Details for Patent: 8,394,964

Title:	Methods of synthesizing factor Xa inhibitors
Abstract:	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. ##STR00001##
Inventor(s):	Pandey; Anjali (Fremont, CA), T. Leitao; Emilia P. (Lisbon, PT), Rato; Jose (Lisbon, PT), Song; Zhiguo Jake (Edison, NJ)
Assignee:	Millennium Pharmaceuticals, Inc. (Cambridge, MA) Portola Pharmaceuticals, Inc. (South San Francisco, CA)
Filing Date:	Dec 15, 2010
Application Number:	12/969,371
Claims:	1. A method of preparing a compound of Formula II, or a salt thereof: ##STR00053## comprising contacting a compound of Formula II-A: ##STR00054## with a compound of Formula II-B: ##STR00055## under reaction conditions to form the compound of Formula II or the salt thereof; wherein R.sup.1 and R.sup.2 are independently C.sub.1-6 alkyl; R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, and methoxy; and R.sup.5 is selected from the group consisting of fluoro, chloro, bromo, and methoxy. 2. The method of claim 1, wherein R.sup.1 and R.sup.2 are both methyl. 3. The method of claim 1, wherein one of R.sup.3 and R.sup.4 is hydrogen and the other of R.sup.3 and R.sup.4 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, and methoxy. 4. The method of claim 1, wherein R.sup.3 is hydrogen and R.sup.4 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, and methoxy. 5. The method of claim 1, wherein R.sup.3 is hydrogen and R.sup.4 is methoxy. 6. The method of claim 1, wherein R.sup.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, ##STR00056## comprising: contacting a compound of Formula A: ##STR00057## with a compound of Formula B: ##STR00058## 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: ##STR00059## 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.degree. C. and 31.degree. 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: ##STR00060## with a compound of Formula E: ##STR00061## 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.degree. C. to 31.degree. 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 ##STR00062## to reaction conditions to form the compound of Formula A; wherein R is C.sub.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 ##STR00063## 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.sup.6 and a solvent, wherein R.sup.6 is C.sub.1-6 alkyl. 36. A method of preparing betrixaban, which is of Formula I, or a salt thereof: ##STR00064## comprising a) contacting a compound of Formula D: ##STR00065## with a compound of Formula E: ##STR00066## under reaction conditions comprising acetonitrile as a solvent to form a compound of Formula C: ##STR00067## 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: ##STR00068## c) contacting the compound of Formula B with a compound of Formula A: ##STR00069## 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: ##STR00070## comprising a) contacting a compound of Formula D: ##STR00071## with a compound of Formula E: ##STR00072## under reaction conditions comprising phosphorous oxychloride, pyridine and acetonitrile to form a compound of Formula C: ##STR00073## 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: ##STR00074## c) contacting the compound of Formula B with a compound of Formula A: ##STR00075## 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.sub.1-4 alkanol and water at a temperature of between 10.degree. C. and 40.degree. 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.