Claims for Patent: 10,947,183

Summary for Patent: 10,947,183

Title:	Fenfluramine compositions and methods of preparing the same
Abstract:	Methods of preparing a fenfluramine active pharmaceutical ingredient are provided. Aspects of the method include (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) reacting the 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (c) reductively aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with ethylamine using a borohydride reducing agent to produce a fenfluramine composition. Also provided are compositions and pharmaceutical ingredients prepared according to the subject methods including a pharmaceutically acceptable salt of fenfluramine and having less than 0.2% by weight in total of trifluoromethyl regioisomers.
Inventor(s):	Londesbrough; Derek J. (Sunderland, GB), Andersen; Marc W. (Raleigh, NC)
Assignee:	ZOGENIX INTERNATIONAL LIMITED (Berkshire, GB)
Application Number:	16/431,391
Patent Claims:	1. A fenfluramine active pharmaceutical ingredient produced by a process comprising the steps of: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition via crystallization to produce a purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with ethylamine using a borohydride reducing agent to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount; wherein the fenfluramine active pharmaceutical ingredient has less than 0.2% by weight of 4-fenfluramine or a salt thereof. 2. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition is prepared from trifluoromethylbenzene. 3. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient is produced by a process where step (c) comprises purification of the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition via a ketone bisulfite adduct. 4. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient: comprises at least 0.01% by weight of trifluoromethyl-phenyl regioisomers of fenfluramine or a salt thereof and is substantially devoid of; metal catalysts; solvents selected from acetonitrile, benzene and substituted benzenes, carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dimethoxyethane, DMF, 1,4-dioxane, methanol, methylbutyl ketone, N-methylpyrrolidinone, pyridine, toluene, 1,1,1-trichloroethane, 1,1,2-trichloroethene, and xylene; and has less than 5% by weight of reduced alcohol side product. 5. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient is produced by a process where step (c) is performed under conditions that comprise contacting the 2-(3-(trifluoromethyl)phenyl)acetic acid composition with about 0.5 equivalents of 1-methylimidazole and about 5 equivalents or more of acetic anhydride in an optional solvent. 6. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient is produced by a process where step (d) is performed under conditions that comprise contacting the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with a solution of 70% by weight of ethylamine in water and about 2.25 equivalents or more of triacetoxyborohydride in methanol solvent. 7. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient has the following profile: at least 80% by weight of fenfluramine or a salt thereof at least 0.01% by weight of 2-fenfluramine or a salt thereof; at least 0.01% by weight of 4-fenfluramine or a salt thereof; and less than 10% by weight of fenfluramine reduced alcohol side product. 8. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient is produced by a process that further comprises the step of purifying fenfluramine free base. 9. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient is produced by a process that further comprises the step of performing a chiral separation of a racemic fenfluramine composition to produce a non-racemic fenfluramine composition comprising a predominant stereoisomer of fenfluramine. 10. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient is produced by a process where the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition of step (b) has less than 0.1% by weight 4-trifluoromethyl-phenyl regioisomer. 11. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient is produced by a process where the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition of step (b) has less than 0.1% by weight 2-trifluoromethyl-phenyl regioisomer. 12. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient comprises at least 0.01% by weight of 4-fenfluramine or a salt thereof. 13. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the fenfluramine active pharmaceutical ingredient comprises at least 0.01% by weight of 2-fenfluramine or a salt thereof. 14. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 0.3% by weight of the fenfluramine active pharmaceutical ingredient. 15. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 0.4% by weight of the fenfluramine active pharmaceutical ingredient. 16. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 0.5% by weight of the fenfluramine active pharmaceutical ingredient. 17. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 1.0% by weight of the fenfluramine active pharmaceutical ingredient. 18. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 1.5% by weight of the fenfluramine active pharmaceutical ingredient. 19. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 2.0% by weight of the fenfluramine active pharmaceutical ingredient. 20. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 3.0% by weight of the fenfluramine active pharmaceutical ingredient. 21. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 4.0% by weight of the fenfluramine active pharmaceutical ingredient. 22. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 5.0% by weight of the fenfluramine active pharmaceutical ingredient. 23. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 10% by weight of the fenfluramine active pharmaceutical ingredient. 24. The fenfluramine active pharmaceutical ingredient of claim 1, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 0.2% by weight of the fenfluramine active pharmaceutical ingredient. 25. A composition, comprising fenfluramine and at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount that is less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers of fenfluramine. 26. A composition, comprising fenfluramine and at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount that is greater than zero and less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers of fenfluramine. 27. A composition, comprising fenfluramine and at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount that is 0.01% by weight in total of trifluoromethyl-phenyl regioisomers of fenfluramine. 28. A fenfluramine active pharmaceutical ingredient produced by a process comprising the steps of: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition via crystallization to produce a purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with ethylamine using a borohydride reducing agent to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount; wherein the fenfluramine active pharmaceutical ingredient has less than 1.0% by weight of a reduced alcohol side product. 29. A fenfluramine active pharmaceutical ingredient produced by a process comprising the steps of: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition via crystallization to produce a purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with ethylamine using a borohydride reducing agent to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount; wherein the fenfluramine active pharmaceutical ingredient is produced by a process that further comprises crystallizing fenfluramine or a salt thereof from a crude fenfluramine composition. 30. A fenfluramine active pharmaceutical ingredient produced by a process comprising the steps of: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition via crystallization to produce a purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with ethylamine using a borohydride reducing agent to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount; wherein the fenfluramine active pharmaceutical ingredient is produced by a process that further comprises the steps of: converting fenfluramine to a pharmaceutically acceptable salt of fenfluramine; and crystallizing the pharmaceutically acceptable salt of fenfluramine, wherein the pharmaceutically acceptable salt of fenfluramine has the following purity profile: at least 95% of the pharmaceutically acceptable salt of fenfluramine; at least 0.01% by weight of 2-fenfluramine; at least 0.01% by weight of 4-fenfluramine; and less than 0.1% by weight of fenfluramine reduced alcohol side product. 31. The fenfluramine active pharmaceutical ingredient produced by the process of any one of claim 1, 2-4, 5-7, 8-24, 28, 29, or 30, further comprising: converting the fenfluramine active pharmaceutical ingredient to fenfluramine HCL. 32. The composition of any one of claim 25, 26, or 27, wherein the fenfluramine is fenfluramine HCL. 33. A fenfluramine active pharmaceutical ingredient produced by a process comprising the steps of: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition via crystallization to produce a purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with ethylamine using a borohydride reducing agent to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount; wherein the fenfluramine active pharmaceutical ingredient is produced by a process that further comprises the steps of: converting fenfluramine to a pharmaceutically acceptable salt of fenfluramine; and crystallizing the pharmaceutically acceptable salt of fenfluramine, wherein the pharmaceutically acceptable salt of fenfluramine has the following purity profile: at least 99% of the pharmaceutically acceptable salt of fenfluramine; at least 0.01% by weight of 4-fenfluramine; and less than 0.1% by weight of fenfluramine reduced alcohol side product.