Process for the preparation of halogenated benzoic acid derivatives

Abstract

The present invention comprises a process for the preparation of 3-chloro-2-fluoro-5-trifluoromethyl benzoic acid of the formula or of a salt thereof. 3-Chloro-2-fluoro-5-trifluoromethyl benzoic acid or salts thereof are versatile intermediates for the preparation of active pharmaceutical or agrochemical agents.

1 . A process for the preparation of 3-chloro-2-fluoro-5-trifluoromethyl benzoic acid of the formula 
     
       
         
         
             
             
         
       
     
     or of a salt thereof, comprising the conversion of 3-chloro-4-fluoro-benzo trifluoride of the formula 
     
       
         
         
             
             
         
       
     
     into 3-chloro-2-fluoro-5-trifluoromethyl benzoic acid, or a salt thereof. 
   
   
       2 . The process of  claim 1  wherein the conversion is performed by
 a 1 ) deprotonating the 3-chloro-4-fluoro-benzo trifluoride with a metalorganic base followed by adding CO 2  as electrophile in an organic solvent at a reaction temperature of −100° C. to 25° C. or   b 1 ) forming a Grignard compound of the 3-chloro-4-fluoro-benzo trifluoride with an alkyl magnesium halide in an organic solvent at a reaction temperature of 20° C. to 100° C. followed by adding CO 2  as electrophile in an organic solvent at a reaction temperature of −100° C. to 25° C.   
   
   
       3 . The process of  claim 2 , wherein the metalorganic base is selected from n-butyl lithium or lithium diisopropylamide. 
   
   
       4 . The process of  claim 2 , wherein the alkyl or aryl magnesium halide is ethyl magnesium bromide. 
   
   
       5 . The process of  claim 1 , wherein the conversion is performed by
 a 2 ) transforming the 3-chloro-4-fluoro-benzo trifluoride of formula II into the 3-chloro-2-fluoro-5-trifluoromethyl benzaldehyde of the formula   
     
       
         
         
             
             
         
       
     
     and
 b 2 ) oxidizing the 3-chloro-2-fluoro-5-trifluoromethyl benzaldehyde with an oxidant to form the 3-chloro-2-fluoro-5-trifluoromethyl benzoic acid of formula I or of a salt thereof. 
 
   
   
       6 . The process of  claim 5 , wherein the transformation into the 3-chloro-2-fluoro-5-trifluoromethyl benzaldehyde of the formula III is performed by deprotonating the 3-chloro-4-fluoro-benzo trifluoride with a metalorganic base followed by adding an electrophile in an organic solvent at a reaction temperature of −100° C. to 25° C. 
   
   
       7 . The process of  claims 6 , wherein a protic acid as quenching agent is added subsequent to the deprotonation and subsequent to the addition of the electrophile. 
   
   
       8 . The process of  claim 6 , wherein the metalorganic base is selected from n-butyl lithium, and lithium diisopropylamide. 
   
   
       9 . The process of  claim 6 , wherein the electrophile is selected from an N,N-dialkylformamide, an N,N-diarylformamide or an N-alkoxy-N-alkyl formamide. 
   
   
       10 . The process of  claim 5 , wherein the oxidant is selected from alkali- or alkali earth hypochlorites, -hypobromites, -chlorites, -chlorates, -persulfates or -permanaganates. 
   
   
       11 . The process of  claim 10 , wherein the reaction is performed in the presence of an alkali hydroxide base and an alkali bromide in an aqueous solvent at a reaction temperature of 10° C. to 100° C. 
   
   
       12 . The process of  claim 5 , wherein the 3-chloro-2-fluoro-5-trifluoromethyl benzaldehyde of the formula III is not isolated prior to the oxidation in step b 2 ). 
   
   
       13 . The process of  claim 1 , wherein the conversion is performed by
 a 3 ) converting the 3-chloro-4-fluoro-benzo trifluoride of formula II into an alkali (3-chloro-2-fluoro-5-trifluoromethyl-phenyl)-hydroxy-methanesulfonate of formula   
     
       
         
         
             
             
         
       
     
     wherein M is an alkali metal atom;
 b 3 ) transforming the alkali (3-chloro-2-fluoro-5-trifluoromethyl-phenyl)-hydroxy-methanesulfonate of formula IV into the 3-chloro-2-fluoro-5-trifluoromethyl benzaldehyde of the formula 
 
     
       
         
         
             
             
         
       
     
     and
 c 3 ) oxidizing the 3-chloro-2-fluoro-5-trifluoromethyl benzaldehyde of formula III with an oxidant to form the 3-chloro-2-fluoro-5-trifluoromethyl benzoic acid of formula I or of a salt thereof. 
 
   
   
       14 . The process of  claim 13 , wherein the step a 3 ) conversion of the 3-chloro-4-fluoro-benzo-trifluoride of formula II into an alkali (3-chloro-2-fluoro-5-trifluoromethyl-phenyl)-hydroxy-methanesulfonate of formula IV is performed by
 a 4 ) deprotonating the 3-chloro-4-fluoro-benzo trifluoride with a metalorganic base followed by   b 4 ) adding an electrophile in an organic solvent at a reaction temperature of −100° C. to 25° C., by   c 4 ) adding a protic acid as quenching agent and   d 4 ) forming the alkali (3-chloro-2-fluoro-5-trifluoromethyl-phenyl)-hydroxy-methanesulfonate of formula IV with an alkali pyrosulfite.   
   
   
       15 . The process of  claim 14 , wherein the metalorganic base is selected from n-butyl lithium, and lithium diisopropylamide. 
   
   
       16 . The process of  claim 15 , wherein the electrophile is selected from an N,N-dialkylformamide, an N,N-diarylformamide or an N-alkoxy-N-alkyl formamide. 
   
   
       17 . The process of  claim 16 , wherein the protic acid is selected from citric acid or acetic acid and sulfuric acid. 
   
   
       18 . The process of  claim 17 , wherein sodium pyrosulfite is used as alkali pyrosulfite. 
   
   
       19 . The process of  claim 13 , wherein the transformation of the (3-chloro-2-fluoro-5-trifluoromethyl-phenyl)-hydroxy-methanesulfonate of formula IV into the 3-chloro-2-fluoro-5-trifluoromethyl benzaldehyde is performed with an aqueous alkali hydroxide base. 
   
   
       20 . The process of  claim 13 , wherein the oxidant is selected from alkali- or alkali earth hypochlorites, -hypobromites, -chlorites, -chlorates, -persulfates or -permanaganates. 
   
   
       21 . The process of  claim 20 , wherein the reaction is performed in the presence of an alkali hydroxide base and an alkali bromide in an aqueous solvent at a reaction temperature of 10° C. to 100° C. 
   
   
       22 . The process of  claim 21 , wherein the 3-chloro-2-fluoro-5-trifluoromethyl benzoic acid can further be purified by crystallization with cyclohexane, heptane, methyl cyclohexane or mixtures thereof.