Processes for preparing AG-10, its intermediates, and salts thereof
Provided herein are improved processes for the preparation of a compound of Formula IX (AG-10). Also provided herein are pharmaceutically acceptable salts of Formula I and Formula Ib as well as crystalline types of Formula IX (AG-10). The processes described herein provide improved yields and efficiency, while the pharmaceutically acceptable salts and crystalline forms provide unexpected pharmacokinetic properties. Other features and aspects of the present disclosure will be apparent to a person of skill in the art upon reading the remainder of the specification.
1. A method for preparing a compound of Formula IX
comprising
(a) contacting a compound of Formula II
with a compound of Formula III
a first base, and a first organic solvent to provide a compound of Formula IV
wherein each R 1 is independently a halogen or a sulfonate ester;
(b) contacting the compound of Formula IV with hydrazine and a second organic solvent
to provide a compound of Formula V
(c) contacting the compound of Formula V with a sulfonating agent or halogenating agent to provide a compound of Formula VI
wherein R 2 is a halogen or a sulfonate ester;
(d) contacting the compound of Formula VI with a compound of Formula VII
a second base, and a third organic solvent to provide a compound of Formula VIII
wherein R 3 is selected from the group consisting of an C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, C 3-12 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted; and
(e) contacting a compound of Formula VIII with a third base to provide a compound of Formula IX.
2. The method of claim 1 , wherein each R 1 is independently selected from the group consisting of chloride, bromide, tosylate, and mesylate.
3. The method of claim 2 , wherein each R 1 is bromide.
4. The method of claim 1 , wherein the first base is an alkali metal carbonate, an alkali metal bicarbonate or a combination thereof.
5. The method of claim 4 , wherein the alkali metal carbonate is selected from the group consisting of Li 2 CO 3 , Na 2 CO 3 , and K 2 CO 3 , or a combination thereof.
6. The method of claim 5 , wherein the alkali metal carbonate is K 2 CO 3 .
7. The method of claim 4 , wherein the alkali metal bicarbonate is selected from the group consisting of LiHCO 3 , NaHCO 3 , and KHCO 3 , or a combination thereof.
8. The method of claim 1 , wherein the first organic solvent is a polar aprotic organic solvent.
9. The method of claim 8 , wherein the polar aprotic organic solvent is selected from the group consisting of acetone, ethyl acetate, dichloromethane, tetrahydrofuran, dimethylformamide and acetonitrile.
10. The method of claim 9 , wherein the polar aprotic organic solvent is acetone.
11. The method of claim 1 , wherein the second organic solvent is a polar protic organic solvent.
12. The method of claim 11 , wherein the polar protic organic solvent is C 1-10 —OH.
13. The method of claim 12 , wherein the polar protic organic solvent is ethanol.
14. The method of claim 1 , wherein the sulfonating agent is mesyl chloride or tosyl chloride.
15. The method of claim 1 , wherein the halogenating agent is selected from the group consisting of PBr 3 , PCl 3 , PCl 5 , SOBr 2 , PBr 5 , and SOCl 2 .
16. The method of claim 15 , wherein the halogenating agent is PBr 3 .
17. The method of claim 1 , wherein R 2 is selected from the group consisting of chloride, bromide, tosylate, and mesylate.
18. The method of claim 17 , wherein R 2 is Br.
19. The method of claim 1 , wherein the second base is an alkali metal carbonate, an alkali metal bicarbonate or a combination thereof.
20. The method of claim 18 , wherein the alkali metal carbonate is selected from the group consisting of Li 2 CO 3 , Na 2 CO 3 , and K 2 CO 3 , or a combination thereof.
21. The method of claim 20 , wherein the alkali metal carbonate is K 2 CO 3 .
22. The method of claim 18 , wherein the alkali metal bicarbonate is selected from the group consisting of LiHCO 3 , NaHCO 3 , and KHCO 3 , or a combination thereof.
23. The method of claim 1 , wherein the third organic solvent is a polar aprotic organic solvent.
24. The method of claim 23 , wherein polar organic solvent is selected from the group consisting of acetone, ethyl acetate, dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and acetonitrile.
25. The method of claim 24 , wherein polar organic solvent is dimethylformamide.
26. The method of claim 24 , wherein polar organic solvent is dimethylsulfoxide.
27. The method of claim 1 , wherein R 3 is C 1-8 alkyl.
28. The method of claim 27 , wherein R 3 is methyl.
29. The method of claim 1 , wherein the third base is a metal hydroxide.
30. The method of claim 29 , wherein the metal hydroxide is an alkali metal hydroxide.
31. The method of claim 30 , wherein the alkali metal hydroxide is a selected from the group consisting of LiOH, NaOH, KOH, RbOH, and CsOH.
32. The method of claim 31 , wherein the alkali metal hydroxide is LiOH.
33. The method of claim 31 , wherein the alkali metal hydroxide is NaOH.
34. The method of claim 1 , wherein the first base is a hydrated base.
35. A method for preparing a compound of Formula Ia
comprising
(e) contacting a compound of Formula VIII
with a solvent and a base to provide a solid,
wherein R 3 is selected from the group consisting of an C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, C 3-12 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted;
(f) removing the solvent to provide a residue;
(g) dissolving the residue in water to form a solution;
(h) acidifying the solution with HCl to form a compound of Formula Ia.
36. The method of claim 35 , further comprising
(i) filtering the solution to provide isolated Formula Ia.
37. The method of claim 35 , wherein the solvent in step (f) is removed via filtration.
38. The method of claim 35 , wherein the solvent is polar protic organic solvent.
39. The method of claim 35 , wherein the solvent is C 1-8 —OH.
40. The method of claim 35 , wherein the solvent is methanol.
41. The method of claim 35 , wherein the base is an alkali metal hydroxide.
42. The method of claim 41 , wherein the alkali metal hydroxide is a selected from the group consisting of LiOH, NaOH, KOH, RbOH, and CsOH.
43. The method of claim 35 , wherein the pH of the solution after step (h) is less than about 2.
44. The method of claim 35 , wherein the pH of the solution after step (h) is less about 1.4-1.6.
45. A method for preparing a compound of Formula Ia
comprising
(e) contacting a compound of Formula VIII
with a solvent and a base to provide an intermediate,
wherein R 3 is selected from the group consisting of an C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, C 3-12 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted;
(f) contacting the intermediate with water;
(g) removing the solvent to provide a concentrated aqueous component;
(h) acidifying the concentrated aqueous component with HCl to form a compound of Formula Ia.
46. The method of claim 45 , further comprising
(i) filtering the concentrated aqueous component to provide isolated Formula Ia.
47. The method of claim 45 , wherein the solvent in step (g) is removed using reduced pressure.
48. The method of claim 45 , wherein the solvent is polar protic organic solvent.
49. The method of claim 45 , wherein the solvent is C 1-8 —OH.
50. The method of claim 45 , wherein the solvent is methanol.
51. The method of claim 45 , wherein the base is an alkali metal hydroxide.
52. The method of claim 51 , wherein the alkali metal hydroxide is a selected from the group consisting of LiOH, NaOH, KOH, RbOH, and CsOH.
53. The method of claim 45 , wherein the pH of the concentrated aqueous component after step (h) is less than about 2.
54. The method of claim 45 , wherein the pH of the concentrated aqueous component after step (h) is less about 1.4-1.6.