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Acta Crystallogr Sect E Struct Rep Online. 2008 March 1; 64(Pt 3): o563.
Published online 2008 February 6. doi:  10.1107/S1600536808003607
PMCID: PMC2960786

4-[(5R*,10bR*)-2-Methyl-1,10b-dihydro­pyrazolo[1,5-c][1,3]benzoxazin-5-yl]benzoic acid

Abstract

In the title compound, C18H16N2O3, a potential inhibitor of the cyclo­oxygenase-2 isoenzyme, the pyrazoline ring exists in a flattened envelope conformation with one C atom deviating by 0.463 Å from the mean plane of the remaining four atoms. The puckering of the central oxazine ring is more severe, with one N atom and one C atom displaced by 0.235 (6) and 0.370 (2) Å, respectively, on opposite sides of the mean plane defined by the other four atoms; the conformation is that of a half-chair. As a result, the mol­ecule as a whole is not planar. The carboxyl group is involved in an inter­molecular O—H(...)N hydrogen bond, which links the mol­ecules into centrosymmetric dimers.

Related literature

For related literature, see: Palomer et al. (2002 [triangle]); Subbaramaiah et al. (2002 [triangle]); Světlík et al. (2005 [triangle]).

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Object name is e-64-0o563-scheme1.jpg

Experimental

Crystal data

  • C18H16N2O3
  • M r = 308.33
  • Triclinic, An external file that holds a picture, illustration, etc.
Object name is e-64-0o563-efi1.jpg
  • a = 6.638 (2) Å
  • b = 10.997 (3) Å
  • c = 11.141 (3) Å
  • α = 70.78 (2)°
  • β = 80.85 (3)°
  • γ = 79.15 (2)°
  • V = 750.1 (4) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.09 mm−1
  • T = 296 (2) K
  • 0.30 × 0.20 × 0.15 mm

Data collection

  • Siemens P4 diffractometer
  • Absorption correction: none
  • 5341 measured reflections
  • 4312 independent reflections
  • 3216 reflections with I > 2σ(I)
  • R int = 0.019
  • 3 standard reflections every 97 reflections intensity decay: none

Refinement

  • R[F 2 > 2σ(F 2)] = 0.051
  • wR(F 2) = 0.152
  • S = 1.01
  • 4312 reflections
  • 210 parameters
  • H-atom parameters constrained
  • Δρmax = 0.29 e Å−3
  • Δρmin = −0.22 e Å−3

Data collection: XSCANS (Siemens, 1991 [triangle]); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: PLATON (Spek, 2003 [triangle]); software used to prepare material for publication: SHELXL97.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808003607/bi2280sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808003607/bi2280Isup2.hkl

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

Acknowledgments

This work was supported by the Grant Agency of the Slovak Republic, project Nos. 1/4298/07 and 1/4299/07.

supplementary crystallographic information

Comment

Recently, based on a pharmacophoric model of the cyclooxygenase-2 (COX-2) inhibitors (Palomer et al., 2002) as novel anticancer drugs (Subbaramaiah et al., 2002), we designed and prepared a series of 2- and 5-substituted derivatives containing the tricyclic system shown in Fig. 1. In order to recognize enzyme binding requirements for this fused heterocycle, we selected the 2-methyl-5-carboxyphenyl derivative, for single-crystal X-ray analysis. The compound was obtained as a 1:1 mixture of the cis (1a) and trans (1 b) diastereomers and we report here the structure of the cis isomer.

The molecular structure and atom-numbering scheme is shown in Fig. 2. Bond distances and angles are close to those generally expected. The atom O6 is essentially sp2-hybridized and involved in conjugation with the benzo ring as indicated by the valence angle at this atom and a non-equivalency of the O6—C5 and O6—C7 bonds.

