Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-one compounds and intermediates thereof

Abstract

A process is provided for the preparation of compounds of formula (I) herein comprising reacting a compound of formula (II), (III), (IV) or (V) in the presence of − OR 3 and a hydroxide trapping agent or in the case of compounds of formula (IV) reacting in the presence of an auxiliary base and a hydroxide trapping agent ( i.e. − OR 3 is substituted by the auxiliary base), wherein X is a leaving group and R 1 to R 4 are as defined.

1 . A process for the preparation of a compound of general formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically or veterinarily acceptable salt, pro-drug, polymorph and/or solvate thereof, wherein 
 Q represents O or NR 5    
 R 1  represents H, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR 6 , OC(O)R 7 , C(O)R 8 , C(O)OR 9 , C(O)NR 10 OR 11 , NR 12 R 13  and SO 2 NR 14 R 15 )  
 R 2  represents H, halo, cyano, nitro, OR 6 , OC(O)R 7 , C(O)R 8 , C(O)OR 9 , C(O)NR 10 OR 11 , NR 12 R 13 , SO 2 NR 14 R 15 , lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR 6 , OC(O)R 7 , C(O)R 8 , C(O)OR 9 , C(O)NR 10 R 11 , NR 12 R 13  and SO 2 NR 14 R 15 )  
 R 3  represents H, lower alkyl, alkylHet or alkylaryl (which latter three groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR 6 , OC(O)R 7 , C(O)R 8 , C(O)OR 9 , C(O)NR 10 OR 11 , NR 12 R 13  and SO 2 NR 14 R 15 )  
 R 4  represents H, halo, cyano, nitro, halo(loweralkyl), OR 6 , OC(O)R 7 , C(O)R 8 , C(O)OR 9 , C(O)NR 10 R 11 , NR 12 R 13 , NR 16 Y(O)R 17 , N[Y(O)R 17 ] 2 , SOR 18 , SO 2 R 19 , C(O)AZ, lower alkyl, lower alkenyl, lower alkynyl, Het, alkylHet, aryl, alkylaryl (which latter seven groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR 6 , OC(O)R 7 , C(O)R 8 , C(O)OR 9 , C(O)NR 10 R 11 , NR 12 R 13  and SO 2 NR 14 R 15 )  
 Y represents C or S(O)  
 A represents lower alkylene  
 Z represents OR 6 , halo, Het or aryl (which latter two groups are both optionally substituted with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR 6 , OC(O)R 7 , C(O)R 8 , C(O)OR 9 , C(O)NR 10 R 11 , NR 12 R 13  and SO 2 NR 14 R 15 )  
 R 10  and R 11  independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR 6 , OC(O)R 7 , C(O)R 8 , C(O)OR 9 , C(O)NR 10a R 11a , NR 12 R 13 , SO 2 NR 14 R 15  and NR 20 S(O) 2 R 21  or Het or aryl optionally substituted with one or more of said latter thirteen groups) or one of R 10  and R 11  may be lower alkoxy, amino or Het, which latter two groups are both optionally substituted with lower alkyl  
 R 10a  and R 11a  independently represent R 10  and R 11  as defined above, except that they do not represent groups that include lower alkyl, Het or aryl, when these three groups are substituted and/or terminated (as appropriate) by one or more substituents that include one or more C(O)NR 10a R 11a  and/or NR 12 R 13  groups  
 R 12  and R 13  independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR 6 , C(O)OR 9 , C(O)NR 22 R 23  and NR 24 R 25 ), one of R 12  or R 13  may be C(O)-lower alkyl or C(O)Het (in which Het is optionally substituted with lower alkyl), or R 12  and R 13  together represent C 3-7  alkylene (which alkylene group is optionally unsaturated, optionally substituted by one or more lower alkyl groups and/or optionally interrupted by O or NR 26 )  
 R 14  and R 15  independently represent H or lower alkyl or R 14  and R 15 , together with the nitrogen atom to which they are bound, form a heterocyclic ring  
 R 16  and R 17  independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR 6 , C(O)OR 9 , C(O)NR 22 R 23  and NR 24 R 25 ) or one of R 16  and R 17  may be Het or aryl, which latter two groups are both optionally substituted with lower alkyl  
 R 5 , R 6 , R 7 , R 8 , R 9 , R 18 , R 19 , R 20 , R 22 , R 23 , R 24  and R 25  independently represent H or lower alkyl  
 R 18  and R 19  independently represent lower alkyl  
 R 21  represents lower alkyl or aryl  
 R 26  represents H, lower alkyl, aryl, C(O)R 27  or S(O) 2 R 28    
 R 27  represents H, lower alkyl or aryl  
 R 28  represents lower alkyl or aryl  
 Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulphur and mixtures thereof  
 said process comprising reacting a compound of formula (II), (III), (IV) or (V) in the presence of  − OR 3  and a hydroxide trapping agent or, alternatively, in the case of compounds of formulae (IV) or (V) reacting in the presence of an auxiliary base and a hydroxide trapping agent (i.e.  − OR 3  is substituted by the auxiliary base)  
                     
 wherein X is a leaving group and Q and R 1  to R 4  are as defined above.  
 
     
     
         2 . A process for the preparation of a compound of formula (IA):  
       
         
           
           
               
               
           
         
       
       said process comprising reacting a compound of formula (IIA), (IIIA) or (IVA) respectively  
       
         
           
           
               
               
           
         
       
       in the presence of  − OR 3  and a hydroxide trapping agent, or alternatively in the case of compounds of formula (IVA) reacting in the presence of a hydroxide trapping agent and an auxiliary base, wherein OR 3  in the case of formation of compound (IA) and (IVA) is CH 3 (CH 2 ) 3 O— and wherein X in formulae (IIA) and (IIIA) is a leaving group.