Process for producing 2', 3'-diethy substituted nucleoside derivatives

Abstract

There can be provided an excellent industrial process for producing compounds having sugar-moiety hydroxyl groups or halogen atoms reduced in nucleic acids or in derivatives thereof by allowing O-thiocarbonyl derivatives of sugar-moiety hydroxyl groups or allowing halogenated derivatives in the sugar-moiety, in the nucleic acids or in derivatives thereof to react with any one of hypophosphorous acids (including salts thereof) and phosphites (esters) which are inexpensive, non-toxic and safely usable as radical reducing agents in industrial scale, in the presence of a radical reaction initiator. The process of the present invention is an industrially useful and highly safe process for reducing sugar-moiety hydroxyl groups and halogen atoms in nucleic acids or derivatives thereof (including nucleic acid-related compounds) at low costs.

What is claimed is:  
     
         1 . A process for producing a nucleic acid derivatives represented by the general formula (II):  
       
         
           
           
               
               
           
         
       
       wherein B represents a nucleic acid base which may be in the form of derivative thereof, R represents a hydrogen atom or a hydroxy group-protecting group, and one of Y′ and X′ represents a hydrogen atom and the other represents a hydrogen atom, a fluorine atom, a hydroxyl group or a protected hydroxyl group, respectively, which comprises allowing a nucleic acid derivative having an eliminating group represented by the general formula (I):  
       
         
           
           
               
               
           
         
       
       wherein B and R have the same meanings as defined above, and one of Y and X represents an eliminating group and the other represents a hydrogen atom, a fluorine atom, a hydroxyl group or a protected hydroxyl group, respectively, to react with at least one compound selected from hypophosphorous acids, which may or may not be in the salts thereof, and esters of phosphorous acid in the presence of a radical reaction initiator.  
     
     
         2 . The process according to  claim 1 , wherein B is a purine base or a pyrimidine base, which may or may not be in the form of derivative thereof.  
     
     
         3 . The process according to  claim 2 , wherein B is any base of hypoxanthine, adenine, guanine, uracil, thymine and cytosine or a derivative thereof.  
     
     
         4 . The process according to  claim 1 , wherein R is any one of a hydrogen atom, an acyl group, an alkyl group, an aralkyl group and a silyl group.  
     
     
         5 . The process according to  claim 4 , wherein the acyl group is an acetyl group or a benzoyl group, and the aralkyl group is a trityl group.  
     
     
         6 . The process according to  claim 1 , wherein the eliminating group represented by either Y or X is any one of halogen atoms (exceeding a fluorine atom) and O-thiocarbonyl derivatives (residue).  
     
     
         7 . The process according to  claim 1 , wherein the protected hydroxyl group in the case where either Y or X represents a protected hydroxyl group is any one of an acyloxy group, an alkyloxy group, an aralkyloxy group and a silyloxy group.  
     
     
         8 . The process according to  claim 7 , wherein the acyloxy group is an acetyloxy group or a benzoyloxy group.  
     
     
         9 . The process according to  claim 1 , wherein hypophosphorous acid is in the form of a sodium salt.  
     
     
         10 . The process according to  claim 1 , wherein the radical reaction initiator is an azo compound.  
     
     
         11 . The process according to  claim 6 , wherein the O-thiocarbonyl derivatives (residue) are O-phenoxythiocarbonyl, O-parafluorophenoxythiocarbonyl, O-methylthiothiocarbonyl, O-phenylthiothiocarbonyl and O-imidazolylthiocarbonyl group.  
     
     
         12 . The process according to  claim 1 , wherein in the general formula (II), B is an adenine, Y′ is a hydrogen atom, X′ is a hydrogen atom or a fluorine atom, R is a hydrogen atom or a hydroxy group-protecting group, and if R is the protecting group, this group is further eliminated to produce ddA or FddA.  
     
     
         13 . The process according to  claim 1 , wherein the compound produced in  claim 1  in which B is a purine base or a derivative thereof, Y′ is a hydrogen atom, X′ is a hydroxyl group or a protected hydroxyl group, is subjected to at least one step of the step of deprotecting the hydroxyl group, the step of halogenation at the 6-position, the step of amination at the 6-position and the step of fluorination at the 2′-position to produce FddA.  
     
     
         14 . The process according to  claim 13 , wherein said produced compound in which B is an adenine, Y′ is a hydrogen atom, X′ is a hydroxyl group or a protected hydroxyl group, is subjected to the step of fluorination at the 2′-position, and if R is the protecting group, the compound is further subjected to the step of deprotection.  
     
     
         15 . The process according to  claim 13 , wherein said produced compound in which B is 6-halogenopurine, Y′ is a hydrogen atom, and X′ is a hydroxyl group or a protected hydroxyl group, is subjected to the step of fluorination at the 2′-position and the step of amination at the 6′-position in this order or in the reverse order, and if R is the protecting group, the compound is further subjected to the step of deprotection.  
     
     
         16 . The process according to  claim 13 , wherein said produced compound in which B is 6-hydroxypurine, Y′ is a hydrogen atom, and X′ is a hydroxyl group or a protected hydroxyl group, is subjected to the step of halogenation at the 6-position to produce the compound substituted with a halogen at the 6-position which is then subjected to the step of fluorination at the 2′-position and the step of amination at the 6-position in this order or in the reverse order, and if R is the protecting group, the compound is further subjected to the step of deprotection, provided that if said compound has a protected hydroxyl group, its protecting group may be eliminated and then the compound may be subjected to the step of halogenation at the 6-position, and if said halogen-substituted compound has a protected hydroxyl group, the protecting group for said hydroxyl group may be eliminated and then the compound may be subjected to the step of amination at the 6-position.