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Title:
METHODS FOR CHIRAL RESOLUTION OF TROLOX
Document Type and Number:
WIPO Patent Application WO/2016/100576
Kind Code:
A1
Abstract:
The invention relates to methods of separating Trolox isomers (R)-Trolox and (S)-Trolox, comprising: (a) contacting a mixture of (R) and (S)-Trolox with a resolving agent selected from the group consisting of (1S,2S)-(+)-Pseudoephedrine, (R)-(+)-2-Amino-3-phenyl-1-propanol, (1R,2R)-(-)-Pseudoephedrine, and (S)-(-)-2-Amino-3-phenyl-1-propanol, wherein the resolving agent forms a solid salt with one of (R)-Trolox and (S)-Trolox, and substantially does not form a solid salt with the other; and (b) separating the solid salt from the Trolox isomer that did not form the solid salt with the resolving agent.

Inventors:
MILLER, Guy M. (Inc.350 North Bernardo Avenu, Mountain View California, 94043, US)
MOLLARD, Paul (Inc.350 North Bernardo Avenu, Mountain View California, 94043, US)
SHRADER, William D. (Inc.350 North Bernardo Avenu, Mountain View California, 94043, US)
KHEIFETS, Viktoria (Inc.350 North Bernardo Avenu, Mountain View California, 94043, US)
TRIMMER, Jeffrey K. (Inc.350 North Bernardo Avenu, Mountain View California, 94043, US)
Application Number:
US2015/066208
Publication Date:
June 23, 2016
Filing Date:
December 16, 2015
Export Citation:
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Assignee:
EDISON PHARMACEUTICALS, INC. (350 North Bernardo Avenue, Mountain View, California, 94043, US)
MILLER, Guy M. (Inc.350 North Bernardo Avenu, Mountain View California, 94043, US)
International Classes:
C07D311/72; A61K31/122; A61P25/28; C07B57/00; C07C235/78
Domestic Patent References:
WO2002012221A12002-02-14
WO2006130775A22006-12-07
Foreign References:
US20090118257A12009-05-07
US4018799A1977-04-19
JPH1180149A1999-03-26
EP2088144A12009-08-12
US5348973A1994-09-20
JP2009278930A2009-12-03
US20080082374W2008-11-04
US3947473A1976-03-30
US4003919A1977-01-18
US4026907A1977-05-31
US20110251407A12011-10-13
US20090035996W2009-03-04
US20090060489W2009-10-13
Other References:
COHEN NOAL ET AL: "Studies on the total synthesis of (2R, 4'R, 8'R)-.alpha.-tocopherol (vitamin E). Stereospecific cyclizations leading to optically active chromans", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 46, no. 12, June 1981 (1981-06-01), pages 2445 - 2450, XP002638190, ISSN: 0022-3263, DOI: 10.1021/JO00325A004
BERGE S.M. ET AL.: "Pharmaceutical salts", 1. PHARM. SCI., vol. 66, no. 1, January 1977 (1977-01-01), pages 1 - 19
ZN, ACOH FUCHS ET AL., EJOC, vol. 6, 2009, pages 833 - 40
LEE, DIFFUSION-CONTROLLED MATRIX SYSTEMS, pages 155 - 198
RON; LANGER: "Treatise on Controlled Drug Delivery", 1992, MARCEL DEKKER, INC., article "Erodible Systems", pages: 199 - 224
PRESCOTT,: "Methods in Cell Biology", vol. XIV, 1976, ACADEMIC PRESS, pages: 33
Attorney, Agent or Firm:
PATHAK, Rahul et al. (Squire Patton Boggs LLP, 600 Hansen WayPalo Alto, California, 94304, US)
Download PDF:
Claims:
CLAIMS

What is claimed is:

1. A method of separating Trolox isomers (R)-Trolox and (S)-Trolox, comprising:

(a) contacting a mixture of (R) and (S)-Trolox with a resolving agent selected from the group consisting of (l S,2S)-(+)-Pseudoephedrine, (R)-(+)-2-Amino-3 -phenyl- 1-propanol, (lR,2R)-(-)-Pseudoephedrine, and (S)-(-)-2-Amino-3 -phenyl- 1-propanol, wherein the resolving agent forms a solid salt with one of (R)-Trolox and (S)-Trolox, and substantially does not form a solid salt with the other; and

(b) separating the solid salt from the Trolox isomer that did not form the solid salt with the resolving agent.

2. The method of claim 1, wherein step (a) comprises dissolving the mixture of (R) and (S)-Trolox and the resolving agent in a solvent.

3. The method of claim 2, wherein step (a) comprises: (i) heating the mixture of (R) and (S)-Trolox and the resolving agent in the solvent until dissolution occurs; and (ii) cooling the mixture from (i).

4. The method of claim 3, wherein the heating in step (a)(i) comprises heating to reflux temperature.

5. The method of claim 3 or 4, wherein the cooling in step (a)(ii) occurs over at least about two hours.

6. The method of claim 3 or 4, wherein the cooling in step (a)(ii) occurs over at least about eight hours.

7. The method of any one of claims 3-6, wherein the cooling in step (a)(ii) comprises cooling to about 0°C to about 30°C.

8. The method of any one of claims 3-6, wherein the cooling in step (a)(ii) comprises cooling to about 20°C to about 26°C.

9. The method of any one of claims 2-8, wherein the solvent is a polar solvent.

10. The method of claim 9, wherein the solvent is ethyl acetate.

11. The method of claim 9, wherein the solvent is isopropyl acetate.

12. The method of claim 9, wherein the solvent is ethyl acetate with 1% water.

13. The method of claim 9, wherein the solvent is 2-methyltetrahydrofuran.

14. The method of any one of claims 2-13, wherein about 3 to about 7 volumes of solvent are added in step (a).

15. The method of claim 14, wherein about 4 to about 6 volumes of solvent are added in step (a).

16. The method of any one of claims 1-15, wherein about 0.50 to about 2.0 equivalents of resolving agent are used in step (a).

17. The method of any one of claims 1-15, wherein about 0.60 to about 1.30 equivalents of resolving agent are used in step (a).

18. The method of any one of claims 1-15, wherein about 0.80 to about 1.30 equivalents of resolving agent are used in step (a).

19. The method of any one of claims 1-15, wherein about 0.95 to about 1.20 equivalents of resolving agent are used in step (a).

20. The method of any one of claims 1-15, wherein about 1.05 equivalents of resolving agent are used in step (a).

21. The method of any one of claims 1-15, wherein about 1.15 equivalents of resolving agent are used in step (a).

22. The method of any one of claims 1-21, wherein step (a) comprises: (i) evaporating any solvents present, and (ii) adding diethyl ether to the mixture.

23. The method of any one of claims 1-22, wherein the mixture in step (a) is seeded with the desired solid salt.

24. The method of any one of claims 1-23, wherein step (b) comprises filtering the solid salt.

25. The method of claim 24, wherein step (b) further comprises a step (b)(1), comprising slurrying the solid salt in the solvent.

26. The method of claim 24 or 25, wherein step (b) and/or step (b)(1) further comprise rinsing and drying the solid salt.

27. The method of any one of claims 1-26, wherein the method further comprises a step (c): a. separating the Trolox isomer contained in the solid salt from the resolving agent.

28. The method of claim 27, wherein step (c) comprises adding an acid to the solid salt.

29. The method of any one of claims 1-28, wherein the resolving agent is (1 S,2S)- (+)-Pseudoephedrine.

30. The method of any one of claims 1-28, wherein the resolving agent is (R)-(+)-2- Amino-3 -phenyl- 1 -propanol .

31. The method of any one of claims 1-30, wherein the Trolox isomer that forms the solid salt with the resolving agent is (R)-Trolox.

32. The method of claim 1, comprising: (1) contacting a mixture of (R)-Trolox and (S)-Trolox with about 1.10 to about 1.20 equivalents of (l S,2S)-(+)-Pseudoephedrine and about 4 to about 6 volumes of ethyl acetate; (2) heating the mixture to between about 35°C to about 55°C until dissolution is achieved; (3) cooling the mixture to about 20°C to about 30°C over at least about 50 minutes; (4) cooling the mixture to about 5°C to about 15°C over about 20 to about 40 minutes; (5) holding the temperature in step (4) for about 50-70 minutes; (7) filtering the resulting slurry; (8) washing the wet cake with about 5 to about 7 volumes of ethyl acetate at room temperature; (9) and drying the solids.

33. The method of claim 31 or 32, wherein the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 98%.

34. The method of claim 31 or 32, wherein the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 99%.

35. The method of claim 31 or 32, wherein the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 99.5%.

36. The method of claim 31 or 32, wherein the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 99.9%.

37. The method of any one of claims 31-36, wherein the (R)-Trolox that is obtained from the method is converted to (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide or the hydroquinone form thereof, or a salt thereof.

38. The method of any one of claims 31-36, wherein the (R)-Trolox that is obtained from the method is converted to (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide, or a salt thereof.

39. A composition comprising (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide or the hydroquinone form thereof, or a salt thereof, produced according to the method of claim 37.

40. A composition comprising (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide or a salt thereof, produced according to the method of claim 38.

41. A pharmaceutical composition comprising the (R)-2-hydroxy-2-methyl-4-(2,4,5- trimethyl-3,6-dioxocyclohexa-l,4-dienyl)butanamide or hydroquinone form thereof of claim 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

42. A pharmaceutical composition comprising the (R)-2-hydroxy-2-methyl-4-(2,4,5- trimethyl-3,6-dioxocyclohexa-l,4-dienyl)butanamide of claim 40, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

43. A method of treating or suppressing an oxidative stress disorder, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 41 or 42 to a subject in need thereof.

44. The compound (R)-Trolox (l S,2S)-(+)-Pseudoephedrine salt.

45. The compound (R)-Trolox (R)-(+)-2-Amino-3 -phenyl- 1-propanol salt.

46. The method of any one of claims 1-28, wherein the resolving agent is (lR,2R)-(- )-Pseudoephedrine.

47. The method of any one of claims 1-28, wherein the resolving agent is (S)-(-)-2- Amino-3 -phenyl- 1 -propanol .

48. The method of any one of claims 1-28, 46 or 47, wherein the Trolox isomer that forms the solid salt with the resolving agent is (S)-Trolox.

49. The method of claim 46 or 47, wherein the enantiomeric excess of the (S)-Trolox obtained from the method is at least about 98%.

50. The method of claim 46 or 47, wherein the enantiomeric excess of the (S)-Trolox obtained from the method is at least about 99%.

51. The method of claim 46 or 47, wherein the enantiomeric excess of the (S)-Trolox obtained from the method is at least about 99.5%.

52. The method of claim 46 or 47, wherein the enantiomeric excess of the (S)-Trolox obtained from the method is at least about 99.9%.

53. The method of any one of claims 46-52, wherein the (S)-Trolox that is obtained from the method is converted to (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa- l,4-dienyl)butanamide or the hydroquinone form thereof, or a salt thereof.

54. The method of any one of claims 46-52, wherein the (S)-Trolox that is obtained from the method is converted to (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa- l,4-dienyl)butanamide, or a salt thereof.

55. A composition comprising (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide or the hydroquinone form thereof, or a salt thereof, produced according to the method of claim 53.

56. A composition comprising (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide or a salt thereof, produced according to the method of claim 54.

57. A pharmaceutical composition comprising the (S)-2-hydroxy-2-methyl-4-(2,4,5- trimethyl-3,6-dioxocyclohexa-l,4-dienyl)butanamide or hydroquinone form thereof of claim 55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

58. A pharmaceutical composition comprising the (S)-2-hydroxy-2-methyl-4-(2,4,5- trimethyl-3,6-dioxocyclohexa-l,4-dienyl)butanamide of claim 56, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

59. A method of treating or suppressing an oxidative stress disorder, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 57 or 58 to a subject in need thereof.

60. The compound (S)-Trolox (lR,2R)-(-)-Pseudoephedrine salt.

61. The compound (S)-Trolox (S)-(-)-2-Amino-3 -phenyl- 1-propanol salt.

Description:
METHODS FOR CHIRAL RESOLUTION OF TROLOX

[0001] The application claims priority to, and the benefit of, U.S. Provisional Patent Application

No. 62/092,743, filed December 16, 2014, entitled POLYMORPHIC AND AMORPHOUS

FORMS OF (R)-2-HYDROXY-2-METHYL-4-(2,4,5-TRFMETHYL-3,6-

DIOXOC YCLOHEXA- 1 ,4-DIENYL)BUT AN AMIDE, and U.S. Provisional Patent Application

No. 62/133,276, filed March 13, 2015, entitled POLYMORPHIC AND AMORPHOUS

FORMS OF (R)-2-HYDROXY-2-METHYL-4-(2,4,5-TRFMETHYL-3,6-

DIOXOC YCLOHEXA- 1 ,4-DIENYL)BUT AN AMIDE, the contents of both of which are herein incorporated by reference in their entirety for all purposes.

BACKGROUND

[0002] PCT Application No. PCT/US2008/082374 describes a synthesis for racemic 2-hydroxy- 2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl)bu tanamide, which is useful for treating and/or suppressing mitochondrial disorders and certain pervasive developmental disorders, from racemic Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid).

[0003] Chiral resolving agents may be useful in separating enantiomers. For example, a chiral resolving agent may form a solid salt with one enantiomer, but not with the other enantiomer (which remains in solution or as an oil); the two enantiomers may then be separated by filtering the solid. However, not all resolving agents are useful for separating the enantiomers of a particular compound. Furthermore, resolving agents differ in their ability to provide, for example, better resolution, higher yields, easier scale up, and/or improved ease of use.

[0004] Racemic Trolox has been previously resolved into its (R) and (S)-isomers with a-methyl benzyl amine (MBA) and R-(+)-N-Benzyl-a-phenylethylamine resolving agents. See, for example, US Patent Nos. 3,947,473, 4,003,919, and 4,026,907, and U.S. Patent Application Publication No. 2011/0251407.

[0005] What is needed are improved methods, reagents, and reagent mixtures and combinations, for synthesizing particular stereoisomers of 2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide, such as (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide and (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide. In particular, what is needed are improved methods for obtaining specific Trolox enantiomers in high purity.

