Processes for the preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)-pyrrolidin-2-yl]imidazo[1,5-a]-pyrazin-1-yl}N-(pyridin-2-yl)-benzamide

1. A process for preparing a compound having the structure of Formula (VIII):

or a salt thereof, wherein the process comprises:

contacting a compound having the structure of Formula (VII):

or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising the compound of Formula (VIII), or salt thereof, and a reaction by-product comprising a compound having the structure of Formula (XIV):

or a salt thereof; and

selectively isolating the compound of Formula (VIII), or salt thereof, from the reaction mixture relative to the compound having the structure of Formula (XIV).

2. The process of claim 1 , wherein the contacting step comprises:

adding the compound of Formula (VII), or salt thereof, and the base to the reaction medium;

adding the 2-butynoic acid, or salt thereof, to the reaction medium comprising the compound of Formula (VII), or salt thereof, and the base; and

adding the 1-propylphosphonic anhydride to the reaction medium comprising the compound of Formula (VII), or salt thereof; 2-butynoic acid, or salt thereof; and the base.

3. The process of claim 1 , wherein the process comprises:

contacting the compound of Formula (VII), or salt thereof, with the 2-butynoic acid, or salt thereof, in the presence of the 1-propylphosphonic anhydride and the base in the reaction medium to form a reaction mixture comprising the compound of Formula (VIII), or salt thereof; unreacted compound of Formula (VII), or salt thereof; and the reaction by-product comprising the compound of Formula (XIV), or a salt thereof; and

selectively isolating the compound of Formula (VIII), or salt thereof, from the reaction mixture relative to the compound of Formula (VII), or salt thereof, and the compound of Formula (XIV), or salt thereof.

4. The process of claim 1 , wherein the process comprises:

contacting the compound of Formula (VII), or a salt thereof, with the 2-butynoic acid, or salt thereof, in the presence of the 1-propylphosphonic anhydride and the base in the reaction medium to form a reaction mixture comprising the compound of Formula (VIII), or salt thereof; unreacted compound of Formula (VII), or salt thereof; and the reaction by-product comprising the compound of Formula (XIV), or a salt thereof;

extracting at least a portion of the compound of Formula (VIII), or salt thereof, from the reaction mixture into an aqueous phase, wherein the compound of Formula (VIII), or salt thereof, is selectively extracted into the aqueous phase relative to the compound of Formula (XIV), or salt thereof;

adjusting the pH of the aqueous phase; and

extracting at least a portion of the compound of Formula (VIII), or salt thereof, from the aqueous phase into an organic phase, wherein the compound of Formula (VIII), or salt thereof, is selectively extracted into the organic phase relative to the compound of Formula (VII), or salt thereof.

5. The process of claim 4 , wherein the process further comprises isolating the compound of Formula (VIII) from the organic phase into which the compound of Formula (VIII) has been selectively extracted.

6. The process of claim 4 , wherein the aqueous phase has a pH less than about 2.5 during the aqueous phase extracting step.

7. The process of claim 4 , wherein the aqueous phase has a pH greater than about 4.0 during the organic phase extracting step.

8. The process of claim 6 , wherein the aqueous phase comprises greater than about 75 area % of the compound of Formula (VIII) and less than about 2.0 area % of the compound of Formula (XIV) as measured by high-performance liquid chromatography upon completion of the aqueous phase extraction.

9. The process of claim 7 , wherein the organic phase comprises at least about 75 area % of the compound of Formula (VIII) and less than about 2.0 area % of the compound of Formula (VII) as measured by high-performance liquid chromatography upon completion of the organic phase extraction.

10. The process of claim 4 , wherein:

the aqueous phase has a pH less than about 2.5 during the aqueous phase extracting step; and

the aqueous phase has a pH greater than about 4.0 during the organic phase extracting step.

11. The process of claim 4 , wherein:

the aqueous phase has a pH from about 1.8 to about 2.2 during the aqueous phase extracting step; and

the aqueous phase has a pH from about 4.5 to about 5.0 during the organic phase extracting step.

12. The process of claim 4 , wherein the base comprises at least one compound selected from the group consisting of triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

13. The process of claim 12 , wherein the base comprises triethylamine.

14. The process of claim 4 , wherein the reaction medium comprises at least one solvent selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-amyl alcohol, acetone, methyl iso-butyl ketone, 2-butanol, methyl ethyl ketone, acetonitrile, and ethyl acetate.

15. The process of claim 14 , wherein the reaction medium comprises dichloromethane.

16. The process of claim 4 , wherein the organic phase comprises at least one compound selected from the group consisting of dichloromethane, methyltetrahydrofuran, and 2-methyltetrahydrofuran, tert-amyl alcohol, methyl iso-butyl ketone, 2-butanol, methyl ethyl ketone, ethyl acetate, isopropylacetate, N-butylacetate, butyronitrile, toluene, xylene, heptane, hexane, isohexane, and chloroform.

17. The process of claim 16 , wherein the organic phase comprises dichloromethane.

18. The process of claim 4 , wherein the compound of Formula (VII) is contacted with about 0.5 to about 5.0 molar equivalents of 2-butynoic acid relative to the compound of Formula (VII).

19. The process of claim 4 , wherein about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride are charged to the reaction medium relative to the compound of Formula (VII).

20. The process of claim 4 , wherein about 1.0 to about 10.0 molar equivalents of the base are charged to the reaction medium relative to the compound of Formula (VII).

21. The process of claim 4 , wherein the reaction medium is maintained at a temperature from about 10° C. to about 30° C. during the contacting step.

22. The process of claim 4 , wherein the organic phase comprises an organic phase solvent, and the process further comprises exchanging the organic phase solvent with a replacement solvent to form a crystallization mixture comprising the compound of Formula (VIII).

23. The process of claim 22 , wherein:

the organic phase solvent is exchanged with the replacement solvent by continuous level distillation; and

the continuous level vacuum distillation is conducted at a temperature that does not exceed about 60° C.

24. The process of claim 22 , wherein the replacement solvent comprises an alcohol.

25. The process of claim 22 , wherein the replacement solvent comprises ethanol.

26. The process of claim 22 , wherein the organic phase solvent comprises dichloromethane and the replacement solvent comprises ethanol.

27. The process of claim 22 , wherein the crystallization mixture is maintained at a temperature greater than about 40° C. for at least about five hours after crystallization initiates.

28. The process of claim 27 , wherein the crystallization mixture is cooled to a temperature of about 20° C. over a period of at least five hours before isolating the compound of Formula (VIII).

29. The process of claim 1 , wherein the compound of Formula (VII) is prepared by a process comprising isolating the compound as a crystalline form characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 9.9±0.2 °2θ, 11.1±0.2 °2θ, 12.8±0.2 °2θ, 14.1±0.2 °2θ, and 19.0±0.2 °2θ.