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

• US 9,126,946 B2
• Filed: 10/27/2009
• Issued: 09/08/2015
• 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): Saeed, Kamal
• Assistant Examiner(s): Coppins, Janet L
• Application Number:
  US13/126,563
• Publication Number:
  US 20110207790A1
• Time in Patent Office: 2,142 Days
• Field of Search: 514/406, 548/356, 548/377.1
• US Class Current: 1/1
• 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 preparing Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea comprising the step of:

converting an acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea to provide said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea by removing acetonitrile, wherein said converting comprises reducing solvent content at a temperature sufficient to minimize conversion of said acetonitrile solvate to Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

2. The process according to claim 1, wherein said acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea 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.

3. The process according to claim 1, wherein said converting an acetonitrile solvate 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.

4. The process according to claim 1, wherein said converting an acetonitrile 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 reduced pressure of about 35 mm Hg or less at a first temperature of about 20°

C. to about 30°

C. until a loss on drying (LOD) for a representative sample from said process is at a level of about 10% or less; and

thereafter raising said first temperature to a second temperature of about 65°

C. to about 75°

C. while maintaining said reduced pressure of about 35 mm Hg or less.

5. The process according to claim 1, wherein said acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea is prepared by the steps comprising:

a) reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate in the presence of acetonitrile to form a reaction mixture comprising 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea; and

b) crystallizing said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea from said reaction mixture to form said acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

6. The process according to claim 5, wherein:

said reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate in the presence of acetonitrile is conducted by adding said 2,4-difluorophenyl-isocyanate to said 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine at a temperature of about −

25°

C. to about 0°

C. and a rate sufficient to form said reaction mixture, wherein said reaction mixture comprises less than about 2% of said 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respect to said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea as determined by HPLC; and

said crystallizing 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 −

15°

C. to about 0°

C.

7. The process of claim 1, wherein said acetonitrile solvate is prepared by a process of comprising the steps of:

a) reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate in the presence of acetonitrile to form a reaction mixture comprising 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl) -4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea; and

b) crystallizing said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea from said reaction mixture to form said acetonitrile solvate of 1[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

8. The process according to claim 7, wherein said acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea 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.

9. The process according to claim 7, wherein said reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate is conducted at a temperature of about −

25°

C. to about 0°

C.

10. The process according to claim 9, wherein said adding 2,4-difluorophenylisocyanate is conducted at a rate sufficient to form said reaction mixture, wherein said reaction mixture comprises less than about 2% of said 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respect to said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea as determined by HPLC.

11. The process according to claim 7, wherein said crystallizing 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 −

15°

C. to about 0°

C.

12. The process according to claim 7, further comprising the step of isolating said acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

wherein said isolating is conducted by filtration of said acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea from said reaction mixture.

13. The process according to claim 7, wherein:

said reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate in the presence of acetonitrile is conducted by adding said 2,4-difluorophenyl-isocyanate to said 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine at a temperature of about −

25°

C. to about 0°

C. and a rate sufficient to form said reaction mixture, wherein said reaction mixture comprises less than about 2% of said 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respect to said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea as determined by HPLC; and

said crystallizing 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 −

15°

C. to about 0°

C.

14. The process according to claim 7, wherein said 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine is prepared by the step comprising:

reacting N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide with an inorganic base in the presence of a mixture of an aromatic solvent and a C₁-C₆ alkanol to form 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine.

15. The process according to claim 14, wherein said reacting N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide with said inorganic base is conducted at a temperature of about 75°

C. to about reflux temperature; and

wherein;

said inorganic base is sodium hydroxide;

said aromatic solvent is a mixture of xylenes; and

said C₁-C₆ alkanol is n-propanol;

wherein the volume ratio of said mixture of xylenes to n-propanol is about 5;

1.

16. The process according to claim 14, wherein said N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide is prepared by the step comprising:

reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with a brominating agent in the presence of a brominating solvent to form said N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide.

