Intermediate products, methods for their preparation and use thereof

Abstract

Novel solid supported intermediate products of the general formula coupled to a solid polymeric support through one or both of the R 1 groups or through the R 4 group which are suitable for synthesis of heterocyclic compounds are disclosed. Methods for preparing such intermediate products are also disclosed and also the use of the intermediate products in simple and fast methods on solid phase for synthesis of heterocycles.

1 . A method of preparing an intermediate product suitable for synthesis of heterocyclic compounds, which is a compound of general formula I  
     
       
         
         
             
             
         
       
     
     coupled to a solid polymeric support through one or both of the R 1  groups, 
 wherein the R 1  groups represent the same or different groups chosen from lower alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms in the ring, heterocyclic compounds including one or more heteroatoms, benzyl groups; two R 1  groups together can be included in heterocyclic ring containing one or more nitrogen atoms;  
 R 2  represents H or a lower alkyl with 1 to 6 carbon atoms;  
 R 4  represents unsubstituted or substituted aromatic ring(s), unsubstituted or substituted heteroaromatic ring(s) with one or more heteroatoms, or OR 5;  
 when R 4  is unsubstituted or substituted aromatic ring(s), unsubstituted or substituted heteroaromatic ring(s), R 3  represents H, alkyl, unsubstituted or substituted aromatic ring, unsubstituted or substituted heteroaromatic ring with one or more heteroatoms, or COOR 5 ;  
 when R 4  is OR 5,  R 3  is CN, COOR 5,  NCOR 5,  NCOOR 5  or COR 5 ; the R 5  groups, which can be the same or different, represent H, alkyl, benzyl, unsubstituted or substituted aromatic ring(s), unsubstituted or substituted heteroaromatic ring(s) with one or more heteroatoms;  
 
 which comprises preparing a polymeric support with a reactive secondary amine according to the following reaction whereby a product of formula IV is obtained  
                     
 wherein Y is a spacer group which can be alkyl, benzyl, trityl or [OCH 2 CH 2 ] n , R 1  is as defined above, X is NH 2 , halogen or triflate; when X is NH 2 , A is halogen or triflate, and when X is halogen or triflate, A is NH 2 ,  
 and reacting the product of formula IV with a N-disubstituted carboxamide acetal of the general formula II  
                     
 wherein the R 7  groups are different or the same chosen from C1 -C6 alkyl, cycloalkyl with 3 to 6 carbon atoms , benzyl groups, cyclic compounds including heteroatoms, the two R 7  groups could together be part of a carbocyclic or heterocyclic ring,  
 the R 8  groups could be the same or different chosen from straight, branched or cyclic alkyl chains, benzyl groups, and alkyl chains with substituents; the two R 8  groups could together be part of a carbocyclic ring  
 and a substance with a methylene or methyl group adjacent to a keto function according to the general formula III  
                     
 where R 3,  R 4  are as defined above, whereby a compound of formula I coupled to the polymeric support through one or both of the R 1  groups is obtained.  
 
   
   
       2 . A method of preparing an intermediate product suitable for synthesis of heterocyclic compounds, which is a compound of general formula I  
     
       
         
         
             
             
         
       
     
     coupled to a solid polymeric support through one or both of the R 1  groups, 
 wherein the R 1  groups represent the same or different groups chosen from lower alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms in the ring, heterocyclic compounds including one or more heteroatoms, benzyl groups; two R 1  groups together can be included in heterocyclic ring containing one or more nitrogen atoms;  
 R 2  represents H or a lower alkyl with 1 to 6 carbon atoms, such as methyl;  
 R 4  represents unsubstituted or substituted aromatic ring(s), unsubstituted or substituted heteroaromatic ring(s) with one or more heteroatoms, or OR 5;    
 when R 4  is unsubstituted or substituted aromatic ring(s), unsubstituted or substituted heteroaromatic ring(s), R 3  represents H, alkyl, unsubstituted or substituted aromatic ring, unsubstituted or substituted heteroaromatic ring with one or more heteroatoms, or COOR 5 ; 
 when R 4  is OR 5,  R 3  is CN, COOR 5,  NCOR 5,  NCOOR 5  or COR 5 ; the R 5  groups, which can be the same or different, represent H, alkyl, benzyl, unsubstituted or substituted aromatic ring(s), unsubstituted or substituted heteroaromatic ring(s) with one or more heteroatoms;  
 
 which comprises preparing a polymeric support with a reactive secondary amine according to the following reaction, whereby a product of formula V is obtained  
                     
 wherein Y is as defined in  claim 1 , R 10  is a secondary amine, B and D are functional groups which form a covalent bond when reacted with each other, and when n=0 B is a leaving group,  
 and reacting the product of formula V with a N-disubstituted carboxamide acetal of the general formula II  
                     
 wherein R 7  and R 8  are defined as in  claim 1 ,  
 and a substance with a methylene or methyl group adjacent to a keto function according to the general formula III  
                     
 where R 3,  R 4  are as defined in  claim 1 , whereby a compound of formula I coupled to the polymeric support through one or both of the R 1  groups is obtained.  
 
   
   
       3 . A method according to  claim 1  or  2 , wherein the reactions are performed under heating.  
   
   
       4 . A method according to  claim 3 , wherein the heating is induced by the use of microwaves.  
   
   
       5 . A method according to  claim 1  or  2 , wherein the solid polymeric support is polystyrene beads that are lightly cross-linked with 1-2% divinylbenzene and optionally grafted with polyethylene glycol.  
   
   
       6 . A method according to  claim 1 , wherein the solid polymeric support is polystyrene beads which are functionalized with halogen and triflate or NH 2 .  
   
   
       7 . A method according to  claim 2 , wherein the solid polymeric support is polystyrene beads which are functionalized with B as defined in formula V.  
   
   
       8 . A method according to  claim 1 , wherein the solid polymeric support is polystyrene beads which are functionalized with halogen or hydroxyl.  
   
   
       9 . A method according to  claim 1  or  2  where the substance with a methylene or methyl group adjacent to a keto function according to the general formula III is a substituted acetophenone or beta ketoester.  
   
   
       10 . A method according to  claim 1  or  2  where the substance according to the general formula III is a N-substituted glycine ester or a substituted acetic acid ester.  
   
   
       11 . A method according to  claim 1  or  2  wherein the disubstituted carboxamide acetal of formula II is dimethylformamide diacetal.  
   
   
       12 . A method according to  claim 1  or  2 , wherein with R 1  the lower alkyl is methyl or ethyl.  
   
   
       13 . A method according to  claim 1  or  2 , wherein with R 1  the cycloalkyl is cyclopentyl or cyclohexyl.