Fenfluramine compositions and methods of preparing the same

Patent metadata

Field	Value
Publication number	US-10351509-B2
Application number	US-201615385525-A
Country	US
Kind code	B2
Filing date	Dec 20, 2016
Priority date	Dec 22, 2015
Publication date	Jul 16, 2019
Grant date	Jul 16, 2019

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 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.

Assignees

• Zogenix International Ltd

Inventors

• Londesbrough Derek J
• Andersen Marc W

Classifications

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07C51/08

  from nitriles · CPC title

• C07C49/233

  containing six-membered aromatic rings · CPC title

• C07C209/84

  Purification · CPC title

• C07C45/72

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