Novel process for the preparation of pyrazoles

Abstract

A “one-pot” process is described herein for the production of pyrazole compounds of general formula (II) comprising the steps of reacting a compound of general formula (III) with an acylating agent in the presence of a base and an optional activating agent followed by the addition of a hydrazine compound in situ.

What we claim is:  
     
         1 . A process for the production of pyrazole compounds of formula (II)  
       
         
           
           
               
               
           
         
       
       wherein 
 R p  is H or R 1 ;  
 R 1  is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl((C 1 -C 6 )alkoxy), Het, (C 1 -C 6 )alkylHet, aryl, or (C 1 -C 6 )alkylaryl, where the latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C 1 -C 6 )alkyl, C(O)NR 4 R 5 , C(O)R 6 , C(O)OR 7 , OR 8 , NR 9a R 9b  and SO 2 NR 10a R 10b ;  
 R 2  is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl((C 1 -C 6 )alkoxy), Het, (C 1 -C 6 )alkylHet, aryl, or (C 1 -C 6 )alkylaryl, where the latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C 1 -C 6 )alkyl, C(O)NR 4 R 5 , C(O)R 6 , C(O)OR 7 , OR 8 , NR 9a R 9b  and SO 2 NR 10a R 10b ;  
 R 3  is OH, (C 1 -C 6 )alkoxy, or NR 4 R 5 ;  
 R 4 , R 5 , R 6 , R 7 , R 8 , R 10a  and R 10b  are each independently H or (C 1 -C 6 )alkyl;  
 R 9a  and R 9b  are each independently H, (C 1 -C 6 )alkyl, or taken together with the nitrogen atom to which they are attached form an azetidinyl, pyrollidinyl, or piperidinyl group,  
 wherein said process comprises the steps of  
 (i) reacting a compound of formula (III),  
                     
 where R 11a  and R 11b  are each independently (C 1 -C 6 )alkyl and R 2  is as defined herein before,  
 with an acylating agent of the formula (IV) in the presence of a base and an optional activating agent,  
                     
 where X is a halogen independently selected from Cl, F or Br and where Y is a halogen or OR 12  where R 12  is (C 1 -C 6 )alkyl, C(O)CX 3 , Het, or (C 1 -C 6 )alkyl(Het), where Het is pyridine or imidazole; and  
 (ii) adding in situ a hydrazine compound of formula (V)  
                     
 where R p  is H or R 1  where R 1  is as defined hereinbefore, and R x , R y  and R z  are each independently selected from H, an electron donating group, or an electron withdrawing group where said electron withdrawing group or said electron donating group is labile under the conditions of the reaction.  
 
     
     
         2 . The process of  claim 1  wherein said compound of formula (III) is reacted with at least one equivalent of said acylating agent of formula (IV) in step (i).  
     
     
         3 . The process of  claim 1  wherein said compound of formula (III) is reacted with at least two equivalents of said acylating agent of formula (IV) in step (i).  
     
     
         4 . The process of  claim 1  wherein said compound of formula (II) is a compound of formula IIA  
       
         
           
           
               
               
           
         
       
       where R p , R 2 , and R 3  are as defined hereinbefore.  
     
     
         5 . The process of  claim 1  wherein said compound of formula (II) is a compound of formula IIB  
       
         
           
           
               
               
           
         
       
       where R p , R 2 , and R 3  are as defined hereinbefore.  
     
     
         6 . A process for the production of pyrazole compounds of formula (IIA),  
       
         
           
           
               
               
           
         
       
       wherein 
 R p  is H or R 1 , where R 1  is (C 1 -C 4 )alkyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C 1 -C 6 )alkyl, C(O)NR 4 R 5 , C(O)R 6 , C(O)OR 7 , OR 8 , NR 9a R 9b  and SO 2 NR 10a R 10b ;  
 R 2  is (C 1 -C 4 )alkyl;  
 R 3  is (C 1 -C 3 )alkoxy,  
 wherein said process comprises the steps of  
 (i) reacting a compound of formula (III),  
                     
 where R 11a  and R 11b  are each independently (C 1 -C 4 )alkyl and R 2  is (C 1 -C 4 )alkyl, with an acylating agent of the formula (IV),  
                     
 where X is Cl or F, and Y is Cl, F or C(O)CX 3 , in the presence of a base and an optional activating agent; and  
 (ii) adding in situ a hydrazine compound of formula (V)  
                     
 where R p  is H or R 1 , where R 1  is as defined hereinbefore, and R x ═EWG,  
 R y  and R z ═H; or R x  and R y ═H and R z ═EDG; or  
 R x ═R y ═R z ═H when R 1 ═EWG; or R x ═EWG, R y ═H and R z ═EDG,  
 wherein EWG is a tri(C 1 -C 2 )alkylsilyl group and EDG is tert-butyloxycarbonyl or trifluoroacetamide,  
 
     
     
         7 . The process of  claim 6  wherein said compound of formula (III) is reacted with at least one equivalent of said acylating agent of formula (IV) in step (i).  
     
     
         8 . The process of  claim 6  wherein said compound of formula (III) is reacted with at least two equivalents of said acylating agent of formula (IV) in step (i).  
     
     
         9 . A process for the production of pyrazole compounds of formula (IIB),  
       
         
           
           
               
               
           
         
       
       wherein 
 R p  is H or R 1 , where R 1  is (C 1 -C 4 )alkyl or (C 1 -C 4 )alkyl((C 1 -C 2 ) alkoxy);  
 R 2  is (C 1 -C 4 )alkyl; and  
 R 3  is (C 1 -C 3 )alkoxy,  
 wherein said process comprises the steps of  
 (i) reacting a compound of formula (III)  
                     
 with an acylating agent of formula (IV) in the presence of pyridine and an optional activating agent  
                     
 where X and Y are each independently Cl or F; and  
 (ii) adding after about 8 hours to about 24 hours a hydrazine compound of formula (V)  
                     
 where R p  is H when  
 R x ═EWG, R y  and R z ═H; or  
 R x  and R y ═H and R z ═EDG; or  
 R x ═R y ═R z ═H when R 1 ═EWG; or  
 R x ═EWG, R y ═H and R z ═EDG, where EDG is a tri(C 1 -C 2 )alkylsilyl group and EWG is teit-butyloxycarbonyl or trifluoroacetamide; and R p  is R 1 , where R 1  is as defined hereinbefore, when  
 R x ═H, R y ═H and R z ═EWG; or  
 R x ═EDG, R y ═H and R z ═H; or  
 R x ═R y ═R z ═H when R 1 ═EDG; or  
 R x ═EDG, R y ═H and R z ═EWG, where EDG is a tri(C 1 -C 2 )alkylsilyl group and EWG is tert-butyloxycarbonyl or trifluoroacetamide.  
 
     
     
         10 . The process of  claim 9  wherein said compound of formula (III) is reacted with at least one equivalent of said acylating agent of formula (IV) in step (i).  
     
     
         11 . The process of  claim 9  wherein said compound of formula (III) is reacted with at least two equivalents of said acylating agent of formula (IV) in step (i).  
     
     
         12 . A process for the production of compounds of formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, 
 wherein  
 A is CH or N;  
 R 1  is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl((C 1 -C 6 )alkoxy), Het, (C 1 -C 6 )aikylHet, aryl, or (C 1 -C 6 )alkylaryl, where the latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C 1 -C 6 )alkyl, C(O)NR 4 R 5 , C(O)R 6 , C(O)OR 7 , OR 8 , NR 9a R 9b  and SO 2 NR 10a R 10b ;  
 R 2  is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl((C 1 -C 6 )alkoxy), Het, (C 1 -C 6 )alkylHet, aryl, or (C 1 -C 6 )alkylaryl, where the latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C 1 -C 6 )alkyl, C(O)NR 4 R 5 , C(O)R 6 , C(O)OR 7 , OR 8 , NR 9a R 9b  and SO 2 NR 10a R 10b ;  
 R t  is NR p R q ;  
 R p , R q , R 6 , R 7 , R 8 , R 10a  and R 10b  are each independently H or (C 1 -C 6 )alkyl;  
 R 9a  and R 9b  are each independently H, (C 1 -C 6 )alkyl, or taken together with the nitrogen atom to which they are attached form an azetidinyl, pyrollidinyl or piperidinyl group;  
 R 4  is CO 2 R 7 , or (C 1 -C 4 )alkyl optionally substituted with OH, NR 5 R 6 , CN, CONR 5 R 6  or CO 2 R 7 ; or  
 R 4  is a pyrrolidinylsulphonyl, piperidinosulphonyl, morpholinosulphonyl, or piperazin-1-ylsulphonyl group having a substituent R 10  at the 4-position of the piperazinyl group where said piperazinyl group is optionally substituted with one or two (C 1 -C 4 )alkyl, (C 1 -C 3 )alkoxy, NR 7 R 8 , or CON R 7 R 8  groups and is optionally in the form of its 4-N-oxide;  
 R 10  is H or (C 1 -C 6 )alkyl;  
 wherein said compounds are prepared from compounds of formula (VIII)  
                     
 wherein R 1 , R 2 , R 4  and R  13  are as defined hereinbefore and said compound of formula (VIII) is prepared from the reaction of a compound of formula (VII)  
                     
 wherein R 4  and R 13  are as defined hereinbefore via coupling with a compound of formula (VI)  
                     
 wherein R 1  and R 2  are as defined hereinbefore and R t  is NR p R q  where R p  and R q  are each independently H or (C 1 -C 6 )alkyl and said compound of formula (VI) is prepared by nitration and hydrogenation of a compound of formula (II)  
                     
 wherein R t  and R 2  are as defined hereinbefore and R p  is R 1  as defined hereinbefore, and said compound of formula (II) is prepared by 
 (i) reacting a compound of formula (III),  
                     
