Solution phase synthesis of oligonucleotides

Abstract

A process for the synthesis in solution phase of a phosphorothioate triester is provided. The process comprises the solution phase coupling of an H-phosphonate with an alcohol in the presence of a coupling agent to form an H-phosphonate diester. The H-phosphonate diester is oxidised in situ with a sulfur transfer agent to produce the phosphorothioate triester. Preferably, the H-phosphonate and alcohol are protected nucleosides or oligonucleotides. Oligonucleotide H-phosphonates which can be used in the formation of phosphorothioate triesters are also provided.

1 - 13 . (canceled)  
   
   
       14 . A process for introducing a group of formula —S-A into an H-phosphonate diester moiety, comprising: reacting a substrate comprising an H-phosphonate diester moiety with a sulfur transfer agent selected from the group consisting of 
 a) compounds of formula:                          wherein A represents an aryl, methyl, substituted alkyl or alkenyl group;    b) compounds of formula:                          wherein A represents an aryl, methyl, substituted alkyl or alkenyl group; and    c) compounds of formula:                          wherein A represents a methyl or alkenyl group.    
   
   
       15 . A process according to  claim 14 , wherein the sulfur transfer agent is selected from the group consisting of  
     
       
         
         
             
             
         
       
     
   
   
       16 . A process according to  claim 14  or  claim 15 , wherein the H-phosphonate diester is an oligonucleotide H-phosphonate diester.  
   
   
       17 . A process according to  claim 16 , wherein the oligonucleotide H-phosphonate diester is a protected oligonucleotide H-phosphonate diester.  
   
   
       18 . A process according to  claim 17 , further comprising one or more subsequent deprotection steps, thereby producing a deprotected oligonucleotide.  
   
   
       19 . A process for the preparation of an oligonucleotide, an oligonucleotide phosphorothioate or a mixed oligonucleotide/oligonucleotide phosphorothioate, said process comprising: introducing a group of formula —S-A into an H-phosphonate diester moiety by the process according to  claim 14 .  
   
   
       20 . A process according to  claim 19 , wherein the sulphur transfer agent is selected from the group consisting of  
     
       
         
         
             
             
         
       
     
   
   
       21 . A compound of formula:  
     
       
         
         
             
             
         
       
     
     wherein A represents an aryl, methyl, substituted alkyl or alkenyl group.  
   
   
       22 . A compound according to  claim 21 , wherein A represents a phenyl group or a —CH 2 CH 2 AN group.  
   
   
       23 . A compound according to  claim 22 , wherein A represents a phenyl group and the phenyl group is unsubstituted or is substituted by a halo or alkyl group.  
   
   
       24 . A compound of formula:  
     
       
         
         
             
             
         
       
     
   
   
       25 . A compound of formula:  
     
       
         
         
             
             
         
       
     
     wherein A represents an alkenyl group.