Fenfluramine compositions and methods of preparing the same

Patent metadata

Field	Value
Publication number	US-11634377-B2
Application number	US-202117159367-A
Country	US
Kind code	B2
Filing date	Jan 27, 2021
Priority date	Dec 22, 2015
Publication date	Apr 25, 2023
Grant date	Apr 25, 2023

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.

First claim

That which is claimed is:

1. A method of treating epilepsy, comprising administering to a patient a therapeutically effective amount of a formulation comprising 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 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.

2. The method of claim 1 , wherein the 2-(3-(trifluoromethyl)phenyl) acetonitrile composition is prepared from trifluoromethylbenzene.

3. The method 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 method of claim 1 , wherein the fenfluramine active pharmaceutical ingredient 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 method 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 method 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 method of claim 1 , wherein the fenfluramine active pharmaceutical ingredient is produced by a process that further comprises the step of purifying fenfluramine free base.

8. The method 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.

9. The method 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.

10. The method 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.

11. A method of treating epilepsy, comprising administering to a patient a therapeutically effective amount of a formulation comprising 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 comprises at least 0.01% by weight of 4-fenfluramine or a salt thereof.

12. The method of claim 11 , wherein the fenfluramine active pharmaceutical ingredient comprises at least 0.01% by weight of 2-fenfluramine or a salt thereof.

13. A method of treating epilepsy, comprising administering to a patient a therapeutically effective amount of a formulation comprising fenfluramine and at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 0.01% by weight and less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers of fenfluramine.

14. The method of claim 13 , wherein the fenfluramine is fenfluramine HCL.

15. The method of claim 13 , wherein the patient suffers from Dravet Syndrome.

16. The method of claim 14 , wherein the patient suffers from Dravet Syndrome.

Assignees

• Zogenix International Ltd

Inventors

• Londesbrough Derek J
• Andersen Marc W

Classifications

• C07C209/84

  Purification · CPC title

• C07C51/43

  by change of the physical state, e.g. crystallisation · CPC title

• C07C211/29

  the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups · CPC title

• C07C45/72

  by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups · CPC title

• C07C209/28 Primary

  by reduction with other reducing agents · CPC title