3-[5-(4-Chloro-phen-yl)-1-(4-methoxy-phen-yl)-1H-pyrazol-3-yl]propionic acid and the corresponding methyl ester

Article abstract of DOI:10.1107/S010827010900941X

The synthesis of 3-[5-(4-chloro-phen-yl)-1-(4-methoxy-phen-yl)-1H-pyrazol- 3-yl]propionic acid, C19H17ClN2O3, (I), and its corresponding methyl ester, methyl 3-[5-(4-chloro-phen-yl)-1-(4-methoxy-phen-yl)-1H-pyrazol-3-yl]propionate, C20H19ClN2O3, (II), is

Full text of DOI:10.1107/S010827010900941X

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
nuclear 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).
ISSN 0108-2701
3-[5-(4-Chlorophenyl)-1-(4-methoxy-
phenyl)-1H-pyrazol-3-yl]propionic
acid and the corresponding methyl
ester
Isuru R. Kumarasinghe, Victor J. Hruby and Gary S.
Nichol*
Department of Chemistry, The University of Arizona, 1306 E University Boulevard,
Tucson, AZ 85721, USA
Correspondence e-mail: gsnichol@email.arizona.edu
Received 11 March 2009
Accepted 13 March 2009
Online 21 March 2009
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) crystal-
lizes with Z0 = 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 methoxy-
benzene 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—Hꢀ ꢀ ꢀA interactions, despite the lack of
any functional groups for classical hydrogen bonding.
The asymmetric unit of (I) is shown in Fig. 1. The compound
crystallizes in the space group P1 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 R22(8), as is
typical of carboxylic acid groups in the solid state (Bernstein et
al., 1995).
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
Comment
˚
of each pyrazole ring (r.m.s. deviation = 0.0062 A; Fig. 2).
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; Young,
1999), 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 investi-
gating 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, iden-
tified 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 hetero-
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 pyra-
zole 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 oꢁf
˚
˚
0.0350 A [0.0288 A]. 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 ꢂ130.75 (16)ꢁ, yet
using the same numbering system for B, the N51—N52—
Acta Cryst. (2009). C65, o163–o166
doi:10.1107/S010827010900941X
# 2009 International Union of Crystallography o163

organic compounds
Figure 1
The asymmetric unit of (I), with anisotropic displacement ellipsoids drawn at the 50% probability level.
C54—C55 torsion angle is 36.4 (2)ꢁ. The related compound
1-(4-methoxyphenyl)-5-phenylpyrazole (Spivey et al., 2000)
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 54.34ꢁ for one molecule
and ꢂ53.12ꢁ for the other.
bonds but rather they result from simple electrostatic attrac-
tion.
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 mol-
ecular structure of (II) is shown in Fig. 3 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
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 A [0.0148 A]. The covalent molecular geometry is
unexceptional, as is the crystal packing, which consists prin-
cipally of van der Waals interactions and some minor C—
Hꢀ ꢀ ꢀꢀ interactions. In some parts of the structure, there is
evidence of favorable ꢁ+ and ꢁꢂ alignment (for example,
C59—H59ꢀ ꢀ ꢀN1). The geometry of these interactions is such
that we do not believe that these are formal weak hydrogen
0.0406 A) and that plane is rotated by 31.79 (5) from the
pyrazole ring plane. As with (I), the methoxy group is essen-
tially 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 A. 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 2
An overlay plot of molecule A (gray; orange in the electronic version of
the paper) with molecule B (black).
Figure 3
The asymmetric unit of (II), with anisotropic displacement ellipsoids
drawn at the 50% probability level.
ꢃ
o164 Kumarasinghe et al.
C19H17ClN2O3 and C20H19ClN2O3
Acta Cryst. (2009). C65, o163–o166

organic compounds
Table 1
Hydrogen-bond geometry (A, ) for (I).
ꢁ
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
O2—H2Oꢀ ꢀ ꢀO53
O52—H52Oꢀ ꢀ ꢀO3
0.90 (3)
0.84 (3)
1.78 (3)
1.84 (3)
2.6815 (18)
2.6790 (18)
178 (3)
177 (3)
Table 2
Hydrogen-bond geometry (A, ) for (II).
ꢁ
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
C2—H2ꢀ ꢀ ꢀO3i
0.95
0.95
0.95
0.98
0.98
2.50
2.41
2.60
2.61
2.92
3.3651 (15)
3.3317 (15)
3.4625 (16)
3.5750 (18)
3.7554 (15)
152
165
152
169
143
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).
C15—H15ꢀ ꢀ ꢀO3i
C18—H18ꢀ ꢀ ꢀO1ii
C20—H20Bꢀ ꢀ ꢀN1iii
C10—H10Cꢀ ꢀ ꢀCl1iv
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) shows
that the ester carbonyl atom O3 is not involved in the O—
Hꢀ ꢀ ꢀO hydrogen bond found in (I) and is available to form
weak C—Hꢀ ꢀ ꢀO hydrogen bonds to atoms H2 and H15,
generating an R12(7) motif. Furthermore, one of the methyl H
atoms (H20B) of the ester function is also able to participate
in a weak C—Hꢀ ꢀ ꢀ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.
1
2
1
2
1
2
1
1
Symmetry codes: (i) ꢂx þ ; ꢂy ꢂ ; ꢂz; (ii) ꢂx þ ; y þ ; ꢂz þ ; (iii) ꢂx; ꢂy; ꢂz; (iv)
2
2
1
2
1
2
x ꢂ ; y ꢂ ; z.
Data collection
Bruker APEXII CCD
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 1996)
Tmin = 0.916, Tmax = 0.974
19183 measured reflections
8218 independent reflections
6174 reflections with I > 2ꢆ(I)
Rint = 0.025
Refinement
R[F2 > 2ꢆ(F2)] = 0.043
wR(F2) = 0.115
S = 1.07
8218 reflections
461 parameters
H atoms treated by a mixture of
independent and constrained
refinement
ꢂ3
˚
Áꢇmax = 0.52 e A
ꢂ3
˚
Áꢇmin = ꢂ0.32 e A
Experimental
Compound (II)
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), using
NaHMDS in place of LiHMDS. Next, a mixture of 6-(4-chloro-
phenyl)-4,6-dioxohexanoic acid (1.27 g, 5 mmol), 4-methoxyphenyl-
hydrazine 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 ꢄ
10 ml) and brine (10 ml), dried over Na2SO4, filtered, and concen-
trated 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%).
Crystal data
3
˚
V = 3562.4 (13) A
Z = 8
C20H19ClN2O3
Mr = 370.82
Monoclinic, C2=c
Mo Kꢂ radiation
ꢅ = 0.24 mmꢂ1
T = 150 K
0.27 ꢄ 0.15 ꢄ 0.09 mm
˚
a = 22.174 (5) A
˚
b = 5.1352 (11) A
˚
c = 31.884 (7) A
ꢃ = 101.126 (2)ꢁ
Data collection
Bruker APEXII CCD
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 1996)
Tmin = 0.919, Tmax = 0.979
18813 measured reflections
4351 independent reflections
3788 reflections with I > 2ꢆ(I)
Rint = 0.022
Refinement
R[F2 > 2ꢆ(F2)] = 0.034
wR(F2) = 0.087
S = 1.02
237 parameters
H-atom parameteꢂrs3 constrained
Compound (I)
˚
Áꢇmax = 0.28 e A
ꢂ3
˚
4351 reflections
Áꢇmin = ꢂ0.24 e A
Crystal data
C19H17ClN2O3
Mr = 356.80
Triclinic, P1
a = 9.131 (2) A
b = 13.759 (3) A
ꢄ = 98.459 (3)ꢁ
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 Uiso(H) values of 1.2Ueq(C) [or
V = 1699.2 (6) A
Z = 4
˚
Mo Kꢂ radiation
ꢅ = 0.25 mmꢂ1
T = 150 K
0.32 ꢄ 0.21 ꢄ 0.11 mm
˚
˚
c = 14.264 (3) A
˚
1.5Ueq(C) for methyl H atoms] and fixed C—H distances of 0.95 A for
ꢂ = 103.733 (3)ꢁ
ꢃ = 96.928 (3)ꢁ
˚
aryl, 0.98 A for methyl and 0.99 A for methylene H atoms.
˚
ꢃ
Acta Cryst. (2009). C65, o163–o166
Kumarasinghe et al.
C19H17ClN2O3 and C20H19ClN2O3 o165

organic compounds
For both compounds, data collection: APEX2 (Bruker, 2007); cell
refinement: SAINT (Bruker, 2007); data reduction: SAINT;
program(s) used to solve structure: SHELXTL (Sheldrick, 2008);
program(s) used to refine structure: SHELXTL; molecular graphics:
DIAMOND (Brandenburg & Putz, 1999) and Mercury (Macrae et al.,
2008); software used to prepare material for publication: SHELXTL,
publCIF (Westrip, 2009) and local programs.
References
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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).
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described at the back of the journal.
ꢃ
o166 Kumarasinghe et al.
C19H17ClN2O3 and C20H19ClN2O3
Acta Cryst. (2009). C65, o163–o166