The structure of two pyrazole esters related to Rimonabant

Article abstract of DOI:10.1016/j.molstruc.2009.08.018

Two 1,5-diarylpyrazoles related to the antiobesity agent Rimonabant have been synthesized and their structure determined by X-ray crystallography. Compound 2, 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxy late, forms strange cry

Full text of DOI:10.1016/j.molstruc.2009.08.018

Journal of Molecular Structure 937 (2009) 10–15
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
The structure of two pyrazole esters related to Rimonabant
a
a
a
a
Ibon Alkorta a, , Pilar Goya , Ruth Pérez-Fernández , Mario Alvarado , José Elguero ,
*
Santiago García-Granda b, , Laura Menéndez-Taboada
b
*
a Instituto de Química Médica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
b Departamento de Química Física y Analítica, Facultad de Química, Universidad de Oviedo, E-33006 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2009
Received in revised form 30 July 2009
Accepted 3 August 2009
Available online 25 August 2009
Two 1,5-diarylpyrazoles related to the antiobesity agent Rimonabant have been synthesized and their
structure determined by X-ray crystallography. Compound 2, 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-
4-methyl-1H-pyrazole-3-carboxylate, forms strange crystals but its only peculiarity involves Clꢀ ꢀ ꢀCl and
Clꢀ ꢀ ꢀ
p
interactions, that were modeled theoretically at the M05-2x/6-31+G(d,p) level. 13C NMR results were
rationalized through GIAO calculations at the B3LYP/6-311+G(d,p) computational level.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Rimonabant
Pyrazole
X-ray
NMR
B3LYP
GIAO
1. Introduction
crystals were colorless but those of 2 formed some hemispherical
shaped aggregates of orange crystals (Fig. 1) resembling an orange
fruit.
Rimonabant [1,2], the first CB1 antagonist approved in the EU
for the treatment of obesity had to be withdrawn from the market
due to psychiatric side effects. The development of other related
structures (Scheme 1) has also been discontinued for similar rea-
sons. However, we and others are still working on these structures
trying to suppress the unwanted central side-effects [3–6] of CB1
antagonists and to discover new CNS properties. We have already
published a paper describing a pyrazole fatty acid amide family de-
signed as multiple ligands with antiobesity and hypophagic prop-
erties [7].
The molecular structure of compound 1 is shown in Figs. 2 and
3 while Figs. 4 and 5 are for compound 2. The single crystal X-ray
data for both structures are listed in Table 3. Hydrogen-bonding
geometry for compound 1 is collected in Table 4 (see Section 3).
The crystal packing of compound 1 at 100 K shows a helix along
a axis as shown in Fig. 6. The helical structure is sustained by
hydrogen bonds involving oxygen and carbon (C15AH15ꢀ ꢀ ꢀO2),
forming an infinite chain. No conventional hydrogen bonds were
found at RT for 1, neither for compound 2.
We present here the structural study of two esters, 1 and 2
(Scheme 2) used as precursors of some biologically active
compounds.
The aryl rings of compounds 1 and 2 (Table 1) were neither pla-
nar nor perpendicular being close to 45 °C. The change in temper-
ature in compound 1 affects significantly the torsion angles,
becoming both angles alike at 100 K. The calculated geometry
(monomer in the gas phase) had lower values but it resembled
the 293 K structure. In compound 2, the presence of an ortho chlo-
rine atom increased 10° the dihedral angle of the N-aryl group. The
calculated geometry of the monomer exaggerated this angle. In the
dimer model (which has an H atom in the place of the ester group)
the angles were modified but further removed from the experi-
mental values.
2. Results and discussion
2.1. Solid-state structures
We have recently published the structural studies of Rimona-
bant [8] and compounds 3–5 [9]. The Rimonabant studies included
X-ray crystallography and NMR data. First, the X-ray molecular
structures of compounds 1 and 2 will be described. Compound 1
Compound 2 crystallized forming dimers stabilized by halogen
bonds between the C-p-chlorophenyl and the N-o-chlorophenyl
(Clꢀ ꢀ ꢀCl = 3.46 Å) and by Clꢀ ꢀ ꢀ
p interactions between the C-p-chlo-
rophenyl and the opposite p-chlorophenyl (Clꢀ ꢀ ꢀcentroid = 4.01 Å,
* Corresponding authors. Tel.: +34 91 5622900; fax: +34 91 5644853 (I. Alkorta).
