Synthesis and crystal structure of ethyl 2-[4-(acetylamino)phenoxy]-2- methylpropanoate, a potential anti-inflammatory and antidyslipidemic hybrid

Article abstract of DOI:10.1007/s10870-010-9964-7

The compound ethyl 2-[4-(acetylamino)phenoxy]-2-methylpropanoate (acetamidofibrate) was prepared by reaction of paracetamol with ethyl 2-bromo-2-methylpropionate. It was characterized by elemental analysis, NMR (¹H, ¹³C) spectroscopy

Full text of DOI:10.1007/s10870-010-9964-7

J Chem Crystallogr (2011) 41:732–736
DOI 10.1007/s10870-010-9964-7
ORIGINAL PAPER
Synthesis and Crystal Structure of Ethyl
2-[4-(acetylamino)phenoxy]-2-methylpropanoate, A Potential
Anti-inflammatory and Antidyslipidemic Hybrid
•
Gabriel Navarrete-Vazquez Hector Torres-Gomez
•
´
Jorge Guerrero-Alvarez Hugo Tlahuext
´
´
´
•
Received: 15 July 2009 / Accepted: 31 December 2010 / Published online: 11 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The compound ethyl 2-[4-(acetylamino)phen-
oxy]-2-methylpropanoate (acetamidofibrate) was prepared
by reaction of paracetamol with ethyl 2-bromo-2-methyl-
propionate. It was characterized by elemental analysis,
NMR (1H, 13C) spectroscopy, and single-crystal X-ray
diffraction. This compound is of interest with respect to its
potential bioactivity as analgesic and antidyslipidemic
agent. The compound crystallizes in the monoclinic space
group P2(1)/c with unit cell dimensions a = 8.2435(8),
Introduction
Fibrates, such as bezafibrate, clofibrate and fenofibrate,
which are ligands for the nuclear receptor PPAR a
(Peroxisome Proliferator-Activated Receptor), are used as
therapeutic agents in the treatment of dyslipidemia, heart
disease and diabetic complications in humans. The fibrates
are a widely used class of lipid-modifying agents that
decrease plasma triglycerides [1–3]. The fibrate pharma-
cophore has been of interest to medicinal chemists ever
since the initial discovery that ethyl chlorophenoxyisobu-
tyrate possessed hypolipidemic properties [4]. On the
other hand, paracetamol is widely used over-the-counter
analgesic and antipyretic agent [5].
˚
b = 9.3390(9), c = 18.2823(18) A, b = 91.123(2)°, V =
3
1407.2(2) A , Z = 4, R1 = 0.0465, and wR2 = 0.1055.
˚
The crystal structure is stabilized by N–HÁÁÁO = C and
C–HÁÁÁO hydrogen-bonding interactions that interconnect
molecules into chains running along b axis. The pre-
liminary in silico screening shown that title compound
could posse’s antidiabetic, anti-inflammatory, hypolipem-
iant and anti-atherosclerosis effects.
In order to assist our knowledge about the electronic and
steric requirements from these kinds of molecules to
shown antihyperlipidemic activity, we have synthesized
and determined the crystal structure of two closed-related
nitro and thio-fibrate analogues [6, 7]. In our ongoing
research on fibrate derivatives with antihyperlipidemic
activity, we have synthesized the compound ethyl
2-[4-(acetylamino)phenoxy]-2-methylpropanoate (acetam-
idofibrate), which is a bioisoster of clofibrate, with an
acetamide group instead of chlorine atom. Also, the
structure resembles to paracetamol, a well-known analgesic
and antipyretic agent (Scheme 1).
Keywords Fibrates Á Antidislypidemic activity Á
Crystal structure Á Hydrogen bonds
´
´
G. Navarrete-Vazquez (&) Á H. Torres-Gomez
´
Both hybridized pharmacophoric groups into the ace-
tamidofibrate, could retain the bioactivities mentioned
before, and the structure of the acetamidofibrate, could be a
promise of a new biologically active chemical entity. The
design of the compounds was based on the biological
activity predictions made by the computer software
PASSÒ (Prediction of Activity Spectra for Substances).
