Processes for producing 7-isoindoline-quinolone carboxylic acid derivative and its intermediate, as well as salt of 7-isoindoline-quinolonecarboxylic acid derivative, its hydrate and composition comprising the same as active ingredient

Abstract

Process for producing a 7-bromoquinolone-carboxylic acid derivative of the following formula or its salt by reacting a 2,4-dibromo-3-hydroxybenzoic acid ester compound of the formula R 7a -x to obtain a 3-alkoxy-2,4-dibromobenzoic acid ester, subjecting the 3-alkoxy-2,4-dibromobenzoic acid ester to elimination reaction of the carboxyl-protecting group to obtain a 3-alkoxy-2,4-dibromobenzoic acid, subjecting the 3-alkoxy-2,4-dibromobenzoic acid to ketoesterification reaction to obtain a 3-alkoxy-2,4-dibromobenyolacetic acid ester, reacting the 3-alkoxy-2,4-dibromobenzoylacetic acid ester with an orthoester or an acetal, then reacting the reaction product with a compound of the formula R 2a —NH or its salt to obtain a 2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid ester and subjecting the 2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid ester to ring-closing reaction, and products thereof.

1 . A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt, characterized in that the process for producing a compound represented by the general formula [1]:  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a hydrogen atom or a carboxyl-protecting group; R 2  represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl or heterocyclic group; R 3  represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups, protected or unprotected hydroxyl groups and protected or unprotected or substituted or unsubstituted amino groups; R 4  represents at least one group selected from hydrogen atom, halogen atom, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl or imino groups, protected or unprotected or substituted or unsubstituted amino groups, alkylidene groups, oxo group and groups each forming a cycloalkane ring together with the carbon atom to which R 4  bonds; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; R 6  represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group, a protected or unprotected hydroxyl or amino group or a nitro group; and A represents CH or C—R 7  in which R 7  represents a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group or a protected or unprotected hydroxyl group, is either the following (i) or (ii) : 
 (i) A process characterized by reacting, in the presence of metallic palladium an isoindoline-5-boronic acid derivative represented by the following general formula [2] or its salt:  
                     
 wherein R 3 , R 4  and R 5  have the same meanings as mentioned above; and R 8  and R 9  represent hydrogen atoms or lower alkyl groups or form a ring comprising the boron atom when taken together, with a 7-leaving group-substituted quinolonecarboxylic acid represented by the following general formula [3] or its salt:  
                     
 wherein R 1 , R 2 , R 6  and A have the same meanings as mentioned above; and X 2  represents a leaving group.  
 (ii) A process characterized by reacting, in the presence of a palladium catalyst selected from metallic palladium, palladium salts and palladium complexes, a 5-halogenoisoindoline derivative represented by the following general formula [4] or its salt:  
                     
 wherein R 3 , R 4  and R 5  have the same meanings as mentioned above; and X 1  represents a halogen atom, with a dialkoxyborane represented by the general formula [5a]:  
                     
 wherein Z represents an alkylene group, or an alkoxydiborane represented by the general formula [5b]:  
                     
 wherein Z has the same meaning as mentioned above, to form an isoindoline-5-boronic acid derivative represented by the following general formula [2a] or its salt:  
                     
 wherein R 3 , R 4 , R 5  and Z have the same meanings as mentioned above; and thereafter, reacting the isoindoline-5-boronic acid derivative or its salt without isolation with a 7-leaving group-substituted quinolonecarboxylic acid represented by the following general formula [3] or its salt:  
                     
 wherein R 1 , R 2 , R 6 , A and X 2  have the same meanings as mentioned above.  
 
     
     
         2 . A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein R 5  represents a hydrogen atom, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group.  
     
     
         3 . A process for producing an isoindoline-5-boronic acid derivative represented by the following general formula [2a] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 3  represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups, protected or unprotected hydroxyl groups and protected or unprotected or substituted or unsubstituted amino groups; R 4  represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl or imino groups, protected or unprotected or substituted or unsubstituted amino groups, alkylidene groups, oxo group and groups each forming a cycloalkane ring together with the carbon atom to which R 4  bonds; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and Z represents an alkylene group, characterized by reacting, in the presence of a palladium catalyst selected from metallic palladium, palladium salts and palladium complexes, a 5-halogenoisoindoline derivative represented by the following general formula [4] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 3 , R 4  and R 5  have the same meanings as mentioned above; and X 1  represents a halogen atom, with a dialkoxyborane represented by the general formula [5a]:  
       
         
           
           
               
               
           
         
       
       wherein Z has the same meaning as mentioned above, or an alkoxydiborane represented by the general formula [5b]:  
       
         
           
           
               
               
           
         
       
       wherein Z has the same meaning as mentioned above.  
     