BRIEF SUMMARY OF THE INVENTION

[0006] In one aspect of the invention is a method of separating Trolox isomers (R)-Trolox and (S)-Trolox, comprising: (a) contacting a mixture of (R) and (S)-Trolox with a resolving agent selected from the group consisting of N-m ethyl -D-glucamine, L-Arginine, L-Lysine, (1 S,2S)- (+)-Pseudoephedrine, (R)-(-)-Leucinol, D-Lysine, (R)-(+)-2-Amino-3 -phenyl- 1-propanol, (lR,2R)-(-)-Pseudoephedrine, and (S)-(-)-2-Amino-3 -phenyl- 1-propanol, wherein a solid salt forms between the resolving agent and only one of (R)-Trolox and (S)-Trolox, and substantially does not form a solid salt with the other; and (b) separating the solid salt from the Trolox isomer that did not form the solid salt with the resolving agent. In some embodiments, the resolving agent is (l S,2S)-(+)-Pseudoephedrine. In some embodiments, the resolving agent is (R)-(+)-2- Amino-3 -phenyl- 1-propanol. In some embodiments, the resolving agent is (lR,2R)-(-)- Pseudoephedrine. In some embodiments, the resolving agent is and (S)-(-)-2-Amino-3 -phenyl- 1- propanol. In some embodiments, the resolving agent is N-methyl-D-glucamine. In some embodiments, the resolving agent is L-Arginine. In some embodiments, the resolving agent is L- Lysine. In some embodiments, the resolving agent is (R)-(-)-Leucinol. In some embodiments, the resolving agent is D-Lysine. In some embodiments, the method is a method of separating Trolox isomers (R)-Trolox and (S)-Trolox, comprising: (a) contacting a mixture of (R) and (S)- Trolox with a resolving agent selected from the group consisting of (1 S,2S)-(+)-

Pseudoephedrine, (R)-(+)-2-Amino-3-phenyl-l-propanol, (lR,2R)-(-)-Pseudoephedrine, and (S)- (-)-2-Amino-3 -phenyl- 1-propanol wherein the resolving agent forms a solid salt with one of (R)- Trolox and (S)-Trolox, and substantially does not form a solid salt with the other; and (b) separating the solid salt from the Trolox isomer that did not form the solid salt with the resolving agent. In some embodiments, step (a) comprises dissolving the mixture of (R) and (S)-Trolox and the resolving agent in a solvent. In some embodiments, including any of the foregoing embodiments, step (a) comprises: (i) heating the mixture of (R) and (S)-Trolox and the resolving agent in the solvent until dissolution occurs; and (ii) cooling the mixture from (i). In some embodiments, including any of the foregoing embodiments, the heating in step (a)(i) comprises heating to reflux temperature. In some embodiments, including any of the foregoing

embodiments, the cooling in step (a)(ii) occurs over at least about one hour. In some embodiments, including any of the foregoing embodiments, the cooling in step (a)(ii) occurs over at least about two hours. In some embodiments, including any of the foregoing

embodiments, the cooling in step (a)(ii) occurs over at least about eight hours. In some embodiments, including any of the foregoing embodiments, the cooling in step (a)(ii) comprises cooling to about 0°C to about 30°C. In some embodiments, including any of the foregoing embodiments, the cooling in step (a)(ii) comprises cooling to about 20°C to about 30°C. In some embodiments, including any of the foregoing embodiments, the cooling in step (a)(ii) comprises cooling to about 20°C to about 26°C. In some embodiments, including any of the foregoing embodiments, the solvent is a polar solvent. In some embodiments, including any of the foregoing embodiments, the solvent is ethyl acetate. In some embodiments, including any of the foregoing embodiments, the solvent is isopropyl acetate. In some embodiments, including any of the foregoing embodiments, the solvent is ethyl acetate with 1% water. In some embodiments, including any of the foregoing embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, including any of the foregoing embodiments, about 3 to about 7 volumes of solvent are added in step (a). In some embodiments, including any of the foregoing

embodiments, about 4 to about 6 volumes of solvent are added in step (a). In various

embodiments, including any of the foregoing embodiments, about 3 volumes of solvent, about 4 volumes of solvent, about 5 volumes of solvent, about 6 volumes of solvent, or about 7 volumes of solvent are added in step (a). In some embodiments, including any of the foregoing embodiments, about 0.50 to about 2.0 equivalents of resolving agent are used in step (a). In some embodiments, including any of the foregoing embodiments, about 0.60 to about 1.30 equivalents of resolving agent are used in step (a). In some embodiments, including any of the foregoing embodiments, about 0.80 to about 1.30 equivalents of resolving agent are used in step (a). In some embodiments, including any of the foregoing embodiments, about 0.95 to about 1.20 equivalents of resolving agent are used in step (a). In some embodiments, including any of the foregoing embodiments, about 1.05 equivalents of resolving agent are used in step (a). In some embodiments, including any of the foregoing embodiments, about 1.15 equivalents of resolving agent are used in step (a). In various embodiments, including any of the foregoing embodiments, about 0.5 to about 2 equivalents, about 0.6 to about 1.5 equivalents, about 0.9 to about 1.5 equivalents, about 1.00 to about 1.10 equivalents, about 0.65 to about 1.25 equivalents, about 0.50 to about 0.60 equivalents, about 0.60 to about 0.70 equivalents, about 0.80 to about 0.90 equivalents, about 0.80 to about 1.30 equivalents, about 0.85 to about 1.25 equivalents, about 0.95 to about 1.05 equivalents, about 0.95 to about 1.20 equivalents, about 0.95 to about 1.20 equivalents, about 1.10 to about 1.20 equivalents, about 1.20 to about 1.30 equivalents, about 0.50 to about 0.60 equivalents, about 0.50 equivalents, about 0.55 equivalents, about 0.60 equivalents, about 0.65 equivalents, about 0.70 equivalents, about 0.75 equivalents, about 0.80 equivalents, about 0.85 equivalents, about 0.90 equivalents, about 0.95 equivalents, about 1.00 equivalents, about 1.05 equivalents, about 1.10 equivalents, about 1.15 equivalents, about 1.20 equivalents, about 1.25 equivalents, or about 1.30 equivalents of resolving agent are used in step (a). In some embodiments, including any of the foregoing embodiments, step (a) comprises: (i) evaporating any solvents present, and (ii) adding diethyl ether to the mixture. In some embodiments, including any of the foregoing embodiments, the diethyl ether is removed. In some embodiments, including any of the foregoing embodiments, the mixture in step (a) is seeded with the desired solid salt. In some embodiments, including any of the foregoing embodiments, step (b) comprises filtering the solid salt. In some embodiments, including any of the foregoing embodiments, step (b) further comprises a step (b)(1), comprising slurrying the solid salt in the solvent. In some embodiments, including any of the foregoing embodiments, step (b) and/or step (b)(1) further comprise rinsing and drying the solid salt. In some

embodiments, including any of the foregoing embodiments, the method further comprises a step (c): (c) separating the Trolox isomer contained in the solid salt from the resolving agent. In some embodiments, including any of the foregoing embodiments, step (c) comprises adding an acid to the solid salt. In some embodiments, including any of the foregoing embodiments, step (c) comprises adding a base to the solid salt. In some embodiments, including any of the foregoing embodiments, the resolving agent is (l S,2S)-(+)-Pseudoephedrine. In some embodiments, including any of the foregoing embodiments, the resolving agent is (R)-(+)-2- Amino-3 -phenyl- 1-propanol. In some embodiments, including any of the foregoing

embodiments, the resolving agent is (lR,2R)-(l)-Pseudoephedrine. In some embodiments, including any of the foregoing embodiments, the resolving agent is (S)-(-)-2- Amino-3 -phenyl- 1- propanol. In some embodiments, including any of the foregoing embodiments, the Trolox isomer that forms the solid salt with the resolving agent is (R)-Trolox. In some embodiments, including any of the foregoing embodiments, the Trolox isomer that forms the solid salt with the resolving agent is (S)-Trolox. In some embodiments, including any of the foregoing embodiments, the mixture of (R)-Trolox and (S)-Trolox is a racemic mixture. [0007] In some embodiments, including any of the foregoing embodiments in the preceding paragraph, the Trolox isomer that forms the solid salt with the resolving agent is (R)-Trolox. In some embodiments, including any of the foregoing embodiments, the resolving agent is (1 S,2S)- (+)-Pseudoephedrine. In some embodiments, including any of the foregoing embodiments, the resolving agent is (R)-(+)-2-Amino-3 -phenyl- 1-propanol. In some embodiments, the method comprises: (1) contacting a mixture of (R)-Trolox and (S)-Trolox with about 0.8 to about 1.30 equivalents of (l S,2S)-(+)-Pseudoephedrine and ethyl acetate; (2) heating the mixture until dissolution is achieved; (3) cooling the mixture to about 20°C to about 30°C over at least about 50 minutes; (4) cooling the mixture to about 5°C to about 15°C; (7) filtering the resulting slurry; (8) washing the wet cake with ethyl acetate; (9) and drying the solids. In some embodiments, the method comprises: (1) contacting a mixture of (R)-Trolox and (S)-Trolox with about 1.10 to about 1.20 equivalents of (l S,2S)-(+)-Pseudoephedrine and about 4 to about 6 volumes of ethyl acetate; (2) heating the mixture to between about 35°C to about 55°C until dissolution is achieved; (3) cooling the mixture to about 20°C to about 30°C over at least about 50 minutes; (4) cooling the mixture to about 5°C to about 15°C over about 20 to about 40 minutes; (5) holding the temperature in step (4) for about 50-70 minutes; (7) filtering the resulting slurry; (8) washing the wet cake with about 5 to about 7 volumes of ethyl acetate at room temperature; (9) and drying the solids. In some embodiments, the method comprises: (1) contacting a mixture of (R)-Trolox and (S)-Trolox with about 1.15 equivalents of (l S,2S)-(+)-Pseudoephedrine and about 5 volumes of ethyl acetate; (2) heating the mixture to between about 40°C to about 50°C until dissolution is achieved; (3) cooling the mixture to room temperature over at least about 50 minutes; (4) cooling the mixture to about 10°C over about 30 minutes; (5) holding the temperature in step (4) for about 50-70 minutes; (7) filtering the resulting slurry; (8) washing the wet cake with about 6 volumes of ethyl acetate at room temperature; (9) and drying the solids. In some embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 98%. In some embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (R)-Trolox or salt thereof obtained from the method is at least about 99%. In some embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (R)-Trolox or salt thereof obtained from the method is at least about 99.5%. In some embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (R)-Trolox or salt thereof obtained from the method is at least about 99.9%. In various embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (R)-Trolox or salt thereof obtained from the method is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%), at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45% at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In various embodiments, including any of the foregoing embodiments, the yield of the (R)-Trolox or salt thereof obtained from the method is at least about 50%, at least about 55%), at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%. In various embodiments, including any of the foregoing embodiments, the purity of the (R)-Trolox or salt thereof obtained from the method, exclusive of any solvents, carriers or excipients, is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%), at least about 99.45% at least about 99.5%, at least about 99.6%, at least about 99.7%), at least about 99.8%, or at least about 99.9%. In some embodiments, the yield of the (R)- Trolox or salt thereof is at least about 50%, the enantiomeric excess is at least about 97%, and the purity is at least about 99%. In some embodiments, the yield of the (R)-Trolox or salt thereof is at least about 70%, the enantiomeric excess is at least about 98%, and the purity is at least about 99%. In some embodiments, the yield of the (R)-Trolox or salt thereof is at least about 75%), the enantiomeric excess is at least about 99%, and the purity is at least about 99%. In some embodiments, the yield of the (R)-Trolox or salt thereof is at least about 80%, the enantiomeric excess is at least about 99.5%, and the purity is at least about 99%. In various embodiments, including any of the foregoing embodiments, the (R)-Trolox or salt thereof that is obtained from the method is converted to (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa -l,4- dienyl)butanamide or a salt thereof. [0008] In some embodiments, including any of the foregoing embodiments in the paragraph preceding the above paragraph, the Trolox isomer that forms the solid salt with the resolving agent is (S)-Trolox. In some embodiments, including any of the foregoing embodiments, the resolving agent is (lR,2R)-(-)-Pseudoephedrine. In some embodiments, including any of the foregoing embodiments, the resolving agent is (S)-(-)-2-Amino-3 -phenyl- 1-propanol.

In some embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (S)-Trolox or salt thereof obtained from the method is at least about 98%. In some embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (S)- Trolox or salt thereof obtained from the method is at least about 99%. In some embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (S)-Trolox or salt thereof obtained from the method is at least about 99.5%. In some embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (S)-Trolox or salt thereof obtained from the method is at least about 99.9%. In various embodiments, including any of the foregoing embodiments, the enantiomeric excess of the (S)-Trolox or salt thereof obtained from the method is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%), at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45% at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In various embodiments, including any of the foregoing embodiments, the yield of the (S)-Trolox or salt thereof obtained from the method is at least about 50%, at least about 55%), at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%. In various embodiments, including any of the foregoing embodiments, the purity of the (S)-Trolox or salt thereof obtained from the method, exclusive of any solvents, carriers or excipients, is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%), at least about 99.45% at least about 99.5%, at least about 99.6%, at least about 99.7%), at least about 99.8%, or at least about 99.9%. In some embodiments, the yield of the (S)- Trolox or salt thereof is at least about 50%, the enantiomeric excess is at least about 97%, and the purity is at least about 99%. In some embodiments, the yield of the (S)-Trolox or salt thereof is at least about 70%, the enantiomeric excess is at least about 98%, and the purity is at least about 99%. In some embodiments, the yield of the (S)-Trolox or salt thereof is at least about 75%), the enantiomeric excess is at least about 99%, and the purity is at least about 99%. In some embodiments, the yield of the (S)-Trolox or salt thereof is at least about 80%, the enantiomeric excess is at least about 99.5%, and the purity is at least about 99%.

[0009] In another aspect of the invention is (R)-Trolox or salt thereof, produced according to a method described herein. In various embodiments, the enantiomeric excess of the (R)-Trolox or salt thereof is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45% at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In various embodiments, including any of the foregoing embodiments, the yield of the (R)-Trolox or salt thereof is at least about 50%, at least about 55%, at least about 60%), at least about 65%>, at least about 70%, at least about 75%, at least about 80%>, at least about 85%). In various embodiments, including any of the foregoing embodiments, the purity of the (R)-Trolox or salt thereof, exclusive of any solvents, carriers or excipients, is at least about 90%), at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%), at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45% at least about 99.5%), at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In some embodiments, the yield of the (R)-Trolox or salt thereof is at least about 50%, the enantiomeric excess is at least about 97%, and the purity is at least about 99%. In some embodiments, the yield of the (R)-Trolox or salt thereof is at least about 70%, the enantiomeric excess is at least about 98%, and the purity is at least about 99%. In some embodiments, the yield of the (R)-Trolox or salt thereof is at least about 75%, the enantiomeric excess is at least about 99%), and the purity is at least about 99%. In some embodiments, the yield of the (R)- Trolox or salt thereof is at least about 80%, the enantiomeric excess is at least about 99.5%, and the purity is at least about 99%.

[0010] In another aspect of the invention is (S)-Trolox or salt thereof, produced according to a method described herein. In various embodiments, the enantiomeric excess of the (S)-Trolox or salt thereof is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45% at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In various embodiments, including any of the foregoing embodiments, the yield of the (S)-Trolox or salt thereof is at least about 50%, at least about 55%, at least about 60%), at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%). In various embodiments, including any of the foregoing embodiments, the purity of the (S)-Trolox or salt thereof, exclusive of any solvents, carriers or excipients, is at least about 90%), at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%), at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45% at least about 99.5%), at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%). In some embodiments, the yield of the (S)-Trolox or salt thereof is at least about 50%, the enantiomeric excess is at least about 97%, and the purity is at least about 99%. In some embodiments, the yield of the (S)-Trolox or salt thereof is at least about 70%, the enantiomeric excess is at least about 98%, and the purity is at least about 99%. In some embodiments, the yield of the (S)-Trolox or salt thereof is at least about 75%, the enantiomeric excess is at least about 99%), and the purity is at least about 99%. In some embodiments, the yield of the (S)- Trolox or salt thereof is at least about 80%, the enantiomeric excess is at least about 99.5%, and the purity is at least about 99%.