17. The process according to claim 16, wherein:

said reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with said brominating agent is conducted at a temperature of about 35°

C. to about 65°

C.;

said brominating agent is N-bromosuccinimide; and

said brominating solvent is N,N-dimethylacetamide.

45. A process for preparing a pharmaceutical composition comprising admixing:

a composition comprising Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea prepared according to the process of claim 1, wherein said composition comprises less than 0.9 mole % of 1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea; and

a pharmaceutically acceptable carrier.

50. The process according to claim 1, wherein said Form I has a powder X-ray diffraction pattern comprising peaks expressed in terms of 2θ

at about 5.6°

, about 7.4°

, about 11.2°

, about 21.1°

, and about 25.0°

.

51. The process according to claim 1, wherein said Form I has a powder X-ray diffraction pattern substantially as shown in FIG. 21.

52. The process according to claim 1, wherein said Form I has a differential scanning calorimetry thermogram substantially as shown in FIG. 22.

53. The process according to claim 1, wherein said converting comprises reducing solvent content of said acetonitrile solvate at a first temperature of about 0°

C. to about 45°

C.

54. The process according to claim 1, wherein said converting comprises reducing solvent content of said acetonitrile solvate at a first temperature of about 15°

C. to about 40°

C.

55. The process according to claim 1, wherein said converting comprises reducing solvent content of said acetonitrile solvate at a first temperature of about 20°

C. to about 30°

C.

56. The process according to claim 1, wherein said converting comprises reducing solvent content of said acetonitrile solvate at a first temperature of less than or equal to ambient temperature.

57. The process according to claim 55, wherein said first temperature is maintained until loss on drying (LOD) is about 35%.

58. The process according to claim 55, wherein said first temperature is maintained until loss on drying (LOD) is about 30%.

59. The process according to claim 55, wherein said first temperature is maintained until loss on drying (LOD) is about 25%.

60. The process according to claim 55, wherein said first temperature is maintained until loss on drying (LOD) is about 20%.

61. The process according to claim 55, wherein said first temperature is maintained until loss on drying (LOD) is about 15%.

62. The process according to claim 55, wherein said first temperature is maintained until loss on drying (LOD) is about 10%.

63. The process according to claim 55, wherein said first temperature is maintained until loss on drying (LOD) is about 5%.

64. The process according to claim 57, further comprising, after said converting at said first temperature, conducting said converting at a second temperature of about 45°

C. to about 90°

C.

65. The process according to claim 57, further comprising, after said converting at said first temperature, conducting said converting at a second temperature of about 60°

C. to about 80°

C.

66. The process according to claim 57, further comprising, after said converting at said first temperature, conducting said converting at a second temperature of about 65°

C. to about 75°

C.

18. A process for preparing 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine, said process comprising:

reacting N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide with an inorganic base in the presence of a mixture of an aromatic solvent and a C₁-C₆ alkanol to form 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine,

wherein said aromatic solvent is a mixture of xylenes;

said C₁-C₆ alkanol is n-propanol; and

the volume ratio of said mixture of xylenes to n-propanol is about 5;

1.

19. The process according to claim 18, wherein said reacting N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide with said inorganic base is conducted at a temperature of about 75°

C. to about reflux temperature.

20. The process according to claim 18, wherein said inorganic base is an alkali metal hydroxide.

21. The process according to claim 18, wherein said reacting N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide with said inorganic base is conducted at a temperature of about 75°

C. to about reflux temperature; and

wherein;

said inorganic base is sodium hydroxide.

22. The process according to claim 18, wherein said N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide is prepared by the process comprising:

reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with a brominating agent in the presence of a brominating solvent to form said N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide.

23. The process according to claim 22, wherein:

said reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with said brominating agent is conducted at a temperature of about 35°

C. to about 65°

C.;

said brominating agent is N-bromosuccinimide; and

said brominating solvent is N,N-dimethylacetamide.

