) with an alkali metal and an electron source to form the compound comprising Formula (IV), wherein the compound comprising Formula (II) is not isolated as a solid prior to step (b) and the compound comprising Formula (III) is not isolated as a solid prior to step (c).
Asymmetric reduction using a formate-ion hydrogen donor
Contacting the compound comprising Formula (II) with an asymmetric catalyst and a hydrogen donor comprising a formate ion to form a compound comprising Formula (III).
Catalyst selection with defined chiral ligands
Selecting the asymmetric catalyst using a metal or metal source selected from ruthenium, osmium, rhodium, iridium, palladium, or platinum, together with a chiral ligand selected from Formula 670, Formula 680, Formula 690, or Formula 700.
Hydrogen donor comprising formic acid/formate sources
Selecting the hydrogen donor from formic acid, a salt of formic acid, or a mixture of formic acid and an organic base.
Temperature ranges and minimum yield of Formula (IV)
Characterizing the process by specified temperature ranges for steps (a), (b), and (c), and obtaining the compound comprising Formula (IV) with a yield of at least about 60%.
Claim coverage is anchored by a one-pot, non-isolation scheme: POCl3 conversion to Formula (II), asymmetric conversion to Formula (III) using an asymmetric catalyst with a formate-ion-containing hydrogen donor, and conversion of Formula (III) to Formula (IV) using an alkali metal and an electron source. Dependent claims additionally specify catalyst metal and ligand options, narrow the hydrogen donor options to formic acid and formate sources, and impose temperature and minimum-yield constraints.
Stated Advantages
Efficient one-pot process for the preparation of optically active hexahydroisoquinolines (Formula (IV)).
High overall performance indicated by a yield of at least about 60% for obtaining the compound comprising Formula (IV).
Documented Applications
Not explicitly described in patent.
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