[0011] In another aspect of the invention is converting the (R)-Trolox or salt thereof that is obtained from any method described herein to (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide or a salt thereof.

In another aspect of the invention is converting the (S)-Trolox or salt thereof that is obtained from any method described herein to (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide or a salt thereof.

[0012] In another aspect of the invention is the compound (R)-Trolox (1 S,2S)-(+)- Pseudoephedrine salt. In some embodiments, the compound is a 1 : 1 salt.

[0013] In another aspect of the invention is the compound (R)-Trolox (R)-(+)-2-Amino-3- phenyl-l-propanol salt. In some embodiments, the compound is a 1 : 1 salt.

In another aspect of the invention is the compound (S)-Trolox (lR,2R)-(-)-Pseudoephedrine salt.

[0014] In some embodiments, the compound is a 1 : 1 salt.

[0015] In another aspect of the invention is the compound (S)-Trolox (S)-(-)-2-Amino-3- phenyl- 1 -prop anol salt. In some embodiments, the compound is a 1 : 1 salt.

[0016] In another aspect of the invention is (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide or the hydroquinone form thereof, or salt thereof, produced according to a method described herein. In some embodiments, is (R)-2-hydroxy-2- methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl)buta namide or salt thereof, produced according to a method described herein.

[0017] In another aspect of the invention is a pharmaceutical composition comprising (R)-2- hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-d ienyl)butanamide or the hydroquinone form thereof as produced by a method described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide as produced by a method described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect of the invention is (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide or the hydroquinone form thereof, or salt thereof, produced according to a method described herein. In some embodiments, is (S)-2-hydroxy-2- methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl)buta namide or salt thereof, produced according to a method described herein.

[0018] In another aspect of the invention is a pharmaceutical composition comprising (S)-2- hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-d ienyl)butanamide or the hydroquinone form thereof as produced by a method described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide as produced by a method described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0019] In another aspect of the invention is a method of treating or suppressing an oxidative stress disorder, comprising administering a pharmaceutical composition as described herein to a subject in need thereof. In some embodiments, the method is a method of treating the oxidative stress disorder. In some embodiments, the method is a method of suppressing the oxidative stress disorder.

[0020] For all compositions described herein, and all methods using or making a composition described herein, the compositions and methods can either comprise the listed components or steps, or can "consist essentially of the listed components or steps. When a composition is described as "consisting essentially of the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as "consisting essentially of the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the synthetic method, but the method does not contain any other steps which substantially affect the synthetic method other than those steps expressly listed. As a non-limiting specific example, when a composition is described as 'consisting essentially of a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.

BRIEF DESCRIPTION OF THE FIGURES

[0021] Figure 1 shows a DSC thermogram of R-Trolox (l S,2S)-(+)-Pseudoephedrine salt (sample 1957-57-6).

DETAILED DESCRIPTION

[0022] The chiral resolving agents of the present invention resolve Trolox enantiomers with improved performance.

[0023] Applicants have resolved Trolox enantiomers with a double a-methylbenzylamine (MBA) resolution, wherein (,S)-(-)-a-methylbenzylamine forms a salt with (S)-Trolox, which is removed to enrich the content of (R)-Trolox, and then subsequently wherein the mother liquor is acidified to remove excess (,S)-(-)-a-methylbenzylamine, and subjected to a second resolution with (R)-(+)-a-methylbenzylamine, thus forming a salt with (R)-Trolox. However, this process involved multiple steps (e.g. resolving with the (,S)-(-)-a-methylbenzylamine in one step, and then resolving with the (R)-(+)-a-methylbenzylamine in another step). Furthermore, the MBA double resolution resulted in reaction product consistencies that were more difficult to work with (e.g. a yogurt-thickness consistency for the (R)-Trolox-(R)-(+)-a-methylbenzyl amine salt), difficulty in removing liquid, difficulty in stirring the reaction, poor filtration, and difficulty in scale-up.

[0024] In contrast, the current method is a single step resolution (e.g. a single chiral resolving agent), and further, in various embodiments, the current method is easier to scale up, is easier to stir, provides readily filterable solids, and provides a higher resolution and/or purity of the desired product. The current method may in some embodiments not require a recrystallization step, in contrast with previous methods.

[0025] In contrast, in various embodiments, the current method is easier to scale up, is easier to stir, provides readily filterable solids, is a single step resolution (e.g. a single chiral resolving agent) and/or provides a higher resolution and/or purity of the desired product. The current method may in some embodiments not require a recrystallization step, in contrast with previous methods. The current method may further, in various embodiments, provide high purity of product and/or high resolution of product at a larger scale.

[0026] The abbreviations used herein have their conventional meaning within the chemical and biological arts, unless otherwise specified.

[0027] Reference to "about" a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X".

[0028] The terms "a" or "an," as used in herein means one or more, unless context clearly dictates otherwise.

[0029] By "subject," "individual," or "patient" is meant an individual organism, preferably a vertebrate, more preferably a mammal, most preferably a human.

[0030] "Treating" a disease with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to reduce or eliminate either the disease or one or more symptoms of the disease, or to retard the progression of the disease or of one or more symptoms of the disease, or to reduce the severity of the disease or of one or more symptoms of the disease. "Suppression" of a disease with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to suppress the clinical manifestation of the disease, or to suppress the manifestation of adverse symptoms of the disease. The distinction between treatment and suppression is that treatment occurs after adverse symptoms of the disease are manifest in a subject, while suppression occurs before adverse symptoms of the disease are manifest in a subject. Suppression may be partial, substantially total, or total. Because many of the

mitochondrial disorders are inherited, genetic screening can be used to identify patients at risk of the disease. The compounds and methods of the invention can then be administered to asymptomatic patients at risk of developing the clinical symptoms of the disease, in order to suppress the appearance of any adverse symptoms. [0031] "Therapeutic use" of the compounds discussed herein is defined as using one or more of the compounds discussed herein to treat or suppress a disease, as defined above. A

"therapeutically effective amount" of a compound is an amount of the compound, which, when administered to a subject, is sufficient to reduce or eliminate either a disease or one or more symptoms of a disease, or to retard the progression of a disease or of one or more symptoms of a disease, or to reduce the severity of a disease or of one or more symptoms of a disease, or to suppress the clinical manifestation of a disease, or to suppress the manifestation of adverse symptoms of a disease. A therapeutically effective amount can be given in one or more administrations. [0032] Methods of the invention utilize a resolving agent to separate the (R)- and (S)-Trolox enantiomers, wherein the resolving agent forms a solid salt with one of (R)-Trolox and (S)- Trolox, and substantially does not form a solid salt with the other under the particular reaction conditions. In some embodiments, when the resolving agent forms a solid salt with a Trolox enantiomer, at least about 50% of that Trolox enantiomer forms the solid salt with the resolving agent under the particular reaction conditions. In various embodiments, when the resolving agent forms a solid salt with a Trolox enantiomer, at least about 60%, at least about 70%, at least about 80%), at least about 85%>, at least about 90%, at least about 95%, at least about 96%, at least about 97%), at least about 98%, or at least about 99% of that Trolox enantiomer forms the solid salt with the resolving agent under the particular reaction conditions. By "substantially does not form a solid salt" indicates that less than about 10% of the (non-solid salt forming) Trolox enantiomer forms a solid salt with the resolving agent under the particular reaction conditions. In various embodiments, "substantially does not form a solid salt" indicates that less than about 9%), less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%), less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% of the (non-solid salt forming) Trolox enantiomer forms a solid salt with the resolving agent under the particular reaction conditions. As a non-limiting example, in some embodiments (l S,2S)-(+)-Pseudoephedrine forms a solid salt with (R)-Trolox (e.g. in some embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, of the (R)-Trolox that is present forms a solid salt with the (l S,2S)-(+)- Pseudoephedrine, and the (l S,2S)-(+)-Pseudoephedrine substantially does not form a solid salt with the (S)-Trolox that is present under the particular reaction conditions (e.g. in some embodiments, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% of the (S)-Trolox that is present forms a solid salt with the (l S,2S)-(+)-Pseudoephedrine under the particular reaction conditions. "Yield" indicates the % of Trolox enantiomer obtained, relative to amount of starting material. For example, if 100 g of a 50/50 racemic mixture of (R)/(S)-Trolox are resolved, and 50 g of (S)-Trolox is recovered, the yield would be 100%. If 30 g of (S)-Trolox are recovered, the yield would be 60%. With regards to recovery of a Trolox salt, the yield is calculated as though only the Trolox, and not the salt counterion, is present. For example, if 100 g of a 50/50 racemic mixture of (R)/(S)-Trolox are resolved, and 40 g of an (S)-Trolox salt is recovered, and if the theoretical weight of the (S)-Trolox contained within that salt is 30 g, then the yield would be 60%.

[0033] While the compounds described herein can occur and can be used as the neutral (non- salt) compound, the description is intended to embrace all salts of the compounds described herein, as well as methods of using such salts of the compounds. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound). The desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. The desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N- dibenzyl ethyl enediamine, and triethylamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared. Additional salts particularly useful for pharmaceutical preparations are described in Berge S.M. et al, "Pharmaceutical salts," 1. Pharm. Sci. 1977 Jan; 66(1): 1-19. [0034] The invention includes methods of separating Trolox isomers (R)-Trolox and (S)- Trolox, comprising: (a) contacting a mixture of (R) and (S)-Trolox with a resolving agent selected from the group consisting of N-m ethyl -D-glucamine, L-Arginine, L-Lysine, (1 S,2S)- (+)-Pseudoephedrine, (R)-(-)-Leucinol, D-Lysine, (R)-(+)-2-Amino-3 -phenyl- 1-propanol, (lR,2R)-(-)-Pseudoephedrine, and (S)-(-)-2-Amino-3 -phenyl- 1-propanol, wherein a solid salt forms between the resolving agent and only one of (R)-Trolox and (S)-Trolox, and substantially does not form a solid salt with the other; and (b) separating the solid salt from the Trolox isomer that did not form the solid salt with the resolving agent. In some embodiments, the resolving agent is selected from the group consisting of (l S,2S)-(+)-Pseudoephedrine and (R)-(+)-2- Amino-3 -phenyl- 1-propanol. In some embodiments, the resolving agent is selected from the group consisting of (lR,2R)-(-)-Pseudoephedrine and (S)-(-)-2-Amino-3 -phenyl- 1-propanol. In some embodiments, the resolving agent is (l S,2S)-(+)-Pseudoephedrine. In some embodiments, the resolving agent is (R)-(+)-2-Amino-3 -phenyl- 1-propanol. In some embodiments, the resolving agent is (lR,2R)-(-)-Pseudoephedrine. In some embodiments, the resolving agent is (S)-(-)-2-Amino-3 -phenyl- 1-propanol. In some embodiments, the resolving agent is N-methyl- D-glucamine. In some embodiments, the resolving agent is L-Arginine. In some embodiments, the resolving agent is L-Lysine. In some embodiments, the resolving agent is (R)-(-)-Leucinol. In some embodiments, the resolving agent is D-Lysine. In some embodiments, the mixture of (R)-Trolox and (S)-Trolox is a racemic mixture.

[0035] In some embodiments, step (a) comprises dissolving the mixture of (R)-Trolox and (S)-Trolox and the resolving agent in a solvent. In some embodiments, step (a) comprises: (i) heating the mixture of (R)-Trolox and (S)-Trolox and the resolving agent in the solvent until dissolution occurs; and (ii) cooling the mixture from (i). In some embodiments, dissolution indicates complete dissolution of all (R)-Trolox, (S)-Trolox, and resolving agent present in the mixture. In some embodiments, the heating in step (a)(i) comprises heating to reflux

temperature. In some embodiments, the cooling in step (a)(ii) occurs over at least about one hour. In some embodiments, the cooling in step (a)(ii) occurs over at least about two hours. In some embodiments, the cooling in step (a)(ii) occurs over at least about eight hours. In some embodiments, the cooling in step (a)(ii) comprises cooling to about 0°C to about 30°C. In some embodiments, the cooling in step (a)(ii) comprises cooling to about 20°C to about 30°C. In some embodiments, the cooling in step (a)(ii) comprises cooling to about 20°C to about 26°C.

[0036] In some embodiments, the solvent is a polar solvent. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is isopropyl acetate. In some embodiments, the solvent is ethyl acetate with 1% water. In some embodiments, the solvent is 2- methyltetrahydrofuran. In some embodiments, about 3 to about 7 volumes of solvent are added in step (a). In some embodiments, about 4 to about 6 volumes of solvent are added in step (a). In some embodiments, about 3 volumes of solvent are added in step (a). In some embodiments, about 4 volumes of solvent are added in step (a). In some embodiments, about 5 volumes of solvent are added in step (a). In some embodiments, about 6 volumes of solvent are added in step (a). In some embodiments, about 7 volumes of solvent are added in step (a).

In some embodiments, about 0.50 to about 2.0 equivalents of resolving agent are used in step (a). In some embodiments, about 0.60 to about 1.30 equivalents of resolving agent are used in step (a). In some embodiments, about 0.80 to about 1.30 equivalents of resolving agent are used in step (a). In some embodiments, about 0.95 to about 1.20 equivalents of resolving agent are used in step (a). In some embodiments, about 1.05 equivalents of resolving agent are used in step (a). In some embodiments, about 1.15 equivalents of resolving agent are used in step (a). In various embodiments, about 0.5 to about 2 equivalents, about 0.6 to about 1.5 equivalents, about 0.9 to about 1.5 equivalents, about 1.00 to about 1.10 equivalents, about 0.65 to about 1.25 equivalents, about 0.50 to about 0.60 equivalents, about 0.60 to about 0.70 equivalents, about 0.80 to about 0.90 equivalents, about 0.80 to about 1.30 equivalents, about 0.85 to about 1.25 equivalents, about 0.95 to about 1.05 equivalents, about 0.95 to about 1.20 equivalents, about 0.95 to about 1.20 equivalents, about 1.10 to about 1.20 equivalents, about 1.20 to about 1.30 equivalents, about 0.50 to about 0.60 equivalents, about 0.50 equivalents, about 0.55

equivalents, about 0.60 equivalents, about 0.65 equivalents, about 0.70 equivalents, about 0.75 equivalents, about 0.80 equivalents, about 0.85 equivalents, about 0.90 equivalents, about 0.95 equivalents, about 1.00 equivalents, about 1.05 equivalents, about 1.10 equivalents, about 1.15 equivalents, about 1.20 equivalents, about 1.25 equivalents, or about 1.30 equivalents of resolving agent are used in step (a).

[0037] In some embodiments, step (a) comprises: (i) evaporating any solvents present, and (ii) adding diethyl ether to the mixture. In some embodiments, the diethyl ether is removed. In some embodiments, the mixture in step (a) is seeded with the desired solid salt. For example, when the desired solid salt is (R)-Trolox (l S,2S)-(+)-Pseudoephedrine salt, the mixture may be seeded with (R)-Trolox (l S,2S)-(+)-Pseudoephedrine salt.

