Solid phase supports

Abstract

Embodiments of the present invention generally relate to carrying out organic chemistry on solid supports comprising derivatised functionalities, methods for synthesizing said supports, methods for synthesizing compounds comprising amine groups or N-containing heterocycles using said solid supports, intermediate compounds linked to said supports and uses thereof.

1 . A solid support comprising a functionalised amide according to Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
   represents the solid support;  
 B is a conventional spacer arm or a bond;  
 R is selected from H, (C 1 -C 6 )alkyl, optionally substituted with halogen, aryl(C 1 -C 6 )alkyl and aryl, optionally substituted with (C 1 -C 6 )alkoxy, OH or halogen;  
 W is selected from O and S;  
 Y is CHR 4  where R 4  is selected from H, (C 1 -C 4 )alkyl, optionally substituted with halogen, and phenyl, optionally substituted with CF 3  or (C 1 -C 6 )alkoxy;  
 Z is CR 5 R 6 -L where R 5  and R 6  are independently selected from H, (C 1 -C 4 )alkyl, and phenyl; L is a leaving group; or  
 Y and Z together form CR 4 ═CR 5 R 6  wherein R 4  and R 5  are as defined above, or wherein R 4  and R 5  together with the carbon atoms to which they are bonded form a (C 4 -C 8 )cycloalkene ring.  
 
     
     
         2 . The solid support according to  claim 1 , wherein B is CH 2 ; R is selected from H, CH 3 , C 2 H 5 , C 3 H 7  (ie straight or branched-chain), and phenyl; W is O; and Y and Z together form CH═CH 2  or Y is CH 2  and Z is CH 2 -L.  
     
     
         3 . The solid support according to  claim 2 , wherein B is CH 2 ; R is H; W is O; Y-Z is CH═CH 2 , and the solid support is a polystyrenedivinylbenzene support of a Merrifield resin.  
     
     
         4 . A functionalised support comprising a quaternary ammonium compound according to Formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein B, R, W, R 4 , R 5 , and R 6  are as defined for Formula (I); 
 R 7  and R 8  are independently selected from H, branched or straight chain (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl ethers, aryl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-0-(C 1 -C 6 )alkylene, and vinyl(C 1 -C 6 ) alkylene; or  
 R 7  and R 8  may form part of a ring structure;  
 R 9  is selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl ether, aryl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O-(C 1 -C 6 )alkylene, and vinyl(C 1 -C 6 )alkylene;  
 with the proviso that when R 7  and/or R 8  are branched chain substituents comprising a quaternary carbon, the quaternary carbon is not located on an atom adjacent to the N;  
 and X −  is an anion, such as Br − , I − , or an acid derived anion.  
 
     
     
         5 . A solid support comprising a functionalised sulphone of Formula (V):  
       
         
           
           
               
               
           
         
       
       wherein 
   represents the solid support;  
 B is a conventional spacer arm or a bond;  
 C is O, NR, S, CH 2  or SO 2 ;  
 R is selected from H, (C 1 -C 6 )alkyl, optionally substituted with halogen, aryl(C 1 -C 6 )alkyl and aryl, optionally substituted with (C 1 -C 6 )alkoxy, OH or halogen;  
 b is an integer selected from 0 and 1;  
 D is selected from (C 1 -C 6 )alkylene, arylene, optionally substituted with halogen, and arylene(C 1 -C 6 )alkylene; or D is absent;  
 Y is CHR 4  where R 4  is selected from H, (C 1 -C 4 )alkyl, optionally substituted with halogen, and phenyl, optionally substituted with CF 3 , (C 1 -C 6 )alkoxy;  
 Z is CR 5 R 6 -L where R 5  and R 6  are independently selected from H, (C 1 -C 4 )alkyl, and phenyl; L is a leaving group; or  
 Y and Z together form CR 4 ═CR 5 R 6  wherein R 4  and R 5  are as defined above, or wherein R 4  and R 5  together with the carbon atoms to which they are bonded form a (C 4 -C 8 )cycloalkene ring; with the proviso that when D is absent C is not SO 2 , S or O and when D is CH 2 , C is not SO 2 .  
 
     
     
         6 . The solid support according to  claim 5 , wherein B is CH 2 ; C is O and D is 1,3-phenylene; or C and D are absent; Y-Z are —CH═CH 2 ; or Y is CH 2  and Z is CH 2 -L where L is a leaving group; and the solid support is the polystyrenedivinylbenzene support of a Merrifield resin.  
     
     
         7 . The solid support according to  claim 6 , wherein B is CH 2 ; C is O and D is 1,3-phenylene; Y is CH 2  and Z is CH 2 -L where L is Cl or Br; and the solid support is the polystyrenedivinylbenzene support of a Merrifield resin.  
     
     
         8 . A functionalised support comprising a quaternary ammonium compound of Formula (VII):  
       
         
           
           
               
               
           
         
       
       wherein B, C, D, R 4 , R 5 , R 6  and b are as defined for Formula (V) and R 7  and R 8  are independently selected from H, branched or straight chain (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl ethers, aryl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-0-(C 1 -C 6 )alkylene, and vinyl(C 1 -C 6 ) alkylene; or 
 R 7  and R 8  may form part of a ring structure; and  
 R 9  is selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl ether, aryl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O-(C 1 -C 6 )alkylene, and vinyl(C 1 -C 6 )alkylene; with the proviso that when R 7  and/or R 8  are branched chain substituents comprising a quaternary carbon, the quaternary carbon is not located on an atom adjacent to the N.  
 
     
     
         9 . A process for the preparation of a tertiary amine or an N-containing heterocyclic compound which comprises: 
 (i) adding a primary or secondary amine to an amide-functionalised support according to Formula (I) or to a sulphone-functionalised support according to Formula (V) by way of a Michael addition to an unsaturated amide or sulphone derivative of the support or by alkylation reaction with a derivative of the support having a leaving group L;    (ii) optionally performing a reductive alkylation on the secondary amine produced in step (i);    (iii) adding an alkylating agent forming a quaternary ammonium compound; and    (iv) performing a Hofmann elimination on the quaternary ammonium compound generated in step (iii).    
     
     
         10 . Use of an amide-functionalised support according to Formulae (I) or (IV), or of a sulphone-functionalised support according to Formulae (V) or (VII) in the synthesis of a tertiary amine or in the synthesis of an N-containing heterocycle capable of quaternisation.  
     
     
         11 . Use of an amide-functionalised support according to Formulae (I) or (IV), or of a sulphone-functionalised support according to Formulae (V) or (VII) in the manufacture of a combinatorial chemistry library or an array of compounds.