The most interesting feature of the structure—the spatial relationship between the pharmacophoric elements (hydrophobic groups and H-bond donors/acceptors)—is given by conformation of the (partially) saturated rings. Thus, the pyrazoline ring adopts a flat-envelope conformation with atom C13 (at the flap) deviating by 0.463 Å from the mean plane of the remaining atoms. The central oxazine ring is also non-planar and is puckered in such a manner that the four atoms O6, C7, C12 and C13 are planar to within 0.006 (2) Å, while atoms N4 and C5 are displaced by 0.235 (6) and 0.370 (2) Å, respectively, on opposite sides of the plane. As a result of the relatively severe puckering of the central ring, the molecule as a whole is non-planar but consists of two approximately planar segments, C5/O6/C7–C13 and C13/C1/C2/N3/N4/C5, folded about the C5···C13 line [dihedral angle 71.7 (1)°]. The carboxyphenyl substituent is rotated by 39.8 (1)° from the mean plane of the oxazine ring.

The crystal packing is dominated by a hydrogen bond between centrosymmetrically related molecules (Table 1) which result in formation of hydrogen-bonded dimers.

Experimental

Synthesis of the title compound has been described previously (Světlík et al., 2005). In short, a solution of 4-carboxybenzaldehyde (0.30 g, 2 mmol) and pyrazoline (0.35 g, 2 mmol) in ethyl acetate (14 ml) and methanol (1 ml) was left to react at room temperature for 1 h. The resulting precipitate was filtered off and crystallized from ethanol to obtain (1a) (70% yield; m.p. 474–480 K) as colourless crystals. Crystals suitable for the X-ray analysis were obtained by slow crystallization from acetone.

Refinement

H atoms were visible in difference maps, but were placed geometrically and subsequently treated as riding atoms with distances C—H = 0.93 Å (CHarom), 0.97 (CH2) or 0.98 Å (CH) and 0.96 Å (CH3) and O—H = 0.82 Å (COOH); Uiso of the H atoms were set to 1.2 (1.5 for the methyl and carboxy H atoms) times Ueq of the parent atom.

Figures

Fig. 1.
The cis title compound (1a) and its trans isomer (1 b).
Fig. 2.
Molecular structure with displacement ellipsoids drawn at 35% probability for non-H atoms.

Crystal data

C18H16N2O3Z = 2
Mr = 308.33F000 = 324
Triclinic, P1Dx = 1.365 Mg m3
Hall symbol: -P 1Melting point: 477 K
a = 6.638 (2) ÅMo Kα radiation λ = 0.71073 Å
b = 10.997 (3) ÅCell parameters from 20 reflections
c = 11.141 (3) Åθ = 7–18º
α = 70.78 (2)ºµ = 0.09 mm1
β = 80.85 (3)ºT = 296 (2) K
γ = 79.15 (2)ºPrism, colourless
V = 750.1 (4) Å30.30 × 0.20 × 0.15 mm

Data collection

Siemens P4 diffractometerRint = 0.019
Radiation source: fine-focus sealed tubeθmax = 30.0º
Monochromator: graphiteθmin = 2.0º
T = 296(2) Kh = −1→9
ω/2θ scansk = −14→14
Absorption correction: nonel = −15→15
5341 measured reflections3 standard reflections
4312 independent reflections every 97 reflections
3216 reflections with I > 2σ(I) intensity decay: none