[0038] In some embodiments, step (b) comprises filtering the solid salt. In some embodiments, step (b) further comprises a step (b)(1), comprising slurrying the solid salt in a solvent. For example, the solid salt filtered from step (b) is added to fresh solvent, and slurried. Step (b)(1) may in some embodiments be used to improve enantiomeric purity. In some embodiments, the slurry solvent is the same solvent used in step (a). In some embodiments, the slurry solvent is a different solvent that the solvent used in step (a). In some embodiments, the slurry time is about 5 minutes to about 5 hours. In some embodiments, the slurry time is about 5 minutes to about 3 hours. In some embodiments, the slurry time is about 5 minutes to about 2 hours. In some embodiments, the slurry time is about 5 minutes to about 1 hour. In some embodiments, the slurry time is about 5 minutes to about 30 minutes. In some embodiments, the slurry time is about 10 minutes to about 20 minutes. In some embodiments, step (b) and/or step (b)(1) further comprise rinsing and drying the solid salt. In some embodiments, the solvent used for rinsing is the same solvent used in step (a). In some embodiments, the slurry used for rinsing is a different solvent that the solvent used in step (a).

[0039] In some embodiments, the method further comprises a step (c): (c) separating the Trolox isomer contained in the solid salt from the resolving agent. In some embodiments, step (c) comprises adding an acid to the solid salt. In some embodiments, step (c) comprises adding a base to the solid salt.

In some embodiments, the Trolox isomer that forms the solid salt with the resolving agent is (R)- Trolox. In some embodiments, the Trolox isomer that forms the solid salt with the resolving agent is (S)-Trolox.

[0040] In some embodiments, the method comprises: (1) contacting a mixture of (R)-Trolox and (S)-Trolox with about 0.8 to about 1.30 equivalents of (l S,2S)-(+)-Pseudoephedrine and ethyl acetate; (2) heating the mixture until dissolution is achieved; (3) cooling the mixture to about 20°C to about 30°C over at least about 50 minutes; (4) cooling the mixture to about 5°C to about 15°C; (7) filtering the resulting slurry; (8) washing the wet cake with ethyl acetate; (9) and drying the solids.

[0041] In some embodiments, the method comprises: (1) contacting a mixture of (R)-Trolox and (S)-Trolox with about 1.10 to about 1.20 equivalents of (l S,2S)-(+)-Pseudoephedrine and about 4 to about 6 volumes of ethyl acetate; (2) heating the mixture to between about 35°C to about 55°C until dissolution is achieved; (3) cooling the mixture to about 20°C to about 30°C over at least about 50 minutes; (4) cooling the mixture to about 5°C to about 15°C over about 20 to about 40 minutes; (5) holding the temperature in step (4) for about 50-70 minutes; (7) filtering the resulting slurry; (8) washing the wet cake with about 5 to about 7 volumes of ethyl acetate at room temperature; (9) and drying the solids.

[0042] In some embodiments, the method comprises: (1) contacting a mixture of (R)-Trolox and (S)-Trolox with about 1.15 equivalents of (l S,2S)-(+)-Pseudoephedrine and about 5 volumes of ethyl acetate; (2) heating the mixture to between about 40°C to about 50°C until dissolution is achieved; (3) cooling the mixture to room temperature over at least about 50 minutes; (4) cooling the mixture to about 10°C over about 30 minutes; (5) holding the temperature in step (4) for about 50-70 minutes; (7) filtering the resulting slurry; (8) washing the wet cake with about 6 volumes of ethyl acetate at room temperature; (9) and drying the solids.

[0043] In some embodiments, the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 98%. In some embodiments, the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 99%. In some embodiments, the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 99.5%. In some embodiments, the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 99.9%. In various embodiments, the enantiomeric excess of the (R)-Trolox obtained from the method is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4% at least about 99.5%), at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%.

[0044] In some embodiments, the enantiomeric excess of the (S)-Trolox obtained from the method is at least about 98%. In some embodiments, the enantiomeric excess of the (S)-Trolox obtained from the method is at least about 99%. In some embodiments, the enantiomeric excess of the (S)-Trolox obtained from the method is at least about 99.5%. In some embodiments, the enantiomeric excess of the (S)-Trolox obtained from the method is at least about 99.9%. In various embodiments, the enantiomeric excess of the (S)-Trolox obtained from the method is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4% at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%.

(R)-Trolox, or a salt thereof, may be produced according to a method described herein. In various embodiments, the enantiomeric excess of the (R)-Trolox or a salt thereof is at least about 95%), at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45% at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. (S)-Trolox or a salt thereof, may be produced according to a method described herein. In various embodiments, the enantiomeric excess of the (S)-Trolox or a salt thereof is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45%> at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%.

[0045] In various embodiments, the purity of the (R)-Trolox or salt thereof, exclusive of any solvents, carriers or excipients, is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45% at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%.

[0046] In various embodiments, the purity of the (S)-Trolox or salt thereof, exclusive of any solvents, carriers or excipients, is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.45% at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%.

[0047] The (R)-Trolox that is obtained from the method may be converted to (R)-2-hydroxy-2- methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl)buta namide or a salt thereof. The (S)- Trolox that is obtained from the method may be converted to (S)-2-hydroxy-2-methyl-4-(2,4,5- trimethyl-3,6-dioxocyclohexa-l,4-dienyl)butanamide or a salt thereof. In some embodiments, the salt is a pharmaceutically acceptable salt. In some examples, the methods include those steps set forth herein. In some examples, the methods include those in PCT Application No.

PCT/US2008/082374. [0048] (R)-2-hydroxy-2-methyl-4-(2,4,54rimethyl-3,6-dioxocyclohexa- l,4-dienyl)butanamide and (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa -l,4-dienyl)butanamide may further be converted into the reduced (hydroquinone) forms (i.e. (R)-4-(2,5-dihydroxy-3,4,6- trimethylphenyl)-2-hydroxy-2-methylbutanamide and (S)-4-(2,5-dihydroxy-3,4,6- trimethylphenyl)-2-hydroxy-2-methylbutanamide, respectively). The reduced (hydroxy) form may readily be converted to the oxidized (quinone) form using methods known in the art. See e.g. air, silica Miller et al PCT Intl Appl 2006130775 7 Dec 2006. The oxidized (quinone) form may readily be converted to the reduced hydroxy form using methods known in the art. See, e.g. Zn, AcOH Fuchs et al EJOC 6 (2009) 833-40. The hydroquinone forms may further be made as salts, in some embodiments, as pharmaceutically acceptable salts.

Pharmaceutical compositions

[0049] The compounds described herein can be formulated as pharmaceutical compositions ("pharmaceutical compositions" is used interchangeably herein with "pharmaceutical formulations") by formulation with additives such as pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, and pharmaceutically acceptable vehicles.

"Pharmaceutically acceptable excipients", "pharmaceutically acceptable carriers", and

"pharmaceutically acceptable vehicles" are used interchangeably herein. Suitable

pharmaceutically acceptable excipients, carriers and vehicles include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-P-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), and "Remington: The Science and Practice of Pharmacy," Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005), incorporated herein by reference.

[0050] A pharmaceutical composition can comprise a unit dose formulation, where the unit dose is a dose sufficient to have a therapeutic or suppressive effect. The unit dose may be sufficient as a single dose to have a therapeutic or suppressive effect. Alternatively, the unit dose may be a dose administered periodically in a course of treatment or suppression of a disorder. [0051] Pharmaceutical compositions containing the compounds of the invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion. Liquid carriers are typically used in preparing solutions,

suspensions, and emulsions. Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof. The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like. Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols. Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like. Compositions of the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.

[0052] Time-release or controlled release delivery systems may be used, such as a diffusion controlled matrix system or an erodible system, as described for example in: Lee, "Diffusion- Controlled Matrix Systems", pp. 155-198 and Ron and Langer, "Erodible Systems", pp. 199- 224, in "Treatise on Controlled Drug Delivery", A. Kydonieus Ed., Marcel Dekker, Inc., New York 1992. The matrix may be, for example, a biodegradable material that can degrade spontaneously in situ and in vivo for, example, by hydrolysis or enzymatic cleavage, e.g., by proteases. The delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, for example in the form of a hydrogel. Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides,

poly(phosphoesters), polyamides, polyurethanes, poly(imidocarbonates) and

poly(phosphazenes).

[0053] The compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation (e.g. as mists or sprays), rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. For example, suitable modes of administration include oral,

subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g. via nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue. For delivery to the central nervous system, spinal and epidural administration, or administration to cerebral ventricles, can be used. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. The compounds are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration. Oral administration is a preferred route of administration, and formulations suitable for oral administration are preferred formulations. The compounds described for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms. Additional methods of administration are known in the art.

[0054] Injectable preparations, for example, sterile injectable aqueous or oleaginous

suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0055] Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

[0056] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

[0057] The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and

metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and

phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 et seq (1976).

[0058] The invention also provides articles of manufacture and kits containing materials useful for treating or suppressing oxidative stress disorder. In some embodiments, the kit of the invention comprises the container described above.

[0059] In other aspects, the kits may be used for any of the methods described herein, including, for example, to treat an individual with an oxidative stress disorder , or to suppress an oxidative stress disorder in an individual.

Diseases amenable to treatment or suppression with compounds, compositions and methods of the invention

[0060] A variety of disorders/diseases are believed to be caused or aggravated by oxidative stress affecting normal electron flow in the cells, such as mitochondrial disorders, impaired energy processing disorders, neurodegenerative diseases and diseases of aging, and can be treated or suppressed using compounds and methods of the invention. [0134] Non-limiting examples of oxidative stress disorders include, for example, mitochondrial disorders (including inherited mitochondrial diseases) such as Alpers Disease, Barth syndrome, Beta-oxidation Defects, Carnitine- Acyl-Carnitine Deficiency, Carnitine Deficiency, Creatine Deficiency Syndromes, Co-Enzyme Q10 Deficiency, Complex I Deficiency, Complex II Deficiency, Complex III Deficiency, Complex IV Deficiency, Complex V Deficiency, COX Deficiency, chronic progressive external ophthalmoplegia (CPEO), CPT I Deficiency, CPT II Deficiency, Friedreich's Ataxia (FA), Glutaric Aciduria Type II, Kearns-Sayre Syndrome (KSS), Lactic Acidosis, Long-Chain Acyl-CoA Dehydrongenase Deficiency (LCAD), LCHAD, Leigh Disease or Syndrome, Leigh-like Syndrome, Leber's Hereditary Optic Neuropathy (LHON, also referred to as Leber's Disease, Leber's Optic Atrophy (LOA), or Leber's Optic Neuropathy (LON)), Lethal Infantile Cardiomyopathy (LIC), Luft Disease, Multiple Acyl-CoA Dehydrogenase Deficiency (MAD), Medium-Chain Acyl-CoA Dehydrongenase Deficiency (MCAD), Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS),

Myoclonic Epilepsy with Ragged Red Fibers (MERRF), Mitochondrial Recessive Ataxia Syndrome (MIRAS), Mitochondrial Cytopathy, Mitochondrial DNA Depletion, Mitochondrial Encephalopathy, Mitochondrial Myopathy, Myoneurogastrointestinal Disorder and

Encephalopathy (MNGIE), Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP), Pearson Syndrome, Pyruvate Carboxylase Deficiency, Pyruvate Dehydrogenase Deficiency, POLG Mutations, Respiratory Chain Disorder, Short-Chain Acyl-CoA Dehydrogenase Deficiency (SCAD), SCHAD, Very Long-Chain Acyl-CoA Dehydrongenase Deficiency (VLC AD);

myopathies such as cardiomyopathy and encephalomyopathy; neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease); motor neuron diseases; neurological diseases such as epilepsy; age- associated diseases, particularly diseases for which CoQIO has been proposed for treatment, such as macular degeneration, diabetes (e.g. Type 2 diabetes mellitus), metabolic syndrome, and cancer (e.g. brain cancer); genetic diseases such as Huntington's Disease (which is also a neurological disease); mood disorders such as schizophrenia and bipolar disorder; pervasive developmental disorders such as autistic disorder, Asperger's syndrome, childhood disintegrative disorder (CDD), Rett's disorder, and PDD-not otherwise specified (PDD-NOS); cerebrovascular accidents such as stroke; vision impairments such as those caused by neurodegenerative diseases of the eye such as optic neuropathy, Leber's hereditary optic neuropathy, dominant inherited juvenile optic atrophy, optic neuropathy caused by toxic agents, glaucoma, age-related macular degeneration (both "dry" or non-exudative macular degeneration and "wet" or exudative macular degeneration), Stargardt's macular dystrophy, diabetic retinopathy, diabetic

maculopathy, retinopathy of prematurity, or ischemic reperfusion-related retinal injury; disorders caused by energy impairment include diseases due to deprivation, poisoning or toxicity of oxygen, and qualitative or quantitative disruption in the transport of oxygen such as haemoglobionopathies, for example thalassemia or sickle cell anemia; other diseases in which mitochondrial dysfunction is implicated such as excitoxic, neuronal injury, such as that associated with seizures, stroke and ischemia; and other disorders including renal tubular acidosis; attention deficit/hyperactivity disorder (ADHD); neurodegenerative disorders resulting in hearing or balance impairment; Dominant Optic Atrophy (DOA); Maternally inherited diabetes and deafness (MIDD); chronic fatigue; contrast-induced kidney damage; contrast- induced retinopathy damage; Abetalipoproteinemia; retinitis pigmentosum; Wolfram's disease; Tourette syndrome; cobalamin c defect; methylmalonic aciduria; glioblastoma; Down's syndrome; acute tubular necrosis; muscular dystrophies; leukodystrophies; Progressive

Supranuclear Palsy; spinal muscular atrophy; hearing loss (e.g. noise induced hearing loss); traumatic brain injury; Juvenile Huntington's Disease; Multiple Sclerosis; NGLY1; Multiple System Atrophy; Adrenoleukodystrophy; and Adrenomyeloneuropathy. It is to be understood that certain specific diseases or disorders may fall within more than one category; for example, Huntington's Disease is a genetic disease as well as a neurological disease. Furthermore, certain oxidative stress diseases and disorders may also be considered mitochondrial disorders.

[0135] For some disorders amenable to treatment with compounds and methods of the invention, the primary cause of the disorder is due to a defect in the respiratory chain or another defect preventing normal utilization of energy in mitochondria, cells, or tissue(s). Non-limiting examples of disorders falling in this category include inherited mitochondrial diseases, such as Myoclonic Epilepsy with Ragged Red Fibers (MERRF), Mitochondrial Myopathy,

Encephalopathy, Lactacidosis, and Stroke (MELAS), Leber's Hereditary Optic Neuropathy (LHON, also referred to as Leber's Disease, Leber's Optic Atrophy (LOA), or Leber's Optic Neuropathy (LON)), Leigh Disease or Leigh Syndrome, Kearns-Sayre Syndrome (KSS), and Friedreich's Ataxia (FA). For some disorders amenable to treatment with compounds and methods of the invention, the primary cause of the disorder is not due to respiratory chain defects or other defects preventing normal utilization of energy in mitochondria, cells, or tissue(s); non-limiting examples of disorders falling in this category include stroke, cancer, and diabetes. However, these latter disorders are particularly aggravated by energy impairments, and are particularly amenable to treatment with compounds of the invention in order to ameliorate the condition. Pertinent examples of such disorders include ischemic stroke and hemorrhagic stroke, where the primary cause of the disorder is due to impaired blood supply to the brain. While an ischemic episode caused by a thrombosis or embolism, or a hemorrhagic episode caused by a ruptured blood vessel, is not primarily caused by a defect in the respiratory chain or another metabolic defect preventing normal utilization of energy, oxidative stress plays a role in the ischemic cascade due to oxygen reperfusion injury following hypoxia (this cascade occurs in heart attacks as well as in strokes). Accordingly, treatment with compounds and methods of the invention will mitigate the effects of the disease, disorder or condition.

