Process for preparing indolinone derivatives

Abstract

The present invention refers to a process for preparing indolinone derivatives of the general formula (VI) as defined in the specification and intermediates of that process.

1 . A process for preparing an indolinone of the general formula (VI)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , R 4  are independently selected from the group consisting of hydrogen, C 1-12  alkyl, C- 1-12  alkoxy, C 5-12  cycloalkyl, C 6-12  aryl, C 5-12  heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C 6-12  aryloxy, C 6-12  alkaryl, C 6-12  alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO 2 NR′R″, —SO 3 R′, —SR′, —NO 2 , —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH 2 ) n CO 2 R′, and —CONR′R″;  
 each R 5  is independently selected from the group consisting of hydrogen, C 1-12  alkyl, C 1-12  alkoxy, C 5-12  cycloalkyl, C 6-12  aryl, C 5-12  heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C 6-12  aryloxy, C 6-12  alkaryl, C 6-12  alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO 2 NR′R″, —SO 3 R′, —SR′, —NO 2 , —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH 2 ) n CO 2 R′, and —CONR′R″;  
 R 6  is —NR 8 (CH 2 ) m R 9  or —NR 10 R 11 ;  
 R 8  is hydrogen or C 1-12  alkyl;  
 R 9  is selected from the group consisting of —NR 10 R 11 , —OH, —C(O)R 12 , C 6-12  aryl, C 5-12  heterocyclic group containing 1 to 3 atoms selected from N, S or O, —N + (O − )R 10 , and —NHC(O)R 13 ;  
 R 10  and R 11  are independently selected from the group consisting of hydrogen, C 1-12  alkyl, C 1-12  cyanoalkyl, C 5-12  cycloalkyl, C 6-12  aryl, and C 5-12  heterocyclic group containing 1 to 3 atoms selected from N, S or O; or R 10  and R 11  may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R 10  and R 11  are bound, provided that the heterocyclic group formed by R 10  and R 11  may optionally be substituted by R′;  
 R 12  is selected from the group consisting of hydrogen, —OH, C 1-12  alkoxy and C 6-12  aryloxy;  
 R 13  is selected from the group consisting of C 1-12  alkyl, C 1-12  haloalkyl, and C 6-12  aralkyl;  
 R′ and R″ are independently selected from the group consisting of hydrogen, C 1-12  alkyl, C 1-12  cyanoalkyl, C 5-12  cycloalkyl, C 6-12  aryl, C 5-12  heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group —NR′R″ the R′ and R″ substituents may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R′ and R″ are bound;  
 J is selected from the group consisting of O, S, and NH;  
 one of K, L and M is C and the group —C(O)R 6  is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR 5 , CR 5   2 , N, NR 5 , O and S;  
 n is 0, 1 or 2;  
 m is 1, 2, 3, or 4; and  
 p is 0, 1 or 2;  
 the process comprising the steps of  
 reacting a compound of the general formula (III)  
                     
 wherein R* is selected from the group consisting of —O—C(O)—C 1-4  alkyl, —O—C(O)—O—(C 1-4 )alkyl, —O—C(O)—O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, —O—C(O)—O—CH 2 -phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms;  
                     
 with a compound of general formula (IV)  
                     
 and an amine of general formula (V)  
   HR 6   (V)  
 to form the indolinone of the general formula (VI).  
 
     
     
         2 . The process of  claim 1 , wherein  
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         3 . The process of  claim 1 , wherein  
       
         
           
           
               
               
           
         
       
     
     
         4 . The process of  claim 1 , wherein R 1  is hydrogen or C 1 — alkyl.  
     
     
         5 . The process of  claim 1 , wherein R 1  is hydrogen.  
     
     
         6 . The process of  claim 1 , wherein R 2  is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4  alkyl, —O—C 1-4  alkyl, phenyl, —COOH, —CN, —C(O)CH 3 , —SO 2 NH 2  and —SO 2 N(CH 3 ) 2 .  
     
     
         7 . The process of  claim 1 , wherein R 2  is fluorine.  
     
     
         8 . The process of  claim 1 , wherein R 3  is selected from the group consisting of hydrogen, C 1-4  alkyl, phenyl, —O—C 1-4  alkyl and —COOH.  
     
     
         9 . The process of  claim 1 , wherein R 3  is hydrogen or C 1-4  alkyl.  
     
     
         10 . The process of  claim 1 , wherein R 4  is hydrogen.  
     
     
         11 . The process of  claim 1 , wherein R 5  is selected from the group consisting of hydrogen, C 1-4  alkyl, —C(O)—C 1-4  alkyl, —C(O)phenyl, and phenyl.  
     
     
         12 . The process of  claim 1 , wherein R 5  is hydrogen, or C 1-4  alkyl.  
     
     
         13 . The process of  claim 1 , wherein R 6  is —NR 8 (CH 2 ) m R 9 , provided that one or two of the CH 2  groups can optionally be substituted by —OH or halogen.  
     
     
         14 . The process of  claim 1 , wherein R 8  is hydrogen or C 1-4  alkyl.  
     
     
         15 . The process of  claim 1 , wherein m is 2 or 3.  
     
     
         16 . The process of  claim 1 , wherein R 9  is —NR 10 R 11 .  
     
     
         17 . The process of  claim 16 , wherein R 10  and R 11  are hydrogen or C 1-4  alkyl.  
     
     
         18 . The process of  claim 1 , wherein R 9  is a C 5-12  heterocyclic group containing 1 to 3 atoms selected from N, S or O.  
     
     
         19 . The process of  claim 18 , wherein the heterocyclic group is a five- to seven-membered heterocyclic group bonded to the (CH 2 ) m  group via a nitrogen atom and optionally containing a further heteroatom selected from N, O, and S.  
     
     
         20 . The process of  claim 19 , wherein the heterocyclic group is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         21 . The process of  claim 20 , wherein the heterocyclic group is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         22 . The process of  claim 13 , wherein R 8  is hydrogen or C 1-4  alkyl, m is 2 or 3 and R 9  is —NR 10 R 11 .  
     
     
         23 . The process of  claim 22 , wherein R 10  and R 11  are hydrogen or C 1-4  alkyl.  
     
     
         24 . The process of  claim 13 , wherein R 9  is a C 5-12  heterocyclic group containing 1 to 3 atoms selected from N, S or O.  
     
     
         25 . The process of  claim 24 , wherein the heterocyclic group is a five- or six-membered heterocyclic group bonded to the (CH 2 ) m  group via a nitrogen atom and optionally containing a further heteroatom selected from N, O, and S.  
     
     
         26 . The process of  claim 25 , wherein the heterocyclic group is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         27 . The process of  claim 26 , wherein the heterocyclic group is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         28 . The process of  claim 1 , wherein the compound of general formula (VI) is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein X is selected from the group consisting of hydrogen, fluorine, chlorine and bromine.  
     
     
         29 . The process of  claim 28 , wherein X is fluorine.  
     
     
         30 . The process of  claim 1 , wherein the compound of general formula (VI) is selected from the group consisting of: