Processes for preparing plasma kallikrein inhibitors

Abstract

A process for preparing and purifying a compound of Formula I is provided: thereof, wherein the subscript m is an integer of from 0 to 3; each R a is independently selected from the group consisting of (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )haloalkyl, halogen, —OH, —OR 1 , —SH, —SR 1 , —S(O)R 1 , —S(O) 2 R 1 , —SO 2 NH 2 , —C(O)NH 2 , —C(O)NHR 1 , —C(O)N(R 1 ) 2 , —C(O)R 1 , —C(O)H, —CO 2 H, —CO 2 R 1 , —NO 2 , —NH 2 , —NHR 1 , —N(R 1 ) 2 , wherein each R 1 is independently (C 1 -C 8 )alkyl; L is a linking group selected from the group consisting of a bond or CH 2 ; Q a , Q b , and Q c are each members independently selected from the group consisting of N, S, O and C(R q ) wherein each R q is independently selected from the group consisting of H, C 1-8 alkyl, halo and phenyl, and the ring having Q a , Q b , Q c and Y as ring vertices is a five-membered ring having two double bonds; and Y is selected from the group consisting of C and N.

1 . A process for preparing a compound of Formula I 
       
         
           
           
               
               
           
         
         wherein the subscript m is an integer of from 0 to 3; 
         each R a  is independently selected from the group consisting of (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )haloalkyl, halogen, —OH, —OR 1 , —SH, —SR 1 , —S(O)R 1 , —S(O) 2 R 1 , —SO 2 NH 2 , —C(O)NH 2 , —C(O)NHR 1 , —C(O)N(R 1 ) 2 , —C(O)R 1 , —C(O)H, —CO 2 H, —CO 2 R 1 , —NO 2 , —NH 2 , —NHR 1 , —N(R 1 ) 2 , wherein each R 1  is independently (C 1 -C 8 )alkyl; 
         L is a linking group selected from the group consisting of a bond or CH 2 ; 
         Q a , Q b , and Q c  are each members independently selected from the group consisting of N, S, O and C(R q ) wherein each R q  is independently selected from the group consisting of H, C 1-8  alkyl, halo and phenyl, and the ring having Q a , Q b , Q c  and Y as ring vertices is a five-membered ring having two double bonds; and 
         Y is selected from the group consisting of C and N;
 the method comprising:
 (a) reacting a compound of Formula IV 
 
 
       
       
         
           
           
               
               
           
         
         
           
             
               with 4-(aminomethyl)benzonitrile hydrochloride under aprotic conditions to provide a compound of Formula III 
             
           
         
       
       
         
           
           
               
               
           
         
         
           
             (b) combining a compound of Formula III with hydroxylamine or a salt thereof under basic conditions to provide the compound of Formula II 
           
         
       
       
         
           
           
               
               
           
         
         
           
             (c) subjecting a compound of Formula II to reducing conditions, to provide the compound of Formula I as a crude product 
           
         
       
     
     
         2 . The process of  claim 1 , wherein the reducing conditions comprise Raney nickel and H 2 . 
     
     
         3 . The process of  claim 2 , wherein the reducing conditions comprise Raney nickel at about 10 to about 40 mol %, and H 2  at about 2 to about 20 kg/cm 3 . 
     
     
         4 . The process of  claim 3 , wherein the reducing conditions comprise Raney nickel at about 20 mol %, and H 2  at about 10 kg/cm 3 . 
     
     
         5 . The process of  claim 1 , wherein the reducing conditions further comprise acetic acid as a solvent, and heating at a temperature of about 30° C. to about 70° C. 
     
     
         6 .- 8 . (canceled) 
     
     
         9 . The process of  claim 2 , further comprising:
 (b) forming a slurry of the crude product in water at a temperature of about 25° C. to about 70° C. to provide a nickel-depleted product.   
     
     
         10 .- 11 . (canceled) 
     
     
         12 . The process of  claim 9 , further comprising:
 (c) heating the nickel-depleted product in a solvent to remove further nickel.   
     
     
         13 . The process of  claim 12 , wherein the solvent comprises a mixture of ethanol and acetic acid. 
     
     
         14 . The process of  claim 12 , wherein the solvent comprises a mixture of methanol, dimethyl glyoxime, and methyl-t-butyl ether. 
     
     
         15 .- 29 . (canceled) 
     
     
         30 . The process of  claim 1 , wherein the compound of Formula I is 1-benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide or a salt thereof. 
     
     
         31 . The process of  claim 30 , wherein the compound of Formula I is 1-benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide acetate. 
     
     
         32 . A compound of Formula II 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         the subscript m is an integer of from 0 to 3; 
         each R a  is independently selected from the group consisting of (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )haloalkyl, halogen, —OH, —OR 1 , —SH, —SR 1 , —S(O)R 1 , —S(O) 2 R 1 , —SO 2 NH 2 , —C(O)NH 2 , —C(O)NHR 1 , —C(O)N(R 1 ) 2 , —C(O)R 1 , —C(O)H, —CO 2 H, —CO 2 R 1 , —NO 2 , —NH 2 , —NHR 1 , —N(R 1 ) 2 , wherein each R 1  is independently (C 1 -C 8 )alkyl; 
         L is a linking group selected from the group consisting of a bond or CH 2 ; 
         Q a , Q b , and Q c  are each members independently selected from the group consisting of N, S, O and C(R q ) wherein each R q  is independently selected from the group consisting of H, C 1-8  alkyl, halo and phenyl, and the ring having Q a , Q b , Q c  and Y as ring vertices is a five-membered ring having two double bonds; and 
         Y is selected from the group consisting of C and N 
       
     
     
         33 . A compound of Formula III 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         the subscript m is an integer of from 0 to 3; 
         each R a  is independently selected from the group consisting of (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )haloalkyl, halogen, —OH, —OR 1 , —SH, —SR 1 , —S(O)R 1 , —S(O) 2 R 1 , —SO 2 NH 2 , —C(O)NH 2 , —C(O)NHR 1 , —C(O)N(R 1 ) 2 , —C(O)R 1 , —C(O)H, —CO 2 H, —CO 2 R 1 , —NO 2 , —NH 2 , —NHR 1 , —N(R 1 ) 2 , wherein each R 1  is independently (C 1 -C 8 )alkyl; 
         L is a linking group selected from the group consisting of a bond or CH 2 ; 
         Q a , Q b , and Q c  are each members independently selected from the group consisting of N, S, O and C(R q ) wherein each R q  is independently selected from the group consisting of H, C 1-8  alkyl, halo and phenyl, and the ring having Q a , Q b , Q c  and Y as ring vertices is a five-membered ring having two double bonds; and 
         Y is selected from the group consisting of C and N