This software illustrates the predicted activity spectrum of
a compound as probable activity (Pa) and probable
Facultad de Farmacia, Universidad Autonoma del Estado de
Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca,
Morelos 62209, Mexico
e-mail: gabriel_navarrete@uaem.mx
´
J. Guerrero-Alvarez Á H. Tlahuext
´
Centro de Investigaciones Quımicas,
Universidad Autonoma del Estado de Morelos,
´
Av. Universidad 1001, Chamilpa, Cuernavaca,
Morelos 62209, Mexico
e-mail: tlahuext@ciq.uaem.mx
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J Chem Crystallogr (2011) 41:732–736
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Scheme 1 Structures of
clofibrate, paracetamol
and the hybrid designed
O
O
O
O
H
N
H
N
HO
O
Cl
O
O
O
Clofibrate
Paracetamol
Acetamidofibrate
Scheme 2 Synthesis of
acetamidofibrate
K2CO3
DMSO, 80°
Synthesis of Ethyl 2-[4-(Acetylamino)phenoxy]-
2-methylpropanoate
inactivity (Pi) with the accuracy of prediction reported to
be as high as 85% [8].
In view of these facts and in order to search for new
compounds with improved biological activity, the present
investigation deals with the synthesis of acetamidofibrate,
as outlined in Scheme 2, which might have useful bio-
logical and therapeutic activities. The crystal structure of
title compound determined by single-crystal X-ray dif-
fraction, and a theoretical and predictive bioactivity spec-
trum are also reported.
Paracetamol (2.5 g, 0.013 mol) and potassium carbonate
(4.57 g, 0.033 mol) were dissolved in the minimum
amount of dimethyl sulfoxide and were heated at 40 °C.
After 20 min, the ethyl 2-bromo-2-methylpropionate
(3.19 mL, 0.0210 mol) was added dropwise and the reac-
tion mixture was heated to reflux (80 °C) and monitored by
TLC (Scheme 2). After the reaction completion (15 h), the
reaction mixture was filtered and solid residue was washed
off with acetone (10 mL). The total mother liquors were
concentrated under reduced pressure and then poured into
water and extracted with ethyl acetate (3 9 15 mL). The
organic layer was dried over anhydrous Na2SO4 and
partially evaporated under reduced pressure. The residues
crystallized as a white solid. The crystals were washed with
cold acetone, yielding 2.3 g after crystallization (53.4%),
m. p. 90–93°C. Elemental analysis (Found: C, 63.38; H,
7.07; N 5.52. Calc. for C14H19NO4: C, 63.38; H, 7.22; N,
5.28). 1H NMR data (200 MHz; DMSO-d6; Me4Si) d: 1.17
(3H, t, J = 7.3, H-12), 1.47 (6H, s, H-9 and H-10), 2.00
(3H, s, H-14), 4.15 (2H, q, J = 7.3, H-11), 6.75 (2H, d,
J = 8.7, H-2 and H-6), 7.45 (2H, d, J = 8.7, H-3 and H-5),
9.83 (1H, bs, N–H). 13C NMR (50 MHz, DMSO-d6) d:
14.62 (C-12), 24.50 (C-14), 25.71 (C-9, C-10), 61.61
(C-11), 79.55 (C-7), 120.30 (C-2, C-6), 120.67 (C-3, C-5),
134.73 (C-4), 150.98 (C-1), 168.44 (C-13), 173.77 (C-8).
EI-MS: m/z (rel. int.) 265 (M?, 25%).
Experimental
Materials and Measurements
All starting materials and reagents were obtained com-
mercially and were used as received. Melting point was
determined on an EZ-Melt MPA120 automated melting
point apparatus from Stanford Research Systems and is
uncorrected. Reactions were monitored by TLC on 0.2 mm
precoated silica gel 60 F254 plates (E.Merck). NMR
studies were carried out with a Varian Mercury 200
instrument. Chemical shifts (dH, dC) and coupling con-
stants values (J) values are given in ppm and Hz, respec-
tively. Standard reference was used: TMS (dH = 0,
dC = 0) in DMSO-d6. The following abbreviations are
used: s, singlet; d, doublet; q, quartet; t, triplet; bs, broad
signal. Mass spectra was recorded on a Jeol JMS-700
equipment. Elemental analysis has been carried out on
an Elementar Vario ELIII instrument. Predictive values
of biological activities were also investigated using the
chemistry software server PASS (http://195.178.207.
233/PASS/).
