Chlorinated heterocyclic compounds and methods of synthesis

Abstract

Compositions of the present invention comprise chlorinated heterocyclic compounds, including racemic monochloroflosequinan, purified enantiomers of monochloroflosequinan and the sulfone derivative of monochloroflosequinan. The methods of the present invention comprise the synthesis of racemic monochloroflosequinan and derivatives thereof, including the sulfone derivative. Intermediates in the synthesis are also provided. The methods further comprise the synthesis of enantiomers of monochloroflosequinan.

We claim:  
     
         1 . A composition comprising racemic 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone.  
     
     
         2 . A composition comprising (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone in enantiomeric excess.  
     
     
         3 . A composition according to  claim 2 , wherein said (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone represents at least 90% of the monochloroflosequinan in the composition.  
     
     
         4 . A composition according to  claim 2 , wherein said (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone represents at least 95% of the monochloroflosequinan in the composition.  
     
     
         5 . A composition comprising (R)-(−)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone in enantiomeric excess.  
     
     
         6 . A composition according to  claim 5 , wherein said (R)-(−)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone represents at least 90% of the monochloroflosequinan in the composition.  
     
     
         7 . A composition according to  claim 5 , wherein said (R)-(−)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone represents at least 95% of the monochloroflosequinan in the composition.  
     
     
         8 . A composition comprising 3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone.  
     
     
         9 . A composition comprising 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone.  
     
     
         10 . A method, comprising: 
 a) providing: 
 i) flosequinan, and  
 ii) triphenyl phosphine; and  
   b) reacting said flosequinan and triphenyl phosphine in an organic solvent under conditions such that desoxyflosequinan (7-fluoro-1-methyl-3-methylthio-4-quinolone) is produced; and    c) further reacting said desoxyflosequinan with N-chlorosuccinimide and 2,2′-azobisisobutyronitrile in an organic solvent under conditions such that chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone) is produced.    
     
     
         11 . The method of  claim 10 , wherein said organic solvent in said reacting step b) is selected from the group consisting of carbon tetrachloride, xylene and toluene.  
     
     
         12 . The method of  claim 10 , wherein said providing step a) optionally provides iii) a catalyst, and said reacting step b) occurs in the presence of said catalyst.  
     
     
         13 . The method of  claim 12 , wherein said organic solvent in said reacting step b) is selected from the group consisting of xylene and toluene.  
     
     
         14 . The method of  claim 12 , wherein said catalyst is tetrabromomethane.  
     
     
         15 . The method of  claim 10 , wherein said organic solvent in step c) is selected from the group consisting of carbon tetrachloride and benzene.  
     
     
         16 . A method, comprising: 
 a) providing: 
 i) flosequinan,  
 ii) thionyl chloride, and  
 iii) pyridine; and  
   b) reacting said flosequinan, thionyl chloride and pyridine in an organic solvent under conditions such that chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone) is produced.    
     
     
         17 . A method, comprising: 
 a) providing: 
 i) chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone),  
 ii) hydrogen peroxide, and  
 iii) potassium carbonate; and  
   b) reacting said chlorodesoxyflosequinan, hydrogen peroxide and potassium carbonate in a solvent under conditions such that monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) is produced.    
     
     
         18 . A method, comprising: 
 a) providing: 
 i) flosequinan, and  
 ii) N-chlorosuccinimide; and  
   b) reacting said flosequinan and N-chlorosuccinimide in an organic solvent under conditions such that monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) is produced.    
     
     
         19 . The method of  claim 18 , wherein said organic solvent is selected from the group consisting of carbon tetrachloride and benzene.  
     
     
         20 . The method of  claim 19 , wherein when said organic solvent is carbon tetrachloride, said reacting step b) additionally includes 2,2′-azobisisobutyronitrile.  
     
     
         21 . A method, comprising: 
 a) providing: 
 i) chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone), and  
 ii) a camphor based reagent; and  
   b) reacting said chlorodesoxyflosequinan and camphor based reagent in an organic solvent under conditions such that an enantiomer of monochloroflosequinan is produced in enantiomeric excess.    
     
     
         22 . The method of  claim 21 , wherein said camphor based reagent is (R)-(−)-(10-camphorsulfonyl) oxaziridine.  
     
     
         23 . The method of  claim 21 , wherein said camphor based reagent is (S)- (+)-(10-camphorsulfonyl) oxaziridine.  
     
     
         24 . The method of  claim 22 , wherein said enantiomer of monochloroflosequinan is (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone.  
     
     
         25 . The method of  claim 23 , wherein said enantiomer of monochloroflosequinan is (R)-(−)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone.  
     
     
         26 . A method, comprising: 
 a) providing: 
 i) monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone), and  
 ii) m-chloroperoxybenzoic acid; and  
   b) reacting said monochloroflosequinan and m-chloroperoxybenzoic acid in an organic solvent under conditions such that monochloroflosequinan sulfone (3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone) is produced.