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Acta Crystallogr Sect E Struct Rep Online. 2008 February 1; 64(Pt 2): o504.
Published online 2008 January 23. doi:  10.1107/S1600536807066500
PMCID: PMC2960186

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

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 [triangle]). For related literature, see: Adams et al. (1998 [triangle]); Clark et al. (2002 [triangle]); De Laszlo et al. (1998 [triangle]); Foster et al. (2000 [triangle]); Laufer & Wagner (2002 [triangle]); Laufer et al. (2006 [triangle]); Ohkawa et al. (2001 [triangle]); Revesz et al. (2000 [triangle]); Wang et al. (1998 [triangle]).

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Object name is e-64-0o504-scheme1.jpg

Experimental

Crystal data

  • C15H11FN2O3
  • M r = 286.26
  • Tetragonal, An external file that holds a picture, illustration, etc.
Object name is e-64-0o504-efi1.jpg
  • 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 [triangle]) 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
  • Δρmax = 0.45 e Å−3
  • Δρmin = −0.34 e Å−3

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

Supplementary Material

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

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

Refinement

Hydrogen atoms attached to carbon were placed at calculated positions with C—H = 0.95 Å (aromatic) or 0.99–1.00 Å (sp3 C). All H atoms were refined with Ueq = 1.2 or 1.5 times Ueq of the parent atom).

Figures

Fig. 1.
Schematic drawing of important interactions between the prototypical pyridin-4-yl imidazole inhibitor SB 203580 and the ATP binding site of p38.
Fig. 2.
PLATON (Spek, 2003) view of (II). Displacement ellipsoids are drawn at the 50% probability level. H atoms are depicted as circles of arbitrary size.
Fig. 3.
Synthesis of (II).

Crystal data

C15H11FN2O3Z = 8
Mr = 286.26F000 = 1184
Tetragonal, P43212Dx = 1.481 Mg m3
Hall symbol: P 4nw 2abwCu Kα radiation λ = 1.54178 Å
a = 10.0828 (6) ÅCell parameters from 25 reflections
b = 10.0828 (6) Åθ = 20–32º
c = 25.257 (5) ŵ = 0.97 mm1
α = 90ºT = 193 (2) K
β = 90ºBlock, yellow
γ = 90º0.40 × 0.20 × 0.10 mm
V = 2567.6 (6) Å3

Data collection

Enraf–Nonius CAD-4 diffractometerRint = 0.081
Monochromator: graphiteθmax = 69.8º
T = 193(2) Kθmin = 4.7º
θ/2ω scansh = −12→12
Absorption correction: multi-scan(MULABS; Blessing, 1995)k = −12→12
Tmin = 0.60, Tmax = 0.88l = −23→30
5114 measured reflections3 standard reflections
1488 independent reflections every 60 min
1129 reflections with I > 2σ(I) intensity decay: 5%

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.068H-atom parameters constrained
wR(F2) = 0.192  w = 1/[σ2(Fo2) + (0.149P)2] where P = (Fo2 + 2Fc2)/3
S = 1.00(Δ/σ)max < 0.001
1488 reflectionsΔρmax = 0.45 e Å3
191 parametersΔρmin = −0.34 e Å3
Primary atom site location: structure-invariant direct methodsExtinction correction: none

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.
Refinement. Refinement of F2 against ALL reflections. Friedel Pairs merged (MERG 3 instruction). The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