E-mail address: ibon@iqm.csic.es (I. Alkorta).
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2009.08.018

I. Alkorta et al. / Journal of Molecular Structure 937 (2009) 10–15
11
O
N
O
N
O
N
N
N
H3C
(CH2)5-CH3
N
H3CH2C
N
N
N
N
H
H
H
N
N
N
N
N
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Rimonabant
LH-21
Surinabant
Rosonabant
(and enantiomer)
Cl
H
H
N
H3C
H3C
N
H
N
N
N
N
N
N
N
Cl
Cl
Cl
H3C
Cl
N
H
S
O
O
Cl
Cl
Cl
PIMSR
SLV319
VCHSR
Scheme 1.
O
O
N
O
O
N
O
C2H5
C2H5
C2H5
C18H33
CH3
H3C
H3C
O
O
O
N
O
H
N
N
N
N
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
1
4
2
3
5
Scheme 2.
Fig. 1. Compound 2 crystals (vial diameter 2 cm).
Clꢀ ꢀ ꢀcloset C = 3.96 Å) (Fig. 1). Compound 5 (GOKFUI) [10] did not
present any similar interaction but compound 4 (GOKGAP) [10]
showed a Clꢀ ꢀ ꢀcentroid distance of 3.62 Å and Clꢀ ꢀ ꢀcloset C distance
of 3.43 Å between the Cl of the 5-aryl group and the aryl of the 1-
phenyl group [9].
In order to study the molecular interactions observed within the
X-ray structure, a model of the dimer 22 was optimized with the
M05-2x/6-31+G* computational level (see Section 3.2.2), a func-
tional known to yield good stacking energies. The structure was
very similar (see Fig. 8) to Fig. 7. This model corresponded to the
replacement of the ethoxycarbonyl groups by H atoms (compound
2a2). Calculations of the frequencies have been carried out to con-
firm that the structure obtained correspond to energetic minima.
The electron density has been analyzed within the atoms in mole-
cules (AIM) methodology with the AIM2000 program. The calcu-
lated interaction energy accounts to ꢁ16.7 kJ molꢁ1
.
Fig. 2. An ORTEP view of an isolated molecule of compound 1.

12
I. Alkorta et al. / Journal of Molecular Structure 937 (2009) 10–15
Fig. 3. X-ray molecular structure of compound 1 (100 K).
Fig. 6. Helical structure of compound 1 (100 K).
Table 1
Torsion angles (°) of the phenyl rings of compounds 1 and 2.
Compd.
Temp. (K)
NAAr
CAAr
Calc.
NAAr
CAAr
1
293
100
293
49.0
51.0
59.1
57.6
53.4
52.9
Monomer
43.2
54.2
2
Monomer
Dimer
65.5
67.2
50.8
45.0
Fig. 4. An ORTEP view of an isolated molecule of compound 2.
Fig. 5. X-ray molecular structure of compound 2.
Fig. 7. View of the dimer of compound 2.
An AIM analysis yielded the following picture (Fig. 8). Four
bon atoms that are located at a distance of 3.63 Å. As previously,
the electron density and Laplacian values of these bcp’s (0.005
and 0.015 au, respectively) are indicative of closed shell interac-
intermolecular bond critical points (bcp) are found, two of them
corresponding to Clꢀ ꢀ ꢀCl interaction and another two to Clꢀ ꢀ ꢀaro-
matic carbon interactions. In the first case, the distance between
the halogen atoms is of 3.52 Å and they are in a perpendicular ori-
entation, orientation that have been shown to be the most favor-
able disposition in order to minimize their electronic repulsion
[11,12]. The values of the electron density and Laplacian for this
bcp (0.006 and 0.023 au, respectively) indicate that it corresponds
to a closed shell interaction. The second set of bcp’s accounts for
the interaction of one chlorine atom and one of the aromatic car-
tions similar to those find in weak contacts with the
matic systems [13,14].
p-cloud of aro-
2.2. NMR results and GIAO calculations
We have gathered in Table 2 the experimental and calculated
13C chemical shifts (d ppm) of compounds 1 and 2 together with

I. Alkorta et al. / Journal of Molecular Structure 937 (2009) 10–15
13
Fig. 8. View of the molecular graph of the dimer of model compound 2a. The position of the bond and ring critical points are indicated with red and yellow points. The bond
paths are shown. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this paper.)
