Purified Pyrroloquinolinyl-Pyrrolidine-2,5-Dione Compositions And Methods For Preparing And Using Same

• US 20110160242A1
• Filed: 12/22/2010
• Published: 06/30/2011
• Est. Priority Date: 12/23/2009
• Status: Active Grant

• Current Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Original Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Inventors: Kane, John C., Lee, Christopher A., Reed, David P., Chen, Jian-Xie, Redmon, Martin P., Barnes, Neil R.
• Granted Patent: US 8,552,192 B2
• Time in Patent Office: Days
• US Class Current: 514/294
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/06 Peri-condensed systems

Abstract

The present invention relates to a form 1 and form 2 polymorph of (−)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione. The present invention also relates to (−)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione compounds having a chiral purity greater than 99%, and methods of preparation of these compounds. The present invention also relates to pharmaceutical compositions comprising these (−)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione compounds. The present invention provides methods of treating a cell proliferative disorder, such as a cancer, by administering to a subject in need thereof a therapeutically effective amount of a composition comprising (−)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione having a chiral purity greater than 99% or a form 1 and form 2 polymorph of (−)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

Claims

1. A polymorph of (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione characterized by an X-ray powder diffraction pattern comprising peaks at approximately 8.2, 10.8 and 14.1°

2θ

using Cu Kα

radiation.

2. The polymorph of claim 1 characterized by an X-ray powder diffraction pattern comprising peaks at approximately 8.2, 10.8, 14.1, 15.5, 17.8, 19.9 and 25.6°

2θ

using Cu Kα

radiation.

3. The polymorph of claim 1 characterized by an X-ray powder diffraction pattern comprising peaks at approximately 8.2, 10.8, 14.1, 14.9, 15.5, 17.1, 17.8, 19.4, 19.9, 21.1, 21.9, 23.0, 25.6 and 28.4°

2θ

using Cu Kα

radiation.

73. A pharmaceutical composition comprising a polymorph of any one of claims 1-3 and 4-6 and a pharmaceutically acceptable carrier or excipient.

75. A method of treating a cancer, comprising administering to a subject a therapeutically effective amount of a polymorph of any one of claims 1-3 and 4-6 in combination with a pharmaceutically acceptable carrier.

76. The method of claim 75, wherein said cancer is selected from lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, chronic myelogenous leukemia, melanoma, ovarian cancer, renal carcinoma, hepatoma, brain cancer and multiple myeloma.

4. A polymorph of (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione characterized by an X-ray powder diffraction pattern comprising peaks at approximately 6.5, 9.9 and 12.0°

2θ

using Cu Kα

radiation.

5. The polymorph of claim 4 characterized by an X-ray powder diffraction pattern comprising peaks at approximately 6.5, 9.9, 12.0, 16.7, 20.1 and 22.8°

2θ

using Cu Kα

radiation.

6. The polymorph of claim 4 characterized by an X-ray powder diffraction pattern comprising peaks at approximately 6.5, 9.9, 12.0, 13.2, 16.4, 16.7, 17.2, 20.1, 20.3, 20.8, 22.8, 23.7, 28.6 and 30.4°

2θ

using Cu Kα

radiation.

7. A (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione dichloromethane.

8. A composition comprising (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione dichloromethane.

9. The composition of claim 8 comprising greater than 90% (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione dichloromethane.

10. The composition of claim 9 comprising greater than 95% (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione dichloromethane.

11. The composition of claim 10 comprising greater than 99% (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione dichloromethane.

12. A (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)-pseudoephedrine.

13. A composition comprising (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)-pseudoephedrine.

14. The composition of claim 13 comprising greater than 90% (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)-pseudoephedrine.

15. The composition of claim 14 comprising greater than 95% (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)-pseudoephedrine.

16. The composition of claim 15 comprising greater than 99% (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)-pseudoephedrine.

17. The composition of claim 13 comprising less than 1% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione pseudoephedrine.

18. The composition of claim 17 comprising less than 0.5% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione pseudoephedrine.

19. The composition of claim 18 comprising less than 0.1% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione pseudoephedrine.

20. A chirally purified (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione comprising less than 1% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

21. The chirally pure (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione of claim 20 comprising less than 0.7% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

22. The chirally pure (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione of claim 21 comprising less than 0.5% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

23. The chirally pure (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione of claim 22 comprising less than 0.1% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

74. A pharmaceutical composition comprising a chirally purified (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione of any one of claims 20-23.

77. A method of treating a cancer, comprising administering to a subject a therapeutically effective amount of a chirally purified (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione of any one of claims 20-23 in combination with a pharmaceutically acceptable carrier.

78. The method of claim 77, wherein said cancer is selected from lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, chronic myelogenous leukemia, melanoma, ovarian cancer, renal carcinoma, hepatoma, brain cancer and multiple myeloma.

24. A method for preparing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, comprising;

a. mixing (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione with (1S,2S)-(+)-pseudoephedrine in a first solvent to form solid (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)-pseudoephedrine;

b. washing the (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)-pseudoephedrine solid formed in step (a) with an aqueous mixture of the first solvent;

c. reacting the (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)-pseudoephedrine from step (b) with an acid in an organic solvent and isolating the organic layer of the resultant solution;

d. washing the organic layer from step (c);

e. adding a second solvent to the organic layer;

f. concentrating the organic layer until the amount of the second solvent in the solution is less than 5%; and

g. crystallizing from the organic layer in step (f) and drying the resultant (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione solution under vacuum, thereby producing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

25. The method of claim 24, wherein said first solvent is a non-aqueous solvent.

26. The method of claim 25, wherein said non-aqueous solvent is methanol, ethanol, acetonitrile, or a mixture thereof.

27. The method of claim 24, wherein said second solvent is a non-aqueous solvent.

28. The method of claim 27, wherein said non-aqueous solvent is methanol, ethanol, acetonitrile, or a mixture thereof.

29. The method of claim 24, wherein said second solvent is the same as said first solvent.

30. The method of claim 24, wherein said second solvent is different from said first solvent.

31. The method of claim 24, wherein said organic solvent in step c is methyltetrahydrofuran

32. The method of claim 24, wherein said organic layer is washed with a salt solution in step d.

33. The method of claim 32, wherein said salt solution is a sodium chloride solution.

34. The method of claim 24, further comprising rinsing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione crystal after step (g).

