Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds

1. A process for preparing a compound of formula I (HOTs)

wherein R 1 and R 2 are each independently hydrogen or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally and independently substituted with up to 3 occurrences of C 1-6 alkyl, aryl or heteroaryl;

the process comprising contacting a mixture, which comprises a compound of formula II

and a solvent, with a compound having the formula

in the presence of a base, to provide a compound of formula I (HOTs) , wherein the solvent is acetonitrile, a mixture of acetonitrile and water, IPA, a mixture of IPA and water, a mixture of acetonitrile and IPA, or a mixture of acetonitrile, IPA and water; isolating the compound of formula I (HOTs) ,

a) forming a mixture comprising the compound of formula I (HOTs) , IPA and water, and heating the mixture to about 70° C. to about 85° C.;

b) cooling the mixture to about 5° C. to about 15° C.; and

c) isolating the solid compound of formula I (HOTs) formed during step b).

2. The process of claim 1 , wherein R 2 is hydrogen.

3. The process of claim 1 , wherein R 1 is C 1-6 alkyl.

4. The process of claim 3 , wherein R 1 is n-propyl.

5. The process of claim 1 , wherein the solvent is a mixture of acetonitrile and water, a mixture of IPA and water, a mixture of acetonitrile and IPA, or a mixture of acetonitrile, IPA and water.

6. The process of claim 5 , wherein the solvent is a mixture of acetonitrile and water.

7. The process of claim 6 , wherein water present is about 0% to about 10% by weight in the mixture of acetonitrile and water.

8. The process of claim 7 , wherein the ratio of the mixture of acetonitrile to water is about 37:1 wt/wt.

9. The process of claim 5 , wherein the solvent is a mixture of acetonitrile, IPA and water.

10. The process of claim 9 , wherein the water present is about 0% to about 10% by weight of the mixture, the acetonitrile present is about 0% to about 50% by weight of the mixture, and the IPA present is about 0% to about 50% by weight of the mixture.

11. The process of claim 1 , wherein the stereochemistry of the carbon atom to which the —NR 1 (R 2 ) moiety is attached is in the (R) configuration.

12. The process of claim 1 , wherein the base is triethylamine, DIPEA, pyridine or DBU.

13. The process of claim 12 , wherein the base is DIPEA.

14. The process of claim 1 , wherein the ratio of IPA to water in step a) is about 2.3:1 v/v to about 4.25:1 v/v.

15. The process of claim 1 , wherein the ratio of IPA to water in step a) is about 2:1 v/v.

16. The process of claim 1 , further comprising the process of producing a compound of formula I

the process comprising the steps of:

d) forming a biphasic mixture comprising a compound of formula I (HOTs) , 2-methyltetrahydrofuran and brine, wherein the brine has a salt content of about 2-20% by weight; and

e) contacting the mixture with a base to produce a compound of formula I.

17. The process of claim 16 , wherein the ratio of 2-methyltetrahydrofuran to brine in step d) is about 3.1:1 v/v to about 1:1 v/v.

18. The process of claim 16 , wherein the ratio of 2-methyltetrahydrofuran to brine in step d) is about 1.8:1 v/v.

19. The process of claim 16 , wherein the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

20. The process of claim 19 , wherein the base is sodium hydroxide.

21. The process of claim 20 , wherein the sodium hydroxide is present in about 1 molar equivalent.

22. The process of claim 16 , further comprising preparing a compound of formula I (2 HCl-H2O)

comprising the steps of:

f) forming a mixture comprising a compound of formula I, 2-methyltetrahydrofuran and IPA;

g) contacting the mixture with HCl; and

h) isolating the solid compound of formula I (2 HCl-H2O) produced in step g).

23. The process of claim 22 , wherein the ratio of 2-methyltetrahydrofuran to IPA in step f) is about 3.1:1 v/v to about 1.1 v/v.

24. The process of claim 23 , wherein the ratio of 2-methyltetrahydrofuran to IPA in step f) is about 1.8:1 v/v.

25. The process of claim 22 , wherein HCl in a solvent is added to the mixture comprising a compound of formula I, 2-methyltetrahydrofuran and IPA.