Table 2
180
13C NMR absolute shieldings and chemical shifts of compounds 1 and 2 (all values in
ppm).
160
Compd.
Atom
r
d calcd.
d exp.
1
C3
C4
C5
C10
34.6488
142.33
125.15
141.97
141.96
125.51
127.89
126.11
132.75
131.48
128.03
127.71
10.36
145.0
119.0
141.1
141.0
124.3
127.9
126.7
132.5
129.0
128.5
127.5
8.4
140
120
100
80
52.4872
35.0231
35.0390
52.1178
49.6484
51.4920
44.6039
45.9203
49.5063
49.8313
171.6946
13.3933
118.4583
168.1801
C20/C60
C30/C50
C40
C100
C200/C600
C300/C500
C400
4-Me
C@O
CH2
60
162.80
61.62
13.74
162.2
61.1
14.3
CH3
40
d 13C (ppm)
d 13C CCl (ppm)
2
C3
C4
33.7715
54.3330
33.1665
38.4531
35.7526
47.7768
32.6966
50.8738
45.4809
48.0830
45.9051
49.1703
32.8185
171.0935
13.7655
119.5178
167.6242
143.18
123.38
143.76
138.67
141.27
129.69
144.21
126.71
131.90
129.40
131.49
128.35
144.10
10.94
143.0
119.2
142.9
136.1
133.1a
130.1
136.0a
127.8
130.7
127.1
130.9
128.9
135.0a
9.7
20
C5
C10
C20
0
C30
0
20
40
60
80
100
120
140
160
180
C40
d 13C calc (ppm)
C50
C60
Fig. 9. Scatter of 13C NMR results.
C100
C200/C600
C300/C500
C400
The excellence of the correlation makes unnecessary the use of
additivity schemes so popular in the past. However, we have
checked comparing 1 and 2 that the signals of the phenyl rings
are consistent with the chlorine substituent effects [17].
4-Me
C@O
CH2
CH3
162.44
60.60
14.28
162.8
61.0
14.4
a
3. Experimental
CACl atoms.
All chemicals were purchased from commercial suppliers and
used without further purification. TLC: precoated silica-gel 60
F254 plates (Merck), detection by UV light (254 nm). Flash-column
Chromatography (FC): Kieselgel 60 (230–400 mesh; Merck). Melting
points (mp) were determined in open capillaries with a Gallenkamp
the absolute shieldings (
311++G(d,p)//B3LYP/6-311++G(d,p) level (see Section 3.2.2). To
r ppm) calculated at the GIAO/B3LYP/6-
transform
r into d we used an equation established empirically
from a set of 461 points [15]: d13C = 175.7 ꢁ 0.963
r
13C. The exper-
capillary melting-points apparatus and are uncorrected. 1H and 13
C
imental values have been assigned by traditional 2D experiments
including NOESY [16].
NMR spectra were recorded on Bruker Advance 300 spectrometer
operating at 300.13 MHz and 75.47 MHz respectively, in CDCl3 as
solvent and Me4Si as the internal standard. Chemical shifts are re-
ported in ppm on the d scale. The mass spectra (EI-MS; 70 eV) were
determined on a MSD 5973 Hewlett Packard instrument. Since
compounds 1 [18] and 2 [19] were only reported in patents we will
describe them here.