35. The method of claim 34, wherein (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione crystal is rinsed with an alcohol selected from ethanol and methanol.

36. The method of claim 24, wherein said produced (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione comprises less than 1% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

37. The method of claim 36, wherein said produced (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione comprises less than 0.7% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

38. A method for preparing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, comprising;

a. mixing (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione with cyclohexylethylamine in a first solvent to form solid (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.cyclohexylethylamine;

b. washing the (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.cyclohexylethylamine solid formed in step (a) with an aqueous mixture of the first solvent;

c. reacting the (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.cyclohexylethylamine from step (b) with an acid in an organic solvent and isolating the organic layer of the resultant solution;

d. washing the organic layer from step (c);

e. adding a second solvent to the organic layer;

f. concentrating the organic layer until the amount of the second solvent in the solution is less than 5%; and

g. crystallizing from the organic layer in step (f) and drying the resultant (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione solution under vacuum, thereby producing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

39. The method of claim 38, wherein said first solvent is a non-aqueous solvent.

40. The method of claim 39, wherein said non-aqueous solvent is acetonitrile.

41. The method of claim 38, wherein said second solvent is a non-aqueous solvent.

42. The method of claim 41, wherein said non-aqueous solvent is methanol, ethanol, acetonitrile, or a mixture thereof.

43. The method of claim 38, wherein said second solvent is the same as said first solvent.

44. The method of claim 38, wherein said second solvent is different from said first solvent.

45. The method of claim 38, wherein said organic solvent in step c is methyltetrahydrofuran

46. The method of claim 38, wherein said organic layer is washed with a salt solution in step d.

47. The method of claim 46, wherein said salt solution is a sodium chloride solution.

48. The method of claim 38, further comprising rinsing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione crystal after step (g).

49. The method of claim 48, wherein (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione crystal is rinsed with an alcohol selected from ethanol and methanol.

50. The method of claim 38, wherein said produced (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione comprises less than 1% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

51. The method of claim 50, wherein said produced (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione comprises less than 0.7% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

52. A method for preparing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, comprising;

a. mixing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)-pseudoephedrine and an acid;

b. adding an alcohol to the mixture from (a) to form a slurry;

c. heating and stirring the slurry formed in (b);

d. cooling and isolating (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione;

e. washing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione isolated in step (d) with a first solvent;

f. dissolving (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione from step (e) in a second solvent to form a solution;

g. adding a third solvent to the solution in (f) and distilling the solution until the amount of said second solvent in the solution is less than 5%;

h. crystallizing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione from the solution in (g);

i. optionally, adding a fourth solvent to mature the crystals from (h);

j. isolating the crystals from (i) by filtration;

k. washing the crystals from (j) with a mixture of the third solvent and fourth solvent; and

l. drying the crystals from (k) under vacuum, thereby producing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

53. The method of claim 52, wherein said alcohol is methanol, ethanol, or a mixture thereof.

54. The method of claim 52, wherein said first solvent is a non-aqueous solvent.

55. The method of claim 54, wherein said non-aqueous solvent is methanol, ethanol, or a mixture thereof.

56. The method of claim 52, wherein said second solvent is a non-aqueous solvent.

57. The method of claim 56, wherein said non-aqueous solvent is tetrahydrofuran.

58. The method of claim 52, wherein said third solvent is a non-aqueous solvent.

59. The method of claim 58, wherein said non-aqueous solvent is methanol, ethanol, or a mixture thereof.

60. The method of claim 52, wherein said fourth solvent is an aqueous solvent.

61. The method of claim 60, wherein said aqueous solvent is water.

62. The method of claim 52, wherein said produced (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione comprises less than 1% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

63. The method of claim 62, wherein said produced (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione comprises less than 0.7% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

64. A method for preparing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, comprising;

a. dissolving (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione in dichloromethane and isolating the (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione dichloromethane;

b. dissolving (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione dichloromethane in a first solvent;

c. distilling the solution of step (b) until the level of dichloromethane in the solution is <

0.1% by weight;

d. diluting the solution of step (c) in a second solvent;

e. introducing the solution of step (d) into a multicolumn chromatography system containing a packing suitable for chiral separation;

f. pooling the resultant raffinate obtained from the system in step (e); and

g. crystallizing the raffinate from step (f) and filtering the resultant (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, thereby producing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

65. The method of claim 64, wherein said first solvent is a non-aqueous solvent.

66. The method of claim 65, wherein said non-aqueous solvent is methanol, ethanol, or a mixture thereof.

67. The method of claim 64, wherein said second solvent is a non-aqueous solvent.

68. The method of claim 67, wherein said non-aqueous solvent is methanol, ethanol, acetonitrile, or a mixture thereof.

69. The method of claim 68, wherein said non-aqueous solvent is a mixture of methanol and acetonitrile.

70. The method of claim 64, wherein said produced (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione comprises less than 1% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

71. The method of claim 70, wherein said produced (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione comprises less than 0.7% (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

72. A method for preparing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, comprising steps a-f of claim 64 and step g′

, wherein step g′

comprises evaporating the raffinate in step f, thereby producing (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.