organic papers
Acta Cryst.(2007). E63, o1423–o1425 doi:10.1107/S1600536807007933 Abadlehet al. C
17H15FN2O2
o1423
Acta Crystallographica Section EStructure Reports Online
ISSN 1600-5368
4-[5-(4-Fluorophenyl)-3-isopropylisoxazol-4-yl]-pyridin-2(1
H
)-one
Mohammed Abadleh,aChristian Peifer,aKatrin Kinkel,aDieter Schollmeyerb and Stefan Laufera*
aPharmazeutisches Institut, Auf der Morgenstelle
8, Universita¨t Tu¨bingen, D-72076 Tu¨bingen, Germany, andb
Institut fu¨r Organische Chemie der Universita¨t Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany
Correspondence e-mail: mohd.abadleh@uni-tuebingen.de
Key indicators
Single-crystal X-ray study
T= 193 K
Mean(C–C) = 0.002 A˚
Rfactor = 0.042
wRfactor = 0.114
Data-to-parameter ratio = 11.2
For details of how these key indicators were automatically derived from the article, see http://journals.iucr.org/e.
Received 1 February 2007 Accepted 16 February 2007
#2007 International Union of Crystallography
All rights reserved
The crystal structure of the title compound, C17H15FN2O2, was
determined as part of a study of the biological activity of pyridine-substituted isoxazole derivatives as mitogen-activ-ated protein kinase (MAPK) inhibitors. In the crystal structure of the title compound, the compound exists in the lactam and not in the tautomeric pyridin-2-ol form. As the aromatic pyridine nitrogen is considered to be important for accepting a hydrogen bond from p38MAPK, the structure of the lactam unit is correlated with the loss of biological activity of the title compound in the p38MAPK assay. In the crystal structure, the lactam is involved in hydrogen bonds, forming chains along thebaxis.
Comment
Compound (II) (Fig. 1) was prepared in the course of our studies on isoxazole derivatives bearing the typical vicinal pyridine-4-fluorophenyl pharmacophore of MAPK inhibitors. These compounds are supposed to bind in the ATP-binding site of p38MAPK and have been shown to be ATP competi-tive; for example 4-[5-(4-fluorophenyl)-3-isopropylisoxazol-4-yl]pyridine, (III) (Fig. 2), has an IC50of 2.2mMfor p38alpha
(Peifer, Abadlehet al., 2006).
silico’ due to the inverted situation. In fact, (II) was found to be inactive in the p38 alpha MAPK assay, indicating the compound to exist in solution under the assay conditions with high probability in the lactam form and hence not capable of interacting with the protein. The same condition of the lactam
form was also confirmed by the X-ray crystallographic analysis of crystals of (II), showing the compound not to have the desired hydroxypyridine but rather the biologically inactive lactam structure. In the crystal structure, the lactam is involved in hydrogen bonds, forming chains along thebaxis (Fig. 3).
Experimental
Compound (II) was obtained by refluxing 1.0 mmol 2-fluoro-4-[5-(4-fluorophenyl)-3-isopropylisoxazol-4-yl]pyridine, (I), with 10 ml of 10% HCl in 10 ml THF for 15 h. After cooling to 195 K, the target compound was precipitated by treating the mixture with ammonia 25% to render it basic, giving (II) (yield 84%) as a white powder. Crystals of (II) suitable for X-ray analysis were obtained by slow evaporation at 278 K of an ethanol–dichloromethane (3:7) solution.
Crystal data
C17H15FN2O2
Mr= 298.31
Monoclinic,P21=c
a= 14.6895 (7) A˚ b= 7.3663 (2) A˚ c= 14.2056 (6) A˚
= 100.266 (5)
V= 1512.54 (10) A˚3
Z= 4
CuKradiation
= 0.79 mm1
T= 193 (2) K 0.260.260.19 mm
Data collection
Enraf–Nonius CAD-4 diffractometer
Absorption correction: none 2980 measured reflections 2853 independent reflections
2644 reflections withI> 2(I) Rint= 0.045
3 standard reflections frequency: 60 min intensity decay: 5%
Refinement
R[F2> 2(F2)] = 0.042 wR(F2) = 0.114
S= 1.07 2853 reflections
255 parameters
All H-atom parameters refined
max= 0.22 e A˚
3
min=0.30 e A˚
[image:2.610.47.296.70.244.2]3
Table 1
Hydrogen-bond geometry (A˚ ,).
