Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-28
2003-09-02
Solola, Taofiq (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C203S048000
Reexamination Certificate
active
06613919
ABSTRACT:
FIELD OF THE INVENTION
This invention provides a method for isolation of one or both enantiomers of 5-substituted or 5,5-disubstituted 4-hydroxy-2-furanones or 3,4-dihydroxy-2-furanones in pure form, by resolution with enantiomerically pure bases.
BACKGROUND OF THE INVENTION
Synthesis of enantiomerically pure compounds is tedious work, and while producing the desired pure compound, often is done by sacrificing yield. Such methods often are not suitable for scale up and the preparation of multi-gram or greater quantities.
Preparation of racemic mixtures of compounds followed by separation or isolation of the desired enantiomers is a more promising approach. Methods for the resolution of racemic mixtures has employed, for example, enantiomers of derivatives of phenoxypropionic acid for the separation of papaverine (WO 97/11927), cinchonidine for the separation of aminocarboxylic acid derivatives (U.S. Pat. No. 4,005,088), or quinine trihydrate for the separation of enantiomers of hydroxyphenylacetic acid derivatives (British Patent Specification 1,241,844).
The enantiomers of 5-substituted or 5,5-disubstituted 4-hydroxy or 3,4-dihydroxy-2(5H)-furanones have numerous therapeutic utilities which take advantage of their anti-inflammatory, anti-lipidemic and anti-aggregatory activities, among others, which are useful in the treatment of numerous conditions and diseases such as cardiovascular disease including atherosclerosis; asthma; rheumatoid arthritis; inflammatory bowel disease; acute respiratory distress syndrome; neurodegenerative disorders such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, traumatic brain injury, and multiple sclerosis; and viral diseases including AIDS. Such compounds and uses are described in, for example, U.S. Pat. Nos. 5,298,526; 5,399,721; 5,504,108; 5,504,107; 5,656,662; 5,095,126; 5,071,872; WO 98/07714; and U.S. Ser. No. 09/406,544, filed Sep. 27, 1999; all of which are incorporated by reference herein in their entireties. However, methods for the separation of the enantiomers of these compounds from the racemic mixture were not previously known. Asymmetric synthesis of such compounds as described, for example, in U.S. Pat. No. 5,399,721, produces a low yield (5-7%) which is unfeasible for large scale or commercial preparation.
It is towards the process for resolving enantiomers of 5-substituted or 5,5-disubstituted 4-dihydroxy-2(5H)-furanones or 3,4-dihydroxy-2(5H)-furanones in pure form that the present invention is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
This invention affords a solution to the technical problem of obtaining one or both enantiomers of 5-substituted or 5,5-disubstituted 4-hydroxy-2(5H)-furanones or 3,4-dihydroxy-2(5H)-furanones in pure form by resolution with enantiomerically pure bases. In the practice of the invention, the 5-substituted 4-hydroxy-2(5H)-furanone is mixed with an enantiomerically pure chiral base, to form a diastereoisomeric salt. The diastereoisomeric salts may then be separated. For example, in an appropriate solvent, one stereoisomeric salt of one enantiomer precipitates, and thus can be separated, washed, and the enantiomerically pure furanone recovered from the salt by hydrolysis. The other enantiomer may be recovered from the stereoisomeric salt which remains dissolved in the mother liquor. Other means for separation of the salts are embraced herein; selective precipitation of one stereoisomeric salt is preferred.
Non-limiting examples of enantiomerically pure bases useful for the practice of the invention include cinchonidine, cinchonine, quinine, quinidine, brucine, strychnine, &agr;-methylbenzylamine, ephedrine, amphetamine, dehydroabietylamine. Cinchonidine is preferred. Non-limiting examples of solvents include ethanol (anhydrous or aqueous), methanol or other alcohols, acetone (anhydrous or aqueous), ethyl acetate, water, dioxane, mixtures of solvents containing at least one alcohol, and others. A solven of 95% ethanol (aq.) is preferred. The skilled artisan will readily be able to determine an appropriate solvent in which the separation may occur.
