Fenfluramine compositions and methods of preparing the same

• US 10,351,509 B2
• Filed: 12/20/2016
• Issued: 07/16/2019
• Est. Priority Date: 12/22/2015
• Status: Active Grant

• Current Assignee: Zogenix International Limited (UCB SA)
• Original Assignee: Zogenix International Limited (UCB SA)
• Inventors: Londesbrough, Derek J., Andersen, Marc W.
• Primary Examiner(s): Brooks, Clinton A
• Application Number:
  US15/385,525
• Publication Number:
  US 20170174613A1
• Time in Patent Office: 938 Days
• Field of Search: None
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 209/28 by reduction with other reducing agents
• CPC Class Codes: C07C 209/84 Purification
• CPC Class Codes: C07C 211/29 the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 45/72 by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
• CPC Class Codes: C07C 45/80 by liquid-liquid treatment
• CPC Class Codes: C07C 49/233 containing six-membered aromatic rings
• CPC Class Codes: C07C 51/08 from nitriles
• CPC Class Codes: C07C 51/43 by change of the physical state, e.g. crystallisation
• CPC Class Codes: C07C 57/58 containing six-membered aromatic rings

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.

Claims

1. A method of preparing a fenfluramine active pharmaceutical ingredient, the method comprising:

(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 to produce a purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition;

(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;

(d) purifying the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition via a ketone bisulfite adduct to produce a purified 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and

(e) reductively aminating the purified 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with ethylamine using a borohydride reducing agent to produce a crude fenfluramine composition having less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers of fenfluramine or a salt thereof.

2. The method of claim 1, wherein the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition comprises at least 1% by weight of trifluoromethyl-phenyl regioisomers.

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

4. The method of claim 1, wherein the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition of step (b) has less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers and 0.5% or less by weight of trifluoromethylbenzaldehyde and benzaldehyde.

5. The method of claim 1, wherein the purifying of step (b) comprises crystallization of 2-(3-(trifluoromethyl)phenyl)acetic acid.

6. The method of claim 1, wherein the purified 1-(3-(trifluoromethyl)phenyl)propan-2-one composition has less than 0.2% by weight of acetate impurity and less than 0.5% by weight of dimer impurity.

7. The method of claim 1, wherein the crude fenfluramine composition:

has less than 0.2% by weight of trifluoromethyl-phenyl regioisomers of fenfluramine or a salt thereof;

is devoid of metal catalysts;

is devoid of 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.

8. The method of claim 1, wherein the crude fenfluramine composition has less than 0.2% by weight of 4-fenfluramine or a salt thereof.

9. The method of claim 8, wherein the crude fenfluramine composition has less than 0.1% by weight of 4-fenfluramine or a salt thereof.

10. The method of claim 9, wherein the crude fenfluramine composition has less than 0.1% by weight of 2-fenfluramine or a salt thereof.

11. The method of claim 1, wherein the crude fenfluramine composition has less than 10% by weight of a reduced alcohol side product.

12. The method of claim 1, further comprising crystallizing fenfluramine or a salt thereof from the crude fenfluramine composition.

13. The method of claim 1, wherein step (c) is performed under conditions that comprise contacting the purified 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.

14. The method of claim 1, wherein step (e) 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.

15. The method of claim 1, wherein the fenfluramine composition has following profile:

at least 80% by weight of fenfluramine or a salt thereof

less than 0.2% by weight of 2-fenfluramine or a salt thereof;

less than 0.2% by weight of 4-fenfluramine or a salt thereof; and

less than 10% by weight of fenfluramine reduced alcohol side product.

16. The method of claim 1, further comprising:

converting fenfluramine in the crude fenfluramine composition 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;

less than 0.2% by weight of 2-fenfluramine;

less than 0.2% by weight of 4-fenfluramine; and

less than 1% by weight of fenfluramine reduced alcohol side product.

17. The method of claim 1, further comprising purifying fenfluramine free base from the crude fenfluramine composition.

18. The method of claim 1, further comprising performing a chiral separation of a racemic fenfluramine composition to produce a non-racemic fenfluramine composition comprising a predominant stereoisomer of fenfluramine.

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

20. The method of claim 1, wherein the crude fenfluramine composition is produced on a kilogram scale.

21. The method of claim 1, wherein the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition of step (b) has less than 0.2% by weight 4-trifluoromethyl-phenyl regioisomer.

22. The method of claim 21, wherein the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition of step (b) has less than 0.2% by weight 2-trifluoromethyl-phenyl regioisomer.