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.051H-atom parameters constrained
wR(F2) = 0.152  w = 1/[σ2(Fo2) + (0.0853P)2 + 0.0987P] where P = (Fo2 + 2Fc2)/3
S = 1.01(Δ/σ)max = 0.001
4312 reflectionsΔρmax = 0.29 e Å3
210 parametersΔρmin = −0.22 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. 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
C10.3065 (2)0.63515 (13)0.03856 (13)0.0364 (3)
H1A0.33690.6320−0.04850.044*
H1B0.43380.61490.07800.044*
C20.1553 (2)0.54630 (12)0.11427 (12)0.0324 (3)
N30.01255 (17)0.59887 (10)0.18002 (10)0.0314 (2)
N40.05040 (17)0.72620 (10)0.16410 (10)0.0304 (2)
C5−0.1328 (2)0.81721 (13)0.17228 (12)0.0342 (3)
H5−0.09110.89760.17360.041*
O6−0.25382 (16)0.84950 (11)0.06661 (9)0.0440 (3)
C7−0.1451 (2)0.87381 (13)−0.05137 (12)0.0371 (3)
C8−0.2589 (3)0.93655 (15)−0.15442 (14)0.0479 (4)
H8−0.39990.9630−0.14090.057*
C9−0.1623 (3)0.95933 (18)−0.27641 (16)0.0586 (5)
H9−0.23811.0010−0.34580.070*
C100.0466 (3)0.92058 (17)−0.29635 (15)0.0560 (5)
H100.11160.9354−0.37920.067*
C110.1589 (3)0.86000 (14)−0.19372 (13)0.0449 (4)
H110.30030.8352−0.20790.054*
C120.0646 (2)0.83525 (12)−0.06896 (12)0.0347 (3)
C130.1871 (2)0.76641 (13)0.04385 (12)0.0330 (3)
H130.28080.82220.05100.040*
C140.1724 (2)0.40903 (14)0.11858 (15)0.0418 (3)
H14A0.29250.35980.15890.063*
H14B0.18400.40440.03320.063*
H14C0.05170.37370.16650.063*
C15−0.2727 (2)0.76809 (12)0.29245 (12)0.0329 (3)
C16−0.2086 (2)0.75161 (17)0.40981 (14)0.0448 (4)
H16−0.08300.77520.41370.054*
C17−0.3307 (3)0.70033 (17)0.52093 (14)0.0462 (4)
H17−0.28650.68900.59950.055*
C18−0.5184 (2)0.66557 (13)0.51636 (12)0.0342 (3)
C19−0.5837 (2)0.68431 (14)0.39930 (13)0.0374 (3)
H19−0.71030.66210.39520.045*
C20−0.4614 (2)0.73595 (14)0.28820 (13)0.0381 (3)
H20−0.50700.74920.20960.046*
C21−0.6403 (2)0.60087 (13)0.63696 (13)0.0361 (3)
O7−0.5895 (2)0.58142 (13)0.74163 (10)0.0520 (3)
O8−0.80628 (16)0.56450 (11)0.61698 (10)0.0454 (3)
H8A−0.85710.51790.68450.068*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C10.0382 (7)0.0364 (7)0.0318 (6)−0.0088 (5)0.0038 (5)−0.0084 (5)
C20.0362 (6)0.0317 (6)0.0286 (6)−0.0074 (5)−0.0017 (5)−0.0077 (5)
N30.0364 (6)0.0285 (5)0.0281 (5)−0.0088 (4)−0.0002 (4)−0.0065 (4)
N40.0362 (5)0.0290 (5)0.0256 (5)−0.0104 (4)0.0017 (4)−0.0072 (4)
C50.0423 (7)0.0310 (6)0.0282 (6)−0.0086 (5)0.0016 (5)−0.0082 (5)
O60.0434 (5)0.0498 (6)0.0273 (5)−0.0018 (5)−0.0005 (4)−0.0009 (4)
C70.0514 (8)0.0290 (6)0.0273 (6)−0.0098 (6)−0.0004 (5)−0.0034 (5)
C80.0585 (9)0.0417 (8)0.0359 (7)−0.0042 (7)−0.0097 (7)−0.0015 (6)
C90.0890 (14)0.0478 (9)0.0316 (7)−0.0059 (9)−0.0143 (8)−0.0009 (6)
C100.0856 (13)0.0474 (9)0.0279 (7)−0.0115 (9)0.0037 (8)−0.0058 (6)
C110.0624 (9)0.0362 (7)0.0313 (7)−0.0126 (7)0.0087 (6)−0.0072 (5)
C120.0507 (8)0.0253 (6)0.0270 (6)−0.0126 (5)0.0018 (5)−0.0055 (4)
C130.0368 (6)0.0331 (6)0.0288 (6)−0.0134 (5)0.0036 (5)−0.0079 (5)
C140.0464 (8)0.0351 (7)0.0449 (8)−0.0074 (6)−0.0004 (6)−0.0149 (6)
C150.0403 (7)0.0287 (6)0.0276 (6)−0.0059 (5)0.0024 (5)−0.0081 (5)
C160.0447 (8)0.0600 (9)0.0340 (7)−0.0227 (7)0.0018 (6)−0.0147 (6)
C170.0524 (9)0.0628 (10)0.0270 (6)−0.0203 (7)−0.0002 (6)−0.0139 (6)
C180.0396 (7)0.0322 (6)0.0289 (6)−0.0055 (5)0.0031 (5)−0.0098 (5)
C190.0359 (7)0.0410 (7)0.0329 (6)−0.0087 (5)−0.0014 (5)−0.0076 (5)
C200.0426 (7)0.0417 (7)0.0277 (6)−0.0085 (6)−0.0042 (5)−0.0063 (5)
C210.0405 (7)0.0337 (6)0.0311 (6)−0.0055 (5)0.0038 (5)−0.0097 (5)
O70.0637 (7)0.0646 (7)0.0285 (5)−0.0204 (6)0.0024 (5)−0.0126 (5)
O80.0457 (6)0.0506 (6)0.0336 (5)−0.0165 (5)0.0032 (4)−0.0029 (4)

