Aqueous Instability of δ-Fluorobutylpiperidines
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Aqueous Instability of δ-Fluorobutylpiperidines. / Vorberg, Raffael; Carreira, Erick M; Müller, Klaus.
I: ChemMedChem, Bind 12, Nr. 6, 17.03.2017, s. 431-437.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 195958758