[0136] The term "oxidative stress disorder" or "oxidative stress disease" encompass both diseases caused by oxidative stress and diseases aggravated by oxidative stress. The terms "oxidative stress disorder" or "oxidative stress disease" encompass both diseases and disorders where the primary cause of the disease is due to a defect in the respiratory chain or another defect preventing normal utilization of energy in mitochondria, cells, or tissue(s), and also diseases and disorders where the primary cause of the disease is not due to a defect in the respiratory chain or another defect preventing normal utilization of energy in mitochondria, cells, or tissue(s). The former set of diseases can be referred to as "primary oxidative stress disorders," while the latter can be referred to as "secondary oxidative stress disorders." It should be noted that the distinction between "diseases caused by oxidative stress" and "diseases aggravated by oxidative stress" is not absolute; a disease may be both a disease caused by oxidative stress and a disease aggravated by oxidative stress. The boundary between "primary oxidative stress disorder" and a "secondary oxidative stress disorder" is more distinct, provided that there is only one primary cause of a disease or disorder and that primary cause is known. [0137] Bearing in mind the somewhat fluid boundary between diseases caused by oxidative stress and diseases aggravated by oxidative stress, mitochondrial diseases or disorders and impaired energy processing diseases and disorders tend to fall into the category of diseases caused by oxidative stress, while neurodegenerative disorders and diseases of aging tend to fall into the category of diseases aggravated by oxidative stress. Mitochondrial diseases or disorders and impaired energy processing diseases and disorders are generally primary oxidative stress disorders, while neurodegenerative disorders and diseases of aging may be primary or secondary oxidative stress disorders.

The compounds of the invention may be further be used in treatment or prophylactic treatment against radiation exposure. Further description of the disorders that can be treated with the compounds of the invention is found in U.S. Provisional Patent Application No. 62/092,743; and PCT Application Nos. PCT/US08/082374; PCT/US09/035996; and PCT/US09/060489. Synthetic Reaction Parameters

[0061] Solvents employed in synthesis of the compounds and compositions of the invention include, for example, water, acetonitrile ("ACN"), diethyl ether, 2-methyl-tetrahydrofuran ("2- MeTHF"), ethyl acetate ("EtOAc"), ethanol ("EtOH"), isopropyl alcohol ("IP A"), isopropyl acetate ("IP Ac"), methanol (MeOH), and the like, as well as mixtures thereof.

[0062] The term "q.s." means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

[0063] Techniques useful in synthesizing the compounds and compositions herein are both readily apparent and accessible to those of skill in the relevant art in light of the teachings described herein. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds and compositions herein. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds and compositions herein.

[0064] Other methods for producing the compounds and compositions of the invention will be apparent to one skilled in the art in view of the teachings herein.

EXAMPLES Example 1. Solubility assessment of (R)-Trolox

[0065] (R)-Trolox (97.89% ee, chemical purity >99.99 % AUC) (100 mg) was weighed out in 12 different vials. 12 different solvents were added (one volume at a time) to the different vials and the mixture was maintained at 40 °C. The volume of each solvent required to dissolve 100 mg of (R)-Trolox was recorded and the solubility was subsequently calculated. Solubility data is presented in Table 1.

Table 1. Solubility assessment of (R)-Trolox

98.7 EtOH 200 494

104.5 Π>Α 200 523

100.8 IPAc 400 252

104.6 EtOAc 500 209

97.4 ACN 500 195

104.8 2-MeTHF 200 524

103.9 5 % water/MeOH 100 1039

102.5 5 % water/EtOH 120 854

97.8 5 % water/IPA 100 978

100.9 5 % water/ACN 220 459

[0066] (R)-Trolox was found to be highly soluble in all solvents except for pure water.

Isopropyl acetate (IPAc), 2-methyltetrahydrofuran (2-MeTHF), and 5 % water/isopropyl alcohol (v/v) were chosen for the initial salt screening experiments.

Example 2. Initial salt screening experiments using (R)-Trolox [0067] (R)-Trolox (4.00 g) was weighed out in a vial and dissolved in -20 mL of EtOH. The total volume of this solution was measured out to be 22.3 mL. Therefore, 0.558 mL of this solution corresponded to 100 mg of (R)-Trolox. 1.05 eq. (100 mg of (R)-Trolox = 1 eq.) of each base was weighed out in 39 different vials (3 vials per base). 0.558 mL of the (R)-Trolox solution was added to each vial and the solvent was evaporated slowly in a vacuum oven at RT. 0.500 mL of each solvent (a: IPAc, b: 2-MeTHF, and c: 5 % water/IPA) was added to the appropriate vial and the solution was stirred at 40 °C for 1.5 hours using magnetic stirrer. Then, the solution was cooled down to RT for at least 1.5 hours. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight. If solids were obtained after evaporation, they were analyzed by XRPD and optical microscopy. If no solids were obtained after evaporation, 0.500 mL of diethyl ether was added to gel in the vial and stirred. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight.

Table 2. Reagents used for the initial salt screening experiments

methylpseudoephedrine

3 (R)-(-)-Epinephrine 183.20 n/a 0.420 1.05 76.9 Sigma

4 (R)-(+)-2-Amino-3- 151.21 n/a 0.420 1.05 63.4 Aldrich phenyl- 1 -propanol

5 (1 S,2S)-(+)-Thiomicamine 213.30 n/a 0.420 1.05 89.5 Aldrich

6 (+)-Cinchonine 294.39 n/a 0.420 1.05 123.5 Aldrich

7 N-methyl-D-glucamine 195.21 n/a 0.420 1.05 81.9 Alfa

Aesar

8 (R)-(+)-l-(l-Naphthyl)- 171.24 1.067 0.420 1.05 67.3 Fluka ethylamine

9 (l S,2S)-(+)- 165.23 n/a 0.420 1.05 69.3 Aldrich

Pseudoephedrine

10 D-Lysine 146.19 n/a 0.420 1.05 61.3 Sigma

11 L-Lysine 146.19 n/a 0.420 1.05 61.3 Aldrich

12 L-Histidine 155.15 n/a 0.420 1.05 65.1 Alfa

Aesar

13 L-Arginine 174.20 n/a 0.420 1.05 73.1 Alfa

Aesar

[0068] In the following Tables 3-4, (a) refers to Isopropyl acetate (IP Ac), (b) refers to 2- methyltetrahydrofuran (2-MeTHF), and (c) refers to 5 % water/isopropyl alcohol (v/v). The base numbers in Tables 3 and 4 correspond to the bases numbered 1-13 in Table 2.

Table 3. Results from the initial salt screening experiments using (R)-Trolox

white solids,

add

bright yellow bright 0.500 mL

a 4 solution yellow gel white solids solvent N/A bright

bright yellow bright bright yellow yellow yellow waxyb solution yellow gel solution solution solid bright

bright yellow bright bright yellow yellow yellow waxyc solution yellow gel solution solution solid thin yellow thin yellow

a 5 solid? thick slurry slurry slurry N/A thin yellow

b solid? thick slurry yellow solution slurry N/A yellow some yellowc solid? thick slurry yellow solution solution solid base did not off white

a 6 dissolve thick slurry off white slurry slurry N/A base did not off white

b dissolve thick slurry off white slurry slurry N/A base did not off white

c dissolve thick slurry off white slurry slurry N/A white solid

chunks, clear

base did not liquid, not

a 7 dissolve thick slurry stirring forced to stir N/A white solids,

add

base did not 0.500 mL

b dissolve thick slurry white solids solvent N/A white solids,

add

base did not 0.500 mL

c dissolve thick slurry white solids solvent N/A orange orange

a 8 solution orange gel orange solution solution orange gel orange orange

b solution orange gel orange solution solution orange gel orange orange

c solution orange gel orange solution solution orange gel yellow yellow

a 9 solution yellow gel yellow solution solution yellow gel yellow yellow

b solution yellow gel yellow solution solution yellow gel yellow yellow

c solution yellow gel yellow solution solution yellow gel a 10 base did not thick slurry white solid white solid N/A dissolve chunks, chunks,

clear liquid clear liquid

white solid

base did not chunks, waxy, not

10b dissolve thick slurry clear liquid stirring N/A

base did not

10c dissolve thick slurry off white slurry N/A

white solid white solid

base did not chunks, chunks,

11a 11 dissolve thick slurry clear liquid clear liquid N/A

white solid white solid

base did not chunks, chunks, l ib dissolve thick slurry clear liquid clear liquid N/A

base did not thin yellow waxy solid

11c dissolve thick slurry slurry slurry N/A

base did not

12a 12 dissolve thick slurry white slurry white slurry N/A

base did not

12b dissolve thick slurry white slurry white slurry N/A

base did not

12c dissolve thick slurry white slurry white slurry N/A

white solid white solid

base did not chunks, chunks,

13a 13 dissolve thick slurry clear liquid clear liquid N/A

white solid white solid

base did not chunks, chunks,

13b dissolve thick slurry clear liquid clear liquid N/A

base did not thin yellow waxy solid

13c dissolve thick slurry slurry slurry N/A

Table 4. Results from the initial salt screening experiments using (R)-Trolox (continued)

4b N/A N/A crystalline salt yellow waxy solid

4c N/A N/A crystalline salt yellow waxy solid

5a 5 N/A N/A base white solid

5b N/A N/A base white solid

5c waxy solid N/A unable to filter N/A

slurry

6a 6 N/A N/A base off white solid

6b N/A N/A base off white solid

6c N/A N/A base off white solid

7a 7 N/A N/A crystalline salt white solid

7b N/A N/A crystalline salt white solid

7c N/A N/A crystalline salt white solid

8a 8 orange solution orange gel no solid N/A

8b orange solution orange gel no solid N/A

8c orange solution orange gel no solid N/A

9a 9 white solid N/A crystalline salt white solid slurry

9b waxy solid N/A unable to filter N/A

slurry

9c yellow solution yellow gel no solid N/A

10a 10 N/A N/A amorphous waxy solid

10b N/A N/A amorphous waxy solid

10c N/A N/A crystalline salt white solid

1 1a 1 1 N/A N/A amorphous waxy solid l ib N/A N/A amorphous white solid

1 1c N/A N/A unable to filter N/A

12a 12 N/A N/A base white solid

12b N/A N/A base white solid

12c N/A N/A base white solid

13a 13 N/A N/A amorphous white solid

13b N/A N/A amorphous white solid

13c N/A N/A unable to filter N/A

[0069] After initial XRPD screening, 6 crystalline salts were isolated and further analyzed by 1 H-NMR and optical microscopy. The bases that produced salts with (R)-Trolox were (1 S,2S)- (+)-N-methylpseudoephedrine, (R)-(-)-Epinephrine, (R)-(+)-2-Amino-3 -phenyl- 1 -propanol, N- methyl-D-glucamine, (l S,2S)-(+)-Pseudoephedrine and D-Lysine. Example 3. Additional salt screening experiments using (R)-Trolox

[0070] (R)-Trolox (1.70 g) was weighed out in a vial and dissolved in -8.5 mL of EtOH. The total volume of this solution was measured out to be 8.8 mL. Therefore, 0.518 mL of this solution corresponded to 100 mg of (R)-Trolox. 1.05 eq. (100 mg of (R)-Trolox = 1 eq.) of each base was weighed out in 12 different vials (3 vials per base). 0.518 mL of the (R)-Trolox solution was added to each vial (plus 3 empty vials as controls) and the solvent was evaporated slowly in a vacuum oven at RT. 0.500 mL of each solvent (a: IP Ac, b: 2-MeTHF, and c: 5 % water/IP A) was added to the appropriate vial and the solution was stirred at 40 °C for 1.5 hours using magnetic stirrer. Then, the solution was cooled down to RT for at least 1.5 hours. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight. If solids were obtained after evaporation, they were analyzed by XRPD and optical microscopy. If no solids were obtained after evaporation, 0.500 mL of diethyl ether was added to gel in the vial and stirred. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight.

[0071] Table 5. Reagents used for the additional salt screening experiments using (R)-Trolox

[0072] In the following Tables 6 and 7, (a) refers to Isopropyl acetate (IP Ac), (b) refers to 2- methyltetrahydrofuran (2-MeTHF), and (c) refers to 5 % water/isopropyl alcohol (v/v). The base numbers in Tables 6 and 7 correspond to the bases numbered 14-17 in Table 5.

[0073] Table 6. Results from the additional salt screening experiments using (R)-Trolox

14c yellow yellow gel yellow solution yellow yellow gel solution solution

15a 15 yellow yellow gel yellow solution yellow yellow gel solution solution

15b yellow yellow gel yellow solution yellow yellow gel solution solution

15c yellow yellow gel yellow solution yellow yellow gel solution solution

16a 16 yellow yellow gel yellow solution yellow yellow gel solution solution

16b yellow yellow gel yellow solution yellow yellow gel solution solution

16c yellow yellow gel yellow solution yellow yellow gel solution solution

17a 17 yellow yellow gel yellow solution cloudy oily bottom solution yellow layer, cloudy solution top layer

17b yellow yellow gel yellow solution yellow yellow gel solution solution

17c yellow yellow gel yellow solution yellow yellow gel solution solution a no yellow white solid yellow solution yellow white solid base solution solution

b yellow white solid yellow solution yellow white solid solution solution c yellow white solid yellow solution yellow white solid solution solution

[0074] Table 7. Results from the additional salt screening experiments using (R)-Trolox (continued)

solution

16 oily bottom N/A

layer, clear

16a top layer

oily bottom N/A

layer, clear

16b top layer

cloudy yellow gel

yellow

16c solution

17a 17 N/A N/A

oily bottom N/A

layer, clear

17b top layer

oily bottom N/A

layer, clear

17c top layer

a no thick white N/A

base slurry

b thick white N/A

slurry

c thick white N/A

slurry

No crystalline salts were isolated.

Example 4. Salt screening experiments using (S)-Trolox and the bases that produced salts with (R)-Trolox

[0075] 1.05 eq. (100 mg of (^-Trolox = 1 eq.) of each base was weighed out in 6 different vials. (^-Trolox (100 mg) was added to each vial. 0.500 mL of the appropriate solvent (IP Ac or 5 % water/IP A) was added to the appropriate vial and the solution was stirred at 40 °C for 1.5 hours using magnetic stirrer. Then, the solution was cooled down to RT for at least 1.5 hours. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight. If solids were obtained after evaporation, they were analyzed by XRPD and optical microscopy. If no solids were obtained after evaporation, 0.500 mL of diethyl ether was added to gel in the vial and stirred. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight. Table 8. Reagents used for the salt screening experiments using (^-Trolox and the bases that produced salts with (R)-Trolox

Table 9. Results from the salt screening experiments using (^-Trolox and the bases that produced salts with (R)-Trolox

Table 10. Results from the salt screening experiments using (^-Trolox and the bases that produced salts with (R)-Trolox (continued)

[0076] The promising bases that formed solid salts with (R)-Trolox but very little or no solid with (^-Trolox were (R)-(+)-2-Amino-3 -phenyl- 1-propanol, N-methyl-D-glucamine, (1 S,2S)- (+)-Pseudoephedrine and D-Lysine.

