TY - JOUR

T1 - Aqueous Instability of δ-Fluorobutylpiperidines

AU - Vorberg, Raffael

AU - Carreira, Erick M

AU - Müller, Klaus

N1 - © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2017/3/17

Y1 - 2017/3/17

N2 - 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.

AB - 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.

KW - Drug Stability

KW - Fluorine/chemistry

KW - Kinetics

KW - Magnetic Resonance Spectroscopy

KW - Piperidines/chemistry

KW - Spectrometry, Mass, Electrospray Ionization

KW - Water/chemistry

U2 - 10.1002/cmdc.201700027

DO - 10.1002/cmdc.201700027

M3 - Journal article

C2 - 28139081

VL - 12

SP - 431

EP - 437

JO - Farmaco

JF - Farmaco

SN - 1860-7179

IS - 6

ER -