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(20)H(22)ClF(2)N(3)O, C(4)H(4)O(4)) (1) was synthesized and characterized by the complete (1)H, (13)C and (19)F 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. (1)H NMR line-shape analysis was used, at temperatures varying between -5 and +60 degrees C, to determine the enthalpy of activation of the rotational barrier around the CN bond. Compound 1 crystallizes in the triclinic space group P1 with a=8.517(3) Angstrom, b=12.384(2) Angstrom, c=12.472(3) Angstrom, alpha=70.88(2) degrees, beta=82.04(2) degrees, gamma=83.58(2) degrees. 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 degrees C (DeltaH=132 J g(-1)).
Ribet
J P
JP
Institut de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106 Castres, France. jean.paul.ribet@pierre-fabre.com
Pena
R
R
Maurel
J L
JL
Belin
C
C
Tillard
M
M
Vacher
B
B
Bonnaud
B
B
Colpaert
F
F
D002152:Calorimetry, Differential Scanning; D017666:Deuterium Oxide; D005650:Fumarates / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D013816:Thermodynamics; D014961:X-Ray Diffraction
C510110:((1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl)methyl)((5-methylpyridin-2-yl)methyl)amine; D005650:Fumarates; D010880:Piperidines; D011725:Pyridines; C032005:fumaric acid; D017666:Deuterium Oxide