 
 where R 11a  and R 11b  are each independently (C 1 -C 6 )alkyl and R 2  is as defined herein before, with an acylating agent of formula (IV) in the presence of a base and an optional activating agent,  
                     
 where X is a halogen independently selected from Cl, F or Br, and Y is a halogen, or OR 12 , where R 12  is (C 1 -C 6 )alkyl, C(O)CX 3 , Het; or (C 1 -C 6 )alkyl(Het), where Het is pyridine or imidazole; and (ii) adding in situ a hydrazine compound of formula (V),  
                     
 where R p  is H or R 1 , where R 1  is as defined hereinbefore, and R x , R y  and R z  are each independently selected from H, an electron donating group, or an electron withdrawing group, where said electron withdrawing group or said electron donating group is labile under the conditions of the reaction.  
 
     
     
         13 . The process of  claim 12  wherein said compound of formula (I) is prepared from a compound of formula (II) wherein 
 R 1  is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl((C 1 -C 6 )alkoxy), Het, (C 1 -C 6 )alkylHet, aryl or (C 1 -C 6 )alkylaryl, where the latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C 1 -C 6 )alkyl, C(O)NR 4 R 5 , C(O)R 6 , C(O)OR 7 , OR 8 , NR 9a R 9b  and SO 2 NR 10a R 10b ;  
 R 2  is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl((C 1 -C 6 )alkoxy), Het, (C 1 -C 6 )alkylHet, aryl, or (C 1 -C 6 )alkylaryl, where the latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C 1 -C 6 )alkyl, C(O)NR 4 R 5 , C(O)R 6 , C(O)OR 7 , OR 8 , NR 9a R 9b  and SO 2 NR 10a R 10b ;  
 R t  is NR p R q ;  
 R p , R q , R 6 , R 7 , R 8 , R 10a  and R 10b  are each independently H or (C 1 -C 6 )alkyl;  
 R 9a  and R 9b  are each independently H, (C 1 -C 6 )alkyl or taken together with the nitrogen atom to which they are attached form an azetidinyl, pyrollidinyl or piperidinyl group;  
 R 4  is CO 2 R 7 , (C 1 -C 4 )alkyl optionally substituted with OH, NR 5 R 6 , CN, CONR 5 R 6  or CO 2 R 7 , or  
 R 4  is a pyrrolidinylsulphonyl, piperidinosulphonyl, morpholinosulphonyl, or piperazin-1-ylsulphonyl group having a substituent, R 10  at the 4-position of the piperazinyl group wherein the piperazinyl group is optionally substituted with one or two (C 1 -C 4 )alkyl, (C 1 -C 3 )alkoxy, NR 7 R 8  or CON R 7 R 8  groups and is optionally in the form of its 4-N-oxide; and  
 R 10  is H or (C 1 -C 6 )alkyl.  
 
     
     
         14 . The process of  claim 12  wherein said compound of formula (I) is prepared from a compound of formula (II) wherein 
 R 1  is (C 1 -C 4 )alkyl, where the (C 1 -C 4 )alkyl group is optionally interrupted by an oxygen atom and is optionally terminated by a Het group;  
 R 2  is (C 1 -C 4 )alkyl;  
 R 3  is (C 1 -C 5 )alkyl optionally interrupted by an oxygen atom; and  
 R 4  is CO 2 R 7 , or a morpholinosulphonyl or piperazin-1-ylsulphonyl group having a substituent R 10  at the 4-position of the piperazinyl group where R 10  is H, methyl, or ethyl.  
 
     
     
         15 . The process of  claim 12  wherein said compound of formula (I) is prepared from a compound of formula (II) wherein 
 R 1  is a linear (C 1 -C 3 )alkyl optionally interrupted by an oxygen atom, or is optionally terminated by a 2-pyridinyl group;  
 R 2  is a linear (C 2 -C 3 )alkyl;  
 R 3  is a linear or branched (C 2 -C 4 )alkyl optionally interrupted by an oxygen atom; and  
 R 4  is CO 2 R 7 , or a morpholinosulphonyl or piperazin-1-ylsulphonyl group having a substituent R 10  at the 4-position of the piperazinyl group where R 10  is methyl or ethyl.  
 
     
     
         16 . The process of  claim 12  wherein said compound of formula (I) is selected from the group consisting of 
 sildenafil,  
 (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,  
 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,  
 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,  
 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and  
 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.  
 
     
     
         17 . The process of  claim 12  wherein said compound of formula (I) is selected from the group consisting of 
 sildenafil,  
 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and  
 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.  
 
     
     
         18 . The process of  claim 12  wherein said compound of formula (II) is prepared by reacting said compound of formula (III) with at least one equivalent of said acylating agent of formula (IV) in step (i).  
     
     
         19 . The process of  claim 12  wherein said compound of formula (II) is prepared by reacting said compound of formula (III) with at least two equivalents of said acylating agent of formula (IV) in step (i).