D—H A D—H H A D A D—H A
N18—H18 O21i
0.91 (2) 1.81 (2) 2.7027 (15) 168.2 (19)
Symmetry code: (i)x;y1 2;zþ
1 2.
All H atoms were located from a difference Fourier map and refined freely [range of refined C—H distances = 0.95 (2)–1.01 (3), N—H = 0.91 (2) A˚ ].
Data collection: CAD-4 Software (Enraf–Nonius, 1989); cell refinement: CAD-4 Software; data reduction: CORINC (Dra¨ger & Gattow, 1971); program(s) used to solve structure:SIR92(Altomare
et al., 1994); program(s) used to refine structure:SHELXL97 (Shel-drick, 1997); molecular graphics: PLATON (Spek, 2003) and
ORTEPII (Johnson, 1976); software used to prepare material for publication:SHELXL97 andPLATON.
The authors thank the DAAD for funding.
References
Altomare, A., Cascarano, G., Giacovazzo, C., Guagliardi, A., Burla, M. C., Polidori, G. & Camalli, M. (1994).J. Appl. Cryst.27, 435.
Dra¨ger, M. & Gattow, G. (1971).Acta Chem. Scand.25, 761–762.
organic papers
o1424
Abadlehet al. C17H15FN2O2 Acta Cryst.(2007). E63, o1423–o1425
Figure 1
[image:2.610.44.297.309.411.2]The molecular structure of (II). Displacement ellipsoids are drawn at the 50% probability level and H atoms are depicted as circles of arbitrary radius.
Figure 2
Modeled binding mode of (III) (left) and (IIa) (right) in the ATP-binding pocket of p38alpha. Key residues and the key protein–ligand hydrogen-bond interactions (dashed lines) are shown.
Figure 3
[image:2.610.71.274.468.645.2]Enraf–Nonius (1989).CAD-4 Software. Version 5.0. Enraf–Nonius, Delft, The Netherlands.
Johnson, C. K. (1976).ORTEPII. Report ORNL-5138. Oak Ridge National Laboratory, Tennessee, USA.
Laufer, S., Thuma, S., Peifer, C., Greim, C., Herweh, Y., Albrecht, A. & Dehner, F. (2005).Anal. Biochem.344, 135–137.
Peifer, C., Abadleh, M., Schollmeyer, D. & Laufer, S. (2006).Acta Cryst.E62, o3647–o3649.
Peifer, C., Wagner, G. & Laufer, S. (2006).Curr. Top. Med. Chem.6, 113– 149.
Sheldrick, G. M. (1997).SHELXL97. University of Go¨ttingen, Germany. Spek, A. L. (2003).J. Appl. Cryst.36, 7–13.
organic papers
Acta Cryst.(2007). E63, o1423–o1425 Abadlehet al. C
supporting information
sup-1 Acta Cryst. (2007). E63, o1423–o1425
supporting information
Acta Cryst. (2007). E63, o1423–o1425 [https://doi.org/10.1107/S1600536807007933]
4-[5-(4-Fluorophenyl)-3-isopropylisoxazol-4-yl]pyridin-2(1
H
)-one
Mohammed Abadleh, Christian Peifer, Katrin Kinkel, Dieter Schollmeyer and Stefan Laufer
(II)
Crystal data
C17H15FN2O2 Mr = 298.31
Monoclinic, P21/c
Hall symbol: -P 2ybc
a = 14.6895 (7) Å
b = 7.3663 (2) Å
c = 14.2056 (6) Å
β = 100.266 (5)°
V = 1512.54 (10) Å3
Z = 4
F(000) = 624