Geometric parameters (Å, °)

C1—C21.4934 (19)C11—C121.3915 (19)
C1—C131.5249 (19)C11—H110.930
C1—H1A0.970C12—C131.5101 (19)
C1—H1B0.970C13—H130.980
C2—N31.2730 (17)C14—H14A0.960
C2—C141.4776 (19)C14—H14B0.960
N3—N41.4178 (15)C14—H14C0.960
N4—C51.4335 (18)C15—C201.376 (2)
N4—C131.4793 (17)C15—C161.3839 (19)
C5—O61.4409 (17)C16—C171.379 (2)
C5—C151.5047 (18)C16—H160.930
C5—H50.980C17—C181.384 (2)
O6—C71.3637 (17)C17—H170.930
C7—C121.379 (2)C18—C191.3783 (19)
C7—C81.387 (2)C18—C211.4856 (19)
C8—C91.371 (2)C19—C201.380 (2)
C8—H80.930C19—H190.930
C9—C101.377 (3)C20—H200.930
C9—H90.930C21—O71.2053 (17)
C10—C111.375 (2)C21—O81.3140 (18)
C10—H100.930O8—H8A0.820
C2—C1—C13100.79 (11)C7—C12—C13120.90 (12)
C2—C1—H1A111.6C11—C12—C13121.16 (14)
C13—C1—H1A111.6N4—C13—C12111.46 (11)
C2—C1—H1B111.6N4—C13—C1100.98 (10)
C13—C1—H1B111.6C12—C13—C1112.93 (11)
H1A—C1—H1B109.4N4—C13—H13110.4
N3—C2—C14122.55 (13)C12—C13—H13110.4
N3—C2—C1113.23 (12)C1—C13—H13110.4
C14—C2—C1124.16 (12)C2—C14—H14A109.5
C2—N3—N4108.71 (11)C2—C14—H14B109.5
N3—N4—C5114.05 (10)H14A—C14—H14B109.5
N3—N4—C13107.26 (9)C2—C14—H14C109.5
C5—N4—C13114.20 (10)H14A—C14—H14C109.5
N4—C5—O6113.73 (11)H14B—C14—H14C109.5
N4—C5—C15112.11 (11)C20—C15—C16119.21 (13)
O6—C5—C15106.99 (11)C20—C15—C5121.22 (12)
N4—C5—H5107.9C16—C15—C5119.55 (13)
O6—C5—H5107.9C17—C16—C15120.12 (14)
C15—C5—H5107.9C17—C16—H16119.9
C7—O6—C5115.49 (11)C15—C16—H16119.9
O6—C7—C12122.64 (12)C16—C17—C18120.50 (13)
O6—C7—C8116.04 (14)C16—C17—H17119.8
C12—C7—C8121.29 (14)C18—C17—H17119.8
C9—C8—C7119.60 (17)C19—C18—C17119.28 (13)
C9—C8—H8120.2C19—C18—C21120.86 (13)
C7—C8—H8120.2C17—C18—C21119.74 (13)
C8—C9—C10120.15 (16)C18—C19—C20120.10 (13)
C8—C9—H9119.9C18—C19—H19119.9
C10—C9—H9119.9C20—C19—H19119.9
C11—C10—C9119.92 (15)C15—C20—C19120.77 (13)
C11—C10—H10120.0C15—C20—H20119.6
C9—C10—H10120.0C19—C20—H20119.6
C10—C11—C12121.10 (16)O7—C21—O8123.78 (13)
C10—C11—H11119.4O7—C21—C18123.50 (14)
C12—C11—H11119.4O8—C21—C18112.71 (12)
C7—C12—C11117.93 (14)C21—O8—H8A109.5
C13—C1—C2—N3−15.79 (15)N3—N4—C13—C1−29.67 (12)
