Process for producing carbostyril derivatives

Abstract

The present invention provides a process for producing carbostyril derivatives (I) which are known to be useful as medical drug such as antithrombotic agent, cerebral circulation improver, anti-inflammatory agent, antiulcer agent, etc. in a high yield and a high purity. The carbostyril derivatives (I) can be produced by reacting a carbostyril derivative (II) with a tetrazole derivative (III) in the presence of a phase transfer catalyst.

1 . A process for producing a carbostyril derivative represented by the following general formula (I):  
       
         
           
           
               
               
           
         
       
       wherein A represents a lower alkylene group, R represents a cycloalkyl group, and the bond between the 3- and 4-positions of the carbostyril skeleton represents a single bond or a double bond, which comprises reacting a carbostyril derivative represented by the following general formula (II):  
       
         
           
           
               
               
           
         
       
       wherein the bond between the 3- and 4-positions of the carbostyril skeleton is as defined above, with a tetrazole derivative represented by the following general formula (III):  
       
         
           
           
               
               
           
         
       
       wherein X represents a halogen atom or a group causing the same substitution reaction as that caused by a halogen atom, and A and R are as defined above, in the presence of a phase transfer catalyst.  
     
     
         2 . A process for producing a carbostyril derivative according to  claim 1 , wherein the reaction is carried out at a reaction temperature not lower than the ambient temperature and not higher than 200° C., in a solvent, in the presence of a basic compound.  
     
     
         3 . A process for producing a carbostyril derivative according to  claim 2 , wherein the reaction temperature is 50° C. to 150° C.  
     
     
         4 . A process for producing a carbostyril derivative according to  claim 2 , wherein the solvent used is a mixture consisting of an aromatic hydrocarbon and water or water alone, and said basic compound is an inorganic base.  
     
     
         5 . A process for producing a carbostyril derivative according to  claim 4 , wherein said aromatic hydrocarbon is benzene, o-dichlorobenzene, chlorobenzene, toluene or xylene, and said inorganic base is potassium carbonate, cesium carbonate or lithium carbonate.  
     
     
         6 . A process for producing a carbostyril derivative according to  claim 1 , wherein X in the tetrazole derivative represented by general formula (III) is a halogen atom.  
     
     
         7 . A process for producing a carbostyril derivative according to  claim 1 , wherein X in the tetrazole derivative represented by general formula (III) is a group causing the same substitution reaction as that caused by a halogen atom, and said group is a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group.  
     
     
         8 . A process for producing a carbostyril derivative according to  claim 6 , wherein X in the tetrazole derivative represented by general formula (III) is a chlorine atom.  
     
     
         9 . A process for producing a carbostyril derivative according to  claim 1 , wherein said phase transfer catalyst is a quaternary ammonium salt substituted with a residue selected from the group consisting of straight or branched chain alkyl groups having 1-18 carbon atoms, phenyl lower alkyl groups and phenyl groups, a phosphonium salt substituted with a straight or branched chain alkyl group having 1-18 carbon atoms, or a pyridinium salt substituted with a straight or branched chain alkyl group having 1-18 carbon atoms, and the salt-forming ion in these salts is a hydroxyl ion, a hydrogen sulfate ion or a halogen ion.  
     
     
         10 . A process for producing a carbostyril derivative according to  claim 9 , wherein said phase transfer catalyst is a quaternary ammonium salt substituted with a residue selected from the group consisting of straight or branched chain alkyl groups having 1-18 carbon atoms, phenyl lower alkyl groups and phenyl groups, and the salt forming ion in these said salt is a halogen ion.  
     
     
         11 . A process for producing a carbostyril derivative according to  claim 10 , wherein said phase transfer catalyst is a quaternary ammonium salt substituted with a straight or branched chain alkyl group having 1-18 carbon atoms.  
     
     
         12 . A process for producing a carbostyril derivative according to  claim 10 , wherein said salt-forming ion in the salt is a chlorine ion.  
     
     
         13 . A process for producing a carbostyril derivative according to  claim 10 , wherein said phase transfer catalyst is tetrabutylammonium chloride.  
     
     
         14 . A process for producing a carbostyril derivative according to  claim 13 , wherein said phase transfer catalyst is used in an amount of 0.1 to 1 mol per mol of the compound of general formula (II).  
     
     
         15 . A process for producing a carbostyril derivative according to  claim 14 , wherein said phase transfer catalyst is used in an amount of 0.1 to 0.5 mol per mol of the compound of general formula (II).  
     
     
         16 . A process for producing a carbostyril derivative according to  claim 1 , which is a process for producing 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril.