Method for the synthesis of 2',3'-dideoxy-2',3'-didehydronucleosides

Abstract

The present invention is an efficient synthetic route to 2′,3′-dideoxy-2′,3′-didehydro-nucleosides from available precursors with the option of introducing functionality as needed, such as, the 2′,3′-dideoxy and 2′- or 3′-deoxyribo-nucleoside analogs as well as additional derivatives obtained by subsequent functional group manipulations. Briefly, the present invention discloses a method for the preparation of β-D and β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleosides starting from appropriately substituted ribonucleosides in two, optionally three steps: Step (1) a haloacylation, such as haloacetylation, and in particular, bromoacetylation; Step (2) a reductive elimination; and optionally, Step (3) a deprotection. The haloacylation of step (1) can form the 2′-acyl-3′-halonucleoside, the 3′-acyl-2′-halonucleoside, or a mixture thereof.

1 - 46 . (canceled)  
   
   
       47 . A compound of Formula (VI) or (VI*):  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein:  
       Q is R 1 CH 2 — or R 1 CH 2 C(═O)OC(R 2 ) 2 —;  
       R 1  is H or C 1 -C 6  alkyl;  
       R 2  is independently selected from methyl, ethyl, and propyl;  
       R 3  is Cl, Br, or IV; and  
       R 4  is R 1 CH 2 C(═O)O—.  
     
   
   
       48 . A compound of  claim 47  of Formula (VI-a) or (VI*-a):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       49 . A compound of Formula (VII):  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein:  
       Q is R 1 CH 2 — or R 1 CH 2 C(═O)OC(R 2 ) 2 —;  
       R 1  is H or C 1 -C 6  alkyl; and  
       R 2  is independently selected from methyl, ethyl, and propyl.  
     
   
   
       50 . A compound of  claim 49  of Formula (VII-a):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       51 . A process for the preparation of a β-D- and β-L-2′,3′-dideoxy-2′,3′-didehydronucleoside comprising: 
 a) activating a compound of structure (1)                          wherein B is a pyrimidine or purine base; and    Y is O, S or CH 2 ;    with an acyl halide of the formula X—C(═O)R 1 , X—C(═O)C(R 1 ) 2 OC(═O)R 1  or X—C(═O)phenylC(═O)OR 1 ;    wherein X is a halogen (F, Cl, Br or I), and    each R 1  is independently hydrogen, lower alkyl, alkyl, aryl or phenyl;    to form a compound of structure (2)                          wherein R is R 1 , —C(R 1 ) 2 OC(═O)R 1  or -phenylC(═O)OR 1 ; and    at least one R is halogen (F, Cl, Br or I), and at least one R is an acyl of the formula —OC(═O)R 1 ; and then    b) reducing the compound of structure (2) with a reducing agent to form a 2′,3′-dideoxy-2′,3′-didehydro-nucleoside of structure (3)                          c) optionally deprotecting the nucleoside if necessary.    
   
   
       52 . The process of  claim 51 , wherein B is 5-fluorouracil or 5-fluorocytosine.  
   
   
       53 . The process of  claim 51 , wherein Y is 0.  
   
   
       54 . The process of  claim 51 , wherein the β-D- and β-L-2α,3α-dideoxy-2′,3′-didehydro-nucleoside is D4FC.  
   
   
       55 . The process of  claim 51 , wherein the β-D- and β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleoside is β-D-D4FC.  
   
   
       56 . The process of  claim 51 , wherein the β-D- and β-L-2β,3′-dideoxy-2′,3′-didehydro-nucleoside is β-D-D4FC.  
   
   
       57 . The process of  claim 51 , further comprising reducing the β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleoside into a β-D or β-L-2′ or 3′-deoxyribo-nucleoside.  
   
   
       58 . The process of  claim 51 , further comprising converting the β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleoside bearing a different nucleobase.  
   
   
       59 . The process of  claim 58 , wherein the β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleoside is β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorouridine which is converted to a β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine.