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

Viktor Kettmann; Jan Světlík

doi:10.1107/S1600536808003607

. 2008 Feb 6;64(Pt 3):o563. doi: 10.1107/S1600536808003607

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

Viktor Kettmann ^a,^*, Jan Světlík ^a

PMCID: PMC2960786 PMID: 21201906

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 ▶); Subbaramaiah et al. (2002 ▶); Světlík et al. (2005 ▶).

Experimental

Crystal data

C₁₈H₁₆N₂O₃
M _r = 308.33
Triclinic,
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
Δρ_max = 0.29 e Å⁻³
Δρ_min = −0.22 e Å⁻³

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

Supplementary Material

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

e-64-0o563-sup1.cif^{(19KB, cif)}

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

e-64-0o563-Isup2.hkl^{(211.3KB, hkl)}

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O8—H8A⋯N3ⁱ	0.82	1.93	2.7356 (17)	168

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Symmetry code: (i) Inline graphic .

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.