Abstract
In a series of partially fluorinated N-propyl- and N-butylpiperidine derivatives, three compounds were found to exhibit unexpected instability under mild biophysical assay conditions. These compounds carry a single terminal fluorine in the δ-position of an N-butyl group as a common structural feature. An adjacent fluorine substituent at the γ-position significantly slows down the reactivity. All other compounds, having either no or more than one fluorine substituent at the δ-position are chemically inert under all assay conditions. The reactivity of the labile compounds is traced to an intramolecular ring-closing fluorine substitution reaction by the moderately basic piperidine unit, leading to a spiro-pyrrolidinium salt. The chemical lability of δ-monofluorinated or γ,δ-difluorinated N-butylpiperidine derivatives even under very mild biophysical assay conditions constitutes a caveat to the molecular design of partially fluorinated alkylamines.
| Original language | English |
|---|---|
| Journal | ChemMedChem |
| Volume | 12 |
| Issue number | 6 |
| Pages (from-to) | 431-437 |
| Number of pages | 7 |
| ISSN | 1860-7179 |
| DOIs | |
| Publication status | Published - 17 Mar 2017 |
Keywords
- Drug Stability
- Fluorine/chemistry
- Kinetics
- Magnetic Resonance Spectroscopy
- Piperidines/chemistry
- Spectrometry, Mass, Electrospray Ionization
- Water/chemistry