Process for the preparation of 5-carboxyphthalide

Abstract

There is described a process for the preparation of 5-carboxy phthalide, which comprises adding terephthalic acid to fuming sulfuric acid containing at least 20% of SO 3 , then adding formaldehyde to the mixture, heating the mixture at a temperature of 120-145° C. and isolating 5-carboxyphthalide from the reaction mixture.

1 . A process for the preparation of 5-carboxyphthalide of formula A  
       
         
           
           
               
               
           
         
       
       which comprises adding formaldehyde and terephthalic acid of formula I  
       
         
           
           
               
               
           
         
       
       to fuming sulfuric acid containing al least 20% of SO 3 , heating the mixture at 120-145° c and isolating the 5-carboxyphthalide thus obtained.  
     
     
         2 . A process according to  claim 1 , in which formaldehyde is used in form of its precursor 1,3,5-trioxane of formula II  
       
         
           
           
               
               
           
         
       
     
     
         3 . A process according to  claim 1 , in which formaldehyde is used in form of its precursor paraformaldehyde.  
     
     
         4 . A process according to  claim 2 , in which the 1,3,5-trioxane of formula II is used in an amount corresponding to 2.5-3.2 mol of formaldehyde/mol of the starting terephthalic acid.  
     
     
         5 . A process according to  claim 4 , in which said 1,3,5-trioxane is added at a temperature of 30-35° C.  
     
     
         6 . A process according to  claim 1 , in which the fuming sulfuric acid contains 22-33% of SO 3 .  
     
     
         7 . A process according to  claim 6 , in which the fuming sulfuric acid is used in an amount of 3-6 litres/Kg of terephthalic acid.  
     
     
         8 . A process according to  claim 7 , in which fuming sulfuric acid is used in an amount of about 3 litres/Kg of terephthalic acid.  
     
     
         9 . A process according to  claim 1 , in which 5-carboxyphthalide is isolated by neutralization of the reaction mixture with a base.  
     
     
         10 . A process according to  claim 1 , in which 5-carboxyphthalide is isolated by diluting the reaction mixture with glacial acetic acid, then adding water and neutralizing with a base.  
     
     
         11 . A process according to  claim 9  or  10 , in which said base is an alkaline metal base.  
     
     
         12 . A process according to  claim 11 , in which said alkaline metal base is sodium hydroxide, carbonate or bicarbonate.  
     
     
         13 . A process according to  claim 1 , in which, at the end of the reaction, the 5-carboxyphthalide is isolated by the formation of a solution containing a salt thereof which is neutralized with an acid.  
     
     
         14 . A process according to  claim 13 , in which said salt is the sodium salt.  
     
     
         15 . A process according to  claim 13 , in which the salt is formed by adding the base to a pH of about 8.  
     
     
         16 . A process according to  claim 13 , in which said acid is hydrochloric acid.  
     
     
         17 . A process according to  claim 1 , in which 5-carboxyphthalide is isolated by treatment of the reaction mixture with water.  
     
     
         18 . A process according to  claim 17 , in which the addition of water is made at 0-5° C. and the exothermia is controlled by keeping the temperature at about 20-25° C.  
     
     
         19 . A process according to  claim 1 , in which the mixture is heated at 130-135° C.  
     
     
         20 . A process according to  claim 1 , in which formaldehyde is added to fuming sulfuric acid after the addition of terephthalic acid.  
     
     
         21 . A process for the synthesis of citalopram, in which a process for the synthesis of 5-carboxyphthalide according to  claim 1  is contained.