Preparation of 2'-fluoro-2'-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives

Abstract

The present invention provides (i) processes for preparing a 2′-deoxy-2′-fluoro-2′-methyl-D-ribonolactone derivatives, (ii) conversion of intermediate lactones to nucleosides with potent anti-HCV activity, and their analogues, and (iii) methods to prepare the anti-HCV nucleosides containing the 2′-deoxy-2′-fluoro-2′-C-methyl-β-D-ribofuranosyl nucleosides from a preformed, preferably naturally-occurring, nucleoside.

1 . A compound of formula 
       
         
           
           
               
               
           
         
       
       wherein
 R′ and R″ are independently H, lower alkyl (C 1 -C 6 ), aryl (C 6 -C 20 ), optionally substituted benzyl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, THP, MOM, MEM, acetyl, benzoyl, or optionally substituted acyl; or R′ and R″ form a cyclopentyl or cyclohexanyl group; 
 R 1  and R 2  are independently H, lower alkyl (C 1 -C 6 ), aryl (C 6 -C 20 ), hydroxymethyl, methoxymethyl, halomethyl, optionally substituted ethenyl, halovinyl, optionally substituted ethynyl, or optionally substituted allyl; and 
 R 3  is H, aryl, arylalkyl, or lower alkyl (C 1 -C 6 ). 
 
     
     
         2 . The compound of  claim 1 , 
       wherein
 R′ and R″ are independently H or lower alkyl (C 1 -C 6 ); 
 R 1  and R 2  are independently H, or lower alkyl (C 1 -C 6 ); and 
 R 3  is H or lower alkyl (C 1 -C 6 ). 
 
     
     
         3 . A compound of formula 
       
         
           
           
               
               
           
         
       
       wherein
 each R 1  is independently lower alkyl (C 1 -C 6 ), optionally substituted phenyl, or optionally substituted benzyl; or R 1  forms a cyclopentyl or cyclohexanyl group; 
 R 2  and R 3  are independently hydrogen, lower alkyl (C 1 -C 6 ), hydroxymethyl, methoxymethyl, halomethyl, optionally substituted ethenyl, halovinyl, optionally substituted ethynyl, or optionally substituted allyl; and 
 R 4  is independently arylalkyl, or lower alkyl (C 1 -C 10 ). 
 
     
     
         4 . The compound of  claim 3 , 
       wherein
 each R 1  is independently lower alkyl (C 1 -C 6 ); 
 R 2  and R 3  are independently hydrogen, or lower alkyl (C 1 -C 6 ); and 
 R 4  is independently lower alkyl (C 1 -C 10 ). 
 
     
     
         5 . The compound of  claim 3 , having the formula 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound of formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  and R 3  are independently H, alkyl (C 1 -C 10 ), hydroxymethyl, methoxymethyl, halomethyl, optionally substituted ethenyl, halovinyl, optionally substituted ethynyl, or optionally substituted allyl; 
 R 5  and R 6  are methoxymethyl, methoxyethyl, benzyloxymethyl, ethoxymethyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyl, pivaloyl, benzoyl, toluoyl, 4-phenyl benzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitrobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, or substituted benzoyl; 
 Nu is F, Cl, Br, N 3 , CN, NO 3 , SCN, OR or NR 2  wherein R is acyl or lower alkyl (C 1 -C 10 ); and 
 L is a leaving group. 
 
     
     
         7 . The compound of  claim 6 , 
       wherein
 R 2  and R 3  are independently H, alkyl (C 1 -C 10 ), or halomethyl; 
 R 5  and R 6  are benzoyl; 
 Nu is F; and 
 L is OAc. 
 
     
     
         8 . The compound of  claim 7 , wherein R 2  is H and R 3  is methyl. 
     
     
         9 . A compound of formula 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound of formula IIIa, IIIb or IIIc 
       
         
           
           
               
               
           
         
       
       wherein
 each R 1  is independently lower alkyl (C 1 -C 6 ), optionally substituted phenyl, or optionally substituted benzyl; 
 R 2  and R 3  are independently hydrogen, lower alkyl (C 1 -C 6 ), hydroxymethyl, methoxymethyl, halomethyl, optionally substituted ethenyl, optionally substituted ethynyl, or optionally substituted allyl; and 
 R 4  is independently hydrogen, aryl, arylalkyl, or lower alkyl (C 1 -C 10 ). 
 
     
     
         11 . The compound of  claim 10 , 
       wherein
 each R 1  is lower alkyl (C 1 -C 6 ); 
 R 2  and R 3  are independently hydrogen, or lower alkyl (C 1 -C 6 ); and 
 R 4  is lower alkyl (C 1 -C 10 ). 
 
     
     
         12 . The compound of  claim 10 , having the formula