Processes for preparing macrolides and ketolides and intermediates therefor

Abstract

The invention described herein pertains to processes for the preparation of macrolide antibacterial agents. In particular, the invention pertains to processes for preparing macrolides and ketolides from erythromycin A.

1 .- 41 . (canceled) 
     
     
         42 . A process for preparing a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 R 10  is hydrogen, acyl, or a prodrug moiety; 
 X is H; and Y is OR 7 ; where R 7  is monosaccharide, disaccharide, alkyl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted, or acyl or C(O)NR 8 R 9 ; where R 8  and R 9  are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, heteroalkyl, alkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, and dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; or R 8  and R 9  are taken together with the attached nitrogen to form an optionally substituted heterocycle; or X and Y are taken together with the attached carbon to form carbonyl; 
 V is C(O), C(═NR 11 ), CH(NR 12 R 13 ), or N(R 14 )CH 2 ; where N(R 14 ) is attached to the C-10 carbon; where R 11  is hydroxy or alkoxy; R 12  and R 13  are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, and dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; R 14  is hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or dimethylaminoalkyl, acyl, sulfonyl, ureido, or carbamoyl; 
 W is H, F, Cl, Br, I, or OH; 
 A is CH 2 , C(O), C(O)O, C(O)NH, S(O) 2 , S(O) 2 NH, or C(O)NHS(O) 2 ; 
 B is (CII 2 ) n  where n is an integer from 0 to 10; or an unsaturated carbon chain of 2 to 10 carbons; and 
 C is hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or acyl, acyloxy, sulfonyl, ureido, or carbamoyl; 
 the process comprising the step (a) contacting a compound of formula (III), 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein Q in combination with the oxime oxygen forms an acetal or ketal, or Q is tropyl, with an acylating agent to form a compound of formula (IV) 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein R is an acyl group; or
 (b) contacting a compound of formula (IV), or a salt thereof, with a methylating agent, to form a compound of formula (V) 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof; or
 (c) contacting a compound of formula (V), or a salt thereof, with a deoximating agent to form a compound of formula (II) or a salt thereof; or 
 
       
         
           
           
               
               
           
         
         (d) any combination of (a), (b), and (c); and 
         the step of converting the compound of formula (IV), (V), or (II) into the compound of formula (I). 
       
     
     
         43 . The process of  claim 42  comprising (a) and (b). 
     
     
         44 . The process of  claim 42  comprising (a) and (c), 
     
     
         45 . The process of  claim 42  comprising (b) and (c). 
     
     
         46 . The process of  claim 42  comprising (a), (b), and (c).