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

Patent metadata

Field	Value
Publication number	US-12448387-B2
Application number	US-202418659338-A
Country	US
Kind code	B2
Filing date	May 9, 2024
Priority date	Aug 29, 2018
Publication date	Oct 21, 2025
Grant date	Oct 21, 2025

Abstract

The present disclosure relates, in general, to improved 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, particularly large-scale processes for manufacturing 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide and intermediates used in such processes.

First claim

What is claimed is:

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

or a salt thereof, wherein the process comprises:
contacting a compound having the structure of Formula (V):

or a salt thereof, with a compound having the structure of Formula (VI):

or a salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising the compound of Formula (VII), or salt thereof;
decreasing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising the compound of Formula (VII), or salt thereof; and
isolating the compound of Formula (VII), or salt thereof, from the substantially anhydrous mixture.

2. The process of claim 1 , wherein isolating comprises filtering the substantially anhydrous mixture.

3. The process of claim 1 , wherein the aqueous reaction medium further comprises an alkali metal halide.

4. The process of claim 1 , wherein the aqueous reaction medium further comprises potassium iodide.

5. The process of claim 1 , wherein the organic solvent comprises 2-butanol.

6. The process of claim 1 , wherein the base comprises at least one compound selected from the group consisting of triethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, tripropylamine, tributylamine, diiso-propylethylamine, N-methylmorpholine, N-methylpyrrolidine, methyldicyclohexylamine, and potassium phosphate.

7. The process of claim 1 , wherein the base comprises triethylamine.

8. The process of claim 1 , wherein the base comprises potassium carbonate.

9. The process of claim 1 , wherein the palladium catalyst comprises bis(tert-butyldicyclohexylphosphine)dichloropalladium(II).

10. The process of claim 1 , wherein the compound of Formula (VI) is contacted with about 0.5 to about 1.5 molar equivalents of the compound of Formula (V) relative to the compound of Formula (VI).

11. The process of claim 1 , wherein the aqueous reaction medium is maintained at a temperature from about 50° C. to about 100° C. during the contacting step.

12. The process of claim 1 , wherein the aqueous reaction medium has a volume ratio of water to organic solvent from about 1:3 to about 3:1.

13. The process of claim 1 , wherein decreasing comprises separating the reaction mixture into an aqueous discard phase and an organic phase comprising the compound of Formula (VII).

14. The process of claim 13 , wherein decreasing further comprises distilling the organic phase under conditions sufficient to decrease the amount of water present in the organic phase and provide the substantially anhydrous mixture; wherein the substantially anhydrous mixture comprises less than about 5 weight % water.

15. The process of claim 14 , wherein the organic phase is treated with a silica scavenger prior to distillation.

16. The process of claim 15 , wherein the silica scavenger comprises QuadraSil™ MP.

17. The process of claim 15 , wherein the process further comprises removing the silica scavenger from the organic phase prior to distillation.

18. The process of claim 15 , wherein decreasing comprises:
separating the reaction mixture into an aqueous discard phase and an organic phase comprising the compound of Formula (VII);
washing the organic phase with water;
treating the organic phase with a silica scavenger;
removing the silica scavenger from the organic phase;
washing the organic phase with an aqueous brine solution; and
distilling the organic phase under conditions sufficient to decrease the amount of water present in the organic phase.

19. The process of claim 14 , wherein the organic phase is distilled by vacuum distillation.

20. The process of claim 14 , wherein the organic phase is distilled at a temperature not exceeding about 60° C.

21. The process of claim 14 , wherein the organic phase comprises an alcohol.

22. The process of claim 21 , wherein during distilling the organic phase is supplemented with the alcohol.

23. The process of claim 21 , wherein the alcohol comprises 2-butanol.

24. The process of claim 1 , wherein the substantially anhydrous mixture comprises less than about 5 weight % water.

25. The process of claim 1 , wherein the substantially anhydrous mixture comprises less than about 3 weight % water.

26. The process of claim 1 , wherein isolating comprises crystallizing the compound of Formula (VII) from the substantially anhydrous mixture.

27. The process of claim 26 , wherein the substantially anhydrous mixture is maintained at a temperature of at least about 70° C. for a period of at least two hours after crystallization initiates.

28. The process of claim 26 , wherein the substantially anhydrous mixture is maintained at a temperature of at least about 70° C. for a period of at least two hours after crystallization initiates and then cooled to crystallize the compound of Formula (VII).

29. The process of claim 1 , wherein the compound of Formula (VII) isolated from the substantially anhydrous mixture comprises a crystalline form of the compound of Formula (VII) 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.

30. The process of claim 1 , wherein the compound of Formula (VII) isolated from the substantially anhydrous mixture comprises a crystalline form of the compound of Formula (VII) characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.4±0.2θ2θ, 11.7±0.2°2θ, 12.5±0.2°2θ, 12.5±0.2° 2θ, 22.3 0.2°2θ, and 21.6 0.2° 2θ.

31. The process of claim 1 , wherein the process further comprises converting the compound of Formula (VII), or salt thereof, to a compound having the structure of Formula (VIII):

or a salt thereof.

Assignees

• Acerta Pharma Bv

Inventors

• Bethel Paul Allen
• Chan Lai Chun
• Cooper Katie Grace
• Cox Robert John
• Golden Michael David
• Hughes Shaun Alan
• Jackson Lucinda Victoria
• Millard Kirsty Jane
• Phillips Andrew John
• Telford Alexander James
• Evarts Jerry
• Lawler Michael Joseph
• Litjens Remy E J N
• Van Eijk Peter Johannes Servaas Savio
• Verstappen Mathilda Maria Henrica
• Vos Frank L M
• Zijp Eric Jurriën
• Junying Qiu
• Garrey Rustam Ferdinand
• Short David Allen
• Wang Angang

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07B63/00

  Purification; Separation (separation of optically-active compounds C07B57/00); Stabilisation; Use of additives · CPC title

• C07F5/025

  Boronic and borinic acid compounds · CPC title

• C07D213/75

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title