Process for preparing 3'-o-amino-ribonucleotide

Abstract

The invention relates to a process for preparing a 3′-O-amino-ribonucleotide. It also relates to a compound of formula (III), and its use as a precursor for the synthesis of a 3′-O-amino-ribonucleotide. In formula (III), B is a nitrogenous base or a protected derivative thereof, G and G′ are identical or different, and are a protecting group, and RN— is a phthalimido or an imino group.

1 . A process for preparing a 3′-O-amino-ribonucleotide, said process comprises the following successive steps:
 (a) reacting a compound of formula (I), 
 
       
         
           
           
               
               
           
         
       
       wherein B represents a nitrogenous base or a protected derivative thereof, and
 G and G′ are identical or different, and represent a protecting group, 
 
       with a source of sulfonyl group(s), under conditions allowing to obtain a compound of formula (II), 
       
         
           
           
               
               
           
         
       
       wherein X represents a sulfonyl group;
 (b) reacting the compound of formula (II) obtained in step (a) with a compound RN—OH, wherein RN— represents a phthalimido or an imino group, under conditions allowing to obtain a compound of formula (III), 
 
       
         
           
           
               
               
           
         
       
       and
 (c) converting the compound of formula (III) into the corresponding 3′-O-amino-ribonucleotide. 
 
     
     
         2 . The process according to  claim 1 , wherein B represents a nitrogenous base selected from the group consisting of adenine, guanine, cytosine, thymine, uracil, and a protected derivative thereof. 
     
     
         3 . The process according to  claim 1  or  2 , wherein the sulfonyl group(s) are selected from the group consisting of tosyl, mesyl, trifluoromethanesulfonyl group, and any combination thereof. 
     
     
         4 . The process according to any one of  claims 1  to  3 , wherein the source of sulfonyl group(s) comprises tosyl chloride. 
     
     
         5 . The process according to any one of  claims 1  to  3 , wherein the source of sulfonyl group(s) comprises trifluoromethanesulfonyl chloride and/or trifluoromethanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride. 
     
     
         6 . The process according to any one of  claims 1  to  5 , wherein G and G′ are identical or different, and represent a protecting group selected from the group consisting of tert-butyldimethylsilyl (TBS), monomethoxytrityl (MMTr), dimethoxytrityl (DMTr), (triisopropyl-siloxy)methyl (TOM) and triisopropylsilyl (TIPS). 
     
     
         7 . The process according to any one of  claims 1  to  6 , wherein RN— represents an imino group of formula (IV), 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  represent independently H, a (C 1 -C 6 )alkyl, a (C 1 -C 6 )alkoxy, or an aryl. 
     
     
         8 . The process according to any one of  claims 1  to  7 , wherein the compound of formula (I) is obtained by the following successive steps:
 (A) reacting a ribonucleoside of formula (I.1), 
 
       
         
           
           
               
               
           
         
       
       with one or more sources of protecting groups G and G′, under conditions allowing to obtain a compound of formula (I.2), wherein 2′- and 5′-hydroxy groups are protected: 
       
         
           
           
               
               
           
         
       
       and
 (B) inverting 3′-hydroxy group of the compound of formula (I.2), under conditions allowing to obtain a compound of formula (I). 
 
     
     
         9 . The process according to  claim 8 , wherein step (B) comprises the following substeps:
 (B-1) oxidizing 3′-hydroxy group of the compound of formula (I.2) into a ketone group, by means of an oxidizing agent, preferably Dess-Martin periodinane or pyridinium dichromate,   (B-2) reducing the ketone group of the compound obtained in step (B-1), by means of a hydride source, preferably sodium borohydride, so as to obtain the compound of formula (I).   
     
     
         10 . The process according to any of  claims 1  to  9 , wherein step (c) comprises the following substeps:
 (c-1) optionally converting the phthalimido group of the compound of formula (III) into an imino group; 
 (c-2) deprotecting 5′-hydroxy group of a compound of formula (III′), 
 
       
         
           
           
               
               
           
         
       
       wherein NR′ is an imino group;
 (c-3) phosphorylating 5′-hydroxy group of the compound obtained in step (c-2); 
 (c-4) converting the imino group of the compound obtained in step (c-3) into an amino group; wherein 3′-hydroxy group is deprotected in step (c-2) or after step (c-4). 
 
     
     
         11 . A compound of formula (III), 
       
         
           
           
               
               
           
         
       
       wherein B represents a nitrogenous base or a protected derivative thereof,
 G and G′ are identical or different, and represent a protecting group, and 
 RN— represents a phthalimido or an imino group. 
 
     
     
         12 . The compound according to  claim 11 , wherein at least one of the following features is fulfilled:
 B represents a nitrogenous base selected from the group consisting of adenine, guanine, cytosine, thymine, uracil, and a protected derivative thereof; and/or   G and G′ are identical or different, and represent a protecting group selected from the group consisting of tert-butyldimethylsilyl, monomethoxytrityl, and (triisopropyl-siloxy)methyl; and/or   RN— represents an imino group of formula (IV),   
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  represent independently H, a (C 1 -C 6 )alkyl, a (C 1 -C 6 )alkoxy, or an aryl. 
     
     
         13 . Use of a compound according to  claim 11  or  12 , as a precursor for the synthesis of 3′-O-amino-ribonucleotide. 
     
     
         14 . Use of a 3′-O-amino-ribonucleotide obtained by a process according to any one of  claims 1  to  10 , for the synthesis of a nucleic acid strand.