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.

What is claimed is: 
     
         1 . A process for preparing a compound of formula (I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable 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 (CH 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 (a) the step of contacting a compound of formula (III), 
 
       
       
         
           
           
               
               
           
         
         or an acid addition 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 an acid addition salt thereof, wherein R is an acyl group; or
 the process comprising (b) the step of contacting a compound of formula (IV), or an acid addition salt thereof, with a methylating agent, to form a compound of formula (V) 
 
       
       
         
           
           
               
               
           
         
         or an acid addition salt thereof; or
 the process comprising (c) the step of contacting a compound of formula (V), or an acid addition salt thereof, with a deoximating agent to form a compound of formula (II) 
 
       
       
         
           
           
               
               
           
         
         or an acid addition salt thereof; or
 the process comprising any combination of (a), (b), and (c). 
 
       
     
     
         2 . The process of  claim 1  comprising (a) and (b). 
     
     
         3 . The process of  claim 1  comprising (a) and (c). 
     
     
         4 . The process of  claim 1  comprising (b) and (c). 
     
     
         5 . The process of  claim 1  comprising (a), (b), and (c). 
     
     
         6 . The process of any one of  claims 1  to  5  wherein step (a) is performed in the presence of a base. 
     
     
         7 . The process of any one of  claims 1  to  5  wherein step (b) is performed in the presence of a base. 
     
     
         8 . The process of any one of  claims 1  to  5  wherein step (b) is performed in an aprotic polar solvent. 
     
     
         9 . The process of any one of  claims 1  to  5  wherein V is C(O). 
     
     
         10 . The process of any one of  claims 1  to  5  wherein W is fluoro. 
     
     
         11 . The process of any one of  claims 1  to  5  wherein W is hydrogen. 
     
     
         12 . The process of any one of  claims 1  to  5  wherein X and Y are taken together with the attached carbon to form carbonyl. 
     
     
         13 . The process of any one of  claims 1  to  5  wherein A is CH 2 . 
     
     
         14 . The process of any one of  claims 1  to  5  wherein B is alkenylene. 
     
     
         15 . The process of any one of  claims 1  to  5  wherein B is (CH 2 ) n , where n is an integer from 2 to 4. 
     
     
         16 . The process of any one of  claims 1  to  5  wherein C is 3-aminophenyl. 
     
     
         17 . The process of any one of  claims 1  to  5  wherein R 10  is benzoyl. 
     
     
         18 . The process of any one of  claims 1  to  5  wherein R is hydrogen. 
     
     
         19 . The process of any one of  claims 1  to  5  wherein the compound of formula (I) is of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . A process for preparing a compound of formula (II); 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R is an acyl group; 
 the process comprising (a) the step of contacting a compound of formula (III), 
 
       
       
         
           
           
               
               
           
         
         or an acid addition 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 an acid addition salt thereof, wherein R is an acyl group; or
 the process comprising (b) the step of contacting a compound of formula (IV), or an acid addition salt thereof, with a methylating agent, to form a compound of formula (V) 
 
       
       
         
           
           
               
               
           
         
         or an acid addition salt thereof; or
 the process comprising (c) the step of contacting a compound of formula (V), or an acid addition salt thereof, with a deoximating agent to form a compound of formula (II); or 
 the process comprising any combination of (a), (b), and (c). 
 
       
     
     
         21 . The process of  claim 20  comprising (a) and (b). 
     
     
         22 . The process of  claim 20  comprising (a) and (c). 
     
     
         23 . The process of  claim 20  comprising (b) and (c). 
     
     
         24 . The process of  claim 20  comprising (a), (b), and (c). 
     
     
         25 . The process of any one of  claims 20  to  24  wherein step (a) is performed in the presence of a base. 
     
     
         26 . The process of any one of  claims 20  to  24  wherein step (b) is performed in the presence of a base. 
     
     
         27 . The process of any one of  claims 20  to  24  wherein step (b) is performed in an aprotic polar solvent. 
     
     
         28 . A compound of formula (IV) 
       
         
           
           
               
               
           
         
         or an acid addition salt thereof, wherein Q in combination with the oxime oxygen forms an acetal or ketal, or Q is tropyl, and R is an acyl group. 
       
     
     
         29 . A compound of formula (V) 
       
         
           
           
               
               
           
         
         or an acid addition salt thereof, wherein Q in combination with the oxime oxygen forms an acetal or ketal, or Q is tropyl, and R is an acyl group. 
       
     
     
         30 . The process or compound of any one of  claims 1  to  5 ,  20  to  24 , or  28  to  29  wherein Q is 2-methoxy-2-propyl, 1-methoxycyclohexyl or 1-isopropoxycyclohexyl. 
     
     
         31 . The process or compound of any one of  claims 1  to  5 ,  20  to  24 , or  28  to  29  wherein Q is 2-methoxy-2-propyl. 
     
     
         32 . The process or compound of any one of  claims 1  to  5 ,  20  to  24 , or  28  to  29  wherein R is a sterically hindered acyl group. 
     
     
         33 . The process or compound of any one of  claims 1  to  5 ,  20  to  24 , or  28  to  29  wherein R is benzoyl. 
     
     
         34 . The process of any one of  claims 1  to  5  or  20  to  24  wherein the acylating agent is the anhydride. 
     
     
         35 . The process of any one of  claims 1  to  5  or  20  to  24  wherein the base in step (a) is a tertiary amine. 
     
     
         36 . The process of any one of  claims 1  to  5  or  20  to  24  wherein step (a) is performed in the presence of 4-dimethylaminopyridine. 
     
     
         37 . The process of any one of  claims 1  to  5  or  20  to  24  wherein the methylating agent in step (b) is methyl bromide, methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate or methyl methanesulfonate. 
     
     
         38 . The process of any one of  claims 1  to  5  or  20  to  24  wherein the base in step (b) is sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride or potassium t-butoxide or a mixture thereof. 
     
     
         39 . The process of any one of  claims 1  to  5  or  20  to  24  wherein the aprotic polar solvent in step (b) is dimethyl sulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, a mixture thereof, optionally further forming a mixture with one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or ethyl acetate. 
     
     
         40 . The process of any one of  claims 1  to  5  or  20  to  24  wherein the deoximating agent in step (c) comprises a reducing agent. 
     
     
         41 . The process of any one of  claims 1  to  5  or  20  to  24  wherein the deoximating agent in step (c) comprises formic acid and sodium metabisulfite.