SYNTHESIS OF CHIRALLY PURIFIED SUBSTITUTED BENZOTHIAZOLES

• US 20080227985A1
• Filed: 03/14/2008
• Published: 09/18/2008
• Est. Priority Date: 03/14/2007
• Status: Active Grant

• Current Assignee: Knopp Biosciences LLC
• Original Assignee: Knopp Neurosciences Inc. (Knopp Biosciences LLC)
• Inventors: McCall, John M., Lapina, Olga V., Raje, Prasad, Chen, Jian-Xie, Gadikota, Rajendrakumar Ruddy
• Granted Patent: US 8,519,148 B2
• Time in Patent Office: Days
• US Class Current: 548/161
• CPC Class Codes: C07D 277/82 Nitrogen atoms

Abstract

Methods for preparing chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamines such as, for example, (6R)2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and purifying a dominant enantiomer of substituted 4,5,6,7-tetrahydro-benzothiazole diamines from entantiomerically enriched mixtures of substituted 4,5,6,7-tetrahydro-benzothiazole diamines are provided herein.

Claims

1. A process for preparing a chirally purified substituted 4,5,6,7,-tetrahydro-benzothaizole diamine comprising:

heating a solution comprising entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine of general formula (I);

2. The process of claim 1, wherein the alkyl sulfonate is a propyl sulfonate selected from n-propyl tosylate, n-propyl methoxysulfonate and combinations thereof.

3. The process of claim 1, wherein the alkyl. halide is a propyl halide selected from n-propyl bromide, n-propyl chloride, n-propyl iodide and combinations thereof.

4. The process of claim 1, wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least greater than about 97% chirally pure.

5. The process of claim 1, wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least greater than about 99% chirally pure.

6. The process of claim 1, wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least about 99.9% chirally pure.

7. The process of claim 1, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 98%.

8. The process of claim 1, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 99.9%.

9. The process of claim 1, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 99.99%.

10. The process of claim 1, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 100%.

11. The process of claim 1, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is substantially free of achiral salts.

12. The process of claim 1, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 1.5 ppm of achiral salts.

13. The process of claim 1, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.

14. The process of claim 1, wherein the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is entantiomerically enriched for an R-entantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an R entantiomer.

15. The process of claim 1, wherein entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is entantiomerically enriched for (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole is (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

16. The process of claim 1, wherein the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is entantiomerically enriched for an S-entantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an S-entantiomer.

17. The process of claim 1, wherein the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is entantiomerically enriched for (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole is (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

18. The process of claim 1, wherein the entantiomerically enriched 4,5,6,7-tetrahydrobenzothiazole diamine comprises a ratio of greater than about 1:

4 R-entantiomer to S-entantiomer to about 4;

1 R-entantiomer to S-entantiomer.

19. The process of claim 1, wherein the solvent is selected from an organic solvent and an organic solvent mixed with water.

20. The process of claim 1, wherein the solvent is selected from. ethanol, 1-propanol, i-propanol, n-butanol, i-butanol, dihydrofuran, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or mixtures or hydrates thereof.

21. The process of claim 1, wherein the steps of heating, reacting and recovering each independently comprise stirring.

22. The process of claim 1, wherein the steps of heating and reacting are each independently carried out at a temperature of from about 50°

C. to about 125°

C.

23. The process of claim 1, further comprising cooling the reaction mixture to a temperature of about 25°

C. after the step of reacting.

24. The process of claim 1, wherein the step of heating further comprises adding the alkyl sulfonate or alkyl halide to the heated 4,5,6,7-tetrahydro-benzothiazole diamine.

25. The process of claim 24, wherein the step of adding is carried out for about 0.5 hours to about 2 hours.

26. The process of claim 1, wherein about 1.0 to about 2.0 molar equivalents of the alkly sulfonate or alkyl halide is added.

27. The process of claim 1, wherein the step of recovering comprises one or more steps selected from filtering the reaction mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.

28. The process of claim 1, wherein the step of reacting is carried out for up to about 12 hours.

29. Chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process comprising:

heating a solution comprising entantiomerically enriched 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and a propyl halide or a propyl sulfonate to form a reaction mixture;

reacting the reaction mixture; and

recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

30. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the propyl sulfonate is selected from n-propyl tosylate, n-propyl methoxysulfonate and combinations thereof.

31. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the propyl halide is selected from n-propyl bromide, n-propyl chloride, n-propyl fluoride, n-propyl iodide and combinations thereof.

32. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than about 97% chirally pure.

33. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than about 99% chirally pure.

34. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least about 99.9% chirally pure.

35. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99%.

36. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.9%.

37. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.99%.

38. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 100%.

39. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is substantially free of achiral salts.

40. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 1.5 ppm of achiral salts.

41. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.

42. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the entantiomerically enriched 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole comprises a ratio of greater than about 2:

1 (6R) 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole to (6S) 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole.

43. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the solvent is selected from an organic solvent and an organic solvent mixed with water.

44. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the solvent is selected from ethanol, 1-propanol, n-butanol, dihydrofuran, dimethylformamide, dimethyl, dimethylacetamide, hexamethylphosphoric triamide or mixtures or hydrates thereof.

45. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the steps. of heating and reacting each independently comprise stirring.

46. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the steps of heating and reacting are each independently carried out at a temperature of from about 50°

C. to about 125°

C.

47. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the process further comprises cooling the reaction mixture to a temperature of about 25°

C. after the step of reacting.

48. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the process further comprises the step of adding the propyl halide or propyl sulfunate to heated entantiomerically enriched 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole.

49. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 48, wherein the step of adding is carried out for up to about 2 hours.

50. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein about 1.0 to about 2.0 molar equivalents of the propyl sulfonate or propyl halide is added.

51. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the step of reacting is carried out for up to about 12 hours.

52. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 29, wherein the step of recovering comprises one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.

53. A process for preparing a chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:

heating a solution comprising 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole in an organic solvent;

adding to the heated solution propyl sulfonate or a propyl halide to form a reaction mixture; and

reacting the reaction mixture for up to about 12 hours.

54. The process of claim 53, wherein the propyl sulfonate is selected from n-propyl tosylate, h-propyl methoxysulfonate and combinations thereof.

55. The process of claim 53, wherein the propyl halide. is selected from n-propyl bromide, n-propyl chloride, n-propyl fluoride, n-propyl iodide and combinations thereof.

56. The process of claim 53, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than about 97% chirally pure.

57. The process of claim 53, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than about 99%, chirally pure.

58. The process of claim 53, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least about 99.9% chirally pure.

59. The process of claim 53, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99%.

60. The process of claim 53, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino benzothiazole is greater than about 99.9%.

61. The process of claim 53, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.99%.

62. The process of claim 53, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 100%.

63. The process of claim 53, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is substantially free of achiral salts.

64. The process of claim 53, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 1.5 ppm of achiral salts.

65. The process of claim 53, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.

66. The process of claim 53, wherein the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole is (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

67. The process of claim 53, wherein the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole is (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

68. The process of claim 53, wherein the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole comprises a mixture of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprises a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

69. The process of claim 68, wherein the mixture is a racemic mixture.

70. The process of claim 68, wherein the mixture comprises a ratio of greater than about 1:

4 (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole to about 4;

1 (6R)-2,6-diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole.

71. The process of claim 53., wherein the organic solvent is selected from a polar solvent and an organic solvent is mixed with water.

72. The process of claim 53, wherein the organic solvent is selected from ethanol, 1-propanol, n-butanol, dihydrofuran, dimethylformamide, dimethyl, dimethylacetamide, hexamethylphosphoric triamide or mixtures or hydrates thereof.

73. The process of claim 53, wherein the steps of heating, adding and reacting each independently comprise stirring.

74. The process of claim 53, wherein the steps of heating, adding and reacting are each independently carried out at a temperature of from about 50°

C. to about 125°

C.

75. The process of claim 53, further comprising cooling the reaction mixture to a temperature of about 25°

C. after the step of reacting.

76. The process of claim 53, wherein the step of adding is carried out for up to about 2 hours.

77. The process of claim 53, further comprising recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

78. The process of claim 77, wherein recovering comprises one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.

79. The process of claim 53, wherein about 1.0 to about 2.0 molar equivalents of the propyl sulfonate or propyl halide is added.

80. A process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:

heating a solution comprising 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole;

adding a propyl halide or a propyl sulfonate to the heated solution slowly over from about 0.5 hours to about 2 hours to form a reaction mixture;

reacting the reaction mixture; and

recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

81. The process of claim 80, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than about 97% chirally pure.

82. The process of claim 80, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than about 99% chirally pure.

83. The process of claim 80, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least about 99.9% chirally pure.

84. The process of claim 80, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99%.

85. The process of claim 80, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.9%.

86. The process of claim 80, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.99%.

87. The process of claim 80, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 100%.

88. The process of claim 80, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is substantially free of achiral salts.

89. The process of claim 80, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 1.5 ppm of achiral salts.

90. The process of claim 80, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.

91. The process of claim 80, wherein the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole is (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

92. The process of claim 80, wherein the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole is (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

93. The process of claim 80, wherein the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole comprises a mixture of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprises a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

94. The process of claim 93, wherein the mixture is a racemic mixture.

95. The process of claim 93, wherein the mixture comprises a ratio of greater than about 1:

4 (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole to about 4;

1 (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole.

