Phenylglyoxylic acid derivatives and their preparation and use

Abstract

The invention provides novel phenylglyoxylic acid derivatives, which may be useful as intermediates for preparing stereoisomerically enriched drug compounds. The invention also provides methods of making phenylglyoxylic acid derivatives, and uses of phenylglyoxylic acid derivatives.

1 . A method of making a phenylglyoxylic acid derivative comprising oxidizing a compound of Formula (II) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 5  are hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy; 
         R 3  is halogen, hydroxyl, cyano, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy; 
         one of R 2  and R 4  is halogen, hydroxyl, cyano, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy, while the other is hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy; 
         R 6 , R 7 , R 8 , R 9  are hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy; 
         R 10  is hydrogen, C 1-6  alkyl, or an alkali metal cation; and 
         Z is C 1-6  alkylene, which is optionally substituted one or more times by substitutents selected independently from the group consisting of halo, cyano, C 1-4  haloalkyl, C 1-4  haloalkoxy, phenyl, and oxo. 
       
     
     
         2 . The method of  claim 1 , where
 R 1 , R 5 , R 6 , R 7 , R 8 , and R 9  are all hydrogen;   R 2  is hydrogen and R 4  is chloro, or R 2  is chloro and R 4  is hydrogen;   R 3  is chloro;   R 10  is methyl; and   Z is methylene.   
     
     
         3 . The method of  claim 1 , where the step of oxidizing comprises contacting the compound with an oxidation catalyst. 
     
     
         4 . The method of  claim 3 , where the oxidation catalyst is a metal oxide. 
     
     
         5 . The method of  claim 3 , where the oxidation catalyst is a transition metal oxide. 
     
     
         6 . The method of  claim 3 , where the oxidation catalyst is manganese (IV) oxide. 
     
     
         7 . The method of  claim 3 , where the oxidation catalyst is an organic oxidation catalyst. 
     
     
         8 . The method of  claim 3 , where the oxidation catalyst is a nitroxyl compound. 
     
     
         9 . The method of  claim 3 , where the oxidation catalyst is 2,2,6,6-tetramethylpiperidinyloxy, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy, 4-acetamido-2,2,6,6-tetramethylpiperidinyloxy, 4-methylsulfonyloxy-TEMPO, 4-(2-bromoacetamido)-TEMPO, 4-(2-iodoacetamido)-TEMPO, 4-amino-TEMPO, 4-carboxy-TEMPO, 4-cyano-TEMPO, 4-benzoyloxy-TEMPO, 4-isothio-cyanato-TEMPO, 4-maleimido-TEMPO, 4-methoxy-TEMPO, 4-oxo-TEMPO, 4-phosphonoxy-TEMPO, or 4-methacrylate-TEMPO. 
     
     
         10 . A method of reducing a phenylglyoxylic acid derivative comprising reducing a compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 5  are hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy; 
         R 3  is halogen, hydroxyl, cyano, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy; 
         one of R 2  and R 4  is halogen, hydroxyl, cyano, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy, while the other is hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy; 
         R 6 , R 7 , R 8 , R 9  are hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, or C 1-4  haloalkoxy; 
         R 10  is hydrogen, C 1-6  alkyl, or an alkali metal cation; and 
         Z is C 1-6  alkylene, which is optionally substituted one or more times by substitutents selected independently from the group consisting of halo, cyano, C 1-4  haloalkyl, C 1-4  haloalkoxy, phenyl, and oxo. 
       
     
     
         11 . The method of  claim 10 , where
 R 1 , R 5 , R 6 , R 7 , R 8 , and R 9  are all hydrogen;   R 2  is hydrogen and R 4  is chloro, or R 2  is chloro and R 4  is hydrogen;   R 3  is chloro;   R 10  is methyl; and   Z is methylene.   
     
     
         12 . The method of  claim 10 , where the step of reducing comprises contacting the compound with a transition metal compound. 
     
     
         13 . The method of  claim 12 , where the transition metal compound is a ruthenium compound. 
     
     
         14 . The method of  claim 13 , where the ruthenium compound is dichloro(p-cymene)-ruthenium(II) dimer. 
     
     
         15 . The method of  claim 12 , where the method also comprises contacting the compound with N-((1R,1R)-2-amino-1,2-diphenylethyl)-2,4,6-triisopropyl-benzenesulfonamide.