Granted Patent B2

US 8,193,204 · App. 12/237,455 · Granted Jun 5, 2012

Abstract

Claims (37)

1. Crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate or a pharmaceutically acceptable salt thereof.

2. A compound, which is crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.

3. The compound of claim 2 , which has a melting point of about 104° C.

4. The compound of claim 2 , which has an X-ray powder diffraction pattern with peaks at one or more of about 10.7, 12.2, 12.8, 17.7 and/or 22.0 degrees 2 θ.

5. The compound of claim 2 , which has an X-ray powder diffraction pattern that is substantially the same as that shown in FIG. 1 .

6. A crystalline salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl) phenyl)propanoate.

7. The crystalline salt of claim 6 , which is a hippurate salt.

8. The crystalline salt of claim 7 , which has a melting point of about 145° C.

9. The crystalline salt of claim 7 , which has an X-ray powder diffraction pattern comprising peaks at one or more of about 8.2, 9.5, 12.6, 16.9, 21.8, 22.0, 22.7, 24.3 and/or 29.1 degrees 2θ.

10. The crystalline salt of claim 7 , which has an X-ray powder diffraction pattern that is substantially the same as that shown in FIG. 2 .

11. The crystalline salt of claim 7 , which has a Raman spectrum that is substantially the same as that shown in FIG. 3 .

12. The crystalline salt of claim 6 , which is a succinate salt.

13. The crystalline salt of claim 12 , which has an X-ray powder diffraction pattern comprising peaks at one or more of about 7.7, 11.5, 11.7, 15.7, 17.9, 21.1 and/or 23.2 degrees 2θ.

14. The crystalline salt of claim 12 , which has an X-ray powder diffraction pattern that is substantially the same as that shown in FIG. 4 .

15. A method of preparing a crystalline salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate, which comprises:

contacting a solution comprising (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate with pharmaceutically acceptable acid under conditions sufficient to provide a salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H -pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate;

reducing the solubility of the salt in the solution under conditions sufficient to provide a crystalline salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate; and

isolating the crystalline salt.

16. The method of claim 15 , wherein the solution comprises isopropyl acetate, ethyl acetate, ethanol, isopropanol, methyl t-butyl ether, or methyl isobutylketone.

17. The method of claim 15 , wherein the acid is hippuric or succinic acid.

18. The method of claim 15 , wherein the solubility of the salt is reduced by cooling the solution.

19. The method of claim 15 , wherein the amount of the dissolved salt is reduced by increasing the concentration of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate in the solution.

20. The method of claim 15 , wherein the solubility of the salt is reduced by adding to the solution an anti-solvent.

21. The method of 20 , wherein the anti-solvent is heptane.

22. A method of preparing crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R) -1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate,which comprises:

adding a basic aqueous solution to an organic suspension to provide a mixture having organic and aqueous components, wherein the organic suspension comprises a salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate and an organic solvent;

isolating the organic component from the mixture; and

cooling and/or concentrating the organic component to provide crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate; and

isolating the crystalline free base.

23. The method of claim 22 , wherein the salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate is a hippurate salt.

24. The method of claim 22 , wherein the organic solvent is an ether.

25. The method of claim 22 , wherein the basic aqueous solution comprises sodium bicarbonate.

26. The method of claim 22 , which further comprises washing the crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate with an organic solvent.

27. A pharmaceutical dosage form comprising crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.

28. A pharmaceutical dosage form comprising a crystalline salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.

29. The dosage form of claim 28 , wherein the salt is a hippurate salt.

30. The dosage form of claim 28 , wherein the salt is a succinate salt.

Assignments (15)