Novel intermediate compounds useful in the preparation of oxazoles and pharmaceutical actives for the regulation of lipid and glucose metabolism

Abstract

The present invention is directed to compounds of Formula III wherein the R1-R7 groups or substituents are defined herein. The present invention also comprises improved methods in the preparation of oxazoles in which the compounds of Formula III are intermediates and which results in higher yields with less impurities and contaminants. Oxazoles constitute valuable intermediates in the synthesis of pharmaceutically active substances such as, for example peroxisome proliferator activated receptor (PPAR) agonists which are pharmaceutical actives which can have a positive influence on both lipid and glucose metabolism.

1 . The compounds of formula III, 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF 3 , OCF 3 , SCF 3 , SC 2 F 5 , OCF 2 —CHF 2 , (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO 2 , COOR 9 , CONR 10 R 11 , SH, or NR 10 R 11 , wherein aryl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl and CF 3 , and; 
 R 9  is selected from the group consisting of H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or trisubstituted by (C1-C4)-alkyl, and is (C1-C8)-alkyl, 
 R 10  and R 11  are each independently selected from the group consisting of H, (C1-C5)-alkyl, phenyl or CH 2 -phenyl,
 wherein phenyl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl and CF 3 ; 
 or 
 R 10  and R 11  together are (C4-C5)-alkylene, in which one CH 2  group may be replaced by O, S, NH, N—CH 3  or N-benzyl; 
 
 R 2  is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C1-C8)-alkylene-H, CF 3 , OCF 3 , SCF 3 , SC 2 F 5 , OCF 2 —CHF 2 , (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO 2 , COOR 9 , CONR 10 R 11 , SH, or NR 10 R 11 , where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl and CF 3 ;
 wherein R 9 , R 10  and R 11  are each as defined above; 
 
 R 3  is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF 3 , OCF 3 , SC 2 F 3 , SF 5 , OCF 2 —CHF 2 , (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO 2 , COOR 9 , CONR 10 R 11 , SH, or NR 10 R 11 , where aryl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl and CF 3 ;
 wherein R 9 , R 10  and R 11  are each as defined above; 
 
 W is CH, N, if o=1; 
 W is O, S, NR12, if o=0; 
 o is 0 or 1; 
 R12 is H, (C1-C6)-alkyl, (C1-C6)-alkylenephenyl, phenyl; 
 R 4  is selected from the group consisting of H, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C3)-alkylene-(C3-C8)-cycloalkyl, phenyl, (C1-C3)-alkylenephenyl, (C5-C6)-heteroaryl, (C1-C3)-alkylene-(C5-C6)-heteroaryl or (C1-C3)-alkyl which is fully or partly substituted by F, or COOR 9 , CONR(10)R(11);
 wherein R 9 , R 10  and R 11  are each as defined above; 
 
 R 5  and R 6  are each independently selected from the group consisting of H, (C1-C8)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, COOR 9 , CONR 10 R 11 , SH or NR 10 R 11 ,
 wherein R 9 , R 10 , R 11  are each as defined above; 
 
 or, 
 R 5  and R 6  together are (C4-C5)-alkylene, in which one CH 2  group may be replaced by O, S, NH, N—CH 3  or N-benzyl; 
 R 7  is selected from the group consisting of H or (C1-C8)-alkyl; 
 and, 
 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and X 1  are each as defined above and 
 n1 is 0, 1, ½ or ⅓; 
 
     
     
         2 . The compounds of formula III as recited in  claim 1 , wherein:
 W=CH and   o=1.   
     
     
         3 . The compounds of formula III as recited in  claim 2 , wherein:
 R1 is H;   R 2  is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C1-C8)-alkylene-H, CF 3 , OCF 3 , SCF 3 , SC 2 F 5 , OCF 2 —CHF 2 , (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR 9 , CONR 10 R 11 , SH, or NR 10 R 11 , where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF 3 ; wherein   R 9  is selected from the group consisting of H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or tri-substituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,
 R 10  and R 11  are each independently H, (C1-C5)-alkyl, phenyl or CH 2 -phenyl, and wherein the phenyl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF 3 ; 
 or 
 R 10  and R 11  together are (C4-C5)-alkylene, in which one CH 2  group may be replaced by O, S, NH, N—CH 3  or N-benzyl; 
   R 3  is H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF 3 , OCF 3 , SCF 3 , SC 2 F 5 , OCF 2 —CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR 9 , CONR 10 R 11 , SH, or NR 10 R 11 , where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF 3 ;   
       wherein R 9 , R 10  and R 11  are each as defined above. 
     
     
         4 . The compounds of formula III as recited in  claim 3  wherein:
 R1 is H;   R 2  is H;   R 3  is H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SF5, OCF2-CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR 9 , CONR 10 R 11 , SH, or NR 10 R 11 , where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
 wherein 
   R 9  is H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or tri-substituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,
 R 10  and R 11  are each independently selected from the group consisting of H, (C1-C5)-alkyl, phenyl or CH 2 -phenyl, 
 wherein phenyl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3; 
 or 
 R 10  and R 11  together form a (C4-C5)-alkylene, in which one CH 2  group may be replaced by O, S, NH, N—CH 3  or N-benzyl. 
   
     
     
         5 . The compounds of formula III as recited in  claim 4 , wherein:
 W=CH;   o=1;   R 1 =H;   R 2 =H, CH 3 , OCH 3 , Br or Cl;   R 3 =H, CH 3 , OCH 3 , Br or Cl;   R 4 =CH 3 , CH 2 CH 3  or CH(CH 3 ) 2 ;   R 5 =H, CH 3 , CH 2 CH 3  or CH(CH 3 ) 2 ;   R 6 =H, CH 3 , CH 2 CH 3  or CH(CH 3 ) 2 ;   X 3 =Cl, CH 3 SO 3  or p-CH 3 —C 6 H 4 —SO 3  and   n2=0 or 1.   
     
     
         6 . The compounds of formula III 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 =H, 
 R 2 =H or CH 3 , 
 R 3 =H or OCH 3 , 
 R 4 =CH 3  or CH(CH 3 ) 2 , a 
 W=CH, 
 X 3 =Cl or CH 3 SO 3 , and 
 n2=0 or 1. 
 
     
     
         7 . A process for the preparation of compounds of formula III as recited in  claim 1 , wherein the reaction temperature for the formation of the N-oxides as depicted by formula III from the reaction of compounds of formulae I and II is between about −20° C. and +150° C. 
     
     
         8 . The process for the preparation of compounds of formula III as recited in  claim 7 , wherein the reaction for the formation of the N-oxides as depicted by formula III is carried out in protic, polar, aprotic non-polar solvents or mixtures thereof. 
     
     
         9 . The process for the preparation of compounds of the formula III as recited in  claim 8 , wherein the reaction temperature for the formation of the halomethyloxazoles as depicted by formula IV from compounds of the formula III is from about −20° C. to +150° C. 
     
     
         10 . The process for the preparation of compounds of formula III as recited in  claim 8  wherein one or more of the compounds of formula I and II are used in the preparation thereof. 
     
     
         11 . The compound of formula XI. 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of formula XIV 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of formula XVII