xyzUiso*/Ueq
C10.4167 (4)0.0719 (4)0.3006 (2)0.0248 (11)
C20.3537 (4)0.1885 (4)0.2905 (2)0.0231 (10)
N30.2782 (4)0.1781 (4)0.24613 (17)0.0272 (10)
O40.2804 (4)0.0427 (3)0.23076 (16)0.0346 (9)
C50.3701 (5)−0.0233 (5)0.2641 (2)0.0302 (11)
C60.1515 (5)0.2379 (6)0.2342 (2)0.0366 (13)
H6A0.08060.18550.25050.055*
H6B0.13870.24030.19580.055*
H6C0.14930.32840.24830.055*
O70.3926 (4)−0.1402 (4)0.25595 (18)0.0409 (10)
C80.5231 (4)0.0446 (4)0.3400 (2)0.0262 (11)
C90.6393 (5)0.1185 (5)0.3410 (2)0.0290 (11)
H90.64990.18960.31670.035*
C100.7405 (5)0.0908 (5)0.3767 (3)0.0348 (13)
H100.81980.14150.37740.042*
C110.7207 (5)−0.0138 (5)0.4112 (2)0.0300 (12)
C120.6096 (5)−0.0891 (5)0.4118 (2)0.0315 (12)
H120.6000−0.15980.43640.038*
C130.5100 (5)−0.0603 (5)0.3757 (3)0.0313 (12)
H130.4318−0.11280.37520.038*
F140.8198 (3)−0.0417 (3)0.44649 (16)0.0477 (10)
C150.3631 (4)0.3142 (4)0.31988 (19)0.0198 (10)
C160.3580 (4)0.4384 (4)0.2958 (2)0.0253 (11)
H160.34480.44380.25860.030*
C170.3714 (5)0.5514 (5)0.3240 (2)0.0265 (11)
H170.36550.63470.30660.032*
N180.3934 (4)0.5467 (4)0.37729 (18)0.0253 (9)
C190.3954 (5)0.4264 (5)0.4021 (2)0.0270 (11)
H190.40760.42280.43940.032*
C200.3804 (4)0.3122 (4)0.3746 (2)0.0254 (10)
H200.38170.22980.39290.030*
O210.4120 (4)0.6544 (3)0.40417 (17)0.0395 (10)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C10.0148 (19)0.020 (2)0.039 (3)0.0011 (17)0.0004 (19)0.000 (2)
C20.022 (2)0.021 (2)0.027 (3)0.0009 (17)0.0007 (19)−0.0004 (19)
N30.033 (2)0.0243 (18)0.025 (2)0.0040 (17)−0.0053 (18)−0.0087 (17)
O40.0338 (19)0.0286 (17)0.041 (2)0.0032 (15)−0.0063 (17)−0.0105 (16)
C50.025 (2)0.022 (2)0.043 (3)0.0028 (19)0.004 (2)−0.004 (2)
C60.036 (3)0.041 (3)0.033 (3)0.010 (2)−0.011 (2)0.002 (2)
O70.040 (2)0.0289 (18)0.053 (3)0.0000 (15)−0.002 (2)−0.0161 (18)
C80.019 (2)0.017 (2)0.042 (3)0.0062 (17)−0.002 (2)−0.005 (2)
C90.026 (2)0.018 (2)0.042 (3)0.0040 (17)−0.002 (2)−0.002 (2)
C100.024 (2)0.028 (2)0.053 (4)0.002 (2)−0.004 (2)−0.013 (2)
C110.025 (2)0.024 (2)0.041 (3)0.0109 (19)−0.010 (2)−0.012 (2)
C120.035 (3)0.023 (2)0.037 (3)0.007 (2)−0.002 (2)0.001 (2)
C130.022 (2)0.023 (2)0.048 (3)0.001 (2)−0.001 (2)0.000 (2)
F140.0400 (17)0.0448 (18)0.058 (2)0.0099 (15)−0.0234 (17)−0.0034 (17)
C150.0172 (19)0.0174 (19)0.025 (3)0.0021 (15)−0.0003 (18)−0.0017 (18)
C160.025 (2)0.022 (2)0.028 (3)0.0062 (18)0.000 (2)0.003 (2)
C170.029 (2)0.020 (2)0.030 (3)0.0014 (18)0.003 (2)0.006 (2)
N180.0232 (19)0.0212 (19)0.031 (3)0.0019 (15)0.0016 (17)−0.0046 (18)
C190.030 (2)0.025 (2)0.026 (3)0.0051 (19)−0.002 (2)0.000 (2)
C200.025 (2)0.018 (2)0.033 (3)0.0015 (18)−0.002 (2)0.0027 (19)
O210.049 (2)0.0213 (17)0.048 (3)−0.0046 (15)−0.0001 (19)−0.0107 (17)

Geometric parameters (Å, °)

