Process for the preparation of macrolide antibacterial agents

Abstract

Described herein are processes for the preparation of compounds of formula (I): and pharmaceutically acceptable salts, solvates, and hydrates thereof.

1 . A process for preparing a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is a monosaccharide or polysaccharide; 
 A is —CH 2 —, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2-, —S(O)2NH—, —C(O)NHS(O)2-; 
 B is —(CH 2 ) n — where n is an integer ranging from 0-10, or B is an unsaturated carbon chain of 2-10 carbons, which may contain any alkenyl or alkynyl group; 
 C represents 1 or 2 substituents independently selected in each instance from the group consisting of hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, each of which is optionally substituted; 
 V is —C(O)—, —C(═NR 11 )—, —CH(NR 12 R 13 )—, or —N(R 14 )CH 2 —; where R 11  is hydroxy or alkoxy, R 12  and R 13  are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl; dimethylaminoalkyl, acyl, sulfonyl, ureyl, and carbamoyl; R 14  is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl; 
 W is hydrogen, F, Cl, Br, I, or OH; 
 X is hydrogen; and Y is OW; where R 7  is hydrogen, a monosaccharide, a disaccharide, alkyl, aryl, heteroaryl, acyl, or —C(O)NR 8 R 9 , where R 8  and R 9  are each independently selected from hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureyl, and carbamoyl; or X and Y taken together with the attached carbon to form C═O; and pharmaceutically acceptable salts, solvates, and hydrates thereof; 
 the process comprising the step of (a) reacting a compound of formula (IV) 
 
       
         
           
           
               
               
           
         
         wherein R 1  is a saccharide that includes a 2′-hydroxyl group, with a sterically hindered acylating agent R 1a -L, wherein R 1a  is a sterically hindered acyl group and L is a leaving or activating group, to form the corresponding 2′-acyl derivative. 
       
     
     
         2 .- 23 . (canceled)