Dx = 1.310 Mg m−3
Melting point: 210 K
Cu Kα radiation, λ = 1.54178 Å Cell parameters from 25 reflections
θ = 60–69°
µ = 0.79 mm−1 T = 193 K Block, colourless 0.26 × 0.26 × 0.19 mm
Data collection
Enraf–Nonius CAD-4 diffractometer
Radiation source: rotating anode Graphite monochromator
ω/2θ scans
2980 measured reflections 2853 independent reflections 2644 reflections with I > 2σ(I)
Rint = 0.045
θmax = 69.9°, θmin = 3.1° h = −17→17
k = −8→0
l = −17→0
3 standard reflections every 60 min intensity decay: 5%
Refinement
Refinement on F2
Least-squares matrix: full
R[F2 > 2σ(F2)] = 0.042 wR(F2) = 0.114 S = 1.07 2853 reflections 255 parameters 0 restraints
Primary atom site location: structure-invariant direct methods
Secondary atom site location: difference Fourier map
Hydrogen site location: difference Fourier map All H-atom parameters refined
w = 1/[σ2(F
o2) + (0.0613P)2 + 0.5807P]
where P = (Fo2 + 2Fc2)/3
(Δ/σ)max < 0.001
Δρmax = 0.22 e Å−3
Δρmin = −0.30 e Å−3
Special details
supporting information
sup-2 Acta Cryst. (2007). E63, o1423–o1425
Refinement. Refinement of F2 against ALL reflections. 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)
x y z Uiso*/Ueq
F1 0.64605 (7) 0.02486 (16) 0.23995 (8) 0.0543 (3) N2 0.31295 (9) 0.44516 (19) 0.52676 (10) 0.0382 (3) O3 0.39003 (7) 0.38647 (15) 0.48846 (7) 0.0359 (3) C1 0.24428 (10) 0.3405 (2) 0.48876 (10) 0.0311 (3) C4 0.36422 (9) 0.24555 (19) 0.42853 (9) 0.0275 (3)
H4 0.3535 (12) 0.107 (2) 0.2533 (12) 0.032 (4)*
C5 0.27276 (9) 0.20878 (19) 0.42549 (9) 0.0264 (3) C6 0.15133 (12) 0.3637 (3) 0.51868 (12) 0.0448 (4)
H6 0.1045 (14) 0.368 (3) 0.4602 (15) 0.049 (5)*
C7 0.14373 (16) 0.5443 (3) 0.56895 (15) 0.0558 (5)
H7A 0.1907 (18) 0.549 (3) 0.6281 (19) 0.074 (4)*
H7B 0.0801 (18) 0.554 (3) 0.5853 (18) 0.074 (4)*
H7C 0.1565 (17) 0.650 (4) 0.5279 (19) 0.074 (4)*
C8 0.1332 (2) 0.2048 (4) 0.5807 (2) 0.0750 (8)
H8A 0.1338 (19) 0.085 (4) 0.547 (2) 0.087 (5)*
H8B 0.179 (2) 0.206 (4) 0.642 (2) 0.087 (5)*
H8C 0.075 (2) 0.223 (4) 0.600 (2) 0.087 (5)*
C9 0.43702 (9) 0.17557 (19) 0.38017 (10) 0.0278 (3)
H9 0.6642 (13) 0.144 (3) 0.4073 (13) 0.042 (5)*
C10 0.52927 (10) 0.1855 (2) 0.42614 (11) 0.0339 (3)
H10 0.5436 (13) 0.237 (3) 0.4911 (14) 0.042 (5)*
C11 0.59993 (10) 0.1327 (2) 0.37927 (12) 0.0387 (4) C12 0.57674 (11) 0.0726 (2) 0.28668 (12) 0.0370 (4) C13 0.48685 (11) 0.0602 (2) 0.23860 (12) 0.0368 (4)
H13 0.4719 (13) 0.017 (3) 0.1747 (15) 0.043 (5)*
C14 0.41666 (10) 0.1122 (2) 0.28629 (11) 0.0316 (3) C15 0.21636 (9) 0.06009 (18) 0.37490 (9) 0.0248 (3) C16 0.12750 (9) 0.09107 (19) 0.32920 (10) 0.0258 (3)