X-Ray Crystallography
X-ray diffraction studies were performed on a Bruker-APEX
diffractometer equipped with
a
CCD area detector
123

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J Chem Crystallogr (2011) 41:732–736
˚
˚
(k = 0.71073 A, monochromator: graphite). Frames were
collected at T = 293 K via x//-rotation at 10 s per frame
(SMART) [12]. The measured intensities were reduced to
F2 and corrected for absorption with SADABS (SAINT-NT)
[13]. Corrections were made for Lorentz and polari-
zation effects. Structure solution, refinement and data
output were carried out with the SHELXTL-NT program
package [14, 15]. Non-hydrogen atoms were refined
anisotropically. N–H hydrogen atom has been localized by
difference Fourier map and could be refined, resulting in
Table 2 Bond distances (A) and angles (°) for the compound
Bond distances
C1–O1
1.3811(19) C7–C10
1.513(3)
1.540(2)
1.202(2)
1.331(2)
1.458(2)
1.504(3)
1.224(2)
1.350(2)
1.505(2)
0.85(2)
C1–C6
1.388(2)
1.391(2)
1.380(2)
1.395(2)
1.385(2)
1.423(2)
1.389(2)
1.441(2)
1.526(2)
C7–C8
C1–C2
C8–O2
C2–C3
C8–O3
C3–C4
C11–O3
C11–C12
C13–O4
C13–N1
C13–C14
N1–H1
C4–C5
C4–N1
C5–C6
˚
N–H distance of 0.85(2) A. Nevertheless, the aryl, meth-
C7–O1
ylene and methyl H atoms were constrained using a riding
model approximation. The crystallographic data for the
compound are summarized in Table 1. Selected bond
lengths, and bond angles are listed in Table 2. Hydrogen
bonding interactions are listed in Table 3. Crystallographic
data for the structure reported in this paper has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication No. CCDC-737613.
C7–C9
Bond angles
O1–C1–C6
O1–C1–C2
C6–C1–C2
C3–C2–C1
C2–C3–C4
C5–C4–C3
C5–C4–N1
C3–C4–N1
C4–C5–C6
C1–C6–C5
O1–C7–C9
O1–C7–C10
C9–C7–C10
O1–C7–C8
126.20(15)
114.50(14)
119.30(15)
120.98(15)
119.97(15)
118.89(15)
118.80(15)
122.26(15)
121.30(15)
119.55(15)
103.91(14)
112.29(14)
110.05(15)
111.00(13)
C9–C7–C8
107.86(14)
111.38(14)
124.66(16)
123.76(16)
111.50(14)
109.75(14)
122.76(16)
121.81(15)
115.42(15)
125.87(15)
116.2(13)
C10–C7–C8
O2–C8–O3
O2–C8–C7
O3–C8–C7
O3–C11–C12
O4–C13–N1
O4–C13–C14
N1–C13–C14
C13–N1–C4
C13–N1–H1
C4–N1–H1
C1–O1–C7
C8–O3–C11
Table 1 Crystal data and refinement parameters for the compound
CCDC
737613
116.4(13)
Molecular formula
Molecular weight
Crystal system
Space group
C14 H19 N O4
265.30
121.45(13)
117.04(14)
Monoclinic
P2(1)/c
Torsion angles [°] for Compound
O4–C13–N1–C4
C8–C7–O1–C1
O1–C7–C8–O3
-2.0(3)
C12–C11–O3–C8
O2–C8–O3–C11
C9–C7–O1–C1
88.08(18)
5.6(2)
Temperature
273(2) K
8.2435(8)
9.3390(9)
18.2823(18)
91.123(2)
1407.2(2)
4
58.30(19)
40.99(18)
˚
a (A)
173.99(14)
˚
b (A)
˚
c (A)
b (°)
3
˚
˚
Table 3 Distances (A) and angles (8) involving hydrogen bonding of
the compound
V (A )
Z
Dcalc (Mg/m3)
1.252
D–HÁÁÁA
D(D–H) D(HÁÁÁA) D(DÁÁÁA) \(D–HÁÁÁA)
˚
(A)
˚
(A)
˚
(A)
Crystal dimensions (mm); colour
Absorption coefficient (mm-1)
Radiation k
0.31 9 0.15 9 0.12, colourless
0.092
N1–H1ÁÁÁO4i
C5–H5ÁÁÁO2ii
C6–H6ÁÁÁO2ii
0.85(2)
0.93
2.03(2)
2.57
2.864(2)
3.182(2)
3.184(2)
3.406(2)
169(2)
124
˚
Mo Ka (0.71073 A)
Tmin/Tmax
0.972/0.989
0.93
2.58
123
C14–H14BÁÁÁO4i 0.96
2.60
142
Reflections measured
Range/indices (h, k, l)
h limit (°)
9,973
-9, 9; -10, 11; -21, 21
Symmetry codes: (i) 2 - x, -1/2 ? y, ‘ - z; (ii) 1 - x, -y, 1 – z
2.23 to 25.0
Total no. of unique data
No. of observed data, I [ 2r(I)
No. of variables
2,480 [Rint = 0.0275]
2,292
In Silico Bioactivity Predictions
180
No. of restraints
0
Before the establishment of an in vitro bioassay, we
