Method of selectively introducing amino substituent

Abstract

Provided are a technique for position-selectively introducing an amino group into a difluorobenzoic acid, a novel process for producing a quinolonecarboxylic acid derivative serving as an antibacterial agent, and intermediates in the production. The process comprises treating a compound represented by formula (6): with a base in a water-containing solvent. The intermediates are represented by formula (6): formula (5): formula (4): or formula (3):

1 - 12 . (canceled) 
   
   
       13 . A compound represented by formula (3), (4), (5) or (6), wherein formula (3) is: 
     
       
         
         
             
             
         
       
       wherein R and R 1  represent each independently a lower alkyl group and A represents an amino-protecting group; 
       wherein formula (4) is: 
     
     
       
         
         
             
             
         
       
       wherein R 1  represents a lower alkyl group and A represents an amino-protecting group; 
       wherein formula (5) is: 
     
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  represent each independently a lower alkyl group and A represents an amino-protecting group; and 
       wherein formula (6) is: 
     
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  represent each independently a lower alkyl group and A represents an amino-protecting group. 
     
   
   
       14 . The compound of  claim 13 , which is the compound of formula (3). 
   
   
       15 . The compound of  claim 13 , which is the compound of formula (4). 
   
   
       16 . The compound of  claim 13 , which is the compound of formula (5). 
   
   
       17 . The compound of  claim 13 , which is the compound of formula (6). 
   
   
       18 . A method for making the compound of formula (3) of  claim 13  comprising:
 reacting a compound represented by formula (2) in a solvent which dissolves the compound of formula (2):   
     
       
         
         
             
             
         
       
       wherein R represents a lower alkyl group and R 1  represents a lower alkyl group; 
       with a compound represented by the following formula: 
     
     
       
         
         
             
             
         
       
       wherein A represents an amino-protecting group. 
     
   
   
       19 . A method for making the compound of formula (4) of  claim 13  comprising:
 hydrolyzing a compound of formula (3), where formula (3) is:   
     
       
         
         
             
             
         
       
       wherein R represents a lower alkyl group, R 1  represents a lower alkyl group, and A represents an amino-protecting group. 
     
   
   
       20 . A method for making the compound of formula (5) from a compound of formula (4) of  claim 13  comprising:
 converting the compound of formula (4) to an acid halide with a halogenating agent or to an acylimidazole with a carbonyldiimidazole condensing agent, and then   reacting the resultant product with a magnesium salt of a lower alkyl monoester of malonic acid; or,   converting the compound of formula (4) to an acid halide in the presence of a base, with a lower alkyl monoester of malonic acid; where formula (4) is:   
     
       
         
         
             
             
         
       
       wherein R 1  represents a lower alkyl group, and A represents an amino-protecting group. 
     
   
   
       21 . A method for making the compound of formula (6) from a compound of formula (5) of  claim 13  comprising:
 reacting the compound of formula (5) with an ortho ester and then with (1R,2S)-2-fluorocyclopropylamine or a salt thereof; where the compound of formula (5) is:   
     
       
         
         
             
             
         
       
       wherein R 1  represents a lower alkyl group, A represents an amino-protecting group, and R 2  represents a lower alkyl group. 
     
   
   
       22 . A compound of formula (I): 
     
       
         
         
             
             
         
       
       wherein R 1  represents a lower alkyl group and A represents an amino-protecting group. 
     
   
   
       23 . A composition comprising the compound of  claim 22  in an amount sufficient to exert an antibacterial effect. 
   
   
       24 . An agricultural chemical or veterinary drug comprising the compound of  claim 22 . 
   
   
       25 . A method for treating a bacterial infection comprising administering the compound of  claim 22  to a subject in need thereof. 
   
   
       26 . The method of  claim 25 , wherein said bacterial infection is caused by gram-positive bacteria.