26. The process of claim 25 , wherein the HCl is added to the mixture as a solution in IPA.

27. The process of claim 22 , wherein the HCl is present in an amount of about 2 molar equivalents.

28. The process of claim 22 , further comprising the steps of:)

i) forming a mixture comprising compound 1 (2Hcl-H2O) , IPA and water;

j) heating the mixture to a temperature of about 60° C. to about 90° C.;

k) cooling the mixture to about 35° C. to about 60° C.;

l) removing water from the mixture;

m) cooling the solution to a temperature of about −10° C. to about 15° C.; and

n) isolating the solid Compound 1 (2HCl-H2O) .

29. The process of claim 28 , wherein the ratio of IPA to water in step i) is about 27:1 to about 6:1.

30. The process of claim 28 , wherein the ratio of IPA to water in step i) is about 6:1.

31. The process of claim 28 , wherein water is removed from the solution in step l) by azeotropic distillation of IPA and water.

32. The process of claim 31 , wherein the distillation is performed at reduced pressure.

33. The process of claim 28 , wherein step 41 of the process further includes the steps of:

i. reducing the volume of the mixture by distillation at reduced pressure;

ii. diluting the mixture with IPA; and

iii. optionally repeating steps i. and ii. one or more times.

34. The process of claim 33 , wherein the water content of the resulting mixture is about 3-10%.

35. The process of claim 33 , further comprising the step of adding a specific volume of IPA to the mixture to produce a final water content in the supernatant portion of the mixture of about 6%, wherein the specific volume of IPA is determined by performing the calculation: Final volume (mL) of IPA to be added to the mixture=((24×KF×S)/(1−6.5×KF))−(2.4×KF), wherein “KF” is the water content, expressed as a decimal, as determined by the Karl Fischer method, and “S” is the weight in grams of starting compound of formula I (2HCl-H2O) .

36. A process for preparing Compound 1 (2 HCl-H2O)

wherein the process comprises the steps of:

a) contacting a mixture comprising Compound 2

and a solvent, with n-PrOTs and DIPEA to provide Compound 1 (HOTs)

wherein the solvent is acetonitrile, a mixture of acetonitrile and water, IPA, a mixture of IPA and water, a mixture of acetonitrile and IPA, or a mixture of acetonitrile, IPA and water;

b) isolating the solid Compound 1 (HOTs) formed in step a);

c) forming a mixture comprising Compound 1 (HOTs) , IPA and water, and heating the mixture to a temperature of about 60° C. to about 90° C.;

d) cooling the mixture to a temperature of about −5° C. to about 15° C.;

e) isolating the solid Compound 1 (HOTs) formed in step d);

f) forming a biphasic mixture comprising Compound 1 (HOTs) , 2-methyltetrahydrofuran and brine, wherein the brine has a salt content of about 2-20% by weight;

g) contacting the mixture with sodium hydroxide to form Compound 1

h) forming a mixture comprising Compound 1, 2-methyltetrahydrofuran and IPA;

i) contacting the mixture with HCl; and

j) isolating the solid Compound 1 (2 HCl-H2O) produced in step i).

37. The process of claim 36 , wherein the temperature in step c) is about 70° C. to about 80° C.

38. The process of claim 37 , wherein the temperature in step c) is about 75° C. to about 80° C.

39. The process of claim 36 , wherein the temperature in step d) is about 0° C. to about 10° C.

40. The process of claim 36 , wherein the solvent is a mixture of acetonitrile and water, a mixture of IPA and water, a mixture of acetonitrile and IPA, or a mixture of acetonitrile, IPA and water.

41. The process of claim 34 , wherein the solvent is a mixture of acetonitrile and water.

42. The process of claim 41 , wherein the water present is about 0% to about 10% by weight in the mixture of acetonitrile and water.

43. The process of claim 42 , wherein the ratio of acetonitrile to water in step a) is about 37:1 wt/wt.

44. The process of claim 36 , wherein the ratio of IPA to water in step c) is about 2.3:1 to about 4.25:1 v/v.

45. The process of claim 44 , wherein the ratio of IPA to water in step c) is about 2.5:1.

46. The process of claim 36 , wherein the brine in step f) has a salt content of about 12%.

47. The process of claim 36 , wherein the ratio of 2-methyltetrahydrofuran to brine in step f) is about 3:1 to about 1:1 v/v.

