Fenfluramine compositions and methods of preparing the same

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.