Process for preparing thiazole derivative and the intermediate compounds for preparing the same

Abstract

The present invention provides a process for preparing thiazole derivatives of formula (XI), that activate the delta subtype of the human Peroxisome Proliferator Activated Receptor (hPPARδ), and also provides processes for compounds of formula (VI), (VII), (VIII) and (IX), intermediate compounds for preparation of the above compounds of formula (XI).

1 - 5 . (canceled)  
   
   
       6 . A compound of formula (XII):  
     
       
         
         
             
             
         
       
     
     wherein R 1  represents a hydrogen atom, —CF 3 , or halogen atom; 
 n is an integer of from 0 to 5;  
 R 2  represents a hydrogen atom, fluorine atom, chlorine atom, —(C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, —S(C 1 -C 4 )alkyl, or —N(C 1 -C 4 alkyl) 2  group; and  
 R 5  represents a hydrogen atom, or a protecting group having a tetrahydropyranyl, —(C 1 -C 4 )alkyl, allyl, or silyl group.  
 
   
   
       7 . A compound of formula (VI), formula (VII), formula (VIII), or formula (IX):  
     
       
         
         
             
             
         
       
     
     wherein R 2  represents a hydrogen atom, fluorine atom, chlorine atom. —(C 1 -C 4 ) alkyl, —O(C 1 -C 4 )alkyl, —S(C 1 -C 4 ) alkyl, or —N(C 1 -C 4  alkyl) 2  group, 
 R 3  represents protecting group having a tetrahydropyranyl, —(C 1 -C 4 ) alkyl, allyl, or silyl group, and  
 X 1  represents a halogen atom;  
                     
 wherein R 2  represents a hydrogen atom, fluorine atom, chlorine atom. —(C 1 -C 4 ) alkyl, —O(C 1 -C 4 )alkyl, —S(C 1 -C 4 ) alkyl, or —N(C 1 -C 4  alkyl) 2  group,  
 R 3  represents protecting group having a tetrahydropyranyl, —(C 1 -C 4 ) alkyl, allyl, or silyl group,  
 M represents a lithium ion or magnesium chloride, magnesium bromide, or magnesium iodide;  
                     
 wherein R 1  represents hydrogen atom, CF 3 , or halogen atom, n is an integer of 0 to 5,  
 R 2  represents a hydrogen atom, fluorine atom, chlorine atom. —(C 1 -C 4 ) alkyl, —O(C 1 -C 4 )alkyl, —S(C 1 -C 4 ) alkyl, or —N(C 1 -C 4  alkyl) 2  group,  
 R 3  represents protecting group having a tetrahydropyranyl, —(C 1 -C 4 ) alkyl, allyl, or silyl group; or  
                     
 wherein R 1  represents hydrogen atom, CF 3 , or halogen atom, n is an integer of 0 to 5, R 2  represents a hydrogen atom, fluorine atom, chlorine atom, —(C 1 -C 4 ) alkyl, —O(C 1 -C 4 )alkyl, —S(C 1 -C 4 ) alkyl, or —N(C 1 -C 4  alkyl) 2  group.  
 
   
   
       8 . A process for preparing a compound of formula (VIII) which comprises reacting a compound of formula (VII) with a compound of formula (IV) to form a compound of formula (VIII)  
     
       
         
         
             
             
         
       
     
     wherein R 1  represents a hydrogen atom, CF 3 , or halogen atom, n is an integer of 0 to 5, R 2  represents a hydrogen atom, fluorine atom, chlorine atom, —(C 1 -C 4 ) alkyl, —O(C 1 -C 4 )alkyl, —S(C 1 -C 4 ) alkyl, or —N(C 1 -C 4  alkyl) 2  group, 
 R 3  represents a protecting group having a tetrahydropyranyl, —(C 1 -C 4 ) alkyl, allyl, or silyl group  
 R 4  represents a —(C 4 ) alkyl group,  
 X 1  represents a halogen atom,  
 X 2  represents a halogen atom or leaving group which can be displaced by nucleophiles, and  
 M represents a lithium ion or magnesium chloride, magnesium bromide or magnesium iodide.  
 
   
   
       9 . A process for preparing a compound of formula (IX) which comprises the process according to  claim 8  and further comprises eliminating the protecting group of a compound of formula (VIII) to obtain a compound of formula (IX)  
     
       
         
         
             
             
         
       
     
   
   
       10 . A process for preparing a compound of formula (X) which comprises the process according to  claim 9  and further comprises reacting a compound of formula (IX) with alkyl halogenated acetate to produce a compound of formula (X)  
     
       
         
         
             
             
         
       
     
   
   
       11 . A process of preparing a compound of formula (XI) as defined in  claim 7  which comprises eliminating the protecting group of a compound of formula (VIII) to obtain a compound of formula (IX), reacting the compound of formula (IX) with alkyl halogenated acetate to produce a compound of formula (X), and hydrolyzing a compound of formula (X) to produce a compound of formula (XI)  
     
       
         
         
             
             
         
       
     
   
   
       12 . A process of preparing a compound of formula (XI) as defined in  claim 7  which comprises reacting a compound of formula (IX) with alkyl halogenated acetate to produce a compound of formula (X), and hydrolyzing the compound of formula (X) to produce a compound of formula (XI)