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Acta Crystallogr C. 2009 April 15; 65(Pt 4): o163–o166.
Published online 2009 March 21. doi:  10.1107/S010827010900941X
PMCID: PMC2724994

3-[5-(4-Chloro­phen­yl)-1-(4-methoxy­phen­yl)-1H-pyrazol-3-yl]propionic acid and the corresponding methyl ester

Abstract

The synthesis of 3-[5-(4-chloro­phen­yl)-1-(4-methoxy­phen­yl)-1H-pyrazol-3-yl]propionic acid, C19H17ClN2O3, (I), and its corresponding methyl ester, methyl 3-[5-(4-chloro­phen­yl)-1-(4-methoxy­phen­yl)-1H-pyrazol-3-yl]propionate, C20H19ClN2O3, (II), is regiospecific. However, correct identification of the regioisomer formed by spectroscopic techniques is not trivial and single-crystal X-ray analysis provided the only means of unambiguous structure determination. Compound (I) crystallizes with Z′ = 2. The propionic acid groups of the two crystallographically unique mol­ecules form a hydrogen-bonded dimer, as is typical of carboxylic acid groups in the solid state. Conformational differences between the meth­oxy­benzene and pyrazole rings give rise to two unique mol­ecules. The structure of (II) features just one mol­ecule in the asymmetric unit and the crystal packing makes greater use than (I) of weak C—H(...)A inter­actions, despite the lack of any functional groups for classical hydrogen bonding.

Comment

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the oldest and most widely accepted way to treat mild to moderate pain. One possible side-effect of NSAIDs is bronchial constriction in patients (Charlier & Michaux, 2003 [triangle]; Young, 1999 [triangle]), and so they are not therapeutically advisable for asthma patients. In addition, prolonged treatment may result in gastric irritation and renal impairment. In order to increase the analgesic efficacy and reduce the side effects, we are investigating the synthesis and properties of a range of bifunctional NSAID precursors containing amino acid groups. In the process of synthesizing a precursor to the NSAID tepoxalin, we found that a mixture of regioisomers were possible, identified as 1 and 2 in the scheme below. Efforts to identify unambiguously the correct regioisomer by NMR spectroscopy, using one-dimensional nuclear Overhauser effect or heteronuclear multiple bond correlation experiments, were not successful, leaving single-crystal X-ray diffraction as the only possible means of unambiguous identification. We report here the structure of the tepoxalin precursor 3-[5-(4-chloro­phen­yl)-1-(4-methoxy­phen­yl)-1H-pyrazol-3-yl]propionic acid, (I), and the corresponding methyl ester, (II).

An external file that holds a picture, illustration, etc.
Object name is c-65-0o163-scheme1.jpg

The asymmetric unit of (I) is shown in Fig. 1 [triangle]. The compound crystallizes in the space group P An external file that holds a picture, illustration, etc.
Object name is c-65-0o163-efi1.jpg with two crystallographically unique mol­ecules in the asymmetric unit and no solvent of crystallization. The compound is unambiguously regioisomer 1. Discussion is restricted to the mol­ecule containing atoms Cl1 to H19 (hereafter ‘mol­ecule A’), with relevant results for the mol­ecule containing atoms Cl51 to H69 (hereafter ‘mol­ecule B’) presented in square brackets. The propionic acid groups of the two crystallographically unique mol­ecules form a hydrogen-bonded dimer with a graph-set motif An external file that holds a picture, illustration, etc.
Object name is c-65-0o163-efi2.jpg(8), as is typical of carboxylic acid groups in the solid state (Bernstein et al., 1995 [triangle]).

Figure 1
The asymmetric unit of (I), with anisotropic displacement ellipsoids drawn at the 50% probability level.

The conformational differences that give rise to two unique mol­ecules can be easily appreciated by considering an overlay of the two mol­ecules, formed by fitting together the five atoms of each pyrazole ring (r.m.s. deviation = 0.0062 Å; Fig. 2 [triangle]). From this it is clear that, although there are some small differences between the conformations of the propionic acid and chloro­benzene rings in mol­ecules A and B, the most striking difference is found in the methoxy­benzene group. Although it first seems that the differences are due to meth­oxy group orientation, we show by careful systematic numbering that it is the angle between the methyoxybenzene and pyrazole rings which gives rise to two different conformations. The meth­oxy group is essentially coplanar with the benzyl ring to which it is bonded, and a mean plane fitted through all six ring C atoms and the two meth­oxy atoms has an r.m.s. deviation of 0.0350 Å [0.0288 Å]. This plane is rotated by 53.51 (5)° [37.32 (8)°] from the central pyrazole ring plane. In mol­ecule A, the N1—N2—C4—C5 torsion angle is −130.75 (16)°, yet using the same numbering system for B, the N51—N52—C54—C55 torsion angle is 36.4 (2)°. The related compound 1-(4-methoxy­phen­yl)-5-phenyl­pyrazole (Spivey et al., 2000 [triangle]) also features two mol­ecules in the asymmetric unit. In both cases, the meth­oxy group is coplanar with the benzyl ring to which it is bonded, but the torsion angle corresponding to the atoms named above is approximately 54.34° for one mol­ecule and −53.12° for the other.

Figure 2
An overlay plot of mol­ecule A (gray; orange in the electronic version of the paper) with mol­ecule B (black).

The chloro­phenol ring is rotated by 37.07 (8)° [42.10 (6)°] from the pyrazole ring. The propionic acid unit has an extended conformation, and a mean plane fitted through atoms O2, O3, C1, C11, C12 and C13 has an r.m.s. deviation of 0.230 Å [0.0148 Å]. The covalent mol­ecular geometry is unexceptional, as is the crystal packing, which consists principally of van der Waals inter­actions and some minor C—H(...)π inter­actions. In some parts of the structure, there is evidence of favorable δ+ and δ− alignment (for example, C59—H59(...)N1). The geometry of these inter­actions is such that we do not believe that these are formal weak hydrogen bonds but rather they result from simple electrostatic attraction.

Obtained as a reaction side-product in the synthesis of (I) was the corresponding methyl ester, (II). This was isolated by flash chromatography and crystallized separately. The mol­ecular structure of (II) is shown in Fig. 3 [triangle] and as with mol­ecule (I) matches that of the predicted regioisomer 1; there is only one mol­ecule in the asymmetric unit of this compound. The mol­ecule adopts an extended conformation with the ester group essentially planar (a mean plane fitted through atoms C1, C11, C12, C13, C20, O2 and O3 has an r.m.s. deviation of 0.0406 Å) and that plane is rotated by 31.79 (5)° from the pyrazole ring plane. As with (I), the meth­oxy group is essentially coplanar with the benzyl ring to which it is bonded, and a mean plane fitted through all six ring C atoms and the two meth­oxy atoms has an r.m.s. deviation of 0.0323 Å. This plane is rotated by 71.01 (3)° from that of the pyrazole ring. Finally, the chloro­benzene group is rotated by 22.93 (5)° from the plane of the central pyrazole ring. The covalent mol­ecular geometry is unexceptional.

Figure 3
The asymmetric unit of (II), with anisotropic displacement ellipsoids drawn at the 50% probability level.

The crystal packing of (II) is more complex than that of (I), despite the lack of any functional groups for classical hydrogen bonding. A b-axis projection of (II) (Fig. 4 [triangle]) shows that the ester carbonyl atom O3 is not involved in the O—H(...)O hydrogen bond found in (I) and is available to form weak C—H(...)O hydrogen bonds to atoms H2 and H15, generating an An external file that holds a picture, illustration, etc.
Object name is c-65-0o163-efi3.jpg(7) motif. Furthermore, one of the methyl H atoms (H20B) of the ester function is also able to participate in a weak C—H(...)N hydrogen bond, as opposed to a purely favorable electrostatic inter­ation by virtue of the way the atoms are oriented, with the pyrazole ring of an adjacent group. Overall, the crystal packing can be most easily described as rippled stacked sheets, as can be seen if a projection is viewed along the ab diagonal.

Figure 4
A b-axis packing plot of (II). Weak hydrogen bonding is illustrated by dashed lines (blue in the electronic version of the paper).

Experimental

The title compounds were synthesized in a two-step procedure. 6-(4-Chloro­phen­yl)-4,6-dioxohexa­noic acid was synthesized by a modification of the method described by Murray et al. (1991 [triangle]), using NaHMDS in place of LiHMDS. Next, a mixture of 6-(4-chloro­phen­yl)-4,6-dioxohexa­noic acid (1.27 g, 5 mmol), 4-methoxy­phenyl­hydrazine hydro­chloride (873 mg, 5 mmol) and Et3N (506 mg, 5 mmol) in MeOH (40 ml) was stirred at room temperature for 6 h. The mixture was then concentrated in vacuo to a residue, which was partitioned between Et2O (40 ml) and 5% aqueous HCl (37.5 ml). The ether layer was separated, washed with 5% aqueous HCl (2 × 10 ml) and brine (10 ml), dried over Na2SO4, filtered, and concentrated to a residue. The crude residue was flash chromatographed on silica gel using hexane–EtOAc–AcOH (6:2:1) as eluant and separated into the two products (I) and (II). Compound (I) was crystallized by slow evaporation of a diethyl ether solution (yield 70%), while compound (II) was crystallized by slow evaporation of a deuterated methanol solution (yield 30%).

Compound (I)

Crystal data

  • C19H17ClN2O3
  • M r = 356.80
  • Triclinic, An external file that holds a picture, illustration, etc.
Object name is c-65-0o163-efi4.jpg
  • a = 9.131 (2) Å
  • b = 13.759 (3) Å
  • c = 14.264 (3) Å
  • α = 103.733 (3)°
  • β = 96.928 (3)°
  • γ = 98.459 (3)°
  • V = 1699.2 (6) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.25 mm−1
  • T = 150 K
  • 0.32 × 0.21 × 0.11 mm

Data collection

  • Bruker APEXII CCD diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 1996 [triangle]) T min = 0.916, T max = 0.974
  • 19183 measured reflections
  • 8218 independent reflections
  • 6174 reflections with I > 2σ(I)
  • R int = 0.025

Refinement

  • R[F 2 > 2σ(F 2)] = 0.043
  • wR(F 2) = 0.115
  • S = 1.07
  • 8218 reflections
  • 461 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.52 e Å−3
  • Δρmin = −0.32 e Å−3

Compound (II)

Crystal data

  • C20H19ClN2O3
  • M r = 370.82
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is c-65-0o163-efi5.jpg
  • a = 22.174 (5) Å
  • b = 5.1352 (11) Å
  • c = 31.884 (7) Å
  • β = 101.126 (2)°
  • V = 3562.4 (13) Å3
  • Z = 8
  • Mo Kα radiation
  • μ = 0.24 mm−1
  • T = 150 K
  • 0.27 × 0.15 × 0.09 mm

Data collection

  • Bruker APEXII CCD diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 1996 [triangle]) T min = 0.919, T max = 0.979
  • 18813 measured reflections
  • 4351 independent reflections
  • 3788 reflections with I > 2σ(I)
  • R int = 0.022

Refinement

  • R[F 2 > 2σ(F 2)] = 0.034
  • wR(F 2) = 0.087
  • S = 1.02
  • 4351 reflections
  • 237 parameters
  • H-atom parameters constrained
  • Δρmax = 0.28 e Å−3
  • Δρmin = −0.24 e Å−3

All H atoms were located from a difference map and constrained to ride on the parent atom, except that the positions and atomic displacement parameters of the hydr­oxy H atoms in (I) were freely refined. H atoms were supplied with U iso(H) values of 1.2U eq(C) [or 1.5U eq(C) for methyl H atoms] and fixed C—H distances of 0.95 Å for aryl, 0.98 Å for methyl and 0.99 Å for methyl­ene H atoms.

For both compounds, data collection: APEX2 (Bruker, 2007 [triangle]); cell refinement: SAINT (Bruker, 2007 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXTL; molecular graphics: DIAMOND (Brandenburg & Putz, 1999 [triangle]) and Mercury (Macrae et al., 2008 [triangle]); software used to prepare material for publication: SHELXTL, publCIF (Westrip, 2009 [triangle]) and local programs.

Table 1
Hydrogen-bond geometry (Å, °) for (I)
Table 2
Hydrogen-bond geometry (Å, °) for (II)

Supplementary Material

Crystal structure: contains datablocks I, II, global. DOI: 10.1107/S010827010900941X/sk3306sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S010827010900941X/sk3306Isup2.hkl

Structure factors: contains datablocks II. DOI: 10.1107/S010827010900941X/sk3306IIsup3.hkl

Acknowledgments

This work was supported by grants from the United States Public Health Service, the National Institute on Drug Abuse. We thank Dr Allen G. Oliver, University of California, Santa Cruz, for data collection of (I) and (II).

Footnotes

Supplementary data for this paper are available from the IUCr electronic archives (Reference: SK3306). Services for accessing these data are described at the back of the journal.

References

  • Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl.34, 1555–1573.
  • Brandenburg, K. & Putz, H. (1999). DIAMOND. Crystal Impact GbR, Bonn, Germany.
  • Bruker (2007). APEX2 and SAINT Bruker AXS Inc., Madison, Wisconsin, USA.
  • Charlier, C. & Michaux, C. (2003). Eur. J. Med. Chem.38, 645–659. [PubMed]
  • Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst.41, 466–470.
  • Murray, W., Wachter, M., Barton, D. & Forero-Kelly, Y. (1991). Synthesis, pp. 18–20.
  • Sheldrick, G. M. (1996). SADABS University of Göttingen, Germany.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Spivey, A. C., Diaper, C. M., Adams, H. & Rudge, A. J. (2000). J. Org. Chem 65, 5253–5263. [PubMed]
  • Westrip, S. P. (2009). publCIF In preparation.
  • Young, R. N. (1999). Eur. J. Med. Chem.34, 671–685.

Articles from Acta Crystallographica Section C: Crystal Structure Communications are provided here courtesy of International Union of Crystallography