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

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)°.

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.
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)°t o 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 Na 2 SO 4 and concentrated under vacuum, affording an oil that was chromatographed over SiO 2 using acetone as eluent, yielding 80% of 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-N-oxide-propionic acid ethyl ester.

supplementary materials sup-2
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 H 2 O 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 Et 3 N 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).

Refinement
Hydrogen atoms attached to carbon were placed at calculated positions with C-H = 0.95 Å (aromatic) or 0.99-1.00 Å (sp 3 C). All H atoms were refined with U eq = 1.2 or 1.5 times U eq of the parent atom). Fig. 1. Schematic drawing of important interactions between the prototypical pyridin-4-yl imidazole inhibitor SB 203580 and the ATP binding site of p38.