Processes for preparing plasma kallikrein inhibitors

1. A process for preparing a compound of Formula I

or a 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;

the method comprising:

(a) subjecting a compound of Formula II to reducing conditions, to provide the compound of Formula I as a crude product, wherein the compound of Formula II is:

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. 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.

7. The process of claim 6 , further comprising:

(c) heating the nickel-depleted product in a solvent to remove further nickel.

8. The process of claim 7 , wherein the solvent comprises a mixture of ethanol and acetic acid.

9. The process of claim 7 , wherein the solvent comprises a mixture of methanol, dimethyl glyoxime, and methyl-t-butyl ether.

10. The process of claim 1 , wherein the compound of Formula II is obtained by combining a compound of Formula III with hydroxylamine or a salt thereof under basic conditions, wherein the compound of Formula III is:

to provide the compound of Formula II.

11. The process of claim 10 , wherein the basic conditions comprise triethylamine and ethanol.

12. The process of claim 11 , wherein the basic conditions further comprise heating at a temperature of about 50° C. to about 75° C.

13. The process of claim 10 , wherein about 3 equivalents of hydroxylamine and triethylamine are used per equivalent of compound of Formula III.

14. The process of claim 10 , wherein the compound of Formula III is obtained by reacting a compound of Formula IV with 4-(aminomethyl)benzonitrile hydrochloride under aprotic conditions, wherein the compound of Formula IV is:

15. The process of claim 14 , wherein the aprotic conditions comprise triethylamine in dichloromethane.

16. The process of claim 14 , wherein the aprotic conditions further comprise 1-propanephosphonic anhydride in ethyl acetate.

17. The process of claim 16 , wherein the aprotic conditions comprise incubating the compound of Formula IV with 4-(aminomethyl)benzonitrile hydrochloride and 1-propanephosphonic anhydride at a temperature of about 5° C. to about 39° C.

18. The process of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

19. 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.

20. The process of claim 19 , wherein the compound of Formula I is 1-benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide acetate.