Fenfluramine compositions and methods of preparing the same
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.
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 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 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 0.5% by weight of 4-trifluoromethyl-phenyl regioisomer.
3. The method of claim 2 , wherein step (c) comprises purification of the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition via a ketone bisulfite adduct.
4. The method of claim 2 , wherein the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition of step (b) has less than 0.1% by weight 4-trifluoromethyl-phenyl regioisomer.
5. The method of claim 4 , wherein the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition of step (b) has less than 0.1% by weight 2-trifluoromethyl-phenyl regioisomer.
6. The method of claim 1 , wherein the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition is prepared from trifluoromethylbenzene.
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 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 (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.
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 0.1% 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 following purity profile:
at least 95% of the pharmaceutically acceptable salt of fenfluramine;
less than 0.1% by weight of 2-fenfluramine;
less than 0.2% by weight of 4-fenfluramine; and
less than 0.1% 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.