As we have previously reported, carbon atoms bearing chlorine
substituents such as C20, C40 and C400 deviated systematically from
the calculated values around ꢁ7.7 ppm (previously we have found
ꢁ8.7 ppm [8] and ꢁ8.2 ppm [9]). The remaining points are fitted to
d
13C exp. = (0.994 0.003) d13C calcd., n = 29, R2 = 1.000 (black line
in Fig. 9).

14
I. Alkorta et al. / Journal of Molecular Structure 937 (2009) 10–15
3.1. Synthesis of ethyl 1,5-diphenyl-4-methyl-1H-pyrazole-3-
carboxylate 1
γ
O
β
O
CH3
H3C
δ
α
4
3
6"
5
γ
5"
4"
2
1
N
O
β
O
CH3
N
1"
H3C
δ
α
Cl
1'
2"
4
Cl
3
6"
6'
3"
2'
3'
5"
4"
5
2
1
N
5'
N
1"
4'
Cl
1'
2"
6'
2'
3'
3"
2
5'
4'
phy (eluent: DCM + 0.1% MeOH) yielding a light yellow solid (4.27 g,
52%). M.p. 126–128 °C. 1H NMR (300 MHz, CDCl3) d 7.40 ꢁ 7.13 (m,
5H, C30, C50, C60, C300), 7.02–6.99 (m, 2H, C200), 4.38 (q, J = 7.1 Hz, 2H,
1
To a solution of ethyl 3-methyl-4-phenyl-2,4-dioxobutanoate [20]
(1.60 g, 6.83 mmol) in a mixture 1:1 of EtOH/H2SO4 (20 mL) was
added phenylhydrazine (0.73 g, 6.83 mmol). The reaction mixture
was refluxed for 12 h and later evaporated under reduced pressure
to give a residue which was treated with aqueous 1 N NaOH and ex-
tracted with CH2Cl2. The extract was dried (Na2SO4) and the solvent
was evaporated off to give predominantly 1H-pyrazole-3-carboxyl-
ate isomer as a viscous yellow oil. The product was purified by FC
(SiO2; EtOAc/n-hexane 1:3) and crystallization (0.5 g, 24% yield). Yel-
lowish solid, mp: 105–106 °C (EtOH); MS/EI: m/z (%) = 306 (100), 234
(24); 1H NMR (300 MHz, CDCl3): d = 7.30–7.05 (m, 10H), 4.38 (q,
J = 7.0 Hz, 2H), 2.37 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H); 13C NMR
Cc
), 2.26 (s, 3H, CACH3), 1.36 (t, J = 7.1 Hz, 3H, Cd). 13C NMR
(75 MHz, CDCl3) d 162.8 (Ca
), 143.0 (C3), 142.9 (C5), 136.1 (C10),
136.0 (C40), 135.0 (C400), 133.1 (C20), 130.9 (C200 & C600), 130.7 (C60),
130.1 (C30), 128.9 (C300 & C500), 127.8 (C50), 127.1 (C100), 119.2 (C4),
61.0 (Cc), 14.4 (Cd), 9.7 (CACH3). Elemental analysis calc. for
C19H15Cl3N2O2 (409.69) C: 55.70; H: 3.69; N: 6.84. Found: C:
55.59; H: 3.81; N: 6.94. HPLC–MS: A: Acetonitrile + 0.01% formic
acid, B: Water + 0.01% formic acid. Grad from 10% to 100% of A in
5 min, 100% of
A for 2 min; column SunFire C18 3.5 lm.
4.6 ꢂ 50 mm. Flow 1 mL/min. m/z 411.3, t = 6.19 min.
(75 MHz, CDCl3): d = 162.2 (C
132.5 (C100), 129.0 (C200 & C600), 128.5 (C300 & C500), 127.9 (C30 & C50),
127.5 (C400), 126.7 (C40), 124.3 (C20 & C60), 119.0 (C4), 61.1 (C
), 14.3
a
), 145.0 (C3), 141.1 (C5), 141.0 (C10),
c
3.2.1. Crystallography
(Cd), 8.4 (CACH3). Elemental analysis calc. for C19H18N2O2 (306.36)
Colorless crystals from compound 1 and 2 were used for data
collection at 100 K and RT, for 1, and only a RT for 2. Mirror-mono-
chromated radiation CuK/a, k = 1.54184 Å was used in all cases.
