Process for preparing macrocyclic compounds

Abstract

Disclosed is a multi-step process for preparing a macrocyclic compound of the formula (I): wherein Q is a radical of the following formula: and the other variables are as defined herein. The compounds of formula (I) are potent active agents for the treatment of hepatitis C virus (HCV) infection.

1 . A process for preparing a compound of the following formula (I):  
       
         
           
           
               
               
           
         
       
       wherein Q is a substituent of the following formula:  
       
         
           
           
               
               
           
         
       
       the olefin group attached to the cyclopropyl ring is in the configuration syn to the A group as represented by the following structure:  
       
         
           
           
               
               
           
         
         W is N;  
         L 0  is selected from H, —OH, —OCH 3  and —N(CH 3 ) 2 ;  
         one of L 1  and L 2  is —CH 3 , —F, —Cl or —Br and the other of L 1  and L 2  is H, or both L 1  and L 2  are H;  
         R 2  is  
         
           
             
             
                 
                 
             
           
         
          wherein R 6  is NH—R 7  or NH—C(O)—R 7 , wherein R 7  is independently: C 1-6  alkyl, or C 3-6  cycloalkyl;  
         R 3  is NH—C(O)—OR 10 , wherein R 10  is C 1-6  alkyl, or C 3-6  cycloalkyl;  
         R 4  is H or C 1-6  alkyl;  
         D is a 5-atom saturated alkylene chain; and  
         A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof;  
         said process comprising the step of cyclyzing a diene compound of formula (IX) in the presence of a suitable catalyst to obtain a compound of the formula (I):  
         
           
             
             
                 
                 
             
           
         
         and when A is a protected carboxylic acid group, optionally subjecting the compound of formula (I) to deprotection (e.g., hydrolysis) conditions to obtain a compound of formula (I) wherein A is a carboxylic acid group;  
         and when A is a carboxylic acid group in the resulting compound of formula (I), optionally coupling this compound with a sulfonamide of formula R 11A SO 2 NH 2  in the presence of a suitable coupling agent, such as TBTU or HATU, to obtain a compound of formula (I) wherein A is —C(O)—NH—SO 2 R A.  
       
     
     
         2 . A process according to  claim 1 , wherein the catalyst is a ruthenium based catalyst.  
     
     
         3 . A process according to  claim 1 , wherein the reaction is carried out in the presence of a diluent in a temperature range from about 30° to about 120° C.  
     
     
         4 . A process according to  claim 3 , wherein the diluent is selected from alkanes, aromatic hydrocarbons, chlorinated hydrocarbons, ether solvents and methyl alcohol.  
     
     
         5 . A process according to  claim 1 , wherein the catalyst is the 2 nd  generation Hoveyda's catalyst, and the reaction is carried out at a temperature in the range of from about 90° to about 108° C., in the presence of an aromatic hydrocarbon diluent, and using portionwise addition of the catalyst in the range of from 2 to 6 portions.  
     
     
         6 . A process according to  claim 1 , wherein the catalyst is the 2 nd  generation Hoveyda's catalyst, and the reaction is carried out at a temperature in the range of from about 30° to about 45° C., in the presence of a suitable activator, in a chlorinated hydrocarbon diluent or an aromatic hydrocarbon diluent, using a one-pot addition of catalyst or a portionwise addition of the catalyst in the range from 2 to 4 portions.  
     
     
         7 . A process according to  claim 1 , wherein the diene compound (IX) is prepared by a process comprising the following steps: 
 (i) reacting a compound of the formula (II) with a compound of the formula (III) to obtain a compound of the formula (IV):                          wherein PG is an amino protecting group, X is a halogen atom and Q is a substituent of the following formula:                          (ii) reacting a compound of the formula (IV) with a compound of the formula (V) to obtain a compound of the formula (VI):                          wherein A is an amide of formula —C(O)—NH—R 11 , wherein R 11  is selected from the group consisting of: C 1-8  alkyl, C 3-6  cycloalkyl, C 6  or C 10  aryl; C 7-16  aralkyl and SO 2 R 11A  wherein R 11A  is C 1-8  alkyl, C 3-7  cycloalkyl or C 1-6  alkyl-C 3-7  cycloalkyl;    or A is a protected carboxylic acid group;    (iii) removing the nitrogen protecting group in the compound of formula (VI) to obtain a compound of the formula (VII):                          (iv) reacting a compound of the formula (VII) with a compound of the formula (VIII) to obtain a compound of the formula (IX):                          wherein W, L 0 , L 1 , L 2 , R 2 , R 3 , R 4 , D, and A in each of the above steps are as defined in  claim 1 .    
     
