Synthesis of chirally purified substituted benzothiazole diamines
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.
1. A process for preparing a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine comprising:
heating a solution to a temperature of from about 50° C. to about 125° C., the solution comprising enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine of formula (1):
wherein:
R1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part;
R2 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms;
R3 is a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 2 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part,
R4 is a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms; and
at least one or R1, R2, R3 or R4 is a hydrogen in an organic solvent; and
an alkyl sulfonate or an alkyl halide in a solvent to form a reaction mixture;
reacting the reaction mixture at a temperature of from about 50° C. to about 125° C.; and
recovering a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine.
2. The process of claim 1 , wherein the alkyl sulfonate is n-propyl tosylate.
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 contains less than 1.5 ppm of achiral salts.
12. The process of claim 1 , wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.
13. The process of claim 1 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically enriched for an R-enantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an R-enantiomer.
14. The process of claim 1 , wherein enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically 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.
15. The process of claim 1 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically enriched for an S-enantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an S-enantiomer.
16. The process of claim 1 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically 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.
17. The process of claim 1 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine comprises a ratio of greater than about 1:4 R-enantiomer to S-enantiomer to about 4:1 R-enantiomer to S-enantiomer.
18. The process of claim 1 , wherein the solvent is selected from an organic solvent and an organic solvent mixed with water.
19. 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.
20. The process of claim 1 , wherein the steps of heating, reacting and recovering each independently comprise stirring.
21. The process of claim 1 , further comprising cooling the reaction mixture to a temperature of about 25° C. after the step of reacting.
22. 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.
23. The process of claim 22 , wherein the step of adding is carried out for about 0.5 hours to about 2 hours.
24. The process of claim 1 , wherein about 1.0 to about 2.0 molar equivalents of the alkyl sulfonate or alkyl halide is added.
25. 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.
26. The process of claim 1 , wherein the solution further comprises a base.
27. The process of claim 26 , wherein the base is selected from sodium hydroxide, sodium hydride, potassium carbonate, sodium acetate, potassium-tertbutyloxide, triethylamine, and di-isopropylethylamine.
28. The process of claim 27 , wherein the base is di-isopropylethylamine.
29. A process for preparing a chirally purified substituted 4,5,6,7-tetrahydro-benzothaizole diamine comprising:
heating a solution comprising a base and enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine of formula (1):
wherein:
R1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part;
R2 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms;
R3 is a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 2 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part,
R4 is a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms; and
at least one or R1, R2, R3 or R4 is a hydrogen in an organic solvent; and
an alkyl sulfonate or an alkyl halide in a solvent to form a reaction mixture;
reacting the reaction mixture; and
recovering a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine;
wherein enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically 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.
30. The process of claim 29 , wherein the base is selected from sodium hydroxide, sodium hydride, potassium carbonate, sodium acetate, potassium-tertbutyloxide, triethylamine, and di-isopropylethylamine.
31. The process of claim 30 , wherein the base is di-isopropylethylamine.
32. A process for preparing a chirally purified substituted 4,5,6,7-tetrahydro-benzothaizole diamine comprising:
heating a solution comprising enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine of formula (1):
wherein:
R1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part;
R2 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms;
R3 is a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 2 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part,
R4 is a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms; and
at least one or R1, R2, R3 or R4 is a hydrogen in an organic solvent; and
an alkyl sulfonate or an alkyl halide in a solvent to form a reaction mixture;
reacting the reaction mixture for up to about 12 hours; and
recovering a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine.
33. The process of claim 32 , wherein the alkyl sulfonate is n-propyl tosylate.
34. The process of claim 32 , wherein the alkyl halide is a propyl halide selected from n-propyl bromide, n-propyl chloride, n-propyl iodide and combinations thereof.
35. The process of claim 32 , wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least greater than about 97% chirally pure.
36. The process of claim 32 , wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least greater than about 99% chirally pure.
