Fenfluramine compositions and methods of preparing the same

Patent metadata

Field	Value
Publication number	US-10947183-B2
Application number	US-201916431391-A
Country	US
Kind code	B2
Filing date	Jun 4, 2019
Priority date	Dec 22, 2015
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

(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.

First claim

That which is claimed is:

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

Assignees

• Zogenix International Ltd

Inventors

• Londesbrough Derek J
• Andersen Marc W

Classifications

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61K31/137 Primary

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title

• A61K31/12

  Ketones · CPC title

• C07C57/58

  containing six-membered aromatic rings · CPC title

• C07C49/233

  containing six-membered aromatic rings · CPC title