     
         4 . A process for producing an isoindoline-5-boronic acid derivative or its salt according to  claim 3 , wherein R 5  represents a hydrogen atom, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group.  
     
     
         5 . A process for producing a 1-alkylisoindoline-5-boronic acid derivative represented by the general formula [2b] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a  represents an alkyl group; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R 8  and R 9  represent hydrogen atoms or lower alkyl groups or form a ring comprising the boron atom when taken together, characterized by reacting a phenylalkylamine derivative represented by the general formula [10] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a  has the same meaning as mentioned above; and R 5a  represents an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, with carbon dioxide, a halogenated formic acid ester or a carbonic acid ester in the presence of a base to form a 2-aminoalkylbenzoic acid derivative represented by the general formula [9] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a  and R 5  have the same meanings as mentioned above; and R 10  represents a hydrogen atom or a carboxyl-protecting group, subsequently subjecting the 2-aminoalkylbenzoic acid derivative or its salt to halogenation reaction to obtain a 2-aminoalkyl-5-halogenobenzoic acid derivative represented by the general formula [8] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a , R 5  and R 10  have the same meanings as mentioned above; and X 1  represents a halogen atom, subsequently subjecting the 2-aminoalkyl-5-halogenobenzoic acid derivative or its salt to reduction reaction to obtain a 2-aminoalkyl-5-halogenobenzyl alcohol derivative represented by the following general formula [6] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above, and thereafter subjecting the 2-aminoalkyl-5-halogenobenzyl alcohol derivative or its salt to ring-closing reaction to obtain a 1-alkyl-5-halogenoisoindoline derivative represented by the general formula [4a] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above and then subjecting the 1-alkyl-5-halogenoisoindoline derivative or its salt to borodation.  
     
     
         6 . A process for producing a 1-alkylisoindoline-5-boronic acid derivative or its salt according to  claim 5 , wherein R 4a  represents a lower alkyl group; R 5a  represents an amino-protecting group; and R 5  represents a hydrogen atom or an amino-protecting group.  
     
     
         7 . A process for producing a 1-alkylisoindoline-5-boronic acid derivative represented by the general formula [2b] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a  represents an alkyl group; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R 8  and R 9  represent hydrogen atoms or lower alkyl groups or form a ring comprising the boron atom when taken together, characterized by reacting a phenylalkylamine derivative represented by the general formula [10] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a  has the same meaning as mentioned above; and R 5a  represents an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, with carbon dioxide, a halogenated formic acid ester or a carbonic acid ester in the presence of a base, to obtain a 2-aminoalkylbenzoic acid derivative represented by the general formula [9] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a  and R 5  have the same meanings as mentioned above; and R 10  represents a hydrogen atom or a carboxyl-protecting group, subsequently subjecting the 2-aminoalkylbenzoic acid derivative or its salt to halogenation reaction to obtain a 2-aminoalkyl-5-halogenobenzoic acid derivative represented by the general formula [8] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a , R 5  and R 10  have the same meanings as mentioned above; and X 1  represents a halogen atom, subsequently subjecting the 2-aminoalkyl-5-halogenobenzoic acid derivative or its salt to ring-closing reaction to obtain a 1-alkyl-3-oxo-5-halogenoisoindoline derivative represented by the general formula [7] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above, subsequently subjecting the 1-alkyl-3-oxo-5-halogenoisoindoline derivative or its salt to reduction reaction to obtain a 1-alkyl-5-halogenoisoindoline derivative represented by the general formula [4a] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above, and then subjecting the 1-alkyl-5-halogenoisoindoline derivative or its salt to borodation.  
     
     
         8 . A process for producing a I-alkylisoindoline-5-boronic acid derivative or its salt according to  claim 7 , wherein R 4a  represents a lower alkyl group; R 5a  represents an amino-protecting group; and R 5  represents a hydrogen atom or an amino-protecting group.  
     
     
         9 . A process for producing a 1-alkyl-5-halogenoisoindoline derivative represented by the general formula [4a] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a  represents an alkyl group; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and X 1  represents a halogen atom, by reacting a 4-halogenobenzylamine derivative represented by the general formula [12] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a  and X 1  have the same meanings as mentioned above; and R 5b , R 5c  and R 5d  may be the same or different and each represents an alkyl group, with a formaldehyde or its derivative in the presence of an aryllithium to obtain a 2-aminoalkyl-5-halogenobenzyl alcohol derivative represented by the general formula [6] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above, subsequently introducing a leaving group thereinto to obtain a 2-aminoalkyl-5-halogenobenzyl derivative represented by the general formula [11] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above; and Y represents a leaving group, and subsequently subjecting the 2-aminoalkyl-5-halogenobenzyl derivative to ring-closing reaction in the presence of a base.  
     
