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.

Abstract: A synthesis of fluoxetine is disclosed. The process begins with benzoylacetonitrile, which is reduced, optionally in the presence of a chiral ligand, to produce the corresponding aminoalcohol, and the amine is carbamoylated without isolation. The alcohol is deprotonated and reacted with 4-chloro- or 4-fluoro benzotrifluoride or with 4-trifluoromethylphenol to provide a carbamate of fluoxetine. The carbamate is reduced with a hydride or with borane to provide fluoxetine free base. The process may be employed for the synthesis of individual enantiomers of fluoxetine.

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.