Processes for the preparation of heteroaryl carboxylic acids

Abstract

Provided herein are processes for the preparation of heteroaryl carboxylic acids.

What is claimed is: 
     
         1 . A process for preparing a thiophene carboxylic acid, the process comprising:
 contacting a compound of Formula Ib:   
       
         
           
           
               
               
           
         
       
       with oxygen in the presence of a catalyst component in an oxidation reaction zone comprising a liquid medium, wherein:
 R 2  is one or more of hydrogen, halogen, aryl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, cyano or —C(O)R 21 , R 21  is hydrogen, hydroxyl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, or C 1 -C 4  alkylamino; or R 2  is aryl, fused to the two adjacent carbons of the thiophene ring; 
 and wherein the catalyst component comprises a first transition metal ion selected from the group consisting of cobalt, copper, manganese, iron, zinc, zirconium, nickel, palladium, cadmium, and mixtures thereof. 
 
     
     
         2 . The process of  claim 1  wherein the first transition metal ion is selected from the group consisting of cobalt, iron, and copper. 
     
     
         3 . The process of  claim 2  wherein the first transition metal ion is cobalt. 
     
     
         4 . The process of  claim 1  wherein the catalyst component further comprises a second transition metal ion. 
     
     
         5 . The process of  claim 4  wherein the second transition metal ion is selected from the group consisting of manganese, iron, and copper. 
     
     
         6 . The process of  claim 5  wherein the second transition metal ion is manganese. 
     
     
         7 . The process of  claim 1  wherein the liquid medium comprises an alkanoic acid. 
     
     
         8 . The process of  claim 7  wherein the alkanoic acid is selected from the group consisting of acetic acid and propionic acid. 
     
     
         9 . The process of  claim 1  wherein the first transition metal ion is introduced to the liquid medium in a salt form of a halide, a C 2 -C 6  alkanoate, a nitrate, a carbonate, or a combination thereof. 
     
     
         10 . The process of  claim 1  wherein the process comprises adding a nitrate salt to the liquid medium prior to or during the contacting step. 
     
     
         11 . The process of  claim 1  wherein the liquid medium further comprises a source of halide ions. 
     
     
         12 . The process of  claim 11  wherein the source of halide ions is selected from the group consisting of hydrohalic acids and halide salts. 
     
     
         13 . The process of  claim 11  wherein the source of halide ions is a halide salt. 
     
     
         14 . The process of  claim 14  wherein the halide salt is a calcium salt, a cesium salt, a lithium salt, a sodium salt, or a potassium salt. 
     
     
         15 . The process of  claim 11  wherein the source of halide ions is selected from the group consisting of sodium bromide, sodium chloride, hydrobromic acid and hydrochloric acid. 
     
     
         16 . The process of  claim 1  wherein the source of oxygen is air. 
     
     
         17 . A process for preparing a 3,5-disubstituted 1,2,4-oxadiazole of Formula IV or a salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein Ar 1  is selected from the group consisting of phenyl, pyridyl, pyrazyl, oxazolyl, and isoxazolyl, each of which can be optionally independently substituted with one or more substituents selected from the group consisting of halogen, CF 3 , CH 3 , OCF 3 , OCH 3 , CN and C(H)O, and Ar 2  is thienyl,
 the process comprising reacting thiophene with dimethylformamide in the presence of phosgene or phosphoryl chloride in a reaction medium comprising an organic solvent, thereby producing 2-thiophenecarboxaldehyde; 
 contacting 2-thiophenecarboxyaldehyde with oxygen in an oxidation reaction zone comprising a liquid medium comprising an alkanoic acid, thereby producing 2-thiophenecarboxylic acid; 
 reacting 2-thiophenecarboxylic acid dissolved in a chlorination medium comprising an organic solvent with thionyl chloride, thereby producing 2-thiophenecarbonyl chloride; 
 and reacting 2-thiophenecarbonyl chloride with an N-hydroxyamidine of Formula V, or a tautomeric form thereof, 
 
       
         
           
           
               
               
           
         
       
       thereby producing a 3,5-disubstituted 1,2,4-oxadiazole or a salt thereof. 
     
     
         18 . The process of  claim 17  wherein the 2-thiophenecarbonyl chloride is reacted with benzamide oxime and the 3,5-disubstituted 1,2,4-oxadiazole of Formula IV is 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole. 
     
     
         19 . The process of  claim 17  wherein the alkanoic acid is selected from the group consisting of acetic acid and propionic acid. 
     
     
         20 . A process for preparing a 3,5-disubstituted 1,2,4-oxadiazole of Formula IV or a salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein Ar 1  is selected from the group consisting of phenyl, pyridyl, pyrazyl, oxazolyl and isoxazolyl, each of which can be optionally independently substituted with one or more substituents selected from the group consisting of halogen, CF 3 , CH 3 , OCF 3 , OCH 3 , CN and C(H)O, and Ar 2  is thienyl,
 the process comprising reacting thiophene with acetic anhydride in an acylation reaction medium comprising a mineral acid or a cation exchange, thereby producing 2-acetylthiophene; 
 contacting 2-acetylthiophene with oxygen in an oxidation reaction zone comprising a liquid medium comprising an alkanoic acid, thereby producing 2-thiophenecarboxylic acid; 
 reacting 2-thiophenecarboxylic acid dissolved in a chlorination medium comprising an organic solvent with thionyl chloride, thereby producing 2-thiophenecarbonyl chloride; 
 and reacting 2-thiophenecarbonyl chloride with an N-hydroxyamidine of Formula V, or a tautomeric form thereof, 
 
       
         
           
           
               
               
           
         
       
       thereby producing the 3,5-disubstituted 1,2,4-oxadiazole or a salt thereof. 
     
     
         21 . A process for preparing a heteroaryl carboxylic acid of Formula II: 
       
         
           
           
               
               
           
         
       
       the process comprising contacting a compound of Formula Ia: 
       
         
           
           
               
               
           
         
       
       with oxygen in the presence of a catalyst component in an oxidation reaction zone comprising a liquid medium comprising an alkanoic acid and a source of halide ions, wherein:
 R 1  is C 1 -C 6  alkyl; 
 A is a heteroaryl which can be optionally independently substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, aryl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, cyano, or —C(O)R a , wherein R a  is hydrogen, hydroxyl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, and C 1 -C 4  alkylamino; 
 and wherein the catalyst component comprises a first transition metal ion selected from the group consisting of cobalt, copper, manganese, iron, zinc, zirconium, nickel, palladium, cadmium, and mixtures thereof, and the source of halide ions comprises a hydrohalic acid or a halide salt of calcium, cesium, lithium, sodium, or potassium. 
 
     
     
         22 . A process for preparing a heteroaryl carboxylic acid of Formula II, 
       
         
           
           
               
               
           
         
       
       the process comprising:
 reacting a heteroaromatic compound of Formula A-H with acetic anhydride in the presence of a cation ion exchange resin in an acylating reaction zone to produce a product mixture comprising a compound of Formula Ia-a; 
 
       
         
           
           
               
               
           
         
         and contacting the compound of Formula Ia-a with oxygen in the presence of a catalyst component in a oxidation reaction zone comprising a liquid medium comprising acetic acid and acetic anhydride; wherein: 
         A is a heteroaryl which can be optionally independently substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, aryl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, cyano, and —C(O)R a , wherein R a  is hydrogen, hydroxyl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 4  haloalkoxy, or C 1 -C 4  alkylamino; and 
         the catalyst component comprises a first transition metal ion selected from the group consisting of cobalt, copper, manganese, iron, zinc, zirconium, nickel, palladium, cadmium, and mixtures thereof.