     
         10 . A process for producing a 1-alkyl-5-halogenoisoindoline derivative or its salt according to  claim 9 , wherein R 5  represents a hydrogen atom or an amino-protecting group.  
     
     
         11 . A process for producing a 7-bromoquinolone-carboxylic acid derivative represented by the general formula [3a] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 1b  represents a carboxyl-protecting group; R 2a , represents a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic group; and R 7a  represents a substituted or unsubstituted alkyl group, characterized by reacting a 2,4-dibromo-3-hydroxybenzoic acid ester represented by the general formula [13] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 1a  represents a carboxyl-protecting group, with a compound represented by the general formula [14]:  
         R 7a —X   [14] 
       wherein R 7a  has the same meaning as mentioned above; and X represents a halogen atom, to obtain a 3-alkoxy-2,4-dibromobenzoic acid ester represented by the general formula [15] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 1a  and R 7a  have the same meanings as mentioned above, subsequently subjecting the 3-alkoxy-2,4-dibromobenzoic acid ester to elimination reaction of the carboxyl-protecting group to obtain a 3-alkoxy-2,4-dibromobenzoic acid represented by the general formula [16] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 7a  has the same meaning as mentioned above, subsequently subjecting the 3-alkoxy-2,4-dibromobenzoic acid to ketoesterification reaction to obtain a 3-alkoxy-2,4-dibromobenzoylacetic acid ester represented by the general formula [17] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 1b  represents a carboxyl-protecting group; and R 7a  has the same meaning as mentioned above, subsequently reacting the 3-alkoxy-2,4-dibromobenzoylacetic acid ester with an orthoester or an acetal, then reacting the reaction product with a compound represented by the general formula [18] or its salt:  
         R 2a —NH   [18] 
       wherein R 2a  has the same meaning as mentioned above, to obtain a 2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid ester represented by the general formula [19] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 1b , R 2a  and R 7a  have the same meanings as mentioned above, and thereafter subjecting the 2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid ester to ring-closing reaction.  
     
     
         12 . (R)-1-Cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate.  
     
     
         13 . (R)-1-Cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate monohydrate.  
     
     
         14 . A composition comprising an active ingredient selected from the group consisting of (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate and (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate monohydrate, and an inactive ingredient.  
     
     
         15 . The composition according to  claim 14 , wherein the inactive ingredient is a carrier acceptable as a preparation.  
     
     
         16 . An isoindolin-5-ylboronic acid derivative represented by the general formula [2a] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 3  represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups, protected or unprotected hydroxyl groups and protected or unprotected or substituted or unsubstituted amino groups; R 4  represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl or imino groups, protected or unprotected or substituted or unsubstituted amino groups, alkylidene groups, oxo group and groups each forming a cycloalkane group together with the carbon atom to which R 4  bonds; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and Z represents an alkylene-group.  
     
     
         17 . A 2-aminoalkyl-5-halogenobenzyl alcohol derivative represented by the general formula [6] or its salt:  
       
         
           
           
               
               
           
         
       
       wherein R 4a  represents an alkyl group; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and X 1  represents a halogen atom.  
     
     
         18 . A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
 the compound represented by the general formula [2] or its salt is a compound represented by the general formula [2b] or its salt obtained by the process according to  claim 5 ,    the compound represented by the general formula [3] or its salt is a compound represented by the general formula [3b] or its salt, and    the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1a] or its salt.    
     
     
         19 . A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
 the compound represented by the general formula [2] or its salt is a compound represented by the general formula [2b] or its salt obtained by the process according to  claim 7 ,    the compound represented by the general formula [3] or its salt is a compound represented by the general formula [3b] or its salt, and    the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1a] or its salt.    
     
     
         20 . A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
 the compound represented by the general formula [2] or its salt is a compound represented by the general formula [2b] or its salt obtained by preparing a compound represented by the general formula [4a] or its salt by the process according to  claim 9  and subjecting the compound represented by the general formula [4a] or its salt to borodation, and    the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1a] or its salt.    
     
     
         21 . A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
 the compound represented by the general formula [3] or its salt is a compound represented by the general formula [3a] or its salt obtained by the process according to  claim 11 , and    the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1b] or its salt.