4-(4-Fluoro­phen­yl)-2-methyl-3-(1-oxy-4-pyridyl)isoxazol-5(2H)-one

Simona Margutti; Dieter Schollmeyer; Stefan Laufer

doi:10.1107/S1600536807066500

. 2008 Jan 23;64(Pt 2):o504. doi: 10.1107/S1600536807066500

4-(4-Fluorophenyl)-2-methyl-3-(1-oxy-4-pyridyl)isoxazol-5(2H)-one

Simona Margutti ^a, Dieter Schollmeyer ^b, Stefan Laufer ^a,^*

PMCID: PMC2960186 PMID: 21201524

Abstract

The crystal structure of the title compound, C₁₅H₁₁FN₂O₃, was determined as part of a study on the biological activity of isoxazolone derivatives as p38 mitogen-activated protein kinase (MAPK) inhibitors. The dihedral angles between rings are isoxazole/benzene = 55.0 (3)°, isoxazole/pyridine = 33.8 (2)° and benzene/pyridine = 58.1 (2)°.

Related literature

Isoxazolones as potent inhibitors of p38 MAP kinases were first described by Laughlin et al. (2005 ▶). For related literature, see: Adams et al. (1998 ▶); Clark et al. (2002 ▶); De Laszlo et al. (1998 ▶); Foster et al. (2000 ▶); Laufer & Wagner (2002 ▶); Laufer et al. (2006 ▶); Ohkawa et al. (2001 ▶); Revesz et al. (2000 ▶); Wang et al. (1998 ▶).

Experimental

Crystal data

C₁₅H₁₁FN₂O₃
M _r = 286.26
Tetragonal,
a = 10.0828 (6) Å
c = 25.257 (5) Å
V = 2567.6 (6) Å³
Z = 8
Cu Kα radiation
μ = 0.97 mm⁻¹
T = 193 (2) K
0.40 × 0.20 × 0.10 mm

Data collection

Enraf–Nonius CAD-4 diffractometer
Absorption correction: multi-scan (MULABS; Blessing, 1995 ▶) T _min = 0.60, T _max = 0.88
5114 measured reflections
1488 independent reflections
1129 reflections with I > 2σ(I)
R _int = 0.081
3 standard reflections frequency: 60 min intensity decay: 5%

Refinement

R[F ² > 2σ(F ²)] = 0.068
wR(F ²) = 0.192
S = 1.00
1488 reflections
191 parameters
H-atom parameters constrained
Δρ_max = 0.45 e Å⁻³
Δρ_min = −0.34 e Å⁻³

Data collection: CAD-4 Software (Enraf–Nonius, 1989 ▶); cell refinement: CAD-4 Software; data reduction: CORINC (Dräger & Gattow, 1971 ▶); program(s) used to solve structure: SIR92 (Altomare et al., 1994 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997 ▶); molecular graphics: PLATON (Spek, 2003 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536807066500/cf2171sup1.cif

e-64-0o504-sup1.cif^{(17.6KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536807066500/cf2171Isup2.hkl

e-64-0o504-Isup2.hkl^{(73.5KB, hkl)}

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

Acknowledgments

The authors thank the EU–Craft Program, Project Macrocept (FP6) for funding.

supplementary crystallographic information

Comment

Compound (II) (Fig. 2) was prepared in the course of our study on isoxazolones derivatives bearing the typical vicinal 4-pyridyl and 4-fluorophenyl pharmacophores of MAP Kinase inhibitors. Isoxazolones are described in the literature as inhibitors for p38 MAP Kinase (Laughlin et al., 2005; Clark et al., 2002).

The prototypical pyridinylimidazole SB 203580 is one of the best studied p38 inhibitors reported until now. Figure 1 shows the most important interactions between the ATP binding sites of p38 kinase and the imidazole inhibitor SB203580 (Wang et al., 1998). The 4-fluorophenyl ring of SB203580 occupies a hydrophobic back pocket, enhancing selectivity. Vicinal to this interaction site, the 4-pyridinyl ring forms a hydrogen bond from the backbone NH group of Met 109 of p38 MAP Kinase (Fig. 1).

However, certain liver toxicities, such as increased liver size and increased cytochrome P450 induction, have been reported (Foster et al., 2000; Adams et al., 1998). In light of this potential toxicity and the risks associated with developing human drugs, a continuing need exists for potent new small-molecule inhibitors of cytokine production with improved pharmacokinetic and safety profiles.

Several research groups have undertaken studies in which the imidazole ring was replaced by other 5- or 6- membered heterocycles (Laufer & Wagner, 2002; De Laszlo et al., 1998; Laufer et al., 2006; Revesz et al., 2000; Ohkawa et al., 2001). Replacement of the core heterocycle represents a strategy to dissect inhibition of p38 from interferences with cytochrome P450 (CYP450).

Accordingly, and based on the research published by Laughlin et al. (2005), we plan to prepare derivatives of isoxazolones in order to obtain more accurate and comparable information about this class of compounds as p38 MAP Kinase inhibitors in terms of biological activity.

The data presented here show the isoxazolone system is almost planar (Fig. 2). It is oriented at a dihedral angle of 55.0 (3)° to the fluorophenyl ring and 33.8 (2)° to the oxy-pyridine system. There are no significant intermolecular interactions.

Experimental

For the synthesis of 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-N-oxide-propionic acid ethyl ester (see Fig. 3), to a suspension of 10 g (72 mmol) of isonicotinic acid N-oxide in 15 ml of DMF, 19.7 g (121 mmol) of CDI were added. The reaction mixture was stirred at 298 K for 1 h. The limpid solution was then cooled at 273 K and 13.3 g (72 mmol) of (4-fluorophenyl)acetic acid ethyl ester and 4.1 g (168 mmol) of NaH were added. The reaction mixture was stirred at 273 K for 15 min, then the temperature was raised to 298 K and kept under vigorous stirring for 4 h. The reaction mixture was then poured into water/ice, the pH adjusted to 6, and the solution extracted with ethyl acetate. The combined organic layers were then collected, dried over Na₂SO₄ and concentrated under vacuum, affording an oil that was chromatographed over SiO₂ using acetone as eluent, yielding 80% of 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-N-oxide-propionic acid ethyl ester.

For the synthesis of (I), a suspension of 1.0 g (3.3 mmol) of 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-N-oxide-propionic acid ethyl ester and 0.3 g (4.0 mmol) of hydroxylamine hydrochloride in 0.5 ml of H₂O was warmed to 353 K. 3 ml of MeOH were added and the resulting solution refluxed for 4 h. The reaction mixture was then cooled to 298 K and stored at 277 K overnight, whereupon a yellow solid precipitated, yielding 83% of (I).

For the synthesis of (II), a suspension of 0.71 g (2.6 mmol) of (I) in 1 ml of DMF was added to 0.620 ml (4.5 mmol) of Et₃N and refluxed for 2 h. The reaction mixture was then cooled to 298 K, added to 0.231 ml (3.75 mmol) of iodomethane and stirred at 298 K for 2 h. Ethyl acetate was then added and the resulting precipitate separated by filtration and then crystalized from MeOH, yielding 40% of (II).