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 - 17 . (canceled)  
     
     
         18 . 6-(4-(1-cyclohexyl-1-H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolin one (Cilostazol) being substantially free of N-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butyl]-6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H-)-quinolinone.  
     
     
         19 . The cilostazol of  claim 18 , having a purity that equals to or is greater than 99.5%.  
     
     
         20 . The cilostazol of  claim 18 , having a purity that equals to or is greater than 99.9%.  
     
     
         21 . The cilostazol of  claim 18 , wherein a content of said N-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butyl]-6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone is less than 0.1 weight percent.  
     
     
         22 . A process of preparing 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolinone (cilostazol), the process comprising: 
 providing 6-hydroxy-3,4-dihydroquinolin-2(1H)-one;    providing 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole;    reacting said 6-hydroxy-3,4-dihydroquinolin-2(1H)-one and said 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in the presence of a hydrated inorganic base, to thereby obtain a reaction mixture containing the cilostazol; and    isolating the cilostazol from the reaction mixture, thereby obtaining cilostazol.    
     
     
         23 . The process of  claim 22 , wherein the cilostazol is substantially free of N-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butyl]-6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H-)-quinolinone.  
     
     
         24 . The process of  claim 23 , wherein the cilostazol has a purity that equals to or is greater than 99.5%.  
     
     
         25 . The process of  claim 23 , wherein the cilostazol contains less than 0.1 weight percent N-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butyl]-6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H-)-quinolinone.  
     
     
         26 . The process of  claim 23 , wherein the cilostazol contains less than 0.06 weight percent N-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butyl]-6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone.  
     
     
         27 . The process of  claim 22 , wherein said hydrated inorganic base contains at least 5 weight percentages of water.  
     
     
         28 . The process of  claim 22 , wherein said hydrated inorganic base contains at least 10 weight percentages of water.  
     
     
         29 . The process of  claim 22 , wherein said hydrated inorganic base contains at least 15 weight percentages of water.  
     
     
         30 . The process of  claim 22 , wherein said reacting is performed in a solvent.  
     
     
         31 . The process of  claim 30 , wherein said solvent comprises at least one organic solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and any combinations thereof.  
     
     
         32 . The process of  claim 31 , wherein said solvent further comprises water.  
     
     
         33 . The process of  claim 32 , wherein said solvent comprises a mixture of 1-propanol and water.  
     
     
         34 . The process of  claim 33 , wherein a ratio between said 1-propanol and said water ranges from 20:1 and 1:1.  
     
     
         35 . The process of  claim 34 , wherein said ratio is 18:1.  
     
     
         36 . The process of  claim 22 , wherein said inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.  
     
     
         37 . The process of  claim 22 , wherein said inorganic base is potassium hydroxide.  
     
     
         38 . The process of  claim 22 , wherein a molar ratio between said 6-hydroxy-3,4-dihydroquinolin-2(1H)-one and said 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole ranges between about 1:1 and about 2:1.  
     
     
         39 . The process of  claim 38 , wherein said molar ratio is about 1.3:1.  
     
     
         40 . The process of  claim 22 , wherein a molar ratio between said hydrated inorganic base and said 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole ranges between about 1:1 and about 2:1.  
     
     
         41 . The process of  claim 40 , wherein said molar ratio is about 1.2:1.  
     
     
         42 . The process of  claim 30 , wherein said reacting is performed at reflux temperature of said solvent.  
     
     
         43 . The process of  claim 22 , wherein said isolating is effected by precipitating the cilostazol from said reaction mixture at a temperature lower than 15° C.  
     
     
         44 . The process of  claim 22 , further comprising purifying the cilostazol.  
     
     
         45 . The process of  claim 44 , wherein said purifying comprises: 
 slurrying the cilostazol in a first organic solvent; and/or    recrystallizing the cilostazol from a mixture containing a second organic solvent and an aqueous solution of an inorganic base.    
     
     
         46 . The process of  claim 45 , wherein said purifying comprises said slurrying and said recrystallizing.  
     
     
         47 . The process of  claim 46 , wherein said slurrying precedes said recrystallizing.  
     
     
         48 . The process of  claim 46 , wherein said recrystallizing precedes said recrystallizing.  
     
     
         49 . The process of  claim 45 , wherein said first organic solvent is ethyl acetate.  
     
     
         50 . The process of  claim 45 , wherein said second organic solvent is 1-propanol.  
     
     
         51 . The process of  claim 45 , wherein said aqueous solution of said inorganic base is an aqueous solution of sodium hydroxide.  
     
     
         52 . Cilostazol prepared by the process of  claim 22 .  
     
     
         53 . Cilostazol having a purity that equals to or is greater than 99.9%.