Processes for preparing isoquinolinones and solid forms of isoquinolinones

Patent metadata

Field	Value
Publication number	US-9290497-B2
Application number	US-201414327499-A
Country	US
Kind code	B2
Filing date	Jul 9, 2014
Priority date	Jan 10, 2011
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

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.

First claim

What is claimed is:

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

comprising:
(i) reacting a compound of Formula (Ia):

wherein
PG 2 is a protecting group selected from methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl, benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl, and
where substituents are selected from alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate, and carbonate;
with one or more reagents to remove the protecting group PG 2 to form the compound of Formula (I); and
(ii) recovering the compound of Formula (I) to provide Form C;
wherein at least one of steps (i) and (ii) occurs in a non-anhydrous condition;
and wherein polymorph Form C has the following characteristic XRPD peaks: 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°).

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 PG 2 is selected from acids, carbonate bases, hydroxide bases, lithium bases, oxidants, hydrogenation conditions, TBAF, and BF 3 .Et 2 O.

6. The method of claim 5 , wherein the one or more reagents to remove the protecting group PG 2 is selected from HCl, HBr, TFA, Na 2 CO 3 , K 2 CO 3 , NaOH, KOH, methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, n-pentyl lithium, n-hexyl lithium, ceric ammonium nitrate, cyclohexadiene/Pd black, and H 2 /Pd on carbon.

7. The method of claim 5 , wherein the reagent to remove the protecting group PG 2 is an acid and PG 2 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 NH 4 OH.

13. The method of claim 1 , wherein PG 2 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 NH 4 OH; and
(iii) recovering polymorph Form C.

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

comprising:
(i) exposing a composition comprising at least one non-Form C polymorph of a compound of Formula (I), or a salt, solvate, or hydrate thereof, to a non-anhydrous condition for a period of time sufficient to convert at least about 50% of the total amount of non-Form C polymorph(s) into Form C; and
(ii) recovering said polymorph Form C;
wherein polymorph Form C has the following characteristic XRPD peaks: 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°).

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):

comprising placing Form A in water or a water-containing solvent system; wherein
polymorph Form C has the following characteristic XRPD peaks: 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°); and
polymorph Form A has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°).

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,

Assignees

• Infinity Pharmaceuticals Inc

Inventors

• Ren Pingda
• Martin Michael
• Isbester Paul
• Lane Benjamin S
• Kropp Jason

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07B2200/07

  Optical isomers · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/4725

  containing further heterocyclic rings · CPC title