Processes and intermediates for the preparation of 1`-substituted carba-nucleoside analogs

Abstract

Provided are processes and intermediates for the syntheses of nucleosides of pyrrolo[1,2-f][1,2,4]triazinyl and imidazo[1,2-f][1,2,4]triazinyl heterocycles of Formula I.

1 . A method for preparing a compound of Formula I: 
       
         
           
           
               
               
           
         
         or an acceptable salt, thereof; 
       
       wherein:
 R 1  is H, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, (C 2 -C 8 )substituted alkynyl, or aryl(C 1 -C 8 )alkyl; 
 each R 2a  or R 2b  is independently H, F or OR 4 ; 
 each R 3  is independently (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 2 -C 20  heterocyclyl, C 2 -C 20  substituted heterocyclyl, C 7 -C 20  arylalkyl, C 7 -C 20  substituted arylalkyl, (C 1 -C 8 ) alkoxy, or (C 1 -C 8 ) substituted alkoxy; 
 each R 4  or R 7  is independently H, optionally substituted allyl, —C(R 5 ) 2 R 6 , Si(R 3 ) 3 , C(O)R 5 , C(O)OR 5 , —(C(R 5 ) 2 ) m —R 15  or 
 
       
         
           
           
               
               
           
         
         or any two of R 4  or R 7  when taken together are —C(R 19 ) 2 —, —C(O)— or —Si(R 3 ) 2 (X 2 ) m Si(R 3 ) 2 —; 
         each R 15  is independently —O—C(R 5 ) 2 R 6 , —Si(R 3 ) 3 , C(O)OR 5 , —OC(O)R 5  or 
       
       
         
           
           
               
               
           
         
         each R 5 , R 18  or R 19  is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 1 -C 8 ) substituted alkenyl, (C 1 -C 8 ) alkynyl, (C 1 -C 8 ) substituted alkynyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 2 -C 20  heterocyclyl, C 2 -C 20  substituted heterocyclyl, C 7 -C 20  arylalkyl or C 7 -C 20  substituted arylalkyl; 
         each R 6  is independently C 6 -C 20  aryl, C 6 -C 20  substituted aryl, or optionally substituted heteroaryl; 
         each R a  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), or —SO 2 NR 11 R 12 ; 
         X 1  is C—R 10  or N; 
         each X 2  is O or CH 2 ; 
         each m is 1 or 2; 
         each n is independently 0, 1 or 2; 
         each R 8  is halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CH(═NR 11 ), —CH═NHNR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, aryl(C 1 -C 8 )alkyl, CN, OR 11  or SR 11 ; 
         each R 9  or R 10  is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , N(R 11 )N(R 11 )(R 12 ), N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NNH(R 11 ), —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , R 11 , OR 11  or SR 11 ; 
         each R 11  or R 12  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, aryl(C 1 -C 8 )alkyl or Si(R 3 ) 3 ; or R 11  and R 12  taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S(O) n — or —NR a —; or R 11  and R 12  taken together are —Si(R 3 ) 2 (X 2 ) m Si(R 3 ) 2 —; 
         each R 20  is independently H, (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl or halo; 
         wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl of each R 1 , R 3 , R 4 , R 5 , R 6 , R 18 , R 19 , R 20 , R 11  or R 12  is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2  or OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl is optionally replaced with —O—, —S(O) n — or —NR a —; 
         said method comprising: 
         (a) providing a compound of Formula II 
       
       
         
           
           
               
               
           
         
         or an acceptable salt thereof; 
         wherein R 16  is OH, OR 18 , —OC(O)OR 18  or —OC(O)R 18 ; 
         (b) treating the compound of Formula II with a cyanide reagent and a Lewis acid; 
         thereby forming the compound of Formula I; 
         provided that when the compound of Formula II is: 
       
       
         
           
           
               
               
           
         
         wherein X 1  is CH or N, R 1  is CH 3 , R 8  is NH 2 , and R 9  is NH 2  or H or; 
         wherein X 1  is CH, R 1  is CH 3 , R 8  is OH, and R 9  is NH 2  or; 
         wherein X 1  is CH, each R 1  and R 9  is H and R 8  is NH 2 ; 
         then said cyanide reagent is not (CH 3 ) 3 SiCN or said Lewis acid is not BF 3 —O(CH 2 CH 3 ) 2 . 
       
