Fluoxetine process from benzoylpropionic acid

摘要

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.