C1—C21.360 (6)C10—H100.950
C1—C51.412 (7)C11—C121.354 (7)
C1—C81.489 (7)C11—F141.368 (6)
C2—N31.359 (6)C12—C131.388 (7)
C2—C151.472 (6)C12—H120.950
N3—O41.419 (5)C13—H130.950
N3—C61.444 (6)C15—C161.393 (6)
O4—C51.403 (6)C15—C201.394 (7)
C5—O71.218 (6)C16—C171.350 (7)
C6—H6A0.980C16—H160.950
C6—H6B0.980C17—N181.364 (7)
C6—H6C0.980C17—H170.950
C8—C91.389 (6)N18—O211.293 (5)
C8—C131.395 (7)N18—C191.366 (6)
C9—C101.391 (8)C19—C201.352 (7)
C9—H90.950C19—H190.950
C10—C111.382 (8)C20—H200.950
C2—C1—C5108.0 (4)C12—C11—F14118.8 (5)
C2—C1—C8128.4 (4)C12—C11—C10123.7 (5)
C5—C1—C8123.5 (4)F14—C11—C10117.5 (5)
N3—C2—C1110.5 (4)C11—C12—C13118.3 (5)
N3—C2—C15121.2 (4)C11—C12—H12120.9
C1—C2—C15128.3 (5)C13—C12—H12120.9
C2—N3—O4106.9 (4)C12—C13—C8121.0 (5)
C2—N3—C6129.5 (4)C12—C13—H13119.5
O4—N3—C6111.0 (4)C8—C13—H13119.5
C5—O4—N3107.6 (4)C16—C15—C20116.8 (4)
O7—C5—O4118.6 (5)C16—C15—C2123.5 (4)
O7—C5—C1134.9 (5)C20—C15—C2119.7 (4)
O4—C5—C1106.5 (4)C17—C16—C15121.6 (5)
N3—C6—H6A109.5C17—C16—H16119.2
N3—C6—H6B109.5C15—C16—H16119.2
H6A—C6—H6B109.5C16—C17—N18120.5 (4)
N3—C6—H6C109.5C16—C17—H17119.7
H6A—C6—H6C109.5N18—C17—H17119.7
H6B—C6—H6C109.5O21—N18—C17120.8 (4)
C9—C8—C13118.4 (5)O21—N18—C19120.2 (4)
C9—C8—C1121.4 (5)C17—N18—C19119.0 (4)
C13—C8—C1120.2 (4)C20—C19—N18121.3 (5)
C8—C9—C10121.5 (5)C20—C19—H19119.4
C8—C9—H9119.2N18—C19—H19119.4
C10—C9—H9119.2C19—C20—C15120.7 (4)
C11—C10—C9117.2 (5)C19—C20—H20119.6
C11—C10—H10121.4C15—C20—H20119.6
C9—C10—H10121.4
C5—C1—C2—N3−5.8 (6)C8—C9—C10—C110.2 (8)
C8—C1—C2—N3170.2 (5)C9—C10—C11—C120.0 (8)
C5—C1—C2—C15176.1 (4)C9—C10—C11—F14180.0 (4)
C8—C1—C2—C15−7.9 (8)F14—C11—C12—C13−179.7 (5)
C1—C2—N3—O47.4 (5)C10—C11—C12—C130.3 (8)
C15—C2—N3—O4−174.4 (4)C11—C12—C13—C8−0.9 (8)
C1—C2—N3—C6144.7 (5)C9—C8—C13—C121.1 (8)
C15—C2—N3—C6−37.1 (7)C1—C8—C13—C12178.5 (5)
C2—N3—O4—C5−6.0 (5)N3—C2—C15—C16−33.2 (7)
C6—N3—O4—C5−151.9 (4)C1—C2—C15—C16144.7 (5)
N3—O4—C5—O7−176.3 (5)N3—C2—C15—C20148.1 (5)
N3—O4—C5—C12.5 (5)C1—C2—C15—C20−34.1 (7)
C2—C1—C5—O7−179.6 (6)C20—C15—C16—C171.0 (6)
C8—C1—C5—O74.1 (10)C2—C15—C16—C17−177.8 (5)
C2—C1—C5—O41.9 (6)C15—C16—C17—N181.5 (7)
C8—C1—C5—O4−174.4 (4)C16—C17—N18—O21177.0 (4)
C2—C1—C8—C9−54.3 (8)C16—C17—N18—C19−3.1 (7)
C5—C1—C8—C9121.2 (5)O21—N18—C19—C20−177.9 (4)
C2—C1—C8—C13128.4 (6)C17—N18—C19—C202.2 (7)
C5—C1—C8—C13−56.1 (7)N18—C19—C20—C150.3 (7)
C13—C8—C9—C10−0.7 (8)C16—C15—C20—C19−1.9 (7)
C1—C8—C9—C10−178.1 (5)C2—C15—C20—C19176.9 (4)

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CF2171).

References

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