Norfluoxetine → Methyl 4-phenylbutyrate

A preferred method of preparing enantiomerically pure enantiomers of norfluoxetine comprises the asymmetric synthesis of the compound from 3-benzoylpropionic acid. According to this method, 3-benzoylpropionic acid is methylated to provide methyl 3-benzylpropionate, which is then contacted with (+)-B-chlorodiisopinocamphenylborane chloride ((+)-DIP-Cl) to provide (R)-χ-phenyl-χ-butrolactone if R-norfluoxetine is being prepared, or with (−)-DIP-Cl to provide (S)-χ-phenyl-χ-butrolactone if S-norfluoxetine is being prepared. The lactone is subsequently contacted with ammonia to provide the corresponding chiral 4-hydroxy-4-phenylbutanamide (i.e., (R)- or (S)-4-hydroxy-4-phenylbutanamide). A cyclic carbamate is then prepared from the amide by contacting the chiral 4-hydroxy-4-phenylbutanamide with iodobenzene diacetate. The carbamate is then contacted with base to provide chiral 3-amino-(1R)-phenyl-propanol-1-ol, which is subsequently converted to the corresponding enantiomer of norfluoxetine free base by contacting it with sodium hydride and 4-chlorobenzotrifluoride. This free base can then be converted into a salt by known methods. For example, (D)-tartaric acid can be contacted with (R)-norfluoxetine free base to provide (R)-norfluoxetine.(D)-tartarate. Similarly, (L)-tartaric acid can be contacted with (S)-norfluoxetine free base to provide (S)-norfluoxetine.(L)-tartarate.

ORD record

ord-094f2dea70874b509cf08f339e336925

Source dataset

uspto-grants-2006_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07034059B2