The methods of the present invention are not limited to any particular 5-substituted 4-hydroxy-2(5H)-furanones. Additional substitutions are embraced herein. Such compounds include both 5-substituted and 5,5-disubstituted compounds, and include 4-hydroxy-2(5H)-furanones and 3,4-dihydroxy-2(5H)-furanones. 5-Substituted and 5,5-disubstituted 3,4-dihydroxy-2(5H)-furanone are preferred.
Thus, in its broadest aspect, the invention is directed to a method for the separation of a racemic mixture of a 5-substituted 4-hydroxy-2(5H)-furanone, comprising the steps of
(a) reacting in a solvent the racemic mixture with an enantiomerically pure base in an amount sufficient to form a diastereoisomeric salt of the 5-substituted 4-hydroxy-2(5H)-furanone; and
(b) separating a stereoisomeric salt of one enantiomer of the 5-substituted 4-hydroxy-2(5H)-furanone from the solvent.
A preferred method of separation is by precipitation of one of the stereoisomeric salts.
The invention is further directed to a method for obtaining an enantiomerically pure 5-substituted 4-hydroxy-2(5H)-furanone from a racemic mixture thereof comprising carrying out the separation in accordance with the above steps, separating one stereoisomeric salt of one of the enantiomers of the 5-substituted 4-hydroxy-2(5H)-furanone, and then hydrolyzing the separated stereoisomeric salt of one enantiomer of said 5-substituted 4-hydroxy-2(5H)-furanone to provide the pure 5-substituted 4-hydroxy-2(5H)-furanone.
In another embodiment of the invention, a method is provided for obtaining an enantiomerically pure 5-substituted 4-hydroxy-2(5H)-furanone from a racemic mixture thereof comprising carrying out the separation in accordance with the above steps, separating one stereoisomeric salt of one of the enantiomers of the 5-substituted 4-hydroxy-2(5H)-furanone by selective precipitation, isolating the precipitate, and then hydrolyzing the separated stereoisomeric salt of one enantiomer of said 5-substituted 4-hydroxy-2(5H)-furanone to provide the pure 5-substituted 4-hydroxy-2(5H)-furanone.
In a further aspect of the above procedures, the other stereoisomeric salt which was not separated by the foregoing methods may be recovered from the solvent, and hydrolyzed to provide the other enantiomer. In the instance wherein the separation was performed by precipitation of one of the stereoisomeric salts from the mother liquor, the other stereoisomeric salt may be recovered from the mother liquor, and hydrolyzed to produce the other enantiomer.
In the foregoing methods, the 5-substituted 4-hydroxy-2(5H)-furanone may be, for example, a 5-substituted 4-hydroxy-2(5H)-furanone; a 5,5′-disubstituted 4-hydroxy-2(5H)-furanone; a 5-substituted 3,4-dihydroxy-2(5H)-furanone; or a 5,5-disubstituted 3,4-dihydroxy-2(5H)-furanone.
Enantiomerically pure bases useful for the practice of the present invention include but are not limited to cinchonidine, cinchonine, quinine, quinidine, brucine, strychnine, &agr;-methylbenzylamine, ephedrine, amphetamine, and dehydroabietylamine. These and other aspects of the present invention will be better appreciated by reference to the following Detailed Description.
DETAILED DESCRIPTION OF THE INVENTION
It has been found by the inventor herein that the enantiomers of 5-substituted and 5,5-disubstituted 4-hydroxy-2(5H)-furanones and 3,4-dihydroxy-2(5H)-furanones may be separated from racemic mixtures of the compound by utilizing an enantiomerically pure chiral base to form a diasteromeric salt with the enantiomers of the racemic mixture. The stereoisomeric salt of one of the enantiomers is subsequently separated. As no previous methods for separating enantiomers from racemic mixtures of 5-substituted 4-dihydroxy-2(5H)-furanones were known, and the chemistry of the 5-substituted 4-dihydroxy-2(5H)-furanones is different from that of c
Klauber & Jackson
Oxis Isle of Man
Solola Taofiq
LandOfFree
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