Fluorinated heterocyclic compounds and methods of synthesis

Details Fluorinated heterocyclic compounds and methods of synthesis Fluorinated heterocyclic compounds and methods of synthesis

2002-10-28

2004-07-27

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S155000

Reexamination Certificate

active

06767914

ABSTRACT:

FIELD OF THE INVENTION
The present invention teaches the synthesis of fluorinated heterocyclic compounds. The present invention also contemplates composition comprising fluorinated heterocyclic compounds.
BACKGROUND
A variety of heterocyclic compounds have been described as having various pharmaceutical applications. However, the synthesis of such compounds, especially on a large scale, is often labor-intensive, expensive and time consuming. What is needed therefore, is a simplified and economical method for the synthesis and purification of fluorinated heterocyclic compounds.
SUMMARY OF THE INVENTION
In one embodiment, the present invention contemplates compositions comprising racemic monofluoroflosequinan (7-fluoro-3-fluoromethylsulfinyl-1-methyl-4-quinolone).
In one embodiments, the present invention contemplates compositions comprising difluoroflosequinan (3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In another other embodiments, the present invention contemplates compositions comprising the sulfone derivative of difluoroflosequinan.
In one embodiment, the present invention contemplates methods for the synthesis of racemic monofluoroflosequinan. In one embodiment, the method comprises: a) providing: i) 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone and ii) m-chloroperbenzoic acid (MCPBA); and b) reacting said 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone and m-chloroperbenzoic acid in a solvent under conditions such that 7-fluoro-3-fluoromethylsulfinyl-1-methyl-4-quinolone is produced. In some embodiments, the solvent is dichloromethane (DCM). In another embodiment, a method of synthesis of 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone is contemplated. In one embodiment, the method comprises: a) providing: i) 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone (flosequinan), and ii) (diethylamino)sulfur trifluoride (DAST); and b) reacting said flosequinan and (diethylamino)sulfur trifluoride in a solvent under conditions such that 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone is produced. In some embodiments, the solvent is dichloromethane (DCM). In some embodiments, a catalyst is provided. The reaction time of step b) is reduced in the presence of the catalyst. In some embodiments, the catalyst is antimony chloride (SbCl
3
).
In one embodiment, the present invention contemplates methods of synthesis of difluoroflosequinan (3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In one embodiment, a second fluorine atom is introduced onto a side chain of 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone, to produce 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone, which is subsequently oxidized to produce 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. In one embodiment, the method comprises: a) providing (i) 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone, (ii) SELECTFLUOR and (iii) triethylamine and b) reacting said 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone, SELECTFLUOR and triethylamine in a solvent under conditions such that 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone is produced and c) further reacting said 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone with m-chloroperbenzoic acid (MCPBA) in a solvent under conditions such that 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced. In some embodiments, the solvent in step b) is acetronitrile. In some embodiments, the solvent in step c) is dichloromethane (DCM)


REFERENCES:
patent: 6307050 (2001-10-01), Kwiatkowski et al.

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