A total of 6618 (ꢁ14 6 h 6 11, ꢁ12 6 k 6 12, ꢁ17 6 l 6 16) reflec-
tions were collected for compound 1 at 100 K with 2740 indepen-
dent reflections, while 13206 (ꢁ14 6 h 6 14, ꢁ12 6 k 6 12,
ꢁ17 6 l 6 17) reflections were collected for compound 1 at RT,
with 2936 independent reflections. For compound 2, 15425
(ꢁ27 6 h 6 21, ꢁ9 6 k 6 7, ꢁ25 6 l 6 27) reflections were col-
lected, with 3688 independent reflections. Data collection for all
measurements was made using the program CrysAllis CCD [21].
Crystal structure was solved by Direct Methods, using the program
Sir92 [22]. Anisotropic least-squares refinement was carried out
with SHELXL-97 [23]. Further details of the X-ray structural analy-
sis are given in Tables 3 and 4. Geometrical calculations were made
C: 74.49; H: 5.92; N: 9.14. Found: C: 74.28; H: 6.01; N: 9.24.
3.2. Synthesis of ethyl 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-
methyl-1H-pyrazole-3-carboxylate 2
A mixture of 6 (5.56 g, 0.02 mmol) and 2,4-dichlorophenylhydra-
zine (4.3 g, 0.02 mmol) was dissolved in EtOH (150 mL). Then,
H2SO4, 50% (60 mL) was carefully added. The reaction mixture
was heated at 100 °C for 16 h. The mixture was cooled down to
room temperature and poured into an ice bath. The precipitated
was filtered and the solid washed extensively with water. Then,
the brownish sticky solid was dissolved in Et2O (30 mL) and washed
with water (2 ꢂ 30 mL). The organic layers were evaporated under
reduced pressure and the crude purified by column chromatogra-
Table 3
Crystal data and structure refinement for compounds 1 and 2.
Compound
1
1
2
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
C19H18N2O2
306.35
100(2)
1.54184
Monoclinic
P21/c
C19H18N2O2
306.35
293(2)
1.54184
Monoclinic
P21/c
C19H15Cl3N2O2
409.68
293(2)
1.54184
Orthorhombic
Pbca
a
(Å)
b (Å)
(Å)
12.4168(3)
10.6745(2)
14.5062(6)
90
12.3959(10)
10.5622(5)
14.957(2)
90
22.042(3)
7.7499(16)
22.375(3)
90
v
a (°)
b (°)
121.994(2)
90
1630.65(8)
4
0.656
648
119.816(8)
90
1699.1(3)
4
0.630
648
90
90
g (°)
V (Å3)
Z
3822.2(11)
8
4.477
m (mmꢁ1
F(0 0 0)
)
1680
Crystal size (mm)
Reflections collected
Unique reflections
R(int)
0.26 ꢂ 0.21 ꢂ 0.08
0.26 ꢂ 0.19 ꢂ 0.15
0.14 ꢂ 0.05 ꢂ 0.014
6618
13206
16759
2740
0.0362
2936
0.0237
3688
0.1613
R1[I > 2
r(I)]
0.0380
0.0369
0.0466
wR2 (all data)
0.0891
0.1156
0.0946

I. Alkorta et al. / Journal of Molecular Structure 937 (2009) 10–15
15
Table 4
(d) L. Hernández-Folgado, P. Goya, J. Frigola. M.R. Cuberes, A. Dordal, J. Holenz,
N. Jagerovic, Monatsh. Chem. 139 (2008) 1073.
[4] WHO Drug Information 21 (2007) 162.
Hydrogen bonds for compound 1 at 100 K (Å, °).
DAHꢀ ꢀ ꢀA (Å)
C15AH15ꢀ ꢀ ꢀO2 0.91(2)
DAH (Å) Hꢀ ꢀ ꢀA (Å) Dꢀ ꢀ ꢀA (Å) Dꢀ ꢀ ꢀA (°)
Symmetrya
1
[5] D. Hurst, U. Umejiego, D. Lynch, H. Seltzman, S. Hyatt, M. Roche, S. McAllister,
D. Fleischer, A. Kapur, M. Abood, S. Shi, J. Jones, D. Lewis, P. Reggio, J. Med.
Chem. 49 (2006) 5969.