24. A process for preparing 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea comprising the steps of:

a) reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with a brominating agent in the presence of a brominating solvent to form said N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide;

b) reacting N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide with an inorganic base in the presence of a mixture of an aromatic solvent and a C₁-C₆ alkanol to form 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine,

wherein said aromatic solvent is a mixture of xylenes;

said C₁-C₆ alkanol is n-propanol; and

the volume ratio of said of mixture of xylenes to n-propanol is about 5;

1; and

c) reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate in the presence of a urea-forming solvent to form 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

25. The process according to claim 24, wherein:

said reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with said brominating agent is conducted at a temperature of about 35°

C. to about 65°

C.;

said brominating agent is N-bromosuccinimide; and

said brominating solvent is N,N-dimethylacetamide.

26. The process according to claim 24, wherein said reacting N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide with said inorganic base is conducted at a temperature of about 75°

C. to about reflux temperature; and

wherein;

said inorganic base is sodium hydroxide.

27. The process according to claim 24, wherein said reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate is conducted at a temperature of about −

25°

C. to about 0°

C.

28. The process according to claim 24, wherein said reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate is conducted by adding said 2,4-difluorophenyl-isocyanate to said 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine in acetonitrile to form a reaction mixture.

29. The process according to claim 28, wherein after completion of said adding of 2,4-difluorophenyl-isocyanate, said reaction mixture is stirred until about 2% or less of said 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine is present in said reaction mixture with respect to said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea as determined by HPLC.

30. The process according to claim 24, wherein said urea-forming solvent is acetonitrile.

31. The process according to claim 30, further comprising the step of crystallizing said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea to form an acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

wherein said 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.

32. The process according to claim 31, further comprising the step of converting said acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea to form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

33. The process according to claim 32, wherein said converting said acetonitrile 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 reduced pressure of about 35 mm Hg or less at a first temperature of about 20°

C. to about 30°

C. until a loss on drying (LOD) for a representative sample from said process is at a level of about 10% or less; and

thereafter raising said first temperature to a second temperature of about 65°

C. to about 75°

C. while maintaining said reduced pressure of about 35 mm Hg or less.

48. A process for preparing a pharmaceutical composition comprising admixing:

a composition comprising 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea prepared according to the process of claim 24, wherein said composition comprises less than 0.9 mole % of 1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea; and

a pharmaceutically acceptable carrier.

34. A process for preparing Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea, said process comprising:

a) dissolving 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 said 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 said first solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea from said 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 said 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 said 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 by removing acetonitile, wherein said converting comprises reducing solvent content at a temperature sufficient to minimize conversion of said second solvate to Form II of 1-[3-(4-bromo- 2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

35. The process according to claim 34, wherein said 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 weight ratio of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea to tetrahydrofuran of about 1:

6 to about 1;

5.

36. The process according to claim 34, wherein said 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.

37. The process according to claim 34, 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).

38. The process according to claim 37, wherein said cooling is to a temperature of about −

35°

C. to about 10°

C.

39. The process according to claim 34, wherein said first solvate is a tetrahydrofuran solvate.

40. The process according to claim 34, wherein said aliphatic solvent is heptane.

41. The process according to claim 40, wherein said first solvate is a heptane solvate.

42. The process according to claim 34, wherein said converting 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 under reduced pressure.

43. The process according to claim 34, wherein said converting second 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 reduced pressure of about 35 mm Hg or less at a first temperature of about 20°

C. to about 30°

C. until a loss on drying (LOD) for a representative sample from said process is at a level of about 10% or less; and

thereafter raising said first temperature to a second temperature of about 65°

C. to about 75°

C. while maintaining said reduced pressure of about 35 mm Hg or less.

44. The process according to claim 34, wherein said second solvate is an acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

wherein said acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea 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.

49. A process for preparing a pharmaceutical composition comprising admixing:

a composition comprising Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea prepared according to the process of claim 34, wherein said composition comprises less than 0.9 mole % of 1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea; and

a pharmaceutically acceptable carrier.

46. An acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

wherein said 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.

47. A composition comprising an acetonitrile solvate of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea according to claim 46.