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 or acyl, 
 X is H; and Y is OR 7 ; where R 7  is a monosaccharide 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; 
 Z is an alkyne, an azide, or a C-substituted 1,2,3-triazole; 
 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 (CH2) 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;
 (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;
 (c) optionally 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; and 
       (d) contacting a compound of formula (V) or (II) with an activating agent and adding H 2 N-A-B-Z to prepare
 the compound of formula (I). 
 
     
     
         43 .- 46 . (canceled) 
     
     
         47 . The process of  claim 42  further comprising (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; and wherein V is C(O). 
     
     
         48 . The process of  claim 42  wherein the deoximating agent prises a reducing agent. 
     
     
         49 . The process of  claim 42  wherein the deoximating agent in (c) comprises formic acid and sodium metabisulfite. 
     
     
         50 . The process of  claim 42  wherein the acylating agent is an anhydride. 
     
     
         51 . The process of  claim 42  wherein the activating agent is carbonyldiimidazole. 
     
     
         52 . The process of  claim 42  wherein Q in combination with the oxime oxygen forms an acetal or ketal. 
     
     
         53 . The process of  claim 42  wherein Q is 2-methoxy-2-propyl, 1-methoxycyclohexyl or 1-isopropoxycyclohexyl. 
     
     
         54 . The process of  claim 42  wherein R is an optionally substituted benzoyl group. 
     
     
         55 . The process of  claim 42  wherein R is benzoyl. 
     
     
         56 . The process of  claim 42  wherein R 10  is hydrogen. 
     
     
         57 . The process of  claim 42  wherein X is H, Y is OR 7 , and R 7  is cladinosyl. 
     
     
         58 . The process of  claim 42  wherein X and Y are taken together with the attached carbon to form carbonyl; and W is H or F. 
     
     
         59 . The process of  claim 42  wherein A is CH 2 ; and B is (CH 2 ) n . 
     
     
         60 . The process of  claim 42  wherein Z is an azide. 
     
     
         61 . The process of  claim 42  wherein Z is a C-substituted 1,2,3-triazole. 
     
     
         62 . The process of  claim 42  wherein C is optionally substituted aryl or optionally substituted arylalkyl. 
     
     
         63 . The process of  claim 42  wherein C is aminophenyl. 
     
     
         64 . The process of  claim 42  wherein the compound of formula (I) is solithromycin or a salt thereof.