Details for Patent: 8,609,865

Title:	Crystals and process of making 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid
Abstract:	The present invention relates to a novel crystals of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid and methods of making the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.
Inventor(s):	Anzalone; Luigi (West Chester, PA), Villani; Frank J. (Perkasie, PA), Teleha; Christopher A. (Fort Washington, PA), Feibush; Penina (Ambler, PA), Fegely; Barry (Quakertown, PA)
Assignee:	Furiex Pharmaceuticals, Inc. (Morrisville, NC)
Filing Date:	Jul 01, 2011
Application Number:	13/175,342
Claims:	1. A method of preparing a crystalline zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid comprising the steps of: combining a strong ionizable acid with 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propi- onyl]-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid to prepare a salt of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-- (4-phenyl-1 H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid; washing said salt of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1H-imidazol-2-yl)-ethyl]-amino }-methyl)-2-methoxy-benzoic acid with an inorganic base to obtain the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid; and crystallizing the zwitterion wherein the crystallizing comprises storing the zwitterion at a relative humidity of between about 0 to about 40% or at greater than about 60%. 2. The method of claim 1, further comprising the step of washing said zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid with water. 3. The method of claim 1, wherein said inorganic base is sodium hydroxide. 4. The method of claim 1, wherein said ionizable acid is hydrochloric acid and wherein said salt is the hydrochloride salt of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid. 5. A method of preparing a crystalline zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid comprising the steps of: combining hydrochloric acid with 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propi- onyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxybenzoi- c acid to prepare the hydrochloride salt of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid; washing said salt of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid with sodium hydroxide to obtain the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4phenyl-1- H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid; washing said zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-- 1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid with water; and crystallizing the zwitterion wherein the crystallizing comprises storing the zwitterion at a relative humidity of between about 0 to about 40% or at greater than about 60%. 6. The method of claim 1, wherein the crystalline zwitterion comprises a Form .alpha. crystal and crystallizing comprises storing the zwitterion at a relative humidity of between about 0 to about 40%. 7. The method of claim 1, wherein the crystalline zwitterion comprises a Form .beta. crystal and crystallizing comprises storing the zwitterion at a relative humidity of greater than about 60%.