Example 5. Repeat of experiments using (R)-Trolox and the 4 bases that previously produced salts with (R)-Trolox but did not produce salts with (S)-Trolox

[0077] 1.05 eq. (100 mg of (R)-Trolox = 1 eq.) of each base was weighed out in 4 different vials. (R)-Trolox (100 mg) was added to each vial. 0.500 mL of the appropriate solvent (IP Ac or 5 % water/IP A) was added to the appropriate vial and the solution was stirred at 40 °C for 1.5 hours using magnetic stirrer. Then, the solution was cooled down to RT for at least 1.5 hours. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight. If solids were obtained after evaporation, they were analyzed by XRPD and optical microscopy. If no solids were obtained after evaporation, 0.500 mL of diethyl ether was added to gel in the vial and stirred. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight.

Table 11. Reagents used for the repeat experiments using (R)-Trolox and the 4 bases that previously produced salts with (R)-Trolox but did not produce salts with (^-Trolox Amino-3- phenyl-1 - propanol

N-methyl-D- Alfa 5 %

7 glucamine 195.21 n/a 0.420 1.05 81.9 Aesar water/IPA

(l S,2S)-(+)-

9 Pseudoephedrine 165.23 n/a 0.420 1.05 69.3 Aldrich IPAc

5 %

10 D-Lysine 146.19 n/a 0.420 1.05 61.3 Sigma water/IPA

Table 12. Results from the repeat experiments using (R)-Trolox and the 4 bases that previously produced salts with (R)-Trolox but did not produce salts with (^-Trolox

* The first time, the solid precipitated after the addition of diethyl ether. This time, the solid was produced after stirring in the solvent at 40 °C. The two solids produced at different times are different polymorphs as suggested by XRPD data

** The first time, the solid was isolated after cooling down over the weekend. The second time, the solid was isolated after cooling down overnight and XRPD data showed the presence of base only. Therefore, seed from the previous experiment (Example 2) was added to the vial and the solution was stirred. After a few hours, the solid was isolated but again XRPD data showed the presence of base only. The solution was then allowed to stir over the weekend. The solid isolated after the weekend was a slightly different polymorph than that obtained in Example 2 as suggested by XRPD data.

[0078] (R)-(+)-2-Amino-3 -phenyl- 1-propanol and N-m ethyl -D-glucamine produced the same polymorphs as the first time. (l S,2S)-(+)-Pseudoephedrine and D-Lysine produced different polymorphs from the first time.

Example 6. Salt screening experiments using (S)-Trolox and bases that did not produce salts with (R)-Trolox [0079] (^-Trolox (1.70 g) was weighed out in a vial and dissolved in -8.5 mL of EtOH. The total volume of this solution was measured out to be 9.6 mL. Therefore, 0.565 mL of this solution corresponded to 100 mg of (^-Trolox. 1.05 eq. (100 mg of (^-Trolox = 1 eq.) of each base was weighed out in 15 different vials (3 vials per base). 0.565 mL of the (^-Trolox solution was added to each vial and the solvent was evaporated slowly in a vacuum oven at RT. 0.500 mL of each solvent (a: IP Ac, b: 2-MeTHF, and c: 5 % water/IP A) was added to the appropriate vial and the solution was stirred at 40 °C for 1.5 hours using magnetic stirrer. Then, the solution was cooled down to RT for at least 1.5 hours. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight. If solids were obtained after evaporation, they were analyzed by XRPD and optical microscopy. If no solids were obtained after evaporation, 0.500 mL of diethyl ether was added to gel in the vial and stirred. If solids precipitated, they were filtered and analyzed by XRPD and optical microscopy. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight. Table 13. Reagents used for the salt screening experiments using (^-Trolox and bases that did not produce salts with (R)-Trolox

[0080] In the following tables, (a) refers to Isopropyl acetate (IP Ac), (b) refers to 2- methyltetrahydrofuran (2-MeTHF), and (c) refers to 5 % water/isopropyl alcohol (v/v).

Table 14. Results from the salt screening experiments using (^-Trolox and bases that did not produce salts with (R)-Trolox a/b/c

yellow sticky yellow sticky

base did not dark yellow material in material in clear

11a 11 dissolve gel clear liquid liquid N/A yellow sticky

base did not dark yellow material in thin yellow

l ib dissolve gel clear liquid slurry N/A base did not dark yellow cloudy yellow cloudy yellow

11c dissolve gel solution solution N/A base did not off white off white

12a 12 dissolve solid slurry off white slurry N/A base did not off white off white

12b dissolve solid slurry off white slurry N/A base did not off white off white

12c dissolve solid slurry off white slurry N/A white solid white solid white solid

base did not in yellow chunks in clear chunks in clear

13a 13 dissolve gel liquid liquid N/A white solid

base did not in yellow white solid, white solid, not

13b dissolve gel not stirring stirring N/A white solid yellow sticky

base did not in yellow thin yellow material in clear

13c dissolve gel slurry liquid N/A yellow dark yellow yellow

15a 15 solution gel solution yellow solution orange gel yellow dark yellow yellow orange waxy

15b solution gel solution yellow solution solid yellow dark yellow yellow

15c solution gel solution yellow solution orange gel yellow dark yellow yellow

17a 17 solution gel solution yellow solution orange gel yellow dark yellow yellow

17b solution gel solution yellow solution orange gel yellow dark yellow yellow

17c solution gel solution yellow solution orange gel

Table 15. Results from the salt screening experiments using (^-Trolox and bases that did not produce salts with (R)-Trolox (continued)

salt yellow sticky yellow sticky

material in material in clear

l ie clear liquid* N/A liquid no solid N/A

12a 12 N/A N/A off white slurry base white solid

12b N/A N/A off white slurry base white solid

12c N/A N/A off white slurry** base white solid white solid chunks in

13a 13 N/A N/A clear liquid amorphous waxy solid crystalline

13b N/A N/A N/A salt waxy solid yellow sticky

material in clear

13c N/A N/A liquid no solid N/A off white crystalline

15a 15 thick slurry N/A N/A salt waxy solid crystalline

15b N/A N/A N/A salt waxy solid yellow

15c solution orange gel N/A no solid N/A yellow sticky

material in

17a 17 clear liquid N/A N/A no solid N/A yellow sticky

material in

17b clear liquid N/A N/A no solid N/A yellow sticky

material in

17c clear liquid N/A N/A no solid N/A

* Since was a cloudy yellow solution after cooling down (see Table 14), 0.250 mL of diethyl ether was added to the vial as an anti-solvent. However, no solid precipitated and the result was a yellow sticky material in clear liquid.

** XRPD data showed the presence of base only. In order to help the base dissolve, 5 % H 2 0 was added to the vial and the solution was allowed to stir over the weekend. Afterwards, XRPD data showed the presence of base only.

[0081] After initial XRPD screening, 3 crystalline salts were isolated and further analyzed by 1 H-NMR and optical microscopy. The promising bases that formed solid salts with (^-Trolox but no solid with (R)-Trolox were L-Lysine, L-Arginine, and (R)-(-)-Leucinol.

[0082] Based on our salt screening experiments using (R) or (S) Trolox isomers, the following ranking table was developed. Preference was for bases that formed salts with only one isomer, and cost from lowest to highest. No changes were based on stoichiometry.

Table 16. Ranking table based on salt screening experiments using (R) or (S) Trolox isomers Ob¬

Cost R- S- served

($) Trolox Trolox MorPolyStoichio-

Base per g Salt Salt phology morphs metry Process of Isolation

R salt:

N-methyl- small to

D- large frozen white solid after

7 glucamine 0.4 yes no crystals 1 l to 1 cooling down

S salt:

medium

sized frozen white solid after

13 L-Arginine 0.8 no yes crystals 1 l to 1.26 cooling down

S salt:

small to off white slurry after large cooling down

11 L-Lysine 2.4 no yes crystals 1 l to 1.17 over the weekend

R salt:

large

crystals white slurry after

(1S,2S)- or small addition of diethyl ether

(+)- needleor

Pseudoeph like frozen white solid after

9 edrine 8.6 yes no crystals 2 l to 1 cooling down orange waxy solid after evaporation from solvent or

S salt: off white thick slurry

(R)-(-)- large after addition of diethyl

15 Leucinol 30.6 no yes crystals 2 l to 1.06 ether

R salt:

medium off white slurry after sized cannot be cooling down

10 D -Lysine 40.8 yes no crystals 2 determined over the weekend

R salt:

small to

(R)-(+)-2- large frozen white solid after Amino-3- needlecooling down or phenyl-1- like waxy solid after

4 propanol 43.0 yes no crystals 1 l to 1.19 evaporation from solvent

Example 7. Chiral resolution experiments using (R/S)-Trolox and the 7 bases that

previously produced salts with (R)-Trolox or (S)-Trolox only

[0083] (R/S)-Trolox (5.8 g) was weighed out in a vial and dissolved in ~ 45 mL of EtOH. The total volume of this solution was measured out to be 49 mL. Therefore, 0.845 mL of this

solution corresponded to 100 mg of (R lS)-Trolox. 1.05 eq. or 0.55 eq. (100 mg of (R S)-Trolox = 1 eq.) of each base was weighed out in different vials (for (R)-(+)-2-Amino-3 -phenyl- 1-propanol and (l S,2S)-(+)-Pseudoephedrine, a stock solution was made in methanol and the appropriate amount of the stock solution was added to different vials). Then, 0.845 mL of the (R lS)-Trolox solution was added to each vial and the solvent was evaporated slowly in a vacuum oven at RT.

[0084] 0.500 mL of each solvent (a: IP Ac, b: 2-MeTHF, c: 5 % water/IP A, and d: EtOAc) was added to the appropriate vial and the solution was stirred at 40 °C for 1.5 hours using magnetic stirrer. Then, the solution was cooled down to RT for at least 1.5 hours. If solids precipitated, they were filtered and analyzed by XRPD and chiral HPLC. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight. If solids were obtained after evaporation, they were analyzed by XRPD and chiral HPLC. If no solids were obtained after evaporation, 0.500 mL of diethyl ether was added to gel in the vial and stirred. If solids precipitated, they were filtered and analyzed by XRPD and chiral HPLC. If no solids precipitated, the solvent was evaporated slowly (uncapping of the vial) at RT overnight.

Table 17. Reagents used for the chiral resolution experiments using (R/S)-Trolox and the 7 bases that previously produced salts with (R)-Trolox or (^-Trolox only

[0085] In the following table, (a) refers to Isopropyl acetate (IP Ac), (b) refers to 2- methyltetrahydrofuran (2-MeTHF), (c) refers to 5 % water/isopropyl alcohol (v/v), and (d) refers to Ethyl acetate (EtOAc). Also, the second number (the first number being the base) corresponds to the equivalent amount: (1) refers to 0.55 equivalents and (2) refers to 1.05 equivalents. Table 18. Results for the chiral resolution experiments using (R/S)-Trolox and the 7 bases that previously produced salts with (R)-Trolox or (^-Trolox only

yellow

solution,

add seed thick

from solids in light yellow Example 2 yellow orange yellowdl 4 solution (4a) solution gel slurry n/a yellow light yellow light yellow

d2 4 solution slurry slurry n/a n/a n/a sticky

material in

clear liquid,

white slurry

sticky sticky after

material in material in agitating

al 7 clear liquid clear liquid with spatula n/a n/a n/a sticky

material in

clear liquid,

white slurry

sticky sticky after

material in material in agitating

a2 7 clear liquid clear liquid with spatula n/a n/a n/a frozen white

solid, add thick white thick white

b 1 7 500 μΐ, slurry slurry n/a n/a n/a cloudy cloudy

yellow yellow cloudy

b2 7 solution solution solution n/a n/a n/a yellow

solution,

add seed

from

yellow Example 2

cl 7 solution (7c) white slurry n/a n/a n/a yellow

solution,

sticky add seed

material in from

yellow Example 2

c2 7 solution (7c) white slurry n/a n/a n/a sticky sticky

material in material in

dl 7 clear liquid clear liquid white slurry n/a n/a n/a sticky sticky

material in material in

d2 7 clear liquid clear liquid white slurry n/a n/a n/aal 9 white slurry white slurry white slurry n/a n/a n/aa2 9 yellow white slurry white slurry n/a n/a n/a solution

yellow

solution,

add seed

from thick

yellow Example 2 yellow yellow white

9b 1 9 solution (9a) solution gel slurry n/a yellow

solution, white add seed slurry,

from solid

yellow Example 2 yellow yellow sticks to

9b2 9 solution (9a) solution gel the sides n/a yellow

solution,

add seed

from

yellow Example 2 yellow yellow white

9cl 9 solution (9a) solution gel slurry n/a yellow

solution,

add seed

from

yellow Example 2 yellow yellow yellow yellow

9c2 9 solution (9a) solution gel solution gel yellow

solution,

add seed

from

yellow Example 2

9dl 9 solution (9a) white slurry n/a n/a n/a yellow

9d2 9 solution white slurry white slurry n/a n/a n/a white slurry,

solid sticks

lOal 10 to the sides white slurry white slurry n/a n/a n/a white slurry, white slurry, white slurry,

solid sticks solid sticks solid sticks

10a2 10 to the sides to the sides to the sides n/a n/a n/a white slurry,

solid sticks

lObl 10 to the sides white slurry white slurry n/a n/a n/a solid chunks solid chunks solid chunks

in clear in clear in clear

10b2 10 liquid liquid liquid n/a n/a n/a thick white thick white thick white

lOcl 10 slurry slurry slurry n/a n/a n/a

10c2 10 white slurry, white slurry, white slurry, n/a n/a n/a solid sticks solid sticks solid sticks

to the sides to the sides to the sides

white slurry,

solid sticks

lOdl 10 to the sides white slurry white slurry n/a n/a n/a white slurry, white slurry, white slurry,

solid sticks solid sticks solid sticks

10d2 10 to the sides to the sides to the sides n/a n/a n/a white slurry, white slurry, white slurry,

solid sticks solid sticks solid sticks

Hal 11 to the sides to the sides to the sides n/a n/a n/a white slurry,

solid sticks

l la2 11 to the sides white slurry white slurry n/a n/a n/a sticky sticky sticky

material in material in material in

l lbl 11 clear liquid clear liquid clear liquid n/a n/a n/a sticky sticky sticky

material in material in material in

l lb2 11 clear liquid clear liquid clear liquid n/a n/a n/a sticky

material in

clear liquid,

white slurry

after

agitating thick white thick white

l lcl 11 with spatula slurry slurry n/a n/a n/a sticky

material in

clear liquid,

frozen white

solid after

agitating

with

spatula, add thick white thick white

\ \c2 11 500 μL· slurry slurry n/a n/a n/a white slurry,

solid sticks

13al 13 to the sides white slurry white slurry n/a n/a n/a white slurry,

solid sticks

13a2 13 to the sides white slurry white slurry n/a n/a n/a white solid solid chunks

chunks in thin white in clear

13bl 13 clear liquid slurry liquid n/a n/a n/a white slurry, solid chunks

solid sticks thin white in clear

13b2 13 to the sides slurry liquid n/a n/a n/a yellow

solution,

thick white

slurry after

agitating thick white thick white

3cl 13 with spatula slurry slurry n/a n/a n/a yellow

solution

with

undissolved

base, add

500 μί, thick white thick white

3c2 13 white slurry slurry slurry n/a n/a n/a thick white thick white thick white

