Process for preparing ligands of ppardelta and the intermediate compounds for preparing the same

Abstract

The present invention provides a process for preparing thiazole derivatives of formula (I), that activate the delta subtype of the human Peroxisome Proliferator Activated Receptor (hPPAR δ), and also provides compounds of formula (II), (IV), (X), (XI) and (XII), intermediate compounds for preparation of the above compounds of formula (I).

1 . A process for preparing a thiazole of formula (II) 
       
         
           
           
               
               
           
         
       
       comprising:
 (a) reacting a compound of formula (IX) 
 
       
         
           
           
               
               
           
         
       
       and 
       a Grignard reagent to form a compound of formula (X) 
       
         
           
           
               
               
           
         
         (b) reacting the compound of formula (X) and a (C 1 -C 10 ) alkyl to lithium to form an organic metal compound of formula (XI) 
       
       
         
           
           
               
               
           
         
         (c) reacting the organic metal compound of the formula (XI) and sulfur (S) to form a metal-sulfur compound of formula (XII) 
       
       
         
           
           
               
               
           
         
       
       and
 (d) reacting the metal-sulfur compound of formula (XII) and a thiazole a compound of formula (VIII) 
 
       
         
           
           
               
               
           
         
       
       to form the thiazole compound of formula (II);
 in which: 
 R 1  represents a hydrogen atom, CF 3 , or a halogen atom; 
 R 2  represents a hydrogen atom, a (C 1 -C 4 ) alkyl, a (C 1 -C 4 ) alkyloxy, a (C 1 -C 4 ) alkylthiooxy, a (C 1 -C 4 ) alkylamine, a fluorine atom, or a chlorine atom; 
 X 1  represents a halogen atom, a methane sulfonyloxy group, or a p-toluenesulfonyloxy group; 
 X 2  represents a halogen atom; 
 X 3  represents a halogen atom; 
 m is an integer of 0 to 4; and 
 n is an integer of 0 to 5. 
 
     
     
         2 . A process for preparing a thiazole compound of formula (VI) 
       
         
           
           
               
               
           
         
       
       comprising:
 (a) reacting a compound of formula (IX) 
 
       
         
           
           
               
               
           
         
       
       and 
       a Grignard reagent to form a compound of formula (X) 
       
         
           
           
               
               
           
         
         (b) reacting the compound of formula (X) and a (C 1 -C 10 ) alkyl lithium to form an organic metal compound of formula (XI) 
       
       
         
           
           
               
               
           
         
         (c) reacting the compound of the formula (XI) and sulfur (S) to form a metal-sulfur compound of formula (XII) 
       
       
         
           
           
               
               
           
         
         (d) reacting the compound of formula (XII) and a thiazole compound of formula (VIII) 
       
       
         
           
           
               
               
           
         
       
       to from a compound of formula (II) 
       
         
           
           
               
               
           
         
         (e) reacting the compound of formula (II) and an alkyl halogen acetate of formula (III) 
       
       
         
           
           
               
               
           
         
       
       to form the thiazole compound of formula (IV);
 in which: 
 R 1  represents a hydrogen atom, CF 3 , or a halogen atom; 
 R 2  represents a hydrogen atom, a (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyloxy, (C 1 -C 4 ) alkylthiooxy, (C 1 -C 4 ) alkylamine, a fluorine atom, or a chlorine atom; 
 X 1  represents a halogen atom, a methane sulfonyloxy group or a p-toluenesulfonyloxy group; 
 X 2  represents a halogen atom; 
 X 3  represents a halogen atom; 
 X represents a halogen atom; 
 R 3  represents a methyl, ethyl, propyl, isopropyl, or a tert-butyl group as a protecting group of carboxyl acids; 
 m is an integer of 0 to 4; and 
 n is an integer of 0 to 5.