H16 0.1006 (11) 0.210 (2) 0.3234 (11) 0.029 (4)*
supporting information
sup-3 Acta Cryst. (2007). E63, o1423–o1425
Atomic displacement parameters (Å2)
U11 U22 U33 U12 U13 U23
F1 0.0390 (6) 0.0582 (7) 0.0718 (7) −0.0059 (5) 0.0264 (5) −0.0186 (5) N2 0.0336 (7) 0.0441 (8) 0.0369 (7) −0.0031 (6) 0.0062 (5) −0.0126 (6) O3 0.0288 (5) 0.0399 (6) 0.0380 (6) −0.0072 (4) 0.0037 (4) −0.0124 (5) C1 0.0305 (7) 0.0361 (8) 0.0263 (7) −0.0015 (6) 0.0037 (5) −0.0021 (6) C4 0.0269 (7) 0.0279 (7) 0.0256 (6) −0.0033 (5) −0.0011 (5) −0.0006 (5) C5 0.0249 (6) 0.0288 (7) 0.0243 (6) −0.0019 (5) 0.0011 (5) 0.0021 (5) C6 0.0346 (8) 0.0641 (12) 0.0378 (8) −0.0030 (8) 0.0122 (7) −0.0136 (8) C7 0.0536 (11) 0.0697 (14) 0.0480 (11) 0.0084 (10) 0.0194 (9) −0.0154 (10) C8 0.0867 (18) 0.0764 (17) 0.0763 (16) −0.0269 (14) 0.0533 (14) −0.0133 (13) C9 0.0247 (7) 0.0260 (7) 0.0317 (7) −0.0032 (5) 0.0026 (5) 0.0018 (5) C10 0.0277 (7) 0.0382 (8) 0.0341 (8) −0.0030 (6) 0.0008 (6) −0.0009 (6) C11 0.0239 (7) 0.0415 (9) 0.0493 (9) −0.0024 (6) 0.0032 (6) −0.0007 (7) C12 0.0317 (8) 0.0314 (8) 0.0511 (9) −0.0024 (6) 0.0160 (7) −0.0041 (7) C13 0.0389 (8) 0.0342 (8) 0.0376 (8) −0.0044 (6) 0.0081 (6) −0.0077 (6) C14 0.0271 (7) 0.0308 (7) 0.0354 (7) −0.0036 (6) 0.0014 (6) −0.0030 (6) C15 0.0237 (6) 0.0272 (7) 0.0233 (6) −0.0032 (5) 0.0038 (5) 0.0017 (5) C16 0.0239 (6) 0.0236 (7) 0.0293 (7) 0.0005 (5) 0.0031 (5) 0.0023 (5) C17 0.0232 (6) 0.0245 (7) 0.0281 (6) −0.0002 (5) 0.0034 (5) 0.0025 (5) N18 0.0231 (6) 0.0223 (6) 0.0322 (6) −0.0021 (4) 0.0020 (4) 0.0013 (5) C19 0.0256 (7) 0.0256 (7) 0.0358 (7) 0.0033 (5) 0.0034 (5) 0.0035 (6) C20 0.0220 (6) 0.0311 (7) 0.0341 (7) 0.0014 (5) −0.0009 (5) 0.0033 (6) O21 0.0224 (5) 0.0255 (5) 0.0486 (6) 0.0000 (4) −0.0052 (4) −0.0001 (4)
Geometric parameters (Å, º)
F1—C12 1.3570 (18) C10—C11 1.385 (2)
N2—C1 1.307 (2) C10—H10 0.984 (19)
N2—O3 1.4087 (16) C11—C12 1.372 (2)
O3—C4 1.3532 (17) C11—H9 0.960 (19)
C1—C5 1.435 (2) C12—C13 1.377 (2)
C1—C6 1.510 (2) C13—C14 1.385 (2)
C4—C5 1.3637 (19) C13—H13 0.95 (2)
C4—C9 1.464 (2) C14—H4 0.963 (17)
C5—C15 1.4799 (18) C15—C16 1.3695 (18)
C6—C8 1.517 (3) C15—C20 1.419 (2)
C6—C7 1.523 (3) C16—C17 1.4288 (19)
C6—H6 0.98 (2) C16—H16 0.959 (18)
C7—H7A 0.99 (3) C17—O21 1.2556 (17)
C7—H7B 1.00 (3) C17—N18 1.3670 (18)
C7—H7C 1.01 (3) N18—C19 1.3573 (18)
C8—H8A 1.00 (3) N18—H18 0.91 (2)
C8—H8B 1.01 (3) C19—C20 1.355 (2)
C8—H8C 0.96 (3) C19—H19 0.976 (18)
C9—C14 1.394 (2) C20—H20 0.995 (17)
supporting information
sup-4 Acta Cryst. (2007). E63, o1423–o1425
C1—N2—O3 105.88 (12) C11—C10—H10 120.3 (11)
C4—O3—N2 108.90 (10) C9—C10—H10 119.1 (11)