5al 15 slurry slurry slurry n/a n/a n/a yellow

solution,

add seed yellow

from oil in yellow Example 2 yellow orange cloudy

5a2 15 solution (15a) solution gel solution n/a yellow

solution,

add seed orange

from gel with thick

yellow Example 2 yellow some white

5bl 15 solution (15a) solution solids slurry n/a yellow

solution,

add seed yellow

from oil in yellow Example 2 yellow yellow cloudy

5b2 15 solution (15a) solution gel solution n/a yellow

solution,

add seed frozen

from white yellow Example 2 yellow white solid, add

5cl 15 solution (15a) solution solids 500 μL· n/a yellow

solution,

add seed

from

yellow Example 2 yellow yellow yellow yellow5c2 15 solution (15a) solution gel solution gel thick white

*al * slurry white slurry white slurry n/a n/a n/a

*a2 * thick white white slurry white slurry n/a n/a n/a slurry

cloudy

yellow yellow

*b l * solution solution white slurry n/a n/a n/a cloudy

yellow

*b2 * solution white slurry white slurry n/a n/a n/a cloudy

yellow

*cl * solution white slurry white slurry n/a n/a n/a

*c2 * white slurry white slurry white slurry n/a n/a n/a

Table 19. Additional results for the chiral resolution experiments using (R/S)-Trolox and the 7 bases that previously produced salts with (R)-Trolox or (^-Trolox only

crystalline

9al 9 salt white solid new polymorph racemic racemic crystalline same polymorph as

9a2 9 salt white solid Example 2 (9a) > 99.9 > 99.9 : 0.1 crystalline

9b 1 9 salt white solid new polymorph racemic racemic crystalline same polymorph as

9b2 9 salt white solid Example 2 (9a) 61.8 80.9 : 19.1 crystalline

9cl 9 salt white solid new polymorph racemic racemic

9c2 9 no solid n/a n/a n/a n/a crystalline

9dl 9 salt white solid new polymorph racemic racemic crystalline same polymorph as

9d2 9 salt white solid Example 2 (9a) > 99.9 > 99.9 : 0.1 crystalline white solid to

lOal 10 salt waxy solid new polymorph racemic racemic crystalline

10a2 10 salt white solid new polymorph racemic racemic lObl 10 no solid n/a n/a n/a n/a base never

10b2 10 dissolved n/a n/a n/a n/a crystalline

lOcl 10 salt white solid new polymorph racemic racemic crystalline

10c2 10 salt white solid new polymorph racemic racemic crystalline white solid to

lOdl 10 salt waxy solid new polymorph racemic racemic crystalline

10d2 10 salt white solid new polymorph racemic racemic crystalline white solid to

Hal 11 salt waxy solid new polymorph racemic racemic crystalline white solid to

l la2 11 salt waxy solid new polymorph racemic racemic l lbl 11 no solid n/a n/a n/a n/a l lb2 11 no solid n/a n/a n/a n/a crystalline white solid to similar polymorph

l lcl 11 salt waxy solid to Example 3 (11a) racemic racemic crystalline white solid to similar polymorph

\ \c2 11 salt waxy solid to Example 3 (11a) racemic racemic crystalline white solid to

13al 13 salt waxy solid new polymorph racemic racemic white solid to

13a2 13 amorphous waxy solid n/a racemic racemic large crystals

13bl 13 n/a to oil n/a n/a n/a

13b2 13 n/a white solid to n/a n/a n/a oily solid

13cl 13 amorphous white solid n/a -36.7 31.7 : 68.3 crystalline

13c2 13 salt white solid new polymorph -18.8 40.6 : 59.4 crystalline

15al 15 salt white solid new polymorph racemic racemic

15a2 15 no solid n/a n/a n/a n/a crystalline

15bl 15 salt white solid new polymorph racemic racemic

15b2 15 no solid n/a n/a n/a n/a crystalline

15cl 15 salt white solid new polymorph racemic racemic

15c2 15 no solid n/a n/a n/a n/a crystalline undesired

*al * salt white solid polymorph racemic racemic crystalline undesired

*a2 * salt white solid polymorph racemic racemic crystalline undesired

*bl * salt white solid polymorph racemic racemic crystalline undesired

*b2 * salt white solid polymorph racemic racemic crystalline undesired

*cl * salt white solid polymorph racemic racemic crystalline undesired

*c2 * salt white solid polymorph racemic racemic

[0086] Solids were isolated from all 7 bases. XRPD and HPLC data suggested that two of the bases ((R)-(+)-2-Amino-3-phenyl-l-propanol and (l S,2S)-(+)-Pseudoephedrine) could successfully resolve racemic Trolox and produce the corresponding (R)-Trolox salts with up to > 99.9 % ee.

Example 8. Stress test experiments using (R/S)-Trolox and the 2 bases that successfully resolved (R S)-Trolox, in the presence of the corresponding undesired polymorphs

[0087] 1.05 eq. or 0.55 eq. (100 mg of (R/5)-Trolox = 1 eq.) of Base #4 or Base #9 was weighed out in 8 different vials. (R/S)-Trolox (100 mg) was added to each vial. A seed of undesired polymorphs (from experiment 10, 4c2 or 9al, respectively) was added to the vials containing Base #4 or Base #9, respectively.

[0088] 0.500 mL of the appropriate solvent (IP Ac or EtOAc) was added to the appropriate vial and the solution was stirred at 40 °C for 1.5 hours using magnetic stirrer. Then, the solution was cooled down to RT for at least 1.5 hours. The solids that precipitated were filtered and analyzed by XRPD and chiral HPLC.

Table 20. Reagents used for the stress test experiments using (R/lS)-Trolox and the 2 bases that successfully resolved (R S)-Trolox, in the presence of the corresponding undesired polymorphs

[0089] In the following table, (a) refers to Isopropyl acetate (IP Ac) and (d) refers to Ethyl acetate (EtOAc). Also, the second number (the first number being the base) corresponds to the equivalent amount: (1) refers to 0.55 equivalents and (2) refers to 1.05 equivalents.

Table 21. Results from the stress test experiments using (R/lS)-Trolox and the 2 bases that successfully resolved (R S)-Trolox, in the presence of the corresponding undesired polymorphs

[0090] XRPD and HPLC data suggested that when using 1.05 equivalents of Q S,2S)-(+)- Pseudoephedrine, the desired polymorph (enantioenriched salt) could form even in the presence of the undesired polymorph (racemic salt).

[0091] Samples from 2 out of the 8 stress test experiments (previously setup) were tested after ~ 5-6 weeks of slurrying by XRPD. These 2 experiments (9a2 and 9d2) had successfully resolved (R/S)-Trolox by forming a salt of R-Trolox and (l S,2S)-(+)-Pseudoephedrine in 2 different solvents (IP Ac and EtOAc). Both experiments had been carried out in the presence of the undesired racemic salt and 1.05 equivalents of the base had been added. IP Ac was used as the solvent in experiment 9a2 while EtOAc was used in experiment 9d2. After ~ 5-6 weeks of slurrying the slurries were filtered, the wet cakes were washed with the respective solvents and were subsequently confirmed to be the salt of R-Trolox by XRPD. XRPD of the samples after 5- 6 weeks of slurrying were similar to XRPD of the original samples from Table 21.

Example 9. Gravimetric solubility analysis of the R-Trolox (lS,2S)-(+)-Pseudoephedrine salt in 12 different solvent systems at room temperature [0092] R-Trolox (l S,2S)-(+)-Pseudoephedrine salt was prepared by weighing out 2 g of (R/S)- Trolox and 1.05 equivalents of (l S,2S)-(+)-Pseudoephedrine in a glass vial. 10 ml of EtOAc was added and the solution was stirred at 40 °C for ~ 1.5 hours and then cooled to room temperature and stirred overnight. Next morning the slurry was filtered and the wet cake was placed in a vacuum oven for drying at room temperature for ~ 2 hours. The dried solids were confirmed to be the R-Trolox (1 S,2S)-(+)- Pseudoephedrme salt by XRPD. This material was used for solubility analysis.

[0093] Gravimetric solubility analysis of the R-Trolox (l S,2S)-(+)-Pseudoephedrine salt in 12 different solvent systems at room temperature was carried out. ~ 45 mg each of the salt was weighed into 12 vials and 1 ml of the respective solvents was added at room temperature. If the solids dissolved completely ~ 100 mg of the salt was added to the vial. If these solids also dissolved completely the solubility was noted as > 145 mg/ml.

[0094] The samples which did not dissolve were slurried overnight. After overnight slurrying, the samples were centrifuged and 0.5 ml of the supernatant was added to pre-weighed glass vials and evaporated in a vacuum oven at room temperature over the weekend. Based on the weight of the solids obtained after evaporation the solubility was calculated. Also, the wet cakes obtained after centrifugation were analyzed by XRPD to confirm that no transformation had taken place. As shown in Table 22, this salt is highly soluble in acetone, ethanol (EtOH) and THF and moderately soluble in 2-MeTHF, IP Ac, IP A, EtOAc and 2-MeTHF/IPAc mixtures. XRPD patterns of the solids obtained after centrifugation were consistent with a reference pattern of the R-Trolox (l S,2S)-(+)-Pseudoephedrine salt.

Table 22. Gravimetric solubility analysis of the R-Trolox (I S, 2S)-(+)-Pseudoephedrine salt in 12 different solvent systems at room temperature

Example 10. Crystallization experiments of the R-Trolox (lS,2S)-(+)-Pseudoephedrine salt in 3 different solvent systems

[0095] To study the effect of solvent system on crystallization of the R-Trolox (l S,2S)-(+)- Pseudoephedrine salt, 3 experiments in EtOAc, IPAc and 2-MeTHF (1957-54-1, 2 and 3 respectively) were setup. ~ 200 mg each of the (R/S)-Trolox and 1.05 equivalents of the (1 S,2S)- (+)-Pseudoephedrine were weighed into a glass vial followed by addition of 1 ml of the respective solvents. The solutions were stirred at 40 °C for ~ 1 hour followed by stirring at room temperature for ~ 1 hour.

[0096] The slurries obtained in experiments with EtOAc and IPAc were filtered and the wet cake was washed with the respective solvents and dried in a vacuum oven at room temperature for ~ 1 hour. The solids were then confirmed as the R-Trolox (l S,2S)-(+)-Pseudoephedrine salt by XRPD and analyzed by chiral HPLC. The results of the chiral HPLC indicated that the % ee of the R-enantiomer was 99.5% for the EtOAc sample and 99.1% for the IP Ac sample.

[0097] No solids were obtained in the experiment with 2-MeTHF (possibly due to relatively higher solubility of the salt). The sample was cooled to 10 °C and stirred overnight however no solids were obtained. The results of all 3 experiments are shown in Table 23. XRPD patterns of the solids obtained in experiments 1957-54-1 and 2 were consistent with the reference pattern of the R-Trolox (l S,2S)-(+)-Pseudoephedrine salt.

Table 23. Crystallization experiments of the R-Trolox (l S,2S)-(+)-Pseudoephedrine salt in 3 different solvent systems

Example 11. Gravimetric solubility analysis of the R-Trolox (lS,2S)-(+)-Pseudoephedrine salt in EtOAc and IPAc at 60 °C and 5 °C

[0098] Solubility of R-Trolox (l S,2S)-(+)-Pseudoephedrine salt was measured gravimetrically at 60°C and 5 °C in EtOAc and IPAc. ~ 20-65 mg of the salt was slurried in the respective solvents overnight at both temperatures. After overnight slurrying, the samples were centrifuged and the supernatant was added to pre-weighed glass vials and evaporated in a vacuum oven at room temperature overnight. Based on the weight of the solids obtained after evaporation the solubility was calculated. Also, the wet cakes obtained after centrifugation were analyzed by XRPD (only for the 60 °C samples) to confirm that no transformation had taken place. Table 24 contains the solubility data at 60 °C and 5 °C in EtOAc and IPAc.

Table 24. Gravimetric solubility analysis of the R-Trolox (I S, 2S)-(+)-Pseudoephedrine salt in EtOAc and IPAc at different temperatures 1957-58-2 IP Ac/5 °C 2.6 mg/ml

1957-56-1 EtO Ac/60 °C 24 mg/ml

1957-56-2 IPAc/60 °C 19 mg/ml

Example 12. Experiments to study the effect of equivalents of (lS,2S)-(+)- Pseudoephedrine added on resolution of (R/S)-Trolox

[0099] To study the effect of equivalents of (l S,2S)-(+)-Pseudoephedrine added on resolution of (R/S)-Trolox, 5 experiments with 0.5, 0.65, 0.85, 1 and 1.25 equivalents of the counterion were setup (experiments 1957-57-3, 4, 5, 6 and 7 respectively). EtOAc was used as the solvent. ~ 200 mg each of the (R/S)-Trolox and the respective equivalents of the (l S,2S)-(+)-Pseudoephedrine were weighed into a glass vial followed by addition of 1 ml of EtOAc. The solutions were stirred at 40 °C for ~ 2 hours followed by stirring at room temperature for ~ 2 hours.

[0100] The slurries obtained in experiments with 0.85, 1 and 1.25 equivalents of the counterion (1957-57-5, 6 and 7 respectively) were filtered and the wet cake was dried in a vacuum oven at room temperature for ~ 2 hours. The solids were then confirmed as the R-Trolox (l S,2S)-(+)- Pseudoephedrine salt by XRPD. In these experiments, solids were obtained while stirring at 40 °C.

[0101] No solids were obtained in experiments with 0.5 and 0.65 equivalents of the counterion (1957-57-3 and 4) after ~ 2 hours of stirring at 40 °C and ~ 4 hours of stirring at room

temperature. Both samples were stirred at 5°C overnight.

[0102] After overnight stirring at 5°C, sample 1957-57-3 (0.5 eq.) was still a clear solution however solids were obtained in sample 1957-57-4 (0.65 eq.). The slurry obtained in experiment 1957-57-4 was filtered and the wet cake was dried in a vacuum oven at room temperature for ~ 2 hours. The solids were then confirmed as the R-Trolox (1 S,2S)-(+)-Pseudoephedrine salt by XRPD.

[0103] Sample 1957-57-3 (0.5 eq.) which did not yield any solids even after overnight stirring at 5°C was brought back to room temperature and seeded with racemic salt (1957-44-9al) and stirred overnight. The sample precipitated out overnight and a small portion of the slurry was filtered and the wet cake was dried in a vacuum oven at room temperature for ~ 2 hours. XRPD analysis revealed that the solids obtained were the racemic salt. [0104] Additional (l S,2S)-(+)-Pseudoephedrine was added to the slurry obtained in experiment 1957-57-3 to increase the equivalents of the counterion added from 0.5 to 1 and the sample was stirred at room temperature over the weekend. Next, a portion of the slurry was filtered and the solids obtained were analyzed by XRPD. The analysis revealed that the solids had transformed from the racemic salt to the R-Trolox (1 S,2S)-(+)-Pseudoephedrine salt on increasing the counterion equivalents from 0.5 to 1.

[0105] The results of experiments 1957-57-3 to 7 are shown in Table 25.

