Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-05-12
2000-10-31
Owens, Amelia
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
554125, 554148, C07D34100
Patent
active
061405124
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel process for obtaining lipoic acid (thioctic acid) either in racemic or single enantiomer form, and intermediates in that process.
BACKGROUND TO THE INVENTION
Lipoic acid (thioctic acid) has been reported to have utility for a wide range of therapeutic applications, including liver disease and poisoning (see DE-A-4338508), hypertension (see DE-A-4343647), pain and infection, especially retroviral infection such as HIV (see EP-A-0427247). It has been reported that (R)-lipoic acid is preferred for conditions associated with diabetes such as polyneuropathy and nephropathy (see DE-A-4343593), and for treating chronic degenerative diseases of the central nervous system (CNS) (see DE-A-4343592). Whereas in EP-A-0572922, it has been reported that a combination of the unnatural (S)-enantiomer and vitamin E provides effective analgesia. Thus, synthetic routes to single enantiomer lipoic acid have been sought.
There are already various synthetic approaches reported, such as in Y. S. Yadav et al, J. Sci. Ind. Rev., (1990) 49: 400-409; P. C. Bullman Page et al, J. Chem. Soc. Perkin Trans. 1, (1990), 1615-18; B. R. Menon et al, Tetrahedron Lett., (1987) 28: 2183-6; S. A. Gopalan and J. H. Jacobs, J. Chem. Soc. Perkin Trans. 1, (1990), 1897-1900; J. D. Elliot et al, Tetrahedron Lett., (1985) 26: 2535-8; M. H. Brookes et al, J. Chem. Soc. Chem. Commun., (1983), 1051-3; and L. G. Chebotareva, Zhim.-Farm. Zh.,(1980) 14: 92-9, including classical resolution; asymmetric epoxidation of an intermediate; enantiomeric control by a chiral auxiliary; or derivation from an available chirality pool material. The existing routes are generally not ideal as they involve many steps, use expensive reagents or starting materials, or result in loss of half the desired material following resolution of a racemate. As a result there is a continuing need for a more economical synthetic route.
SUMMARY OF THE INVENTION
According to a first aspect of the present invention, a process for preparing lipoic acid (thioctic acid), or a derivative thereof, is one in which a 2-substituted cyclohexanone is transformed in an oxidation reaction to a lactone having the formula (2), below, wherein X is a heteroatom substituent and the lactone is converted to lipoic acid.
According to a second aspect of the present invention, a novel lactone has the formula (2), below, wherein X is a heteroatom substituent, and is in substantially single enantiomer form. By substantially single enantiomer we mean typically at least 50% ee, preferably at least 80% ee, more preferably at least 90% ee, or higher. Lactones of this type are particularly useful as intermediates in the preparation of single enantiomer lipoic acid.
DESCRIPTION OF THE INVENTION
One synthetic route to single enantiomer lipoic acid (or for that matter the racemate) embodied by the present invention starts with the very readily available starting material cyclohexanone and is outlined in Scheme 1 below. It is characterised by a Baeyer Villiger oxidation of a 2-substituted cyclohexanone.
In Scheme 1, X is generally a heteroatom substituent, such as an oxygen-containing substituent, e.g. --OH, -Oacyl, --OCOR (in which R is generally C.sub.1-20 alkyl, but can be other groups), or a halogen atom.
Benefits of such a route are that (i) the starting material is inexpensive, as there are various ways to achieve substitution at the 2-position of cyclohexanone; and (ii) if the 2-substituted cyclohexanone is obtained in single enantiomer form through resolution, the incorrect enantiomer can be racemised (by virtue of the acidity of the proton at the stereogenic centre), and recycled into the resolution.
The resolution can be conducted by a variety of methods, such as by esterase bio-resolution where X is chosen to provide an 0-acyl derivative and kinetic resolution with an asymmetric Baeyer Villiger reaction, as is the case described below using a monooxygenase, or by fractional crystallisation if X is an ester (--O--COR) with a chiral acid whi
REFERENCES:
patent: 5489694 (1996-02-01), Paust et al.
Adger Brian Michael
McCague Raymond
Roberts Stanley Michael
Asta Medica Aktiengesellschaft
Owens Amelia
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