Conformational analysis and crystal structure of {[1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4yl]methyl}[(5-methylpyridin-2-yl)methyl]amine, fumaric acid salt

{[1-(3-Chloro-4-fluorobenzoyl)-4-fluoropiperidin-4yl]methyl}[(5-methylpyridin-2-yl)methyl]amine, fumaric acid salt (C 20H 22ClF 2N 3O, C 4H 4O 4) ( 1) was synthesized and characterized by the complete 1H, 13C and 19F NMR analyses. The conformation of the piperidin ring, in the solution state, was pa...

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Published in:Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy Molecular and biomolecular spectroscopy, 2005-11, Vol.62 (1), p.353-363
Main Authors: Ribet, J.P., Pena, R., Maurel, J.L., Belin, C., Tillard, M., Vacher, B., Bonnaud, B., Colpaert, F.
Format: Article
Language:English
Subjects:
5-HT 1A receptor agonist
Calorimetry, Differential Scanning
Chemical Sciences
Conformational analysis
Cristallography
Crystal structure
Deuterium Oxide
Fumarates - chemistry
Magnetic Resonance Spectroscopy - methods
Medicinal Chemistry
Models, Molecular
Molecular Conformation
Piperidines - chemistry
Polymorphism study
Pyridines - chemistry
Thermal analysis
Thermodynamics
X-Ray Diffraction
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Summary:{[1-(3-Chloro-4-fluorobenzoyl)-4-fluoropiperidin-4yl]methyl}[(5-methylpyridin-2-yl)methyl]amine, fumaric acid salt (C 20H 22ClF 2N 3O, C 4H 4O 4) ( 1) was synthesized and characterized by the complete 1H, 13C and 19F NMR analyses. The conformation of the piperidin ring, in the solution state, was particularly studied from the coupling constants determined by recording a double-quantum filtered COSY experiment in phase-sensitive mode. 1H NMR line-shape analysis was used, at temperatures varying between −5 and +60 °C, to determine the enthalpy of activation of the rotational barrier around the C N bond. Compound 1 crystallizes in the triclinic space group P 1 ¯ with a = 8.517(3) Å, b = 12.384(2) Å, c = 12.472(3) Å, α = 70.88(2)°, β = 82.04(2)°, γ = 83.58(2)°. The results strongly indicate that the solid and solution conformations are similar. Thermal stability and phases transitions were investigated by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Furthermore polymorphism screening was studied from recrystallization of 1 performed in seven solvents and by slurry conversion in water. The X-ray powder diffraction (XRPD) and differential scanning calorimetry results suggested that 1 crystallizes into one crystalline form which melts at 157 °C (Δ H = 132 J g −1).
ISSN:1386-1425
0584-8539
DOI:10.1016/j.saa.2005.01.002