Methods of synthesizing factor Xa inhibitors
View Patent ↗Described herein are novel methods of preparing a compound of Formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for preparing betrixaban or a pharmaceutically acceptable salt thereof. Also described are compositions comprising substantially pure betrixaban free base or salt thereof.
1. A method of preparing a compound of Formula II, or a salt thereof:
comprising
contacting a compound of Formula II-A:
with a compound of Formula II-B:
under reaction conditions to form the compound of Formula II or the salt thereof;
wherein
R 1 and R 2 are independently C 1-6 alkyl;
R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, and methoxy; and
R 5 is selected from the group consisting of fluoro, chloro, bromo, and methoxy.
2. The method of claim 1 , wherein R 1 and R 2 are both methyl.
3. The method of claim 1 , wherein one of R 3 and R 4 is hydrogen and the other of R 3 and R 4 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, and methoxy.
4. The method of claim 1 , wherein R 3 is hydrogen and R 4 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, and methoxy.
5. The method of claim 1 , wherein R 3 is hydrogen and R 4 is methoxy.
6. The method of claim 1 , wherein R 5 is chloro.
7. The method of claim 1 , further comprising contacting the compound of Formula II or the salt thereof with an acid under salt forming conditions to give a pharmaceutically acceptable salt of the compound of Formula II.
8. The method of claim 7 , further comprising recovering the pharmaceutically acceptable salt of the compound of Formula II.
9. A method of preparing betrixaban, which is of Formula I, or a salt thereof,
comprising:
contacting a compound of Formula A:
with a compound of Formula B:
under reaction conditions to form betrixaban or the salt thereof.
10. The method of claim 1 or 9 , wherein the reaction conditions comprise a solvent.
11. The method of claim 10 , wherein the solvent is selected from the group consisting of dimethylformamide, ethyl acetate, dichloromethane, dimethylacetamide, acetone, acetonitrile, tetrahydrofuran, N-methylpyrrolidone, and mixtures thereof.
12. The method of claim 11 , wherein the solvent is dimethylformamide or dimethylacetamide.
13. The method of claim 1 or 9 , wherein the reaction conditions comprise an amide coupling reagent.
14. The method of claim 13 , wherein the amide coupling reagent is selected from the group consisting of 2-propanephosphonic acid anhydride, carbonyldiimidazole, 2-chloro-4,6-dimethoxy-1,3,5-triazine, N,N′-dicyclohexyl-carbodiimide, N,N′-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, and combinations thereof, optionally in combination with hydroxybenzotriazole.
15. The method of claim 14 , wherein amide coupling reagent is selected from the group consisting of N,N′-dicyclohexyl-carbodiimide, N,N′-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, and combinations thereof, optionally in combination with hydroxybenzotriazole.
16. The method of claim 15 , wherein the coupling agent is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide in combination with hydroxybenzotriazole or is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in combination with hydrochloric acid.
17. The method of claim 16 , wherein the method further comprises recovering the free base of betrixaban by adding base.
18. The method of claim 17 , wherein the base is sodium carbonate and is added in at least about a 2 molar excess or a 3 molar excess.
19. The method of claim 9 , wherein the contacting is carried out under coupling conditions to afford betrixaban or a salt thereof in a yield of at least 65%.
20. The method of claim 9 , wherein the compound of Formula B is prepared by exposing a compound of Formula C:
to reaction conditions to form the compound of Formula B.
21. The method of claim 20 , wherein the reaction conditions to form the compound of Formula B comprise hydrogen gas in the presence of a catalyst.
22. The method of claim 21 , wherein the catalyst is sulfided 5% platinum on carbon.
23. The method of claim 21 , wherein the reaction conditions to form the compound of Formula B comprise a temperature of between 19° C. and 31° C.
24. The method of claim 21 , wherein the reaction conditions to form the compound of Formula B comprise a solvent selected from the group consisting of methylene chloride, ethanol, methanol, ethyl acetate and combinations thereof.
25. The method of claim 24 , wherein the solvent is methylene chloride.
26. The method of claim 21 , wherein the compound of Formula B is afforded in a yield of at least 80%.
27. The method of claim 20 , wherein the compound of Formula C is prepared by contacting a compound of Formula D:
with a compound of Formula E:
under reaction conditions to form the compound of Formula C.
28. The method of claim 27 , wherein the reaction conditions to form the compound of Formula C comprise a temperature of between 19° C. to 31° C.
29. The method of claim 27 , wherein the reaction conditions to form the compound of Formula C comprise acetonitrile as a solvent.
30. The method of claim 27 , wherein the reaction conditions to form the compound of Formula C comprise phosphorous oxychloride and pyridine.
31. The method of claim 27 , wherein the contacting is carried out under reaction conditions to afford the compound of Formula C in a yield of at least 84%.
32. The method of claim 9 , wherein the compound of Formula A is prepared by exposing a compound of Formula G
to reaction conditions to form the compound of Formula A;
wherein R is C 1-6 alkyl or benzyl.
33. The method of claim 32 , wherein R is methyl or ethyl and the reaction conditions to form the compound of Formula A comprise an inorganic base and a solvent.
34. The method of claim 32 , wherein the compound of Formula G is prepared by exposing a compound of Formula H
to reaction conditions to form the compound of Formula G.
35. The method of claim 34 , wherein the reaction conditions of forming the compound of Formula G comprise dimethylamine, LiR 6 and a solvent, wherein R 6 is C 1-6 alkyl.
36. A method of preparing betrixaban, which is of Formula I, or a salt thereof:
comprising
a) contacting a compound of Formula D:
with a compound of Formula E:
under reaction conditions comprising acetonitrile as a solvent to form a compound of Formula C:
b) exposing the compound of Formula C to reduction conditions comprising hydrogen gas in the presence of a catalyst to form a compound of Formula B:
c) contacting the compound of Formula B with a compound of Formula A:
under reaction conditions comprising an amide coupling reagent to form betrixaban or the salt thereof
37. The method of claim 36 , wherein the amide coupling reagent is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride optionally in combination with hydroxybenzotriazole or hydrochloric acid.
38. A method of preparing betrixaban, which is of Formula I, or a salt thereof:
comprising
a) contacting a compound of Formula D:
with a compound of Formula E:
under reaction conditions comprising phosphorous oxychloride, pyridine and acetonitrile to form a compound of Formula C:
b) exposing the compound of Formula C to reduction conditions comprising hydrogen gas in the presence of 5% sulfided platinum on carbon to form a compound of Formula B:
c) contacting the compound of Formula B with a compound of Formula A:
under reaction conditions comprising N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride to form betrixaban or the salt thereof.
39. The method of any one of claims 9 , 36 , and 38 , further comprising recovering the free base of betrixaban by contacting the reaction with base which optionally is sodium carbonate.
40. The method of any one of claims 9 , 36 and 38 , further comprising contacting betrixaban or the salt thereof with an acid under salt forming conditions to form a pharmaceutically acceptable salt of betrixaban.
41. The method of claim 40 , further comprising recovering the pharmaceutically acceptable salt of betrixaban.
42. The method of claim 40 , wherein the acid is maleic acid and the pharmaceutically acceptable salt of betrixaban is the maleate salt.
43. The method of claim 40 , wherein salt forming conditions comprises contacting betrixaban with at least a molar equivalent of maleic acid in a solvent mixture of C 1-4 alkanol and water at a temperature of between 10° C. and 40° C. under reaction conditions to form the maleate salt of betrixaban.
44. A method of any one of claims 9 , 36 and 38 , wherein betrixaban or the salt of betrixaban is prepared on a kilogram scale.