N-{4-[4-(4-Fluoro­phen­yl)-1-(2-methoxy­ethyl)-2-methyl­sulfanyl-1H-imidazol-5-yl]-2-pyrid­yl}-2-methyl-3-phenyl­propionamide

Katharina Ziegler; Dieter Schollmeyer; Stefan Laufer

doi:10.1107/S1600536809048661

. 2009 Nov 21;65(Pt 12):o3128. doi: 10.1107/S1600536809048661

N-{4-[4-(4-Fluorophenyl)-1-(2-methoxyethyl)-2-methylsulfanyl-1H-imidazol-5-yl]-2-pyridyl}-2-methyl-3-phenylpropionamide

Katharina Ziegler ^a, Dieter Schollmeyer ^b, Stefan Laufer ^a,^*

PMCID: PMC2972069 PMID: 21578851

Abstract

In the crystal structure of the title compound, C₂₈H₂₉FN₄O₂S, the imidazole ring makes dihedral angles of 11.85 (7), 73.33 (7) and 22.83 (8)° with the 4-fluorophenyl, pyridine and phenyl rings, respectively. The 4-fluorophenyl ring makes dihedral angles of 77.91 (7) and 26.93 (8)° with the pyridine and phenyl rings, respectively. The phenyl and pyridine rings are nearly perpendicular, making a dihedral angle of 86.47 (9)°. The crystal packing shows an intermolecular N—H⋯O hydrogen-bonding interaction between the N—H and carbonyl groups of the amide functions.

Related literature

For related compounds and their biological activity, see: Laufer et al. (2004 ▶). For the biological activity of the title compound, see: Ziegler et al. (2009 ▶). graphic file with name e-65-o3128-scheme1.jpg

Experimental

Crystal data

C₂₈H₂₉FN₄O₂S
M _r = 504.61
Monoclinic,
a = 10.6254 (5) Å
b = 28.542 (1) Å
c = 9.8380 (4) Å
β = 117.953 (1)°
V = 2635.5 (2) Å³
Z = 4
Mo Kα radiation
μ = 0.16 mm⁻¹
T = 173 K
0.50 × 0.50 × 0.20 mm

Data collection

Bruker SMART with APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2006 ▶) T _min = 0.685, T _max = 0.746
21744 measured reflections
6183 independent reflections
6019 reflections with I > 2σ(I)
R _int = 0.020

Refinement

R[F ² > 2σ(F ²)] = 0.029
wR(F ²) = 0.078
S = 1.03
6183 reflections
328 parameters
2 restraints
H-atom parameters constrained
Δρ_max = 0.27 e Å⁻³
Δρ_min = −0.17 e Å⁻³
Absolute structure: Flack (1983 ▶), 3058 Friedel pairs
Flack parameter: 0.13 (4)

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: SAINT (Bruker, 2006 ▶); data reduction: SAINT; program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: PLATON.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809048661/im2161sup1.cif

e-65-o3128-sup1.cif^{(25.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809048661/im2161Isup2.hkl

e-65-o3128-Isup2.hkl^{(302.7KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N7—H7⋯O9ⁱ	0.82	2.21	3.025 (1)	173

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Symmetry code: (i) Inline graphic .

supplementary crystallographic information

Comment

N1 substituted 2-alkylsulfanyl-4-(4-fluorophenyl)-5-(pyridin-4-yl)-imidazoles are known to be potent p38 mitogen-activated protein (MAP) kinase inhibitors (Laufer et al. 2004, Ziegler et al. 2009).

The title compound, N-{4-[4-(4-fluorophenyl)-1-(2-methoxyethyl)-2-(methylsulfanyl)-1H-imidazol-5-yl]pyridin-2-yl}-2-methyl-3-phenylpropionamide (I), was prepared in the course of our studies on 5-(2-acylpyridin-4-yl)-4-(4-fluorophenyl)-1-(2-methoxyethyl)-2-(methylsulfanyl)-1H-imidazoles as potent p38 MAP kinase inhibitors (Ziegler et al. 2009).

As might be expected the 4-fluorophenyl, the pyridine ring, the phenyl as well as the imidazole ring are planar (Figure 1). The imidazole ring makes dihedral angles of 11.85 (7)°, 73.33 (7)° and 22.83 (8)° to the 4-fluorophenyl ring (C30–C36), the pyridine ring and the phenyl ring (C13–C18), respectively. The 4-fluorophenyl ring (C30–C36) makes dihedral angles of 77.91 (7)° and 26.93 (8)° to the pyridine and the phenyl ring (C13–C18). The phenyl ring (C13—C18) and the pyridine ring are nearly perpendicular to one another with a dihedral angle of 86.47 (9)°. The amide function forms an N–H···O hydrogen bond to O9 of a symmetry related molecule resulting in an infinite chain of alternated enantiomers along the c axis of the unit cell (Figure 2). The length of the hydrogen bond is 2.21Å (Table 1).

Experimental

Under an argon atmosphere, N,N'-carbonyldiimidazole (0.45 g, 2.8 mmol, 1 eq.) was added to a stirred solution of the 2-methyl-3-phenylpropionic acid (0.46 g, 2.8 mmol, 1.0 eq.) in 50 ml dry tetrahydrofuran at room temperature. When the effervescence stopped, 4-[5-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-ylamine (1.0 g, 2.8 mmol, 1 eq.) was added and the reaction was allowed to proceed at room temperature for three hours until the reaction was completed. After removing the solvent in vacuo ethylacetate was added to the residue. The organic layer was washed with water, dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified via column chromatography (RP-18, acetonitrile: water = 6:4) yielding the title compound as a lightly brown solid (130 mg, 0.26 mmol, 9%). Crystals of compound I suitable for X-ray diffraction were obtained by slow evaporation at 298 K of a solution in n-hexane/diethyl ether.