Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto

• US 10,543,193 B2
• Filed: 08/07/2018
• Issued: 01/28/2020
• Est. Priority Date: 10/28/2008
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Carlos, Marlon, Dong, Weitong, Macias, Mark, Sato, Suzanne Michiko, Selvey, Lee Alani
• Primary Examiner(s): Ricci, Craig D
• Assistant Examiner(s): Coppins, Janet L
• Application Number:
  US16/057,587
• Publication Number:
  US 20180344698A1
• Time in Patent Office: 539 Days
• Field of Search: 514406, 5483771
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/16 Halogen atoms or nitro radicals

Abstract

The present invention is directed to processes and intermediates useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (Compound I), crystalline forms and solvate forms thereof; and compositions comprising 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea, crystalline forms and solvate forms thereof prepared by processes as described herein.

Claims

1. A process for reprocessing or recrystallizing Form II, Form IV, amorphous, or mixtures thereof of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea to give Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea comprising the steps of:

a) dissolving Form II, Form IV, amorphous, or mixtures thereof of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in tetrahydrofuran to form a solution;

b) adding an aliphatic solvent to the solution to form a mixture comprising a first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

c) isolating the first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea from the mixture to provide an isolated first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

d) washing the isolated first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea with acetonitrile to form a second solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea; and

e) converting the second solvate to provide Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

2. The process of claim 1 wherein the weight ratio of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea to tetrahydrofuran is about 1:

6 to about 1;

5.

3. The process of claim 2 wherein the weight ratio of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea to tetrahydrofuran is about 1.3:

5.6.

4. The process of claim 1 wherein the dissolving 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in tetrahydrofuran is conducted at a temperature of about 25°

C. to about reflux temperature.

5. The process of claim 1 wherein the dissolving 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in tetrahydrofuran is conducted at a temperature of about 55°

C. to about reflux temperature.

6. The process of claim 1 wherein the dissolving 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in tetrahydrofuran is conducted at a temperature of about 60°

C. to about reflux temperature.

7. The process of claim 1 further comprising the step of cooling said solution of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in tetrahydrofuran in step a) prior to step b).

8. The process of claim 7 wherein the cooling is to a temperature of about −

35°

C. to about 10°

C.

9. The process of claim 7 wherein the cooling is to a temperature of about −

25°

C. to about −

5°

C.

10. The process of claim 1 wherein the aliphatic solvent is selected from a C₅-C₁₀ alkane, a C₅-C₈ cycloalkane, or a mixture thereof.

11. The process of claim 1 wherein the aliphatic solvent is selected from hexane, cyclohexane, or heptane.

12. The process of claim 1 wherein the aliphatic solvent is heptane.

13. The process of claim 1 wherein adding aliphatic solvent to the solution to form a first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea is conducted at a temperature of about −

35°

C. to about 10°

C.

14. The process of claim 1 wherein adding aliphatic solvent to the solution to form a first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea is conducted ate a temperature of about −

25°

C. to about −

5°

C.

15. The process of claim 1 wherein said first solvate is a tetrahydrofuran solvate.

16. The process of claim 1 wherein said first solvate is a heptane solvate.

17. The process of claim 1 wherein isolating the first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea from the mixture is conducted by filtration.

18. The process of claim 1 wherein washing the isolated first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea with acetonitrile is conducted at a temperature of about −

20°

C. to about 10°

C.

19. The process of claim 1 wherein washing the isolated first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea with acetonitrile is conducted at a temperature of about −

10°

C. to about 10°

C.

20. The process of claim 1 wherein washing the isolated first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea with acetonitrile is conducted at a temperature of about −

5°

C. to about 5°

C.

21. The process of claim 1 wherein the second solvate is an acetonitrile solvate.

22. The process of claim 21 wherein the acetonitrile solvate has a molecular ratio of acetonitrile to 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea of about 1:

2.

23. The process of claim 1 wherein converting the isolated first solvate to provide Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea is conducted under reduced pressure.

24. The process of claim 23 wherein the reduced pressure is about 100 mm Hg or less.

25. The process of claim 23 wherein the reduced pressure is about 35 mm Hg or less.

26. The process of claim 23 wherein the reduced pressure is about 10 mm Hg or less.

27. The process of claim 23 wherein the reduced pressure is about 5 mm Hg or less.

28. The process of claim 1 wherein converting the second solvate to provide Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea is conducted during at least two time periods, wherein the conversion is conducted at a first temperature during a first time period and wherein the conversion is conducted at a second temperature during a second time period, and wherein the first temperature is not equivalent to the second temperature.

29. The process of claim 28 wherein the first temperature is at about 0°

C. to about 45°

C.

30. The process of claim 28 wherein the first temperature is at about 15°

C. to about 40°

C.

31. The process of claim 28 wherein the first temperature is at about 20°

C. to about 30°

C.

32. The process of claim 28 wherein the second temperature is about 45°

C. to about 90°

C.

33. The process of claim 28 wherein the second temperature is about 60°

C. to about 80°

C.

34. The process of claim 28 wherein the second temperature is about 65°

C. to about 75°

C.

35. The process of claim 28 wherein the step of maintaining the first temperature until a loss on drying for a representative sample from the process is at a level of about 30% or less.

36. The process of claim 28 wherein the step of maintaining the first temperature until a loss on drying for a representative sample from the process is at a level of about 20% or less.

37. The process of claim 28 wherein the step of maintaining the first temperature until a loss on drying for a representative sample from the process is at a level of about 15% or less.

38. The process of claim 28 wherein the step of maintaining the first temperature until a loss on drying for a representative sample from the process is at a level of about 10% or less.