C13—C1—C2—C14166.98 (12)C5—N4—C13—C1−157.08 (11)
C14—C2—N3—N4174.46 (11)C7—C12—C13—N411.07 (17)
C1—C2—N3—N4−2.82 (15)C11—C12—C13—N4−167.94 (12)
C2—N3—N4—C5148.89 (11)C7—C12—C13—C1123.94 (13)
C2—N3—N4—C1321.40 (13)C11—C12—C13—C1−55.08 (17)
N3—N4—C5—O6−68.94 (13)C2—C1—C13—N426.12 (12)
C13—N4—C5—O654.89 (15)C2—C1—C13—C12−93.01 (13)
N3—N4—C5—C1552.60 (14)N4—C5—C15—C20−112.18 (15)
C13—N4—C5—C15176.43 (10)O6—C5—C15—C2013.15 (17)
N4—C5—O6—C7−44.40 (16)N4—C5—C15—C1666.12 (17)
C15—C5—O6—C7−168.75 (11)O6—C5—C15—C16−168.55 (12)
C5—O6—C7—C1217.97 (19)C20—C15—C16—C171.7 (2)
C5—O6—C7—C8−164.03 (12)C5—C15—C16—C17−176.64 (14)
O6—C7—C8—C9−177.12 (14)C15—C16—C17—C18−0.4 (3)
C12—C7—C8—C90.9 (2)C16—C17—C18—C19−0.8 (2)
C7—C8—C9—C10−0.3 (3)C16—C17—C18—C21175.18 (15)
C8—C9—C10—C11−0.6 (3)C17—C18—C19—C200.7 (2)
C9—C10—C11—C120.9 (3)C21—C18—C19—C20−175.28 (13)
O6—C7—C12—C11177.24 (13)C16—C15—C20—C19−1.9 (2)
C8—C7—C12—C11−0.7 (2)C5—C15—C20—C19176.45 (13)
O6—C7—C12—C13−1.8 (2)C18—C19—C20—C150.7 (2)
C8—C7—C12—C13−179.70 (13)C19—C18—C21—O7179.54 (14)
C10—C11—C12—C7−0.2 (2)C17—C18—C21—O73.6 (2)
C10—C11—C12—C13178.82 (14)C19—C18—C21—O81.05 (19)
N3—N4—C13—C1290.51 (12)C17—C18—C21—O8−174.89 (13)
C5—N4—C13—C12−36.89 (15)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O8—H8A···N3i0.821.932.7356 (17)168

Symmetry codes: (i) −x−1, −y+1, −z+1.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: BI2280).

References

  • Palomer, A., Cabré, F., Pascual, J., Campos, J., Trujillo, M. A., Entrena, A., Gallo, M. A., Garcia, L., Mauleón, D. & Espinosa, A. (2002). J. Med. Chem.45, 1402–1411. [PubMed]
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Siemens (1991). XSCANS Siemens Analytical X-ray Instruments Inc., Madison, Wisconsin, USA.
  • Spek, A. L. (2003). J. Appl. Cryst.36, 7–13.
  • Subbaramaiah, K., Norton, L., Gerald, W. & Dannenberg, A. J. (2002). J. Biol. Chem.277, 18649–18659. [PubMed]
  • Světlík, J., Pronayova, N. & Kubista, J. (2005). J. Heterocycl. Chem.42, 1143–1147.

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