Process for the preparation of 4-amino-3-chloro-5-fluoro-6-(substituted) picolinates

Abstract

4-Amino-3-chloro-5-fluoro-6-(substituted)picolinates are conveniently prepared from 3,4,5,6-tetrachloropicolinonitrile by a series of steps involving fluorine exchange, amination, halogen exchange and hydrolysis, esterification and transition metal assisted coupling.

1 . A process for the preparation of a 4-amino-3-chloro-5-fluoro-6-(substituted)picolinate of the Formula I 
       
         
           
           
               
               
           
         
         wherein 
         R represents C 1 -C 4  alkyl, cyclopropyl, C 2 -C 4  alkenyl or phenyl substituted with from 1 to 4 substituents independently selected from halogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy or C 1 -C 4  haloalkoxy; 
         R 1  represents C 1 -C 12  alkyl or an unsubstituted or substituted C 7 -C 11  arylalkyl; which comprises the following steps: 
         a) fluorinating 3,4,5,6-tetrachloropicolinonitrile (Formula A) 
       
       
         
           
           
               
               
           
         
       
       with a source of fluoride ion to produce 3-chloro-4,5,6-trifluoropicolinonitrile (Formula B) 
       
         
           
           
               
               
           
         
         b) aminating 3-chloro-4,5,6-trifluoro-2-picolinonitrile (Formula B) with ammonia to produce 4-amino-3-chloro-5,6-difluoropicolinonitrile (Formula C) 
       
       
         
           
           
               
               
           
         
         c) exchanging the fluoro substituent in the 6-position of 4-amino-3-chloro-5,6-difluoropicolinonitrile (Formula C) with hydrogen bromide (HBr), hydrogen chloride (HCl) or hydrogen iodide (HI) and hydrolyzing the nitrile to produce a 4-amino-3-chloro-5-fluoro-6-halopicolinamide of Formula D 
       
       
         
           
           
               
               
           
         
         wherein L is Br, Cl or I; 
         d) esterifying the 4-amino-3-chloro-5-fluoro-6-halopicolinamide of Formula D with a strong acid and an alcohol (R 1 OH) to produce a 4-amino-3-chloro-5-fluoro-6-halopicolinate of Formula E 
       
       
         
           
           
               
               
           
         
         wherein L and R 1  are as previously defined; and 
         e) coupling the 4-amino-3-chloro-5-fluoro-6-halopicolinate of Formula E with an aryl, alkyl or alkenyl metal compound of the Formula F
   R-Met   F
 
 wherein R is as previously defined and Met represents Zn-halide, Zn—R, tri-(C 1 -C 4  alkyl)tin, copper, or B(OR 2 )(OR 3 ), where R 2  and R 3  are independent of one another, hydrogen, C 1 -C 4  alkyl, or when taken together form an ethylene or propylene group in the presence of a transition metal catalyst to produce the 4-amino-3-chloro-5-fluoro-6-(substituted)picolinate of Formula I. 
 
       
     
     
         2 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein X and Y independently represent F or Cl; 
       
       
         
           
           
               
               
           
         
         wherein X and Y independently represent F or Cl with the proviso that at least one of X and Y are F; 
       
       
         
           
           
               
               
           
         
         wherein W 1  represents F, Cl, Br or I; 
       
       
         
           
           
               
               
           
         
         wherein W 2  represents Cl, Br or I; or 
       
       
         
           
           
               
               
           
         
         wherein R 1  represents C 1 -C 12  alkyl or an unsubstituted or substituted C 7 -C 11  arylalkyl and W 3  is Br or I.