US 10,351,509 B2Granted

Fenfluramine compositions and methods of preparing the same

AssigneeZogenix International Limited

InventorsDerek J. Londesbrough, Marc W. Andersen

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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.

Claims22

Dependent claims

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.

3 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/385,525Filed 20 Dec 2016 · us provisional application
Priority: 22 Dec 2015
Published: US 2017/0174613 A122 Jun 2017
Granted: 16 Jul 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07C 209/28
By reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds: by reduction with other…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
C07C 45/72
By increase in the number of carbon atoms: by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
C07C 45/80
Separation; Purification; Stabilisation; Use of additives: by liquid-liquid treatment