[6] H. Pettersson, A. Bülow, F. Ek, J. Jensen, L.K. Ottesen, A. Fejzic, J.N. Ma, A.L. Del
Tredici, E.A. Currier, L.R. Gardell, A. Tabatabaei, D. Craig, K. McFarland, T.R. Ott,
F. Piu, E.S. Burstein, R. Olsson, J. Med. Chem. 52 (2009) 1975.
[7] M. Alvarado, P. Goya, M. Macías-González, F.J. Pavón, A. Serrano, N. Jagerovic, J.
Elguero, A. Gutiérrez-Rodríguez, S. García-Granda, M. Suardíaz, F. Rodríguez de
Fonseca, Bioorg. Med. Chem. 16 (2008) 10098.
2.61(2)
3.346(2)
138.4(16)
a
Symmetry transformations used to generate equivalent atoms: (1) x + 1,
ꢁy ꢁ 1/2, z + 1/2.
with PARST97 [24] and molecular graphics with ORTEP-3 [25] for
Windows.
[8] I. Alkorta, M. Alvarado, J. Elguero, S. García-Granda, P. Goya, M.L. Jimeno, L.
Menéndez-Taboada, Eur. J. Med. Chem. 44 (2009) 1864.
[9] I. Alkorta, M. Alvarado, J. Elguero, S. García-Granda, P. Goya, L. Torre-
Fernández, L. Menéndez-Taboada, J. Mol. Struct. 920 (2009) 82.
[10] CSD database version 5.28 (November 2006). Jan-07 and May-07 updates;
(a) F.H. Allen, Acta Crystallogr. Sect. B 58 (2002) 380;
(b) F.H. Allen, W.D.S. Motherwell, Acta Crystallogr. Sect. B 58 (2002) 407.
[11] I. Alkorta, F. Blanco, J. Elguero, Struct. Chem. 20 (2009) 63.
[12] T.T.T. Bui, S. Dahaoui, C. Lecomte, G.R. Desiraju, E. Espinosa, Angew. Chem. Int.
Ed. 48 (2009) 3838.
[13] I. Alkorta, I. Rozas, J. Elguero, J. Org. Chem. 62 (1997) 4687.
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[17] J.B. Stothers, Carbon-13 NMR Spectroscopy, Academic Press, New York, 1972.
[18] N. Kanaya, H. Ishihara, Y. Kimura, T. Ishiyama, Y. Ochiai, PCT Int. Appl. (2004).
WO 2004069824 A1 20040819.
3.2.2. Computational details
The optimization of the geometries of the structures were first
carried out at the B3LYP/6-31G* (and then reoptimized at the
B3LYP/6-311++G** computational level [26–31] within the Gauss-
ian-03 package [32]. Frequency calculations at the B3LYP/6-31G*
were carried out to confirm that the obtained structures corre-
spond to energy minima. GIAO absolute shieldings [33,34] were
calculated on the B3LYP/6-311++G** optimized geometries
[B3LYP/6-311++G(d,p)//B3LYP/6-311++G(d,p)]. The structure of
the dimer has been obtained using the M052x functional [35]
and the 6-31+G(d,p) basis set. This functional has been shown to
be suitable for the description of a variety of weak molecular inter-
actions [36].
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Acknowledgements
This work was carried out with financial support from the Min-
isterio de Educación y Ciencia (Project No. CTQ2007-62113 and
61901/BQU) and Comunidad Autónoma de Madrid (Project MAD-
RISOLAR, ref. S-0505/PPQ/0225). Mario Alvarado acknowledges a
Grant from RETICS RD06/001/0014 (Instituto de Salud Carlos III).
S.G.-G. gratefully acknowledges the financial support from MEC,
projects MAT2006-01997 and Consolider Ingenio-2010, ‘Factoría
Española de Cristalización’.
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