37. The process of claim 32 , wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least about 99.9% chirally pure.
38. The process of claim 32 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 98%.
39. The process of claim 32 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 99.9%.
40. The process of claim 32 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 99.99%.
41. The process of claim 32 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 100%.
42. The process of claim 32 , wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 1.5 ppm of achiral salts.
43. The process of claim 32 , wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.
44. The process of claim 32 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically enriched for an R-enantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an R-enantiomer.
45. The process of claim 32 , wherein enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically 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.
46. The process of claim 32 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically enriched for an S-enantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an S-enantiomer.
47. The process of claim 32 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically 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.
48. The process of claim 32 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine comprises a ratio of greater than about 1:4 R-enantiomer to S-enantiomer to about 4:1 R-enantiomer to S-enantiomer.
49. The process of claim 32 , wherein the solvent is selected from an organic solvent and an organic solvent mixed with water.
50. The process of claim 32 , 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.
51. The process of claim 32 , wherein the steps of heating, reacting and recovering each independently comprise stirring.
52. The process of claim 32 , further comprising cooling the reaction mixture to a temperature of about 25° C. after the step of reacting.
53. The process of claim 32 , wherein the step of heating further comprises adding the alkyl sulfonate or alkyl halide to the heated 4,5,6,7-tetrahydro-benzothiazole diamine.
54. The process of claim 53 , wherein the step of adding is carried out for about 0.5 hours to about 2 hours.
55. The process of claim 32 , wherein about 1.0 to about 2.0 molar equivalents of the alkyl sulfonate or alkyl halide is added.
56. The process of claim 32 , 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.
57. The process of claim 32 , wherein the solution further comprises a base.
58. The process of claim 32 , wherein the base is selected from sodium hydroxide, sodium hydride, potassium carbonate, sodium acetate, potassium-tertbutyloxide, triethylamine, and di-isopropylethylamine.
59. The process of claim 58 , wherein the base is di-isopropylethylamine.
60. The process of claim 29 , wherein the alkyl sulfonate is n-propyl tosylate.
61. The process of claim 29 , wherein the alkyl halide is a propyl halide selected from n-propyl bromide, n-propyl chloride, n-propyl iodide and combinations thereof.
62. The process of claim 29 , wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least greater than about 97% chirally pure.
63. The process of claim 29 , wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least greater than about 99% chirally pure.
64. The process of claim 29 , wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least about 99.9% chirally pure.
65. The process of claim 29 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 98%.
66. The process of claim 29 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 99.9%.
67. The process of claim 29 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 99.99%.
68. The process of claim 29 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 100%.
69. The process of claim 29 , wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 1.5 ppm of achiral salts.
70. The process of claim 29 , wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.
71. The process of claim 29 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically enriched for an R-enantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an R-enantiomer.
72. The process of claim 29 , wherein enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically 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.
73. The process of claim 29 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically enriched for an S-enantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an S-enantiomer.
74. The process of claim 29 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enantiomerically 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.
75. The process of claim 29 , wherein the enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine comprises a ratio of greater than about 1:4 R-enantiomer to S-enantiomer to about 4:1 R-enantiomer to S-enantiomer.
76. The process of claim 29 , wherein the solvent is selected from an organic solvent and an organic solvent mixed with water.
77. The process of claim 29 , 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.
78. The process of claim 29 , wherein the steps of heating, reacting and recovering each independently comprise stirring.
79. The process of claim 29 , further comprising cooling the reaction mixture to a temperature of about 25° C. after the step of reacting.
80. The process of claim 29 , wherein the step of heating further comprises adding the alkyl sulfonate or alkyl halide to the heated 4,5,6,7-tetrahydro-benzothiazole diamine.
81. The process of claim 80 , wherein the step of adding is carried out for about 0.5 hours to about 2 hours.
82. The process of claim 29 , wherein about 1.0 to about 2.0 molar equivalents of the alkyl sulfonate or alkyl halide is added.
83. The process of claim 29 , 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.