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 10,071,075 B2
• Filed: 08/21/2017
• Issued: 09/11/2018
• Est. Priority Date: 10/28/2008
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• 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:
  US15/681,766
• Publication Number:
  US 20180072680A1
• Time in Patent Office: 386 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 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 at a reduced pressure of about 100 mm Hg or less at a first temperature of about 0°

C. to about 45°

C. until the loss on drying is about 35%; and

thereafter raising said first temperature to a second temperature of about 45°

C. to about 90°

C., while maintaining said reduced pressure of about 100 mm Hg or less.

2. The process of claim 1 wherein said reduced pressure is about 10 mm Hg or less.

3. The process of claim 1 wherein said reduced pressure is about 5 mm Hg or less.

4. 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 step of reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl isocyanate in the presence of acetonitrile;

wherein the reaction is conducted in the presence of 10% of H₂O or less;

wherein the temperature is about −

30°

C. to about 10°

C.;

wherein the resultant reaction mixture comprises less than about 1% of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respect to 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea as determined by HPLC.

5. The process of claim 4 wherein the reaction is conducted in the presence of 1% of H₂O or less.

6. The process of claim 4 wherein the reaction is conducted in the presence of 0.1% of H₂O or less.

7. The process of claim 4 wherein the temperature is about −

15°

C. to about −

5°

C.

8. The process of claim 4 wherein the resultant reaction mixture comprises less than about 0.1% of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respect to 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea as determined by HPLC.

9. The process of claim 4 further comprising the crystallization of said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea wherein the crystallization is conducted at a temperature of about −

25°

C. to about 5°

C.

10. The process of claim 9 wherein said crystallization is conducted at a temperature of about −

10°

C. to about −

5°

C.

11. The process of claim 4 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 xylenes and n-propanol;

wherein the reaction is conducted at a temperature of about 75°

C. to reflux;

wherein the reaction is conducted in the presence of 4% or less of water;

wherein the volume ratio of the mixture of xylenes and n-propanol is about 7;

1 to about 1;

1.

12. The process of claim 11 wherein the inorganic base is selected from lithium hydroxide or potassium hydroxide.

13. The process of claim 11 wherein the reaction is conducted at a temperature of about 100°

C. to reflux.

14. The process of claim 11 wherein the reaction is conducted at a temperature of about 105°

C. to reflux.

15. The process of claim 11 wherein the reaction is conducted at a temperature of about 110°

C. to reflux.

16. The process of claim 11 wherein the reaction is conducted at a temperature of about 112°

C. to reflux.

17. The process of claim 11 wherein the reaction is conducted in the presence of 2% or less of water.

18. The process of claim 11 wherein the reaction is conducted in the presence of 1% or less of water.

19. The process of claim 11 wherein the reaction is conducted in the presence of 0.5% or less of water.

20. The process of claim 11 wherein the volume ratio of the mixture of xylenes and n-propanol is about 6:

1 to about 4;

1.

21. The process of claim 11 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 N,N-dimethylformamide at a temperature of about 25°

C. to about 100°

C.;

wherein the molar ratio of brominating agent to N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide is about 2;

1.

22. The process of claim 21 wherein said brominating agent is selected from the list consisting of Br₂, 1,3-dibromo-5,5-dimethylhydantoin, and pyridinium tribromide.

23. The process of claim 21 wherein the molar ratio is about 1.9:

1.

24. The process of claim 21 wherein the molar ratio is about 1.8:

1.

25. The process of claim 21 wherein the molar ratio is about 1.7:

1.

26. The process of claim 21 wherein the molar ratio is about 1.6:

1.

27. The process of claim 21 wherein the molar ratio is about 1.5:

1.

28. The process of claim 21 wherein the molar ratio is about 1.4:

1.

29. The process of claim 21 wherein the molar ratio is about 1.3:

1.

30. The process of claim 21 wherein the molar ratio is about 1.2:

1.

31. The process of claim 21 wherein the molar ratio is about 1.1:

1.

32. The process of claim 21 wherein the molar ratio is about 1:

1.

33. The process of claim 21 wherein the temperature is about 25°

C. to about 75°

C.

34. The process of claim 21 wherein the temperature is about 25°

C. to about 65°

C.