title: Utilizing capillary gas chromatography mass spectrometry to determine 4-benzotrifluoride t-butyl ether as a reaction by-product in fluoxetine synthesized using potassium t-butoxide as base.
abstract: Fluoxetine hydrochloride has been prepared using two similar synthetic routes, both of which rely upon an ether formation reaction mediated by a base. The base used can affect the impurity profile of this reaction. It was proposed that the synthesis of fluoxetine carried out using potassium t-butoxide as base and 4-chlorobenzotrifluoride (or 4-fluorobenzotrifluoride) in the ether formation step may result in the formation of 4-benzotrifluoride t-butyl ether as a reaction by-product. To test this hypothesis, capillary gas chromatography-mass spectrometry (GC/MS) was utilized to evaluate samples of free base fluoxetine synthesized using sodium hydride (NaH) or potassium t-butoxide as the base. Assay conditions using selected ion monitoring (SIM) were developed, which allowed detection of trace levels (parts per million, ppm) of 4-benzotrifluoride t-butyl ether in fluoxetine free base sample matrix. Response linearity, precision, and standard spike recovery were examined during development, and were found to be suitable. Comparisons of fluoxetine samples generated from both NaH and potassium t-butoxide processes were performed using the GC/MS assay.
authors.affiliation: Lilly Research Laboratories, Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Robbins
authors.forename: Paul N
authors.initials: PN
authors.lastname: Dodson
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Buccilli
authors.forename: David
authors.initials: D
authors.lastname: Mitchell
mesh_terms: D000440:Butanols / Q000737:chemistry*; D005464:Fluorobenzenes / Q000032:analysis*; D005473:Fluoxetine / Q000138:chemical synthesis / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D010647:Phenyl Ethers / Q000032:analysis*; D012015:Reference Standards; D015203:Reproducibility of Results; D012997:Solvents
chemical_list: C476887:4-benzotrifluoride tert-butyl ether; D000440:Butanols; D005464:Fluorobenzenes; D010647:Phenyl Ethers; D012997:Solvents; D005473:Fluoxetine; C044697:benzotrifluoride; C077664:tert-butoxide, potassium