Table 25. Experiments to study the effect of equivalents of (l S,2S)-(+)-Pseudoephedrine added on resolution of (R/S)-Trolox with EtOAc as solvent

Example 13. DSC analysis on R-Trolox (lS,2S)-(+)-Pseudoephedrine salt

[0106] Sample 1957-57-6 was analyzed by DSC to obtain a reference thermogram for the R- Trolox (l S,2S)-(+)-Pseudoephedrine salt (Figure 1).

Example 14. Resolution of (R/S)-Trolox at ~ 5g scale

[0107] Two experiments were carried out with 4 and 6 volumes (1957-61-3 and 4 respectively) of EtOAc as the solvent. In each experiment ~ 4.75 g of (RZS)-Trolox and 2.67 g of (l S,2S)-(+)- Pseudoephedrine (0.85 eq.) were charged to a reactor at 40 °C and the respective volumes of EtOAc were added. The reactor was held at 40 °C for 1 hour, then cooled to 25 °C over 1 hour, followed by cooling to 10 °C over 30 minutes. Finally, the reactor was held at 10 °C for 1 hour. [0108] The slurries obtained were filtered and the wet cake was washed with EtOAc (at 10 °C) and dried in a vacuum oven at room temperature over the weekend. Next, the solids obtained were weighed to calculate the yield and analyzed by XRPD and chiral HPLC. The results of both experiments are shown in Table 26. XRPD patterns of the solids obtained in experiments 1957- 61-3 and 4 were consistent with the reference pattern of the R-Trolox (1 S,2S)-(+)- Pseudoephedrine salt.

Table 26. Resolution of (R/S)-Trolox at ~ 5g scale

[0109] Two experiments were carried out with 0.7 and 1 eq. (1957-63-1 and 2 respectively) of (l S,2S)-(+)-Pseudoephedrine and 5 volumes of EtOAc as the solvent. In each experiment ~ 4.75 g of (R/S)-Trolox, the respective equivalents of (l S,2S)-(+)-Pseudoephedrine and 5 volumes of EtOAc were charged to a reactor at room temperature with 500 rpm overhead stirring. The reactor was heated to 40 °C over 30 minutes, held at 40 °C for 1 hour, cooled to 25 °C over 1 hour, followed by cooling to 10 °C over 30 minutes. Finally, the reactor was held at 10 °C for 1 hour. [0110] Experiment 1957-63-1 (0.7 eq) was seeded (1 %) with the (R)-Trolox-(l S,2S)-(+)-

Pseudoephedrine salt to induce crystallization after no crystals were formed after 1 hour at 40 °C. The slurries obtained in both experiments were filtered and the wet cake was washed with 1.5 volumes of EtOAc (at 10 °C) and dried in a vacuum oven at room temperature overnight. Next, the solids obtained were weighed to calculate the yield and analyzed by XRPD and chiral HPLC. The results of both experiments are shown in Table 27. XRPD patterns of the solids obtained in experiments 1957-63-1 and 2 were consistent with the reference pattern of the R- Trolox (l S,2S)-(+)-Pseudoephedrine salt.

[0111] Two experiments were carried out with 5 volumes of EtOAc and EtOAc with 1 % water (1957-65-1 and 2 respectively) and 1.15 equivalents of (l S,2S)-(+)-Pseudoephedrine. In each experiment ~ 4.75 g of (R/S)-Trolox, 1.15 equivalents of (l S,2S)-(+)-Pseudoephedrine and 5 volumes of the respective solvents were charged to a reactor at room temperature with 500 rpm overhead stirring. The reactor was heated to 40 °C over 30 minutes, held at 40 °C for 1 hour, cooled to 25 °C over 1 hour, followed by cooling to 10 °C over 30 minutes. Finally, the reactor was held at 10 °C for 1 hour. [0112] The slurries obtained were filtered and a sample of the wet cake was saved for chiral HPLC analysis. The wet cake was washed with 6 volumes of EtOAc (at room temperature) and dried in a vacuum oven at room temperature overnight. Next, the solids obtained were weighed to calculate the yield and analyzed by XRPD and chiral HPLC. The results of both experiments are shown in Table 28. XRPD patterns of the solids obtained in experiments 1957-65-1 and 2 were consistent with the reference pattern of the R-Trolox (1 S,2S)-(+)-Pseudoephedrine salt

Table 27. Resolution of (R/S)-Trolox at ~ 5g scale

Table 28. Resolution of (R/S)-Trolox at ~ 5g scale

Example 15. Slurry Experiments to Improve Enantiomeric Purity [0113] Samples 1957-61-3, 4 and 1957-63-1, 2 (from pseudoephedrine salt formation experiments at ~ 5g scale) were slurried in EtOAc at room temperature to try and improve their enantiomeric purity. ~ lg of each of the samples was slurried in 2 volumes of EtOAc. [01 14] The slurries were sampled after 15 minutes and after 3 hours and were analyzed by chiral HPLC. The results of the analysis are shown in Table 29.

[01 15] Table 29. Slurry Experiments to Improve Enantiomeric Purity

Example 16. Process for resolving (R)-Trolox [01 16] 4.750 g of (R/S)-Trolox were added to reactor at room temperature. 1.15 equivalents (with respect to (R/S)-Trolox) of (l S,2S)-(+)-Pseudoephedrine (3.606 g) were added. 5 volumes of EtOAc (23.75 ml) were added. The reactor contents were heated to 40 °C, the temperature held at 40 °C for 1 hour, then the reactor was cooled to 25 °C over 1 hour, then the reactor was cooled to 10 °C over 30 minutes, then the reactor was held at 10 °C for 1 hour. The slurry obtained was filtered, the wet cake washed with 6 volumes of EtOAc (28.5 ml) at room temperature, and the solids dried overnight in vacuum oven at 25-30 °C. 2.569 g (65.2 % yield) of (R)-Trolox-(l S,2S)-(+)-Pseudoephedrine salt (99.9% ee) was obtained.

Example 17. Synthesis of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa - l,4-dienyl)butanamide from (R)-Trolox Example 17A. Extraction of (I S, 2S)-(+)-Pseudoephedrine free base.

[01 17] To a suspension of (IS, 2 i S)-(+)-Pseudoephedrine hydrochloride salt (300 g, Spectrum) in 2-MeTHF (1.5 L, 5 vol) was added 20% Aq NaOH solution (750 mL, 2.5 vol) and the mixture was stirred for 30 min (some solids remained undissolved) and transferred to a separately funnel. The lower aqueous layer was drained along with solids that remained at the interphase and back extracted with 2-MeTHF (750 mL, 2.5 vol), the undissolved solids completely dissolved to form two clear layers. The combined organic layers were evaporated to dryness on rotavapor and the solids obtained were dried in a vacuum oven at 50 °C overnight to afford 240.3 g of free base as a white solid (97.7% recovery).

Example 17B. Precipitation of (l S,2S)-Pseudoephedrine from 2-MeTHF/heptane [01 18] (lS,2S)-pseudoephedrine (Sigma-Aldrich, sku#212464, 8.2 g) was dissolved at 50 °C in 2-MeTHF (41 ml, 5 vol). The resulting solution was diluted with heptane (82 ml, 10 vol) and the resulting suspension was stirred at room temperature overnight. The crystallized (\S,2S)- pseudoephedrine was filtered off and dried overnight at 40 °C under vacuum affording 6.4 g (78%) of white crystalline material. Filtrate was discarded to general waste.

[01 19] Relatively low (78%) crystallization yield prompted an additional crystallization experiment with higher heptane to 2-MeTHF ratio. Crystalline (l^^-pseudoephedrine obtained in the experiment above was dissolved at 50 °C in 2-MeTHF (32 ml, 5 vol). The resulting solution was diluted with heptane (32 ml, 5 vol) and the resulting suspension was chased with heptane (3 x 50 ml) on rotary evaporator until molar ration of 2-MeTHF to heptane became lower than 6% by NMR. The resulting suspension was filtered off and the product dried overnight at 40 ° under vacuum affording 6.3 g (98%) of white crystalline material.

Example 17C. Chiral resolution of Trolox using (I S, 2S)-(+)-Pseudoephedrine.

Racemic Trolox (316.6 g, 1.27 mol) and (IS, 2 ( S)-(+)-Pseudoephedrine free base described in Example 17A (240.0 g, 1.46 mol) were charged to a 4L jacketed reactor equipped with an overhead stirrer, temperature probe and a nitrogen purge. Ethyl acetate (EtOAc, 1585 mL, 5 vol) was charged and the slurry was heated to 50°C resulting in clear solution. (Premature (prior to complete dissolution of rac -trolox) precipitation of the (R)-trolox-pseudoephedrine salt ((R)- trolox-PE salt) was occasionally observed at 40°C. If premature precipitation takes place the reaction mixture was heated (usually to reflux temperature) to achieve complete dissolution.) The reaction mixture was cooled overnight to room temperature at which time massive precipitation was observed. The mixture was cooled to 10 °C over 30 min and held at this temperature for 1 h. The solids formed were collected by filtration, the wet cake was washed with EtOAc (1.9 L, 6 Vol) and the filter cake was dried in a vacuum oven at 25-30 °C to constant weight to afford 188.1 g (71.3% based on (R)-trolox) of a white solid. Chiral HPLC data indicated nearly 100% enantiomeric purity.

Example 17D. Recovery of (R)-Trolox from its salt with (I S, 2S)-(+)-Pseudoephedrine.

R-Trolox PE salt

[0120] The resulting (R)-Trolox PE salt (187.3 g, 0.45 mol) was charged to a 2L round-bottom flask followed by 2-MeTHF (570 ml, 3 vol.) to form a slurry. Hydrochloric acid (2.5 M, 325 ml, 0.81 mol, 1.75 eq) was added portionwise while maintaining temperature below 25°C. The (R)- trolox-PE salt was dissolved and (R)-Trolox was extracted into organic phase. Small black rag layer was observed in the interface and was kept with the aqueous. The aqueous phase was additionally extracted with 2-MeTHF (2x200 ml). The combined organic layer was then washed with 15%) NaCl (200 ml) followed by water (200 ml). The organic layer was dried over anhydrous sodium sulfate (150 g), filtered and evaporated to dryness to afford white solid which was dried under vacuum oven at 30 °C to constant weight of 128.3 g, which is an

overstoichiometric amount.

Example 17E. Preparation of (R)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxamide.

[0121] CDI (Sigma-Aldrich) (188 g, 1.16 mol) was charged to a 3-neck 2L RBF equipped with an overhead stirrer, nitrogen inlet and temperature probe. 2-MeTHF (290 mL) was added to give a stirrable slurry followed by slow addition of (R)-trolox (126.0 g, 504 mmol) in 2-MeTHF (500 ml) at below 30 °C. A slightly exothermic reaction accompanied by C0 2 evolution was observed. Outgassing started after addition of approximately one third of (R)-trolox. Complete dissolution of the starting materials was observed in approximately 15 min. [0122] The content of this flask was slowly added to a pre-cooled to 5 °C 28-30% aqueous ammonia (380 ml) maintaining temperature below 30 °C. The resulting biphasic suspension was stirred at room temperature and monitored by HPLC. The reaction was found to be complete at 36 h and was further processed after 48 h. [0123] The reaction mixture was acidified to pH 1-2 with sulfuric acid (1 :4 v/v) (850 ml) maintaining the temperature < 28 °C, reaction was highly exothermic. The aqueous layer (pH=l) was removed and the organic layer was washed with NaCl (15% aqueous w/v, 250 mL), NaHC0 3 (1 M, 250 mL), NaCl (15% aqueous w/v, 250 mL) and water (250 ml). The majority of the organic layer was used for the subsequent steps. Example 17F. Preparation of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa - 1 ,4-dienyl)butanamide.

[0124] A solution of (R)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxamide (708 ml) which contains ~ 0.39 mole of the intermediate amide and water (126 ml) were charged to a 2L 3N RBF equipped with an overhead stirrer and a thermocouple.

[0125] A stock solution of FeCl 3 x6H 2 0 (480 g, 1.78 mol) in water (336 ml) was divided into 4 equal parts (204 g each) and one-fourth of the iron(III) chloride solution was added to the reaction flask. A weak (~3 °C) exotherm was observed, the color of the organic layer turned nearly black then lightened to dark-brown. The biphasic reaction mixture was vigorously stirred for 40 min at room temperature. After removal of the lightly colored aqueous phase another portion of the iron(III) chloride solution was added and stirred for 40 min. The operation was repeated one more time and the organic phase was stored overnight at room temperature. The fourth treatment with FeCl 3 x6H 2 0 was performed next morning. Nearly complete (99.44%) conversion of (R)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxamide to (R)-2-hydroxy-2- methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl)buta namide was observed. Initial iron extraction was performed withlM trisodium citrate solution (2x350 ml); the AUC% of (R)-6- hydroxy-2,5,7,8-tetramethylchromane-2-carboxamide increased to 0.84%. pH of the organic phase remained highly acidic (pH=l). A 1 ml aliquot of the organic phase was treated with 1M NaHC0 3 resulting in massive precipitation of red Fe(OH) 3 . Based on this observation one more trisodium citrate wash (175 ml) was performed (0.74% (R)-6-hydroxy-2,5,7,8- tetramethylchromane-2-carboxamide). The repeat testing of the 1 ml aliquot with 1M NaHC0 3 gave no precipitation in the aqueous layer and the color of the aqueous layer was yellow, not red, indicating complete or nearly complete iron removal.

[0126] The organic layer was heated to 40 °C to prevent premature precipitation of (R)-2- hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-d ienyl)butanamide and washed with 1M sodium bicarbonate solution (175 ml). The phase split was not immediate but was complete in 15 min forming two clear yellow layers. The organic layer (0.30% (R)-6-hydroxy- 2,5,7,8-tetramethylchromane-2-carboxamide) was additionally washed with water (350 ml) giving 0.22% (R)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxamide. Evaporation of the organic layer gave 96 g of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa -l,4- di enyl)butanami de . [0127] The combined bicarbonate/water layers were back extracted with 2x250 ml of 2-MeTHF. Evaporation of these extracts separately gave 4.0 and 0.9 g of (R)-2-hydroxy-2-methyl-4-(2,4,5- trimethyl-3,6-dioxocyclohexa-l,4-dienyl)butanamide.

[0128] The combined solids (100.9 g - crude (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanamide, 84% yield based on (R)-trolox-pseudoephedrine salt) were dissolved in isopropanol (600 ml) at 70 °C and the resulting yellow solution was charged to a 2L 3N RBF equipped with an overhead stirrer a heating mantle and a thermocouple.

[0129] Heptane (600 ml) was added, no precipitation was observed. The reaction mixture was reheated to 55 °C and slowly cooled down to room temperature. Seeds of the desired polymorph (0.2 g) were added and the reaction mixture was stirred overnight at room temperature. Massive precipitation was observed overnight. The reaction mixture was cooled to 7 °C and stirred for additional 8 hours. The product was filtered, washed with isopropanol-heptane 1 : 1 v/v (2x75 ml) and dried over the weekend at 40 °C. Yield 69.4 g of (R)-2-hydroxy-2-methyl-4-(2,4,5- trimethyl-3,6-dioxocyclohexa-l,4-dienyl)butanamide (58% based on (R)-trolox - pseudoephedrine salt). [0130] The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.

[0131] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.