1-alkyl-3-aminoindazoles

Abstract

Methods of making 1-alkylindazoles are described. The methods involve reacting a 2-alkylaminobenzonitrile with a nitrosating agent followed by reduction-cyclization of the resulting nitrosamine to form a 1-alkyl-3-aminoindazole. The 1-alkyl-3-aminoindazole can be deaminated to form a 1-alkylindazole which ultimately can be used to form desired indazoles which are preferably pharmaceutically active products. The process of the present invention further permits the formation of enantiomerically enriched or pure indazoles such as aminoalkyl indazoles.

1 . A method of making a 1-alkylindazole comprising: 
 (a) the nitrosation and reduction-cyclization of a 2-alkylaminobenzonitrile to form a 1-alkyl-3-aminoindazole; and (b)    (b) deamination of the 1-alkyl-3-aminoindazole to form a 1-alkylindazole.    
   
   
       2 . The method of  claim 1 , wherein the 1-alkylindazole is a 1-(hydroxyalkyl)indazole.  
   
   
       3 . The method of  claim 2  wherein the (hydroxyalkyl)indazole has the formula:  
     
       
         
         
             
             
         
       
     
     wherein R is a C 2  to C 12  (hydroxy)alkyl group optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)R 5 , N(R 5 )C(═O)OR 5 , or with one or more F atoms; 
 R 1 , R 2 , R 3  and R 4  are independently H, F, Cl, Br, CF 3 , OH, OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)R 5 , N(R 5 )C(═O)OR 5 , NO 2 , CN, N 3 , SH, S(O) n R 5 , C(═O)R 5 , COOH, COOR 5 , CON(R 5 ) 2 , C 1  to C 6  alkyl optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, C(═O)R 5 , COOH, COOR 5 , CON(R 5 ) 2 , CN, OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)R 5 , or N(R 5 )C(═O)OR 5 ; or R 1  and R 2  as herein defined taken together form a ring, or R 2  and R 3  as herein defined taken together form a ring, or R 3  and R 1  as herein defined taken together form a ring;  
 R 5  is C 1  to C 6  alkyl optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, methoxy, ethoxy, benzyloxy, or with one or more F atoms, or R 5  is phenyl, methoxyphenyl, or (dimethylamino)phenyl; and  
 n=0, 1, or 2.  
 
   
   
       4 . The method of  claim 3 , wherein R is a C 2  to C 6  (hydroxy)alkyl optionally substituted with phenyl, OR 5 , N(R 5 )C(═O)R 5 , N(R 5 )C(═O)OR 5 , or with one or more F atoms; 
 R 1 , R 2 , R 3  and R 4  are independently H, F, Cl, CF 3 , OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)R 5 , N(R 5 )C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , COOR 5 , CON(R 5 ) 2 , C 1  to C 6  alkyl optionally substituted with phenyl, C(═O)R 5 , COOR 5 , CON(R 5 ) 2 , CN, OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)OR 5 , or N(R 5 )C(═O)OR 5 ; or R 1  and R 2  as herein defined taken together form a ring, or R 2  and R 3  as herein defined taken together form a ring, or R 3  and R 4  as herein defined taken together form a ring;    R 5  is C 1  to C 6  alkyl optionally substituted with phenyl, methoxyphenyl, methoxy, benzyloxy, or with one or more F atoms.    
   
   
       5 . A 1-alkyl-3-amino indazole having the formula  
     
       
         
         
             
             
         
       
     
     wherein R is a C 2  to C 12  hydroxy)alkyl group optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)R 5 , N(R 5 )C(═O)OR 5 , or with one or more F atoms; 
 R 1 , R 2 , R 3  and R 4  are independently H, F, Cl, Br, CF 3 , OH, OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)R 5 , N(R 5 )C(═O)OR 5 , NO 2 , CN, N 3 , SH, S(O) n R 5 , C(═O)R 5 , COOH, COOR 5 , CON(R 5 ) 2 , C 1  to C 6  alkyl optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, C(═O)R 5 , COOH, COOR 5 , CON(R 5 ) 2 , CN, OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)R 5 , or N(R 5 )C(═O)OR 5 ; or R 1  and R 2  as herein defined taken together form a ring, or R 2  and R 3  as herein defined taken together form a ring, or R 3  and R 4  as herein defined taken together form a ring;  
 R 5  is C 1  to C 6  alkyl optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, methoxy, ethoxy, benzyloxy, or with one or more F atoms, or R 5  is phenyl, methoxyphenyl, or (dimethylamino)phenyl; and  
 n=0, 1, or 2.  
 
   
   
       6 . The compound of  claim 5 , wherein 
 R is a C 2  to C 6  (hydroxy)alkyl group optionally substituted with phenyl, OR 5 , N(R 5 )C(═O)R 5 , N(R 5 )C(═O)OR 5 , or with one or more F atoms;    R 1 , R 2 , R 3  and R 4  are independently H, F, Cl, CF 3 , OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)R 5 , N(R 5 )C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , COOR 5 , CON(R 5 ) 2 , C 1  to C 6  alkyl optionally substituted with phenyl, C(═O)R 5 , COOR 5 , CON(R 5 ) 2 , CN, OR 5 , OC(═O)R 5 , OC(═O)OR 5 , N(R 5 ) 2 , N(R 5 )C(═O)R 5 , or N(R 5 )C(═O)OR 5 ; or R 1  and R 2  as herein defined taken together form a ring, or R 2  and R 3  as herein defined taken together form a ring, or R 3  and R 4  as herein defined taken together form a ring; and    R 5  is C 1  to C 6  alkyl optionally substituted with phenyl, methoxyphenyl, methoxy, benzyloxy, or with one or more F atoms, or R 5  is phenyl or methoxyphenyl.