Methods for producing nucleoside derivatives and intermediates therefor

Abstract

Novel intermediates of nucleoside derivatives, of which the 6-position of the nucleic acid base moiety is substituted with a halogen atom, are produced. Using those novel intermediates, even substrates, of which the 3′-position of the saccharide moiety is deoxylated, can be substituted at the 2′-position at an extremely high yield. Specifically, by subjecting a 3′-deoxy derivative of inosine to 6-halogenation to give a 6-halide of the derivative, and then subjecting it to 2′-deoxylation/substitution with a fluorine atom or the like, followed by further subjecting it to substitution with an amino group, a hydroxyl group or any other intended substituent at the 6-positioned halogen atom, nucleoside derivatives are produced at a high yield. Methods for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (FddA) and their related compounds, in a simplified manner, at a high yield and at low costs, and especially Economical methods for substituting substrates, of which the 3′-position of the saccharide moiety is deoxylated, at the 2′-position to produce those nucleoside derivatives on an industrial scale are also provided.

What is claimed is:  
     
         1 . A method for producing a nucleoside derivative represented by the following general formula (8) or (9), which comprises subjecting a 3′-deoxy derivative of inosine to 6-halogenation step to give a 6-halide of the derivative, and then subjecting it to 2′-deoxylation/Y-substitution reaction step followed by further subjecting it to Z-substitution reaction at its 6-halogen atom:  
       
         
           
           
               
               
           
         
       
       wherein Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group; 
 Z represents any one of a hydrogen atom, an amino group, a hydroxyl group, an azido group, a  
 substituent of a formula OR 4 , a substituent of a formula SR 4  and a substituent of a formula NHR 4 ;  
 R 1  represents a protective group for the hydroxyl group; and  
 R 4 represents a lower alkyl group which may or may not be optionally substituted with one or more phenyl groups.  
 
     
     
         2 . A method for producing a nucleoside derivative represented by the following general formula (8) or (8′), which comprises subjecting a compound represented by the following general formula (1) to 2′-deoxylation/Y-substitution reaction step to give a compound represented by the following general formula (3);  
       and then subjecting the resulting compound to substitution with a group Z at its 6-halogen atom to give the compound (8),  
       or subjecting the resulting compound (3) to the deprotecting reaction to remove the protective group R 1  therefrom to give the compound (8′):  
       
         
           
           
               
               
           
         
       
       wherein X represents a halogen atom; 
 Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group;  
 Z represents any one of a hydrogen atom, an amino group, a hydroxyl group, an azido group, a  
 substituent of a formula OR 4 , a substituent of a formula SR 4  and a substituent of a formula NHR 4 ;  
 R 1  represents a protective group for the hydroxyl group; and  
 R 4  represents a lower alkyl group which may or may not be optionally substituted with one or more phenyl groups.  
 
     
     
         3 . The method as claimed in the  claim 2 , wherein said reaction step includes a compound represented by the following formula (2) as the intermediate:  
       
         
           
           
               
               
           
         
       
       wherein X represents a halogen atom; 
 R 1  represents a protective group for the hydroxyl group; and  
 SO 2 R 2  represents a sulfonic acid-type leaving group.  
 
     
     
         4 . The method as claimed in the  claim 1  or  2 , wherein said Y-substitution reaction step is a substitution reaction step with a fluorine atom.  
     
     
         5 . The method as claimed in the  claim 1  or  2 , wherein the group Z is an amino group.  
     
     
         6 . The method as claimed in the  claim 1  or  2 , which additionally comprises deprotecting the product (8) to remove the protective group R 1  therefrom;  
       or subjecting the compound (8′) to substitution with a group Z at its 6-halogen atom,  
       to give a compound represented by the following general formula (9):  
       
         
           
           
               
               
           
         
       
       wherein Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group; 
 Z represents any one of a hydrogen atom, an amino group, a hydroxyl group, an azido group, a  
 substituent of a formula OR 4 , a substituent of a formula SR 4  and a substituent of a formula NHR 4 ; and  
 R 4  represents a lower alkyl group which may or may not be optionally substituted with one or more phenyl groups.  
 
     
     
         7 . A method for producing a compound represented by the following general formula (3), which comprise; 
 (a) subjecting a compound represented by the following general formula (1) to 2′-deoxylation/Y-substitution reaction step, or    (b) subjecting a compound represented by the following general formula (2) to removal of leaving group/Y-substitution reaction step:                          wherein X represents a halogen atom;    Y represents any one of a fluorine atom, an azido group and a cyano group;    R 1  represents a protective group for the hydroxyl group; and    SO 2 R 2  represents a sulfonic acid-type leaving group.    
     
     
         8 . The method as claimed in the  claim 7 , wherein said compound represented by the formula (2) is prepared by subjecting said compound represented by formula (1) to a reaction step for inserting a sulfonic acid-type leaving group thereinto.  
     
     
         9 . The method as claimed in the  claim 1  or  2 , which comprises at least one of the following steps (A) to (E): 
 (A): the method of the  claim 7 ,  
 (B): a step of dehalogenating a compound represented by the following general formula (7) to give a compound represented by the following general formula (4),  
 (C): a step of reacting a compound represented by the following general formula (6) with a reagent for selectively protecting the 5′-position of said compound to give a compound represented by the following general formula (1),  
 (D): a step of subjecting a compound represented by the following general formula (1) to reaction of inserting a sulfonic acid-type leaving group thereinto to give a compound represented by the following general formula (2), and  
 (E): a step of selectively halogenating a compound represented by the following general formula (4) at its 6-position with a halogenating agent to give a compound represented by the following general formula (5):  
                     
 wherein W represents a halogen atom;  
 X represents a halogen atom;  
 R 1  represents a protective group for the hydroxyl group;  
 SO 2 R 2  represents a sulfonic acid-type leaving group;  
 R 3  represents a protective group for the hydroxyl group;  
 Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group;  
 Z represents any one of a hydrogen atom, an amino group, a hydroxyl group, an azido group, a  
 substituent of a formula OR 4 , a substituent of a formula SR 4  and a substitutent of a formula NHR 4 ;  
 R 1  represents a protective group for the hydroxyl group; and  
 R 4  represents a lower alkyl group which may or may not be optionally substituted with one or more phenyl groups.  
 
     
     
         10 . An intermediate represented by any one in the following general formulae (4), (1) and (2):  
       
         
           
           
               
               
           
         
       
       wherein X represents a halogen atom; 
 Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group;  
 R 1  represents a protective group for the hydroxyl group;  
 SO 2 R 2  represents a sulfonic acid-type leaving group; and  
 R 3  represents a protective group for the hydroxyl group.  
 
     
     
         11 . A method for producing nucleoside derivative represented by the following general formula (8) (8′) or (9), in which is used any one of the intermediates in the  claim 10  in their production:  
       
         
           
           
               
               
           
         
       
       wherein Y represents a substituent of any one of a fluorine atom, an azido group and a cyano group; 
 Z represents any one of a hydrogen atom, an amino group, a hydroxyl group, an azido group, a  
 substitutent of a formula OR 4 , a substituent of a formula SR 4  and a substitutent of a formula NHR 4 ;  
 R 1  represents a protective group for the hydroxyl group; and  
 R 4  represents a lower alkyl group which may or may not be optionally substituted with one or more phenyl groups.  
 
     
     
         12 . The method as claimed in the  claim 9 , wherein said reaction of inserting a sulfonic acid-type leaving group into the compound comprises reacting the compound with a sulfonyl halide or a sulfonic acid anhydride, or reacting the compound with sulfuryl chloride and then with an amine or a halogen.  
     
     
         13 . The method as claimed in the  claim 7 , wherein the reagent for said 2′-deoxylation/Y-substitution reaction is an alkylaminosulfur trifluoride reagent or a fluoroalkylamine reagent, and the reagent for said removal of leaving group/Y-substitution reaction is any one of azides, cyanides and fluorides.