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-benzothaizole diamine dihydrochloride comprising:
a. heating a solution to a temperature of from about 65° C. to about 125° C., the solution comprising enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine of formula (1):
wherein:
R 1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group 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;
R 2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms;
R 3 is a hydrogen atom, an alkyl group having 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;
R 4 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms; and
at least one or R 1 , R 2 , R 3 or R 4 is a hydrogen in an organic solvent; and
a propyl sulfonate or a propyl halide in a solvent to form a reaction mixture;
b. reacting the reaction mixture at a temperature of from about 65° C. to about 125° C.;
c. recovering a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine or salt thereof and
d. converting the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine to the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine dichloride salt.
2. The process of claim 1 , wherein the steps of heating in step a., and reacting in step b., are carried out from about 65° C. to about 100° C.
3. The process of claim 1 , wherein the steps of heating in step a., and reacting in step b., are carried out from about 65° C. to about 95° C.
4. The process of claim 1 , wherein the propyl halide selected from an n-propyl bromide, n-propyl chloride, n-propyl iodide, and combinations thereof.
5. The process of claim 4 , wherein the propyl chloride is n-propyl chloride.
6. The process of claim 1 , wherein the propyl sulfonate is n-propyl tosylate.
7. The process of claim 1 , wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least greater than about 90% chirally pure.
8. 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.
9. 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.
10. The process of claim 1 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 98%.
11. The process of claim 1 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 99%.
12. The process of claim 1 , wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 97%.
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 chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an R-enantiomer.
14. The process of claim 1 , wherein the 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 diamine 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 diamine 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 steps a., b., and each further comprise stirring.
20. The process of claim 1 , wherein step c. comprises one or more steps selected from filtering the reaction mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.
21. The process of claim 1 , wherein the solution of step a. comprises enantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine of formula (1) and a propyl halide and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine of step c. is a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine monohydrochloride salt.
22. The process of claim 1 , wherein the solution of step a. comprises enantiomerically enriched4,5,6,7-tetrahydro-benzothiazole diamine of formula (1) and a propyl sulfonate and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine of step c. is a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine sulfonic acid salt.
23. The process of claim 1 , wherein step d comprises i) dissolving the 4,5,6,7-tetrahydro-benzothiazole diamine or salt thereof of step c. in a solvent; ii) adding hydrochloric acid and iii) isolating the 4,5,6,7,-tetrahydro-benzothaizole diamine dihydrochloride.
24. The process of claim 23 wherein the 4,5,6,7-tetrahydro-benzothiazole diamine or salt thereof of step c. is the 4,5,6,7-tetrahydro-benzothiazole diamine sulfonic acid salt and step i) comprises i-a) dissolving the 4,5,6,7-tetrahydro-benzothiazole diamine sulfonic acid salt in a solvent selected from dichloromethane/water or water i-b)adding NaOH to increase the pH, i-c) isolating the 4,5,6,7-tetrahydro-benzothiazole diamine, and i-d) dissolving the 4,5,6,7-tetrahydro-benzothiazole diamine in a solvent.
25. The process of claim 20 , wherein steps a. and b. further comprise stirring.
26. The process of claim 20 wherein step c. comprises one or more steps selected from filtering the reaction mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.
27. A process for preparing a chirally purified (6R)-4,5,6,7,-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride comprising:
a. heating a solution to a temperature of from about 65° C. to about 125° C., the solution comprising entantiomerically enriched (6R)2,6 diamino-4,5,6,7-tetrahydro-benzothiazole in an organic solvent; and
an n-propyl halide in a solvent to form a reaction mixture;
b. reacting the reaction mixture at a temperature of from about 65° C. to about 125° C.;
c. recovering a chirally purified substituted (6R)-4,5,6,7,-tetrahydro-N6-propyl-2,6-benzothiazole-diamine monohydrochloride salt, and
d. converting the chirally purified substituted (6R)-4,5,6,7,-tetrahydro-N6-propyl-2,6-benzothiazole-diamine monohydrochloride salt to the chirally purified (6R)-4,5,6,7,-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride.
28. The process of claim 23 , wherein the steps of heating in step a., and reacting in step b., are carried out from about 65° C. to about 100° C.
29. The process of claim 23 , wherein the steps of heating in step a., and reacting in step b., are carried out from about 65° C. to about 95° C.
30. The process of claim 23 , wherein the n-propyl halide is n-propyl chloride.
31. The process of claim 23 , wherein the solvent is selected from an organic solvent and an organic solvent mixed with water.
32. The process of claim 23 , wherein steps a., b., and each further comprise stirring.
33. The process of claim 23 , wherein step c. comprises one or more steps selected from filtering the reaction mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.
34. The process of claim 23 , wherein step d comprises i) dissolving the (6R)-4,5,6,7,-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or salt thereof of step c. in a solvent; ii) adding hydrochloric acid and iii) isolating the (6R)-4,5,6,7,-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride.
35. The process of claim 30 , wherein steps a. and b further comprise stirring.
36. The process of claim 30 wherein step c. comprises one or more steps selected from filtering the reaction mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.