Fluoxetine process from benzoylpropionic acid
AssigneeSepacor Inc.
InventorsJames Wallace Hilborn, Alex Roger Jurgens, Chris Hugh Senanayake
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Abstract
A synthesis of fluoxetine is disclosed. The process begins with a lower alkyl ester of 3-benzoylpropionic acid, which is reduced in the presence of a chiral ligand to produce the corresponding .gamma.-hydroxy ester, and the ester is cleaved. The free acid is then condensed with the alcohol to form a .gamma.-lactone, which is treated with ammonia to provide the .gamma.-hydroxy amide. The amide undergoes a Hoffman rearrangement to provide a 2-oxo-1,3 oxazine, which is reduced to 3-(methylamino)-1-phenyl-1-propanol. The alcohol is deprotonated and reacted with a 4-chloro- or 4-fluoro benzotrifluoride to provide fluoxetine free base.
Claims16
A process for preparing 3-(methylamino)-1-phenylpropanol comprising the steps of:
- (a) reacting 5-phenyltetrahydrofuran-2-one with an excess of ammonia to provide 4-hydroxybenzenebutanamide;
- (b) reacting said 4-hydroxybenzenebutanamide with an oxidant to provide 6-phenyltetrahydrooxazin-2-one;
- and
- (c) reducing said 6-phenyltetrahydrooxazin-2-one to provide 3-(methylamino)-1-phenylpropanol.
A process for preparing fluoxetine free base comprising the steps of:
- (a) reacting 5-phenyltetrahydrofuran-2-one with an excess of ammonia to provide 4-hydroxybenzenebutanamide;
- (b) reacting said 4-hydroxybenzenebutanamide with an oxidant to provide 6-phenyltetrahydrooxazin-2-one;
- (c) reducing said 6-phenyltetrahydrooxazin-2-one to provide 3-(methylamino)-1-phenylpropanol;
- and
- (d) reacting said 3-(methylamino)-1-phenylpropanol with a strong base followed by 4-chlorobenzotrifluoride to provide fluoxetine free base.
Dependencies are inferred from the claim text.