Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
The present invention is related to an improved process for the preparation of amino-substituted 4,5,6,7-tetrahydrobenzothiazole compounds of formula I, such as the compound 2-amino-4,5,6,7-tetrahydro-6-(n-propylamino)benzothiazole. The invention further relates to an improved synthesis of (R)-2-amino-4,5,6,7-tetrahydro-6-(n-propylamino)benzothiazole. The invention also relates to the methods and intermediates associated with the synthetic process.
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 78° C.;
b) cooling the mixture to about 5° 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 is present from 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 water is present in an amount from about 0% to about 10% by weight of the mixture, acetonitrile is present in an amount from about 0% to about 50% by weight of the mixture, and IPA is present in an amount from 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 2:1 v/v.
15. The process of claim 1 , further comprising the process of producing a compound of formula I
the process comprising the steps of:
a) 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
b) contacting the mixture with a base to produce a compound of formula I.
16. The process of claim 15 , wherein the ratio of 2-methyltetrahydrofuran to brine in step a is about 1.8:1 v/v.
17. The process of claim 15 , wherein the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
18. The process of claim 17 , wherein the base is sodium hydroxide.
19. The process of claim 18 , wherein the sodium hydroxide is present in about 1 molar equivalent.
20. The process of claim 15 , further comprising preparing a compound of formula I (2 HCl—H2O)
comprising the steps of:
a) forming a mixture comprising a compound of formula I, 2-methyltetrahydrofuran and IPA;
b) contacting the mixture with HCl; and
c) isolating the solid compound of formula I (2 HCl—H2O) produced in step b.
21. The process of claim 20 , wherein the ratio of 2-methyltetrahydrofuran to IPA in step a is about 1.8:1 v/v.
22. The process of claim 20 , wherein HCl in a solvent is added to the mixture comprising a compound of formula I, 2-methyltetrahydrofuran and IPA.
23. The process of claim 22 , wherein the HCl is added to the mixture as a solution in IPA.
24. The process of claim 20 , wherein the HCl is present in an amount of about 2 molar equivalents.
25. The process of claim 20 , further comprising the steps of:
a) forming a mixture comprising compound 1 (2 HCl—H2O) , IPA and water;
b) heating the mixture to a temperature from about 75° C. to about 80° C.;
c) cooling the mixture to about 50° C.;
d) removing water from the mixture;
e) cooling the solution to a temperature from about 0° C. to about 5° C.; and
f) isolating the solid Compound 1 (2 HCl—H2O) .
26. The process of claim 25 , wherein the ratio of IPA to water in step a is about 6:1.
27. The process of claim 25 , wherein water is removed from the solution in step d by azeotropic distillation of IPA and water.
28. The process of claim 27 , wherein the distillation is performed at reduced pressure.
29. The process of claim 25 , wherein step d of the process further includes the steps of:
a) reducing the volume of the mixture by distillation at reduced pressure;
b) diluting the mixture with IPA; and
c) optionally repeating steps a and b one or more times.
30. The process of claim 29 , wherein the water content of the resulting mixture is about 3-10%.
31. The process of claim 29 , 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 (2 HCl—H2O) .
32. 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 about 78° C.;
d) cooling the mixture to about 5° 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.
33. The process of claim 32 , 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.
34. The process of claim 33 , wherein the solvent is a mixture of acetonitrile and water.
35. The process of claim 34 , wherein water is present from about 0% to about 10% by weight in the mixture of acetonitrile and water.
36. The process of claim 35 , wherein the ratio of acetonitrile to water in step a is about 37:1 wt/wt.
37. The process of claim 33 , wherein the solvent is a mixture of acetonitrile, IPA and water.
38. The process of claim 37 , wherein water is present in an amount from about 0% to about 10% by weight of the mixture, acetonitrile is present in an amount from about 0% to about 50% by weight of the mixture, and IPA is present in an amount from about 0% to about 50% by weight of the mixture.
39. The process of claim 32 , wherein the ratio of IPA to water in step c is about 3:1 v/v.
40. The process of claim 32 , wherein the yield of Compound 1 (HOTs) isolated in step e is greater than 80%, the chemical purity of Compound 1 (HOTs) isolated in step e is greater than 95%, and the enantiomeric excess of Compound 1 (HOTs) isolated in step e is greater than the enantiomeric excess of the starting Compound 2.
41. The process of claim 32 , wherein the ratio of 2-methyltetrahydrofuran to brine in step f is about 1.8:1 v/v.
42. The process of claim 32 , wherein the ratio of 2-methyltetrahydrofuran to IPA in step h is about 1.8:1 v/v.
43. The process of claim 32 , further comprising the steps of:
a) forming a mixture comprising Compound 1 (2 HCl—H2O) , IPA and water;
b) heating the mixture to a temperature from about 75° C. to about 80° C.;
c) cooling the solution to about 50° C.;
d) removing water from the solution;
e) cooling the solution to a temperature from about 0° C. to about 5° C.; and
f) removing the solid Compound 1 (2 HCl—H2O) from the liquid phase.
44. The process of claim 43 , wherein the ratio of IPA to water in step a is about 8:1.
45. The process of claim 43 , wherein water is removed from the solution in step d by azeotropic distillation of IPA and water.
46. The process of claim 45 , wherein the distillation is performed at reduced pressure.
47. The process of claim 43 , wherein step d of the process further includes the steps of:
a) reducing the volume of the mixture by distillation at reduced pressure;
b) diluting the mixture with IPA; and
c) optionally repeating steps a and b one or more times.
48. The process of claim 47 , wherein the water content of the resulting mixture is about 3-10%.
49. The process of claim 47 , wherein the yield of Compound 1 (2 HCl—H2O) removed in step f is greater than 90%, the chemical purity is greater than 99%, and the enantiomeric excess is from about 99% to about 100%.
50. The process of claim 49 , wherein the enantiomeric excess of Compound 1 (2 HCl—H2O) removed in step f is about 100%.
51. The process of claim 47 , 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) .
52. The process of claim 47 , wherein the solid Compound 1 (2 HCl—H2O) isolated from the process is in the polymorphic Form A.
53. The process of claim 52 , wherein the water content of the solid Compound 1 (2 HCl—H2O) in the polymorphic Form A is from about 5% to about 7% as determined by the Karl Fischer method.