Claims for Patent: 10,829,465

Summary for Patent: 10,829,465

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):	Phadke; Deepak (Olathe, KS), Platt; Natalie M. (Columbia, MD), Pandrapragada; Ravi K. (Clarksburg, MD)
Assignee:	VANDA PHARMACEUTICALS INC. (Washington, DC)
Application Number:	16/800,721
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 and 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 comprises 0.15 wt % or less of each of Impurity 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyc- lopropyl) (propionamido)methyl) cyclopropyl)methyl)propionamide) and Impurity 6 (2-hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate). 2. The composition of claim 1, wherein the reducing agent comprises LiAlH.sub.4. 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 comprising 0.15 wt % or less of each of each of Impurity 1 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbu- tanamide), Impurity 2 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamid- e), and Impurity 3 (1,3-bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea). 11. The composition of claim 1 comprising 0.15 wt % or less of each 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)propi- onamide). 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)cyc- lopropyl)(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 reducing agent comprises LiAlH.sub.4, the acid comprises HCl, or both. 15. The composition of claim 13, wherein the propionylating agent comprises propionyl chloride. 16. The composition of claim 13, 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. 17. The composition of claim 13 comprising 0.15 wt % or less of each of each of Impurity 1 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbu- tanamide), Impurity 2 (N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-pentanamid- e), and Impurity 3 (1,3-bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea). 18. The composition of claim 13 comprising 0.15 wt % or less of each 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)propi- onamide). 19. The composition of claim 13 comprising 100 ppm or less of ethyl diazaoacetate (EDA). 20. A pharmaceutical composition comprising the composition according to claim 13 and at least one pharmaceutically acceptable excipient.