Processes for preparing isoquinolinones and solid forms of isoquinolinones

• US 9,290,497 B2
• Filed: 07/09/2014
• Issued: 03/22/2016
• Est. Priority Date: 01/10/2011
• Status: Active Grant

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Ren, Pingda, Martin, Michael, Isbester, Paul, Lane, Benjamin S., Kropp, Jason
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Neagu, Irina
• Application Number:
  US14/327,499
• Publication Number:
  US 20140371450A1
• Time in Patent Office: 622 Days
• Field of Search: 514/263.22, 514/263.2, 514/263.4, 514/309, 544/277
• US Class Current: 1/1
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine

Abstract

Polymorphs of chemical compounds that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including P13 kinase activity, are described herein. Also provided herein are processes for preparing compounds, polymorphs thereof, and pharmaceutical compositions thereof.

Claims

1. A method of preparing polymorph Form C of a compound of Formula (I):

2. The method of claim 1, wherein step (i) occurs in a non-anhydrous condition.

3. The method of claim 1, wherein step (ii) involves addition of an anti-solvent either with or without a cooling step to cause precipitation of Form C.

4. The method of claim 3, wherein the anti-solvent comprises water.

5. The method of claim 1, wherein the one or more reagents to remove the protecting group PG² is selected from acids, carbonate bases, hydroxide bases, lithium bases, oxidants, hydrogenation conditions, TBAF, and BF₃.Et₂O.

6. The method of claim 5, wherein the one or more reagents to remove the protecting group PG² is selected from HCl, HBr, TFA, Na₂CO₃, K₂CO₃, NaOH, KOH, methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, n-pentyl lithium, n-hexyl lithium, ceric ammonium nitrate, cyclohexadiene/Pd black, and H₂/Pd on carbon.

7. The method of claim 5, wherein the reagent to remove the protecting group PG² is an acid and PG² is 2-tetrahydropyranyl.

8. The method of claim 7, wherein the acid is HCl, HBr, or TFA.

9. The method of claim 8, wherein the acid is HCl.

10. The method of claim 7, further comprising adjusting pH of the reaction mixture after step (i) to from about 8 to about 9.

11. The method of claim 10, wherein the pH is adjusted by adding a hydroxide base.

12. The method of claim 11, wherein the hydroxide base is NH₄OH.

13. The method of claim 1, wherein PG² is 2-tetrahydropyranyl and the method comprises:

(i) reacting the compound of Formula (Ia) with HCl in a solvent of EtOH and water to form the compound of Formula (I);

(ii) adjusting pH of the reaction mixture after step (i) to from about 8 to about 9 by adding NH₄OH; and

(iii) recovering polymorph Form C.

32. The method of claim 1, wherein compound of Formula (Ia), or a salt, solvate, or hydrate thereof, is prepared by reacting compound 9 of the formula:

33. The method of claim 32, wherein PG² is 2-tetrahydropyranyl.

34. The method of claim 32, wherein compound 9 is prepared by converting a compound 8 of the formula:

35. The method of claim 34, wherein the acid is trifluoroacetic acid.

36. The method of claim 34, wherein compound 8 is prepared by reacting compound 7 of the formula:

37. The method of claim 36, wherein the reaction mixture formed after adding compound 2 is added to a solution of anisole and isobutyric acid.

14. A method of preparing polymorph Form C of a compound of Formula (I):

15. The method of claim 14, wherein the non-anhydrous condition comprises liquid water.

16. The method of claim 15, wherein the non-anhydrous condition comprises a water-miscible solvent and liquid water solvent system.

17. The method of claim 16, wherein the liquid water is present in an amount selected from about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100% by volume of the solvent system.

18. The method of claim 17, wherein said liquid water is present in an amount between about 85% to about 95% by volume of the solvent system.

19. The method of claim 14, wherein the one or more non-Form C polymorphs are selected from the group consisting of Form A, Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J, amorphous form, or a salt, solvate, or hydrate thereof, and mixtures thereof;

wherein

polymorph Form A has the following characteristic XRPD peaks;

2θ

=9.6°

(±

0.2°

), 12.2°

(±

0.2°

), and 18.3°

(±

0.2°

);

polymorph Form B has the following characteristic XRPD peaks;

2θ

=7.9°

(±

0.2°

), 13.4°

(±

0.2°

), and 23.4°

(±

0.2°

);

polymorph Form D has the following characteristic XRPD peaks;

2θ

=11.4°

(±

0.2°

), 17.4°

(±

0.2°

), and 22.9°

(±

0.2°

);

polymorph Form E has the following characteristic XRPD peaks;

2θ

=6.7°

(±

0.2°

), 9.3°

(±

0.2°

), and 24.4°

(±

0.2°

);

polymorph Form F has the following characteristic XRPD peaks;

2θ

=9.6°

(±

0.2°

), 17.3°

(±

0.2°

), and 24.6°

(±

0.2°

);

polymorph Form G has the following characteristic XRPD peaks;

2θ

=6.7°

(±

0.2°

), 9.5°

(±

0.2°

), and 19.0°

(±

0.2°

);

polymorph Form H has the following characteristic XRPD peaks;

2θ

=8.9°

(±

0.2°

), 9.2°

(±

0.2°

), and 14.1°

(±

0.2°

);

polymorph Form I has the following characteristic XRPD peaks;

2θ

=9.7°

(±

0.2°

), 19.3°

(±

0.2°

), and 24.5°

(±

0.2°

); and

polymorph Form J has the following characteristic XRPD peaks;

2θ

=9.1°

(±

0.2°

), 17.3°

(±

0.2°

), and 18.3°

(±

0.2°

).

20. The method of claim 19, wherein the one or more non-Form C polymorphs comprise at least about 50% by weight polymorph Form A.

21. The method of claim 19, wherein the one or more non-Form C polymorphs comprise at least about 50% by weight amorphous form.

22. A method of preparing polymorph Form C of a compound of Formula (I):

23. The method of claim 22, wherein the solvent system comprises water and isopropanol.

24. The method of claim 22, wherein Form A is placed in water or a water-containing solvent system to form a slurry for about 18-24 hours.

25. The method of claim 22, wherein Form A is prepared by re-slurrying one or more non-Form A polymorph(s) in an anhydrous solvent.

26. The method of claim 25, wherein the anhydrous solvent is chloroform, dichloromethane, isopropyl alcohol, ethanol, or a mixture thereof.

27. The method of claim 26, wherein the anhydrous solvent is dichloromethane.

28. The method of claim 25, wherein the one or more non-Form A polymorph(s) is Form C.

29. A method of preparing polymorph Form C of a compound of Formula (I):

30. The method of claim 29, wherein the solids recovered in the first slurry is polymorph Form A, wherein polymorph Form A has the following characteristic XRPD peaks:

2θ

=9.6°

(±

0.2°

), 12.2°

(±

0.2°

), and 18.3°

(±

0.2°

).

31. The method of claim 29, wherein the second slurry is prepared in a water-containing solvent system that further comprises isopropanol.