     
         8 . A process according to  claim 1 , wherein: 
 W is N;    L 0  is —OCH 3 ;    L 1  is —CH 3 , —F, —Cl or —Br and L 2  is H, or both L 1  and L 2  are H;    R 2  is                           wherein R 6  is NH—R 7  or NH—C(O)—R 7 , wherein R 7  is independently: C 1-6  alkyl or C 3-6  cycloalkyl;    R 3  is NH—C(O)—OR 10 , wherein R 10  is butyl, cyclobutyl or cyclopentyl;    R 4  is H or C 1-3  alkyl;    D is a 5-atom saturated alkylene chain; and    A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.    
     
     
         9 . A compound of the following formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein PG is an amino protecting group and Q is a substituent of the following formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 W is N;  
 L 0  is selected from H, —OH, —OCH 3  and —N(CH 3 ) 2 ;  
 one of L 1  and L 2  is —CH 3 , —F, —Cl or —Br and the other of L 1  and L 2  is H, or both L 1  and L 2  are H; and  
 R 2  is  
                     
  wherein R 6  is NH—R 7  or NH—C(O)—R 7 , wherein R 7  is independently: C 1-6  alkyl, or C 3-6  cycloalkyl.  
 
     
     
         10 . A compound of formula (IV) according to  claim 9 , wherein: 
 W is N;    L 0  is —OCH 3 ;    L 1  is —CH 3 , —F, —Cl or —Br and L 2  is H, or both L 1  and L 2  are H;    R 2  is                           wherein R 6  is NH—R 7  or NH—C(O)—R 7 , wherein R 7  is independently: C 1-6  alkyl or C 3-6  cycloalkyl;    R 3  is NH—C(O)—OR 10 , wherein R 10  is butyl, cyclobutyl or cyclopentyl;    R 4  is H or C 1-3  alkyl;    D is a 5-atom saturated alkylene chain; and    A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.    
     
     
         11 . A process for preparing a compound of formula (IV) according to  claim 9 , said process comprising the step of reacting a compound of the formula (II) with a compound of the formula (III) to obtain a compound of the formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein PG is an amino protecting group, X is a halogen atom and Q is a substituent of the following formula:  
       
         
           
           
               
               
           
         
       
       wherein W, L 0 , L 1 , L 2 , and R 2  are as defined in  claim 9 .  
     
     
         12 . A compound of the following formula (IX):  
       
         
           
           
               
               
           
         
       
       wherein Q is a substituent of the following formula:  
       
         
           
           
               
               
           
         
       
       the olefin group attached to the cyclopropyl ring is in the configuration syn to the A group as represented by the following structure:  
       
         
           
           
               
               
           
         
         W is N;  
         L 0  is selected from H, —OH, —OCH 3  and —N(CH 3 ) 2 ;  
         one of L 1  and L 2  is —CH 3 , —F, —Cl or —Br and the other of L 1  and L 2  is H, or both L 1  and L 2  are H;  
         R 2  is  
         
           
             
             
                 
                 
             
           
         
          wherein R 6  is NH—R 7  or NH—C(O)—R 7 , wherein R 7  is independently: C 1-6  alkyl, or C 3-6  cycloalkyl;  
         R 3  is NH—C(O)—OR 10 , wherein R 10  is C 1-6  alkyl, or C 3-6  cycloalkyl;  
         R 4  is H or C 1-6  alkyl;  
         D is a 5-atom saturated alkylene chain; and  
         A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.  
       
     
     
         13 . A compound of formula (IX) according to  claim 12 , wherein: 
 W is N;    L 0  is —OCH 3 ;    L 1  is —CH 3 , —F, —Cl or —Br and L 2  is H, or both L 1  and L 2  are H;    R 2  is                           wherein R 6  is NH—R 7  or NH—C(O)—R 7 , wherein R 7  is independently: C 1-6  alkyl or C 3-6  cycloalkyl;    R 3  is NH—C(O)—OR 10 , wherein R 10  is butyl, cyclobutyl or cyclopentyl;    R 4  is H or C 1-3  alkyl;    D is a 5-atom saturated alkylene chain; and    A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.