Production method for 3,3-dimethyl-3,4-dihydro-1h-quinoxalin-2-one derivative and intermediate for said production method

Abstract

An object is to provide a novel production method suitable for industrial production of a 3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one derivative and a synthetic intermediate for the method. Provided is a method for producing a compound represented by formula (1): wherein R 1 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group, R 2 represents a hydrogen atom, an optionally substituted alkyl group, a hydroxy group, or a nitrogen atom-protecting group, R 3 represents a hydrogen atom, an optionally substituted alkyl group, a hydroxy group, or a nitrogen atom-protecting group, and X represents a hydroxy group or a leaving group, or a salt thereof, the method comprising the steps of: reacting a compound represented by formula (2): wherein R 1 , R 2 , and X are the same as defined in formula (1), R 4 represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group, or a salt thereof with a nitrating agent to obtain a compound represented by formula (3): wherein R 1 , R 2 , R 4 , and X are the same as defined in formulae (1) and (2), or a salt thereof, and reducing the compound represented by formula (3) or the salt thereof to obtain the compound represented by formula (1) or the salt thereof.

1 . A method for producing a compound represented by formula (2): 
       
         
           
           
               
               
           
         
         wherein R 1  represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group, 
         R 2  represents a hydrogen atom, an alkyl group, a hydroxy group, or a t-butoxycarbonyl group, 
         R 4  represents an alkyl group, a cycloalkyl group, or an aryl group, and 
         X represents a hydroxy group or a halogen atom, 
         or a salt thereof, the method comprising the step of reacting a compound represented by formula (6): 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and X are the same as defined in formula (2), 
         or a salt thereof with a compound represented by formula (7):
   R 4 OH  (7),
 
 
         wherein R 4  is the same as defined in formula (2), 
         in the presence of an acid to obtain the compound represented by formula (2) or the salt thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein
 R 1  in formula (6) represents a hydrogen atom.   
     
     
         3 . The method according to  claim 1 , further comprising the step of reacting a compound represented by formula (4): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and X are the same as defined in formula (2), 
         or a salt thereof with a compound represented by formula (5): 
       
       
         
           
           
               
               
           
         
         wherein Y represents a hydroxy group or halogen atom, 
         or a salt thereof to obtain the compound represented by formula (6) or the salt thereof. 
       
     
     
         4 . A method for producing a compound represented by formula (2): 
       
         
           
           
               
               
           
         
         wherein R 1  represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group, 
         R 2  represents a hydrogen atom, an alkyl group, a hydroxy group, or a t-butoxycarbonyl group, 
         R 4  represents an alkyl group, a cycloalkyl group, or an aryl group, and 
         X represents a hydroxy group or a halogen atom, 
         or a salt thereof, the method comprising the step of reacting a compound represented by formula (4): 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and X are the same as defined in formula (2), 
         or a salt thereof with a compound represented by formula (5′): 
       
       
         
           
           
               
               
           
         
         wherein R 4  is the same as defined in formula (2), and 
         Y represents a hydroxy group or a halogen atom, 
         or a salt thereof to obtain the compound represented by formula (2) or the salt thereof. 
       
     
     
         5 . A compound represented by formula (2) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group, 
         R 2  represents a hydrogen atom, an alkyl group, a hydroxy group, or a t-butoxycarbonyl group, 
         R 4  represents an alkyl group, a cycloalkyl group, or an aryl group, and 
         X represents a hydroxy group or a halogen atom. 
       
     
     
         6 . The compound or the salt thereof according to  claim 5 , wherein
 the compound represented by formula (2) or the salt thereof is methyl 2-bromo-5-(1-methoxycarbonyl-1-methylethyl)aminobenzoate.   
     
     
         7 . A compound represented by formula (6) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group, 
         R 2  represents a hydrogen atom, an optionally substituted alkyl group, a hydroxy group, or a t-butoxycarbonyl group, and 
         X represents a hydroxy group or a leaving group. 
       
     
     
         8 . The compound or the salt thereof according to  claim 7 , wherein
 the compound represented by formula (6) or the salt thereof is selected from the group consisting of 2-bromo-5-(1-carboxy-1-methylethyl)aminobenzoic acid and methyl 2-bromo-5-(1-carboxy-1-methylethyl)aminobenzoate.   
     
     
         9 . A method for producing a compound represented by formula (8): 
       
         
           
           
               
               
           
         
         wherein R 1  represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group, 
         R 2  represents a hydrogen atom, an alkyl group, a hydroxy group, or a t-butoxycarbonyl group, and 
         R 3  represents a hydrogen atom, an optionally substituted alkyl group, a hydroxy group, or a nitrogen atom-protecting group, 
         or a salt thereof, the method comprising the step of reacting a compound represented by formula (9): 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and R 3  are the same as defined in formula (8), 
         or a salt thereof with a compound represented by formula (5″): 
       
       
         
           
           
               
               
           
         
         wherein R 5  represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group, and 
         Y represents a hydroxy group or a halogen atom, 
         or a salt thereof to obtain the compound represented by formula (8) or the salt thereof. 
       
     
     
         10 . A compound represented by formula (8) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group, 
         R 2  represents a hydrogen atom, an alkyl group, a hydroxy group, or a t-butoxycarbonyl group, and 
         R 3  represents a hydrogen atom, an alkyl group, a hydroxy group, or a t-butoxycarbonyl group. 
       
     
     
         11 . The compound or the salt thereof according to  claim 10 , wherein the compound represented by formula (8) or the salt thereof is 8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one.