N2—C1—C5 111.59 (13) C12—C11—C10 118.18 (14)
N2—C1—C6 119.12 (13) C12—C11—H9 119.0 (11)
C5—C1—C6 129.21 (13) C10—C11—H9 122.7 (11)
O3—C4—C5 109.65 (12) F1—C12—C11 118.22 (14)
O3—C4—C9 114.78 (12) F1—C12—C13 118.49 (14)
C5—C4—C9 135.50 (13) C11—C12—C13 123.29 (14)
C4—C5—C1 103.97 (12) C12—C13—C14 118.09 (14)
C4—C5—C15 128.71 (13) C12—C13—H13 122.3 (12)
C1—C5—C15 127.18 (12) C14—C13—H13 119.6 (12)
C1—C6—C8 109.70 (17) C13—C14—C9 120.60 (13)
C1—C6—C7 112.11 (15) C13—C14—H4 119.2 (10)
C8—C6—C7 111.50 (17) C9—C14—H4 120.2 (10)
C1—C6—H6 107.3 (12) C16—C15—C20 119.19 (12)
C8—C6—H6 110.4 (12) C16—C15—C5 120.71 (12)
C7—C6—H6 105.6 (12) C20—C15—C5 120.04 (12)
C6—C7—H7A 109.5 (15) C15—C16—C17 121.43 (12)
C6—C7—H7B 108.6 (15) C15—C16—H16 122.5 (10)
H7A—C7—H7B 110 (2) C17—C16—H16 116.1 (10)
C6—C7—H7C 111.5 (15) O21—C17—N18 119.06 (12)
H7A—C7—H7C 107 (2) O21—C17—C16 124.95 (12)
H7B—C7—H7C 111 (2) N18—C17—C16 115.99 (12)
C6—C8—H8A 112.5 (17) C19—N18—C17 123.29 (12)
C6—C8—H8B 109.8 (17) C19—N18—H18 118.0 (13)
H8A—C8—H8B 111 (2) C17—N18—H18 118.6 (13)
C6—C8—H8C 108.7 (18) C20—C19—N18 121.07 (13)
H8A—C8—H8C 110 (2) C20—C19—H19 122.8 (9)
H8B—C8—H8C 104 (2) N18—C19—H19 116.1 (9)
C14—C9—C10 119.30 (13) C19—C20—C15 118.92 (12)
C14—C9—C4 121.11 (12) C19—C20—H20 118.4 (10)
C10—C9—C4 119.40 (12) C15—C20—H20 122.7 (11)
C11—C10—C9 120.53 (14)
C1—N2—O3—C4 −0.48 (16) C9—C10—C11—C12 0.6 (2)
O3—N2—C1—C5 0.64 (17) C10—C11—C12—F1 178.48 (14)
O3—N2—C1—C6 177.50 (13) C10—C11—C12—C13 −0.7 (3)
N2—O3—C4—C5 0.13 (16) F1—C12—C13—C14 −178.88 (14)
N2—O3—C4—C9 177.50 (11) C11—C12—C13—C14 0.3 (2)
O3—C4—C5—C1 0.24 (15) C12—C13—C14—C9 0.2 (2)
C9—C4—C5—C1 −176.36 (15) C10—C9—C14—C13 −0.2 (2)
O3—C4—C5—C15 −175.71 (13) C4—C9—C14—C13 174.69 (14)
C9—C4—C5—C15 7.7 (3) C4—C5—C15—C16 −139.88 (15)
N2—C1—C5—C4 −0.57 (17) C1—C5—C15—C16 45.0 (2)
C6—C1—C5—C4 −177.03 (16) C4—C5—C15—C20 42.8 (2)
N2—C1—C5—C15 175.47 (13) C1—C5—C15—C20 −132.26 (15)
supporting information
sup-5 Acta Cryst. (2007). E63, o1423–o1425
N2—C1—C6—C8 −108.0 (2) C5—C15—C16—C17 −174.42 (12)
C5—C1—C6—C8 68.3 (2) C15—C16—C17—O21 179.66 (13)
N2—C1—C6—C7 16.5 (2) C15—C16—C17—N18 −0.20 (19)
C5—C1—C6—C7 −167.28 (16) O21—C17—N18—C19 177.63 (13)
O3—C4—C9—C14 −144.17 (14) C16—C17—N18—C19 −2.50 (19)
C5—C4—C9—C14 32.3 (2) C17—N18—C19—C20 2.4 (2)
O3—C4—C9—C10 30.76 (19) N18—C19—C20—C15 0.5 (2)
C5—C4—C9—C10 −152.77 (16) C16—C15—C20—C19 −3.1 (2)
C14—C9—C10—C11 −0.2 (2) C5—C15—C20—C19 174.28 (13)
C4—C9—C10—C11 −175.19 (14)
Hydrogen-bond geometry (Å, º)
D—H···A D—H H···A D···A D—H···A
N18—H18···O21i 0.91 (2) 1.81 (2) 2.7027 (15) 168.2 (19)