Stereospecific enrichment of heterocyclic enantiomers

Details Stereospecific enrichment of heterocyclic enantiomers Stereospecific enrichment of heterocyclic enantiomers

2001-10-25

2003-11-18

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S312000

Reexamination Certificate

active

06649764

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods for the stereoselective synthesis of heterocyclic enantiomers. The methods of the present invention incorporate the stereo-preferred oxidation of quinolone intermediates in methods for the stereoselective enrichment of the R(+) or S(−) enantiomer from a quinolone raceme mixture.
BACKGROUND
The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration. Enantiomers are identical with respect to certain physical properties, such as melting and boiling points. However, enantiomers may differ in their chemical properties, particularly within biological systems. While one enantiomer may confer a desired biological function through interactions with natural binding sites, another enantiomer may not demonstrate the same function and, in some cases, may present deleterious side effects.
For example the teratogenic effects of the drug thalidomide is likely due to only one enantiomer of the drug, while the other enantiomer is believed to be a safe and useful tranquilizer devoid of teratogenic side effects. Consequently, the preparation of pharmaceutical agents as substantially pure enantiomers can offer therapeutic advantages as compared to the corresponding racemic mixture.
In view of the advantages associated with the administration of substantially pure enantiomers, chemists have explored many approaches for acquiring enantiomerically pure compounds including the resolution of the racemates using chiral stationary phases, structural modifications of naturally occurring chiral substances (as reagents for running stereospecific reactions) and asymmetric catalysis using chiral catalysts or enzymes.
Optically active catalysts or enzymes have limited application in multiple step and kilo scale processes due to their high prices. Similarly the use of chiral stationary phases, for optical resolution, is a very expensive means for kilo scale production.
What is needed, therefore, is a simplified and economical method for the stereospecific synthesis of therapeutic compounds.
SUMMARY OF THE INVENTION
The present invention relates to methods for the stereoselective synthesis of heterocyclic enantiomers. In one embodiment, the heterocyclic enantiomer is a quinolone. In another embodiment, the heterocyclic enantiomer is a substituted 4-quinolone. In a preferred embodiment, the 4-quinolone is 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone (flosequinan).
In one embodiment, the present invention describes the stereoselective oxidation of 7-fluoro-1-methyl-3-methylthio-4-quinolone as an intermediate step in the synthesis of (R)-(+) or (S)-(−) flosequinan enantiomers. In one embodiment, the methods of the present invention describe stereospecific synthesis of the (R)-(+) enantiomer of flosequinan of at least 86% optical purity. In a preferred embodiment the present invention describes stereospecific synthesis of (R)-(+)-flosequinan of at least 96% optical purity.
In one embodiment, the methods of the present invention describe the stereospecific synthesis of (S)-(−)-flosequinan of at least 86% optical purity. In a preferred embodiment the present invention describes stereospecific synthesis of (S)-(−)-flosequinan with at least 96% optical purity.
Without limiting the invention to any particular mechanism, it is believed that the R(+) and S(−) enantiomers of flosequinan differentially regulate specific phoshodiesterases as compared to racemic flosequinan. This differential effect of the R(+) or S(−) enantiomer on phosphodiesterase activity is a useful tool in therapeutic design.
In one embodiment, the present invention provides a method comprising: a) providing, i) an optically inactive, heterocyclic intermediate, and ii) an optically active camphor based reagent and; b) contacting said heterocyclic intermediate with said optically active camphor based reagent to form a mixture, c) reacting said mixture under conditions such that the (R)-(+) or (S)-(−) enantiomer of said heterocyclic intermediate is generated in excess as compared to the racemic mixture; d) recovering said R(+) or S(−) enantiomer from said mixture.
In another embodiment, the present invention further comprises, e) contacting said racemic mixture with a reducing agent under conditions such that an optically inactive heterocyclic intermediate is generated, and f) contacting said optically inactive heterocyclic intermediate with said optically active camphor based reagent under conditions such that the (R)-(+) or (S)-(−) enantiomer is generated in excess as compared to the ratio of said enantiomer in said racemic mixture.
In one embodiment, the present invention comprises a method, comprising: a) providing: i) a flosequinan racemate; ii) triphenylphosphine; and b) reacting, in a solvent, said flosequinan racemate with said triphenylphosphine under conditions such that a racemic mixture of 7-fluoro-1-methyl-3-methylthio-4-quinolone is produced. In some embodiments, said solvent is selected from the group consisting of carbon tetrachloride and a mixture of xylene and carbon tetrabromide. In some embodiments, the method further comprises the step of c) treating said racemic mixture of 7-fluoro-1-methyl-3-methylthio-4-quinolone with (1R)-(−)-(10-camphorsulfonyl)oxaziridine under conditions such that R-(+)-flosequinan is produced in enantiomeric excess.
In another embodiment, the present invention comprises a method, comprising: a) providing: i) a flosequinan racemate; ii) triphenylphosphine; and b) reacting, in a solvent, said flosequinan racemate with said triphenylphosphine under conditions such that a racemic mixture of 7-fluoro-1-methyl-3-methylthio-4-quinolone is produced, and c) treating said racemic mixture of 7-fluoro-1-methyl-3-methylthio-4-quinolone with (1S)-(+)-(10-camphorsulfonyl)oxaziridine under conditions such that S-(−)-flosequinan is produced in enantiomeric excess.


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Morita et al., “Synthesis and Absolute Configuration of the Enantiomers of 7-Fluoro-1-methyl-3-(methylsulfinyl)-4(1H)-quinolinone (Flosequinan),”Chem. Pharm. Bull.,42(10):2157-2160 (1994).

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