Claims for Patent: 12,049,457

Summary for Patent: 12,049,457

Title:	Highly purified pharmaceutical grade tasimelteon
Abstract:	A process for preparing a batch of highly purified, pharmaceutical grade tasimelteon comprises analyzing a batch of tasimelteon synthesized under GMP conditions for the presence of one or more identified impurities.
Inventor(s):	Deepak Phadke, Natalie M. Platt, Ravi K. Pandrapragada
Assignee:	Vanda Pharmaceuticals Inc
Application Number:	US18/362,073
Patent Claims:	1. A composition comprising tasimelteon prepared by a process comprising the steps of: contacting and reacting (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane carboxamide with a reducing agent followed by contacting the reaction product thereof with an acid in an organic solvent to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine or a salt thereof; and contacting and reacting the ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine with a propionylating reagent to prepare tasimelteon, wherein the composition is substantially free of Impurity 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) (propionamido)methyl)cyclopropyl)methyl) propionamide). 2. The composition of claim 1, wherein the reducing agent comprises LiAlH4. 3. The composition of claim 1, wherein the acid comprises HCl. 4. The composition of claim 1, wherein the organic solvent comprises TBME. 5. The composition of claim 1, wherein the propionylating agent comprises propionyl chloride. 6. The composition of claim 1, wherein the propionylation step further includes an organic solvent and a base. 7. The composition of claim 6, wherein the base comprises NaOH. 8. The composition of claim 1, wherein the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane carboxamide is reduced to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a salt thereof. 9. A pharmaceutical composition comprising the composition according to claim 1 and at least one pharmaceutically acceptable excipient. 10. The composition of claim 1 which is substantially free of at least one additional impurity selected from a group consisting of: Impurity 1 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropyl)methyl)-3-methylbutanamide), Impurity 2 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamide), and Impurity 3 (1,3-bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea). 11. The composition of claim 1 which is substantially free of at least one additional impurity selected from a group consisting of: Impurity 4 (N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl) propionamide) and Impurity 7 (N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl) methyl)propionamide). 12. The composition of claim 1 comprising 100 ppm or less of ethyl diazaoacetate (EDA). 13. The composition of claim 1, wherein the process further comprises the steps of: crystallizing the tasimelteon; and assaying the crystallized tasimelteon from step (b) for the presence of one or both of Impurity 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) (propionamido)methyl) cyclopropyl)methyl)propionamide) and Impurity 6 (2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate). 14. The composition of claim 13, wherein the composition comprises no Impurity 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamido)methyl) cyclopropyl)methyl) propionamide). 15. A composition comprising tasimelteon prepared by a process comprising the steps of: contacting and reacting (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane carboxamide with a reducing agent followed by contacting the reaction product thereof with an acid in an organic solvent to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) methanamine or a salt thereof; and contacting and reacting the ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine with a propionylating reagent to prepare tasimelteon, wherein the composition is substantially free of Impurity 6 (2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate). 16. The composition of claim 15, wherein the reducing agent comprises LiAlH4. 17. The composition of claim 15, wherein the acid comprises HCl. 18. The composition of claim 15, wherein the organic solvent comprises TBME. 19. The composition of claim 15, wherein the propionylating agent comprises propionyl chloride. 20. The composition of claim 15, wherein the propionylation step further includes an organic solvent and a base. 21. The composition of claim 20, wherein the base comprises NaOH. 22. The composition of claim 15, wherein the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane carboxamide is reduced to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine or a salt thereof. 23. A pharmaceutical composition comprising the composition according to claim 15 and at least one pharmaceutically acceptable excipient. 24. The composition of claim 15 which is substantially free of at least one additional impurity selected from a group consisting of: Impurity 1 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide), Impurity 2 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamide), and Impurity 3 (1,3-bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea). 25. The composition of claim 15 which is substantially free of at least one additional impurity selected from a group consisting of: Impurity 4 (N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide) and Impurity 7 (N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide). 26. The composition of claim 15 comprising 100 ppm or less of ethyl diazaoacetate (EDA). 27. The composition of claim 15, wherein the process further comprises the steps of: crystallizing the tasimelteon; and assaying the crystallized tasimelteon from step (b) for the presence of one or both of Impurity 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl) (propionamido)methyl) cyclopropyl)methyl)propionamide) and Impurity 6 (2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate). 28. The composition of claim 15, wherein the composition comprises no Impurity 6 (2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)c yclopropyl)phenyl carbonate).