Processes for preparing isoquinolinones and solid forms of isoquinolinones
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-473/34
A61K-031/52
A61P-035/00
출원번호
US-0327499
(2014-07-09)
등록번호
US-9290497
(2016-03-22)
발명자
/ 주소
Ren, Pingda
Martin, Michael
Isbester, Paul
Lane, Benjamin S.
Kropp, Jason
출원인 / 주소
Infinity Pharmaceuticals, Inc.
대리인 / 주소
Jones Day
인용정보
피인용 횟수 :
6인용 특허 :
268
초록▼
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 ar
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.
대표청구항▼
1. A method of preparing polymorph Form C of a compound of Formula (I): comprising: (i) reacting a compound of Formula (Ia): wherein PG2 is a protecting group selected from methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benz
1. A method of preparing polymorph Form C of a compound of Formula (I): comprising: (i) reacting a compound of Formula (Ia): wherein PG2 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, andwhere 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 PG2 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 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. 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°); andpolymorph 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°); andpolymorph 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, 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): wherein the method comprises: (i) preparing a first slurry of polymorph Form C in dichloromethane;(ii) recovering the solids in the first slurry by filtration;(iii) preparing a second slurry of the solids recovered in step ii) in water or a water-containing solvent system; and(iv) recovering the solids in the second slurry by filtration to give 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°). 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. 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: with a protected chloropurine compound of the formula: in the presence of Et3N in an alcoholic solvent selected from MeOH, EtOH, PrOH, and iPrOH. 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: in the presence of an acid selected from trifluoroacetic acid and methanesulfonic acid in a solvent selected from methanol or isopropyl alcohol. 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: with n-hexyl lithium, and adding compound 2 of the formula: wherein compound 2 is previously treated with isopropyl Grignard before being added to the mixture of compound 7 and n-hexyl lithium. 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.
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이 특허에 인용된 특허 (268)
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