Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-28
2004-12-21
Chang, Celia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S321000
Reexamination Certificate
active
06833458
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a new method for the preparation of chiral trans-3,4-disubstituted piperidines, and particularly to the preparation of chiral paroxetine by using a chiral amine as a chiral auxiliary.
2. Description of the Prior Art
Paroxetine, a type of a trans-3,4-disubstituted piperidine derivative, is a potent selective serotonin (5-hydroxytryptamine) reuptake inhibitor and has been widely used as antidepressant and anti-Parkinson agents.
The trans-(−)-(3S,4R) paroxetine, the pharmacologically active enantiomer, is generally synthesized from the corresponding chiral precursors. Current processes for the production of these chiral precursors involve a selective recrystallization of diastereomeric salts,
1b,e
a biocatalytically kinetic resolution of a racemic ester,
1f
and a chiral auxiliary assisted asymmetric Michael addition.
2
In general, the requirement of a successful resolution of a racemic compound is that its diastereomeric salt must be in the form of good crystals. However, it has been reported that some racemic trans-3,4-piperdine derivatives could not be resolved owing to the non-crystalline salts.
1g
It is also observed that some of the diastereomeric salts of racemic paroxetine and piperidine analogues were not crystalline. Over the past years, although several chiral 3- or 4-substituted piperidine derivatives have been prepared in high enantiomeric purity via chemical or enzymatic method,
2-5
it has been found that the use of chromatography in the purification of non-solid products may retard the application in a large scale process and in industry. The related references are listed at the end of the specification and are incorporated herein for reference in their entirety.
Recently, the asymmetric synthesis of a few specific chiral 3-, 4-substituted, and 3,4-disubstituted 2-piperidinones have been published in the literature.
2-3
However, the general synthetic methods used for the preparation of chiral 3,4-disubstituted 2-piperidinone and piperidine derivatives are still very limited.
2-3
Because chiral 2-piperidinones have been regarded as useful precursors for the synthesis of the corresponding chiral piperidines, the present invention is interested in developing a convenient method for the preparation of these compounds. Herein, the present invention provides a diastereoselective synthesis of a chiral 4-substituted as well as 3,4-disubstituted 2-piperidinones using commercially available chiral amines comprising chiral primary amines or chiral amino acid derivatives, such as (S)-methyl benzylamine as a chiral auxiliary, and the application of this methodology in the preparation of several chiral trans-3,4-disubstituted piperidine derivatives such as paroxetine.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a new method for the preparation of chiral 4-substituted 2-piperidinones from the corresponding 3-substituted glutaric anhydride and a chiral amine as the intermediates for the synthesis of chiral 3,4-disubstituted 2-piperidinones.
A further object of the present invention is to provide a diastereoselective synthesis of chiral 4-substituted as well as 3,4-disubstituted 2-piperidinones using a commercially available chiral amine as a chiral auxiliary which can be used in a large scale process.
It is still a further object of the present invention is to provide a method for the preparation of trans-3,4-disubstituted piperidines by acylation at the alpha carbon of 4-substituted 2-piperidinones to create trans-3,4-disubstituted 2-piperidinones, followed by reduction
Another object of the present invention is to provide a convenient method for the preparation of a chiral paroxetine from a chiral 4-aryl substituted 2-piperidinone via four steps: acylation at the alpha carbon to create a chiral trans-3,4-disubstituted 2-piperidinone, reduction to form a pure trans 3,4-disubstituted piperidine, convertion of the amino alcohol to an aryl ether, and hydrogenolysis of the chiral auxiliary to obtain a chiral paroxetine.
These and other objects, advantages and features of the present invention will be more fully understood and appreciated by reference to the written specification and appended drawings.
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Chen Shyh-Fong
Hong Pao-Chiung
Huang Hsiang-Ling
Liu Lee Tai
Chang Celia
Development Center for Biotechnology
Morgan & Finnegan , LLP
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