Synthetic Processes of Carprofen

Abstract

Methods and intermediates for the synthesis of carprofen and its derivatives starting from cyclohexanone are disclosed.

What is claimed is: 
     
         1 . A process for preparing carprofen comprising the steps of:
 (1) heating cyclohexanone and a first base in a first organic solvent to form an enamine; wherein the first base is an organic secondary base;   (2) reacting the enamine with an α-substituted carboxylic acid ester in a second organic solvent to afford a 2-substituted cyclohexanone;   (3) reacting the 2-substituted cyclohexanone with a formic acid ester in the presence of a second base to form a compound of formula 7;   
       
         
           
           
               
               
           
         
       
       R 1  is Me, Et, or C 3 -C 6  alkyl
 (4) reacting the compound of formula 7 in a third organic solvent with an aqueous solution of a substituted phenyldiazonium salt of formula 9′ to give a compound of formula 10; 
 
       
         
           
           
               
               
           
         
       
       Y −  is chloride or tetrafluoroboric anion 
       
         
           
           
               
               
           
         
       
       R 1  is Me, Et, C 3 -C 6  alkyl
 (5) heating a mixture of the compound of formula 10 in a fourth organic solvent to form a compound of formula 11; and 
 
       
         
           
           
               
               
           
         
       
       R 1  is Me, Et, C 3 -C 6  alkyl
 (6) heating a mixture of the compound of formula 11 in the presence of an organic salt to yield carprofen. 
 
     
     
         2 . The process of  claim 1 , wherein the organic secondary base is pyrrolidine or piperidine. 
     
     
         3 . The process of  claim 1 , wherein the enamine formation step (1) further comprises using an acidic catalyst. 
     
     
         4 . The process of  claim 3 , wherein the acidic catalyst is selected from the group consisting of toluene sulfonic acid, molecular sieves, and macroporous sulfonic acid resin. 
     
     
         5 . The process of  claim 1 , wherein the second base is sodium methoxide. 
     
     
         6 . The process of  claim 1 , wherein the substituted phenyldiazonium salt of formula 9′ is prepared from an aniline compound reacting with sodium nitrite in hydrochloric acid and water. 
     
     
         7 . The process of  claim 6 , wherein the aniline compound is aniline, 4-chloroaninline, 4-bromoaniline, or 3-chloroaniline. 
     
     
         8 . The process of  claim 1 , wherein the fourth organic solvent is selected from a group consisting of acetonitrile, acetic acid, methanol, and dioxane. 
     
     
         9 . The process of  claim 1 , wherein the step (5) further comprises using an acidic catalyst, wherein the acidic catalyst is hydrochloric acid or sulfuric acid. 
     
     
         10 . The process of  claim 1 , wherein the organic salt is pyridine hydrochloride. 
     
     
         11 . A compound having the following structure: 
       
         
           
           
               
               
           
         
         R 1  is H, Me, Et, or C 3 -C 6  alkyl; 
         R 2  is H, 4-Cl, 3-Cl, 2-Cl, 4-Br, 4-F, or 3,4-di-Cl 2 ; 
         R 3  is H, Me, Et, or C 3 -C 6  alkyl; 
         X is O, or 
       
       
         
           
           
               
               
           
         
          BF 4   − ; 
         n is 0, 1, 2, or 3. 
       
     
     
         12 . A compound having the following structure: 
       
         
           
           
               
               
           
         
         R 1  is H, Me, Et, or C 3 -C 6  alkyl; 
         R 2  is H, 4-Cl, 3-Cl, 2-Cl, 4-Br, 4-F, or 3,4-di-Cl 2 ; 
         R 3  is H, Me, Et, or C 3 -C 6  alkyl; 
         X is O, or 
       
       
         
           
           
               
               
           
         
          BF 4   − ; 
         n is 0, 1, 2, or 3.