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 preparing cilostazol comprising: 
 a) dissolving 6-hydroxy-3,4-dihydroquinolinone and a water-soluble base in water to form an aqueous phase,    b) dissolving a 1-cyclohexyl-5-(4-halobutyl)tetrazole in a water-immiscible solvent to form an organic phase,    c) forming a biphasic mixture by contacting the aqueous phase and the organic phase in the presence of a quaternary ammonium phase transfer catalyst,    d) and recovering cilostazol from the biphasic mixture.    
     
     
         2 . The process of  claim 1  wherein the molar quantity of the 6-hydroxy-3,4-dihydroquinolinone is greater than the molar quantity of the l-cyclohexyl-5-(4-halobutyl)tetrazole.  
     
     
         3 . The process of  claim 1  wherein the water-immiscible solvent is selected from the group consisting of toluene, hexane, dichloromethane and mixtures thereof.  
     
     
         4 . The process of  claim 1  wherein the quaternary ammonium phase transfer catalyst is selected from the group consisting of tricaprylylmethylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium chloride, cetyltrimethylammonium bromide, cetylpyridinium bromide, N-benzylquininium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetra-ethylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, tetramethylammonium chloride, hexadecyltrimethyl ammonium chloride, and octyltrimethylammonium chloride.  
     
     
         5 . The process of  claim 4  wherein the quaternary ammonium phase transfer catalyst is selected from the group consisting of tricaprylylmethyl ammonium chloride, tetrabutylammonium bromide, triethylbenzylammonium bromide and mixtures thereof.  
     
     
         6 . The process of  claim 5  wherein the quaternary ammonium phase transfer catalyst is tricaprylylmethyl ammonium chloride.  
     
     
         7 . The process of  claim 1  wherein the water-soluble base is an alkali metal hydroxide, carbonate or bicarbonate.  
     
     
         8 . The process of  claim 7  wherein the water-soluble base is selected from the group consisting of NaOH, KOH, K 2 CO 3 , Na 2 CO 3  and NaHCO 3 .  
     
     
         9 . The process of  claim 8  wherein the water-soluble base is NaOH.  
     
     
         10 . The process of  claim 1  further comprising dissolving a reaction promoter selected from the group consisting of potassium carbonate and sodium sulfate in the water.  
     
     
         11 . The process of  claim 1  wherein the 1-cyclohexyl-5-(4-halobutyl)-tetrazole is 1-cyclohexyl-5-(4-chlorobutyl)tetrazole.  
     
     
         12 . Substantially pure cilostazol prepared by the process of  claim 1 .  
     
     
         13 . A process for purifying cilostazol by recrystallization from a solvent selected from the group consisting of 1-butanol, acetone, toluene, methyl ethyl ketone, dichloromethane, ethyl acetate, methyl t-butyl ether, dimethyl acetamide-water mixtures, THF, methanol, isopropanol, benzyl alcohol, 2-pyrrolidone, acetonitrile, Cellosolve, monoglyme, isobutyl acetate, sec-butanol, tert-butanol, DMF, chloroform, diethyl ether and mixtures thereof.  
     
     
         14 . Highly pure cilostazol free of impurities.  
     
     
         15 . Micronized cilostazol of small particle size and narrow particle size distribution.  
     
     
         16 . Cilostazol having an average particle size of less than 200 micrometer.  
     
     
         17 . Cilostazol having an average particle size of less than 20 micrometer.