48. The process of claim 47 , wherein the ratio of 2-methyltetrahydrofuran to brine in step f) is about 1:1 v/v.

49. The process of claim 36 , wherein the ratio of 2-methyltetrahydrofuran to IPA in step h) is about 1.8:1 v/v.

50. The process of claim 36 , further comprising the steps of:

k) forming a mixture comprising Compound 1 (2 HCl-H2O) , IPA and water;

l) heating the mixture to a temperature of about 60° C. to about 90° C.;

m) cooling the solution to a temperature of about 35° C. to about 60° C.;

n) removing water from the solution;

o) cooling the solution to a temperature of about −10° C. to about 15° C.; and

p) removing the solid Compound 1 (2HCl-H2O) from the liquid phase.

51. The process of claim 50 , wherein the temperature in step l) is about 75° C. to about 80° C.

52. The process of claim 50 , wherein the temperature in step m) is about 40° C.

53. The process of claim 50 , wherein the temperature in step m) is about 50° C.

54. The process of claim 50 , wherein the ratio of IPA to water in step k) is about 8:1.

55. The process of claim 50 , wherein water is removed from the solution in step n) by azeotropic distillation of IPA and water.

56. The process of claim 55 , wherein the distillation is performed at reduced pressure.

57. The process of claim 50 , wherein step n) of the process further includes the steps of:

i. reducing the volume of the mixture by distillation at reduced pressure;

ii. diluting the mixture with IPA; and

iii. optionally repeating steps i. and ii. one or more times.

58. The process of claim 57 , wherein the water content of the resulting mixture is about 3-12%.

59. The process of claim 58 , wherein the water content of the resulting mixture is about 5.5% to about 6.5%.

60. The process of claim 59 , wherein the water content of the resulting mixture is about 6%.

61. The process of claim 57 , further comprising the step of adding a specific volume of IPA to the mixture to produce a final water content in the supernatant portion of the mixture of about 6%, wherein the specific volume of IPA is determined by performing the calculation: Final volume (mL) of IPA to be added to the mixture=((24×KF×S)/(1−6.5×KF))−(2.4×KF), wherein “KF” is the water content, expressed as a decimal, as determined by the Karl Fischer method, and “S” is the weight in grams of starting compound of Compound 1 (2 HCl-H2O) .

62. The process of claim 57 , wherein the solid Compound 1 (2 HCl-H2O) isolated from the process is in the polymorphic Form A.

63. The process of claim 62 , wherein the water content of the solid Compound 1 (2HCl-H2O) in the polymorphic Form A is about 5% to about 7% as determined by the Karl Fischer method.

64. A process for preparing Compound 1 (2HCl-H2O)

wherein the process comprises the steps of:

a) contacting a mixture comprising Compound 2

and a solvent, with n-PrOTs and DIPEA to provide Compound 1 (HOTs)

wherein the solvent is a mixture of acetonitrile and water;

b) isolating the solid Compound 1 (HOTs) formed in step a);

c) forming a mixture comprising Compound 1 (HOTs) , IPA and water, and heating the mixture to a temperature of about 75° C., wherein the ratio of IPA to water is about 2.5:1;

d) cooling the mixture to a temperature from about 0° C. to about 10° C.;

e) isolating the solid Compound 1 (HOTs) formed in step d);

f) forming a biphasic mixture comprising Compound 1 (HOTs) , 2-methyltetrahydrofuran and brine, wherein the brine has a salt content of about 12% by weight and wherein the ratio of 2-methyltetrahydrofuran to brine is about 1:1;

g) contacting the mixture with sodium hydroxide to form Compound 1

h) forming a mixture comprising Compound 1, 2-methyltetrahydrofuran and IPA;

i) contacting the mixture with HCl; and

j) isolating the solid Compound 1 (2HCl-H2O) produced in step i).

65. The process of claim 64 , further comprising the steps of:

k) forming a mixture comprising Compound 1 (2HCl-H2O) , IPA and water, wherein the ratio of IPA to water is 8:1;

l) heating the mixture to a temperature of about 75° C. to about 80° C.;

m) cooling the solution to a temperature of about 40° C. to about 55° C.;

n) removing water from the solution;

o) cooling the solution to a temperature of about −10° C. to about 15° C.; and

p) removing the solid Compound 1 (2HCl-H2O) from the liquid phase.