     
     
         2 . The method of  claim 1  wherein the Lewis acid is (R 20 ) 3 CS(O) 2 OSi(R 3 ) 3  or a metal salt of (R 20 ) 3 CS(O) 2 OH;
 at least two R 20  are halogen; and 
 said metal is selected from the group consisting aluminum, gallium, indium, thallium, tin, lead, bismuth, an alkaline earth metal, a transition metal and a lanthanide. 
 
     
     
         3 . The method of  claim 2  wherein the compound of Formula I is a compound of Formula Ib: 
       
         
           
           
               
               
           
         
       
       or a salt thereof and the compound of Formula II is represented by Formula IIb: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         4 . The method of  claim 3  wherein R 16  is —OH or OR 18 . 
     
     
         5 . The method of  claim 4  wherein the compound of Formula Ib is represented by Formula Ic: 
       
         
           
           
               
               
           
         
         or a salt thereof and the compound of Formula IIb is represented by Formula IIc: 
       
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         6 . The method of  claim 5  wherein each R 20  is F and the cyanide reagent is (CH 3 ) 3 SiCN. 
     
     
         7 . The method of  claim 6  wherein the Lewis acid is CF 3 S(O) 2 OSi(CH 3 ) 3  or a metal salt of CF 3 S(O) 20 H wherein said metal is indium. 
     
     
         8 . The method of  claim 7  wherein X 1  is CH. 
     
     
         9 . The method of  claim 3  further comprising a method for preparing a compound of Formula IIb wherein R 16  is OH,
 the method comprising: 
 providing a compound of Formula IIIb: 
 
       
         
           
           
               
               
           
         
         and treating the compound of Formula IIIb with an organometallic compound of Formula IV: 
       
       
         
           
           
               
               
           
         
         wherein M is MgX 3  or Li and X 3  is halogen; 
         thereby forming a compound of Formula IIb wherein R 16  is OH; 
         provided that when M is Li, the compound of Formula IIb is not a compound of Formula 
       
       
         
           
           
               
               
           
         
         wherein R 17  is OH; and
 (a) X 1  is CH, R 1  is CH 3 , R 8  is NH 2  and R 9  is NH 2  or H; or 
 (b) X 1  is CH, R 1  is CH 3 , R 8  is OH and R 9  is NH 2 ; or 
 (c) X 1  is CH, each R 1  and R 9  is H and R 8  is NH 2 ; or 
 (d) X 1  is N, R 1  is CH 3 , R 8  is NH 2 , and R 9  is H, NH 2  or SCH 3 ; or 
 (e) X 1  is N, R 1  is CH 3 , R 8  is SCH 3  or NHCH 3 , and R 9  is SCH 3 ; or 
 (f) X 1  is N, R 1  is CH 3 , R 8  is OCH 3 , and R 9  is SCH 3 , SO 2 CH 3  or NH 2 . 
 
       
     
     
         10 . The method of  claim 9  wherein M is MgX 3 . 
     
     
         11 . The method of  claim 10  wherein X 1  is CH. 
     
     
         12 . The method of  claim 9  further comprising a method of preparing a compound of Formula IV,
 the method comprising: 
 providing a compound of Formula V: 
 
       
         
           
           
               
               
           
         
         wherein X 3  is Cl, Br or I and 
         treating the compound of Formula V with an organometallic reagent comprising an organomagnesium or organolithium compound; 
         thereby forming a compound of Formula IV. 
       
     
     
         13 . The method of  claim 12  wherein the organometallic reagent comprises an organomagnesium compound. 
     
     
         14 .- 20 . (canceled)