96. The process of claim 80, wherein the steps of heating, reacting and cooling each independently comprise stirring.

97. The process of claim 80, wherein recovering comprises cooling the mixture to a temperature of about 25°

C.

98. The process of claim 80, wherein recovering comprises stirring the reaction mixture for at least about 2 hours.

99. The process of claim 80, wherein recovering comprises one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.

100. The process of claim 80, wherein the steps of heating, adding and reacting are each independently carried out at a temperature of from about 50°

C. to about 125°

C.

101. The process of claim 80, wherein reacting comprises stirring the reaction mixture for up to about 12 hours at from about 50°

C. to about 125°

C.

102. Chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process comprising:

heating a solution comprising 2,6 diamino-4 5,6,7-tetrahydro-benzothiazole;

adding a propyl halide or a propyl sulfonate to the heated solution slowly over from about 0.5 hours to about 2 hours to form a reaction mixture;

reacting the reaction mixture; and

recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

103. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the propyl sulfonate is selected from n-propyl tosylate, n-propyl methoxysulfonate and combinations thereof.

104. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the propyl halide is selected from n-propyl bromide, n-propyl chloride, n-propyl fluoride, n-propyl iodide and combinations thereof.

105. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than about 97% chirally pure.

106. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater-than about 99% chirally pure.

107. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least about 99.9% chirally pure.

108. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99%.

109. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.9%.

110. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.99%.

111. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 160%.

112. The chirally purified 2-amino-4,5 6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is substantially free of achiral salts.

113. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 1.5 ppm of achiral salts.

114. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.

115. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole comprises a mixture of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprises a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S) 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

116. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the mixture is a racemic mixture.

117. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the mixture comprises a ratio of greater than about 4:

1 (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole.

118. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the organic solvent is selected from a polar solvent and an organic solvent is mixed with water.

119. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the organic solvent is selected from ethanol, 1-propanol, n-butanol, dihydrofuran, dimethylformamide, dimethyl, dimethylacetamide, hexamethylphosphoric triamide or mixtures or hydrates thereof.

120. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the steps of heating, reacting and cooling each independently comprise stirring.

121. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the steps of heating, adding and reacting are each independently carried out at a temperature of from about 150°

C. to about 125°

C.

122. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, further comprising cooling the reaction mixture to a temperature of about 25°

C. after the step of reacting.

123. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein the step of adding is carried out for up to about 2 hours.

124. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein recovering comprises one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.

125. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 102, wherein about 1.0 to about 2.0 molar equivalents of the propyl sulfonate or propyl halide is added.

126. A process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:

dissolving entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in an organic solvent to form a solution;

heating the solution to from about 50°

C. to about 125°

C.;

adding an acid to the solution to form a reaction mixture; and

recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

127. The process of claim 126, wherein about 1 molar equivalent to about 4 molar equivalents of the acid is added.

128. The process of claim 126, wherein recovering comprises one or more steps selected from:

cooling the reaction mixture to a temperature of about 25°

C.;

stirring the reaction mixture for at least about 2 hours;

filtering the mixture to isolate a precipitate;

washing a precipitate; and

drying a precipitate.

129. A chirally pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process of claim 126.

130. A process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:

dissolving entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in an organic solvent to form a solution;

heating the solution to from about 50°

C. to about 125°

C.;

adding an achiral salt to the solution to form a reaction mixture; and

recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

131. The process of claim 130, wherein about. 1 molar equivalent to about 4 molar equivalents of the achiral salt is added.

132. The process of claim 130, wherein recovering comprises one or more steps selected from:

cooling the reaction mixture to a temperature of about 25°

C.;

stirring the reaction mixture for at least about 2 hours;

filtering the mixture to isolate a precipitate;

washing a precipitate; and

drying a precipitate.

133. A chirally pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process of claim 1304.

134. A process for preparing a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride comprising:

dissolving a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt in an organic solvent to form a solution;

cooling the solution to a temperature of from about 0°

C. to about 5°

C.;

adding concentrated HCl and an organic solvent to the cooled solution; and

stirring the solution at a temperature of about 0°

C. to about 5°

C.