4'-substituted nucleoside reverse transcriptase inhibitors and preparations thereof

Abstract

and their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC. The present invention also provides processes for the preparation of 4′-substituted nucleoside derivatives of Formula I and derivatives thereof.

1 - 12 . (canceled) 
     
     
         13 . A process for preparing a compound of Formula (IA) 
       
         
           
           
               
               
           
         
       
       wherein
 X is H, F, Cl, or Br; 
 Y is N, C(H), C(F), C(Cl), C(Br), C(CH 3 ); 
 Z is NH 2 ; 
 
       comprising:
 (a.) coupling sugar 
 
       
         
           
           
               
               
           
         
       
       with nucleobase 
       
         
           
           
               
               
           
         
       
       to provide protected nucleoside 
       
         
           
           
               
               
           
         
       
       and
 (b.) converting the protected nucleoside (A) to the compound of Formula (IA); wherein 
 Z 1  is Cl, N(H)PG, or N(PG) 2 , 
 R d  is
 (i) a group of the formula 
 
 
       
         
           
           
               
               
           
         
          wherein R p  is C 1 -C 3  alkyl, C 1 -C 3  alkoxy, halo, CF 3 , or N(CH 3 ) 2 ;
 (ii) —Si(R s ) 3 ; 
 (iii) —C(O)C 1 -C 3  alkyl; or 
 (iv) —C(O)CH 2 N(H)C(O)CH 3 ; 
 each R s  is independently C 1 -C 6  alkyl; unsubstituted phenyl; phenyl substituted by on to three C 1 -C 3  alkyl, halo, or C 1 -C 3  alkoxy; 
 
         LG is OAc, OBz, halo, or —O—C 2 -C 8  alkenyl; and 
         PG is an amino protecting group. 
       
     
     
         14 . The process of  claim 13 , wherein R d  is 4-methylbenzoyl. 
     
     
         15 . The process of  claim 14 , wherein in the compound of Formula (IA), X is F, Y is N, and Z is NH 2 . 
     
     
         16 . The process of  claim 15 , wherein LG is —OAc in the sugar (C); and Z 1  is N(H)Si(R s ) 3  in the protected nucleoside. 
     
     
         17 . The process of  claim 16 , wherein in step (a) said coupling is conducted in the presence of a Lewis or Brçnsted acid in an aprotic solvent to provide nucleoside (A). 
     
     
         18 . The process of  claim 16 , wherein Z 1  is —N(H)Si(CH 3 ) 3 . 
     
     
         19 . The process of  claim 16 , wherein converting in step (b) comprises reacting the protected nucleoside (A) with an alkali metal C 1 -C 3  alkoxide. 
     
     
         20 . The process of  claim 16 , wherein the sugar (C) is prepared by reacting lactol 
       
         
           
           
               
               
           
         
       
       with acetic anhydride. 
     
     
         21 . The process of  claim 15 , wherein
 LG is —O(CH 2 ) 3 C(H)═CH 2  in the sugar (C); and   Z 1  is N(H)C(O)—OR s  and X is F in the nucleobase (B) and in the protected nucleoside   
     
     
         22 . The process of  claim 21 , wherein in step (a) said coupling is conducted by
 treating sugar (C) with an activating agent selected from iodine, bromine, N-iodosuccinimide, N-bromosuccinimide, Balarenga's reagent (Py 2 I), or diiodo-dimethylhydantoin;   in the presence of nucleobase (B) in an aprotic solvent.   
     
     
         23 . The process of  claim 21 , wherein Z is N(H)C(O)—OC(CH 3 ) 3 . 
     
     
         24 . The process of  claim 21 , wherein converting in step (b) comprises treating the protected nucleoside (A) with an alkali metal C 1 -C 3  alkoxide and then with a strong acid. 
     
     
         25 . The process of  claim 21 , wherein the sugar (C) is prepared by
 reacting lactol   
       
         
           
           
               
               
           
         
       
       with pent-4-en-1-ol to provide the sugar 
       
         
           
           
               
               
           
         
       
     
     
         26 . The process of  claim 13 , wherein the sugar (C) is prepared by reducing lactone 
       
         
           
           
               
               
           
         
       
       with a selective reducing agent to provide lactol 
       
         
           
           
               
               
           
         
       
       and
 converting lactol (10A) to the sugar (C). 
 
     
     
         27 . The process of  claim 26 , wherein the selective reducing agent is sodium bis(2-methoxyethoxy)aluminum hydride. 
     
     
         28 . The process of  claim 26 , wherein the lactone (10) is prepared by:
 reacting dioxolane   
       
         
           
           
               
               
           
         
       
       with an acid to provide a deprotected intermediate; and
 acylating the deprotected intermediate with a p-methylbenzoylating agent to provide the lactone (10). 
 
     
     
         29 . The process of  claim 28 , wherein the p-methylbenzoylating agent is p-methylbenzoyl chloride. 
     
     
         30 . The process of  claim 28 , wherein the process further comprises isolating the deprotected intermediate, wherein the deprotected intermediate is 
       
         
           
           
               
               
           
         
       
     
     
         31 . The process of  claim 28 , wherein the dioxolane (9) is prepared by reacting TIPS intermediate 
       
         
           
           
               
               
           
         
         with a fluoride agent to provide the dioxolane (91. 
       
     
     
         32 . The process of  claim 31 , wherein the TIPS intermediate (8) is prepared by reducing ketone ester 
       
         
           
           
               
               
           
         
       
     
     
         33 . The process of  claim 32 , wherein the reducing comprises asymmetric transfer hydrogenation of the ketone ester (7) with formic acid/triethylamine in the presence of a chiral catalyst. 
     
     
         34 . The process of  claim 32 , wherein the chiral catalyst is RuCl—(S,S)-Ts-DENEB catalyst. 
     
     
         35 . A compound of the formula 
       
         
           
           
               
               
           
         
       
     
     
         36 - 38 . (canceled)