obtained predictive values concerning biological activities
by comparing the chemical structures of the compound
designed, with structures or substructures of more than
Goodness-of-fit on F2
R1, wR2 [I [ 2r(I)]
R1, wR2 (all data)
1.134
0.0465, 0.1035
0.0504, 0.1055
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J Chem Crystallogr (2011) 41:732–736
735
46,000 well-known biologically active drugs included in
the database of software named Prediction of Activity
Spectra for Substances (PASS) [8–11]. Thus, PASS-based
computer pre-screening of large databases of diverse
compounds can increase the probability of finding bioactive
new chemical agents, and reduce the number of compounds
that have to be synthesized and tested experimentally. The
results of prediction, estimate that compounds will be active
respect to the probability Pa. For Pa values [0.7, the cor-
responding compound is very likely to reveal this activity in
experiments, but in that case, the chance of the compound
being the analogue of a known pharmaceutical agent is also
high. For Pa values between 0.5 and 0.7, the compound is
likely to reveal this activity in experiments and the com-
pound exhibits less similarity to the known pharmaceutical
agents. For Pa values lower than 0.5, the compound is
unlikely to reveal this activity in experiments, but if the
presence of this activity is confirmed in experiments, the
compound might be a new biologically active chemical
entity.
Results and Discussion
Single crystal of acetamidofibrate was grown at room
temperature by slow evaporation of ethyl acetate solution.
Figure 1 gives perspective view of the compound with the
atomic labeling system.
Crystal Structure Description
All the bond lengths in the compound are within nor-
mal ranges [16], and comparable to those of the simi-
lar compounds [6, 7]. The dihedral angle between
Fig. 1 Molecular structure of the compound. Displacements ellip-
soids are drawn at the 50% probability level and H atoms are shown
as small spheres of arbitrary radii; numbering according to Table 2
Fig. 2 Perspective view of the
molecular packing of
compound. The intermolecular
hydrogen bonds N–HÁÁÁO and
C–HÁÁÁO are shown as dotted
lines. Most of the hydrogen
atoms are omitted for clarity
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J Chem Crystallogr (2011) 41:732–736
Atherosclerosis treatment
Table 4 Predictive values of biological activities calculated with PASS for title compound
Antidiabetic
Anti-inflammatory
Hypolipemic
PPARa agonist
Pa
Pi
Pa
Pi
Pa
Pi
Pa
Pi
0.003
Pa
Pi
0.841
0.002
0.743
0.086
0.918
0.002
0.841
0.898
0.002
4-(acetylamino)phenoxy moiety and the ethyl-2-methyl-
propanoate is 58.30(19)8. Intermolecular N1–H1ÁÁÁO4i and
C14-H14BÁÁÁO4i hydrogen bonds [symmetry code: (i) 2 - x,
-1/2 ? y, 1/2 - z], links molecules into chains running
along the b axis (Table 3). In the crystal packing there are
also weak C–HÁÁÁO interactions between the aryl H atoms on
C5 and C6 and the O2 atom of an adjacent molecule, forming
R12(6) motifs [17]. Two ring structures can be identified (I and
II) (Fig. 2).
charge at http://www.ccdccam.ac.uk/const/retrieving.html
or from the Cambridge Crystallographic Data Centre
(CCDC), 12 Union Road, Cambridge CB2 1EZ, UK;
fax: ? 441223-336033 or e-mail: deposit@ccdc.cam.
ac.uk.
Acknowledgments This work was supported by the Consejo
´
Nacional de Ciencia y Tecnologıa (CONACyT) under grant No.
100608, Facultad de Farmacia internal grant, and Fondo de Consol-
´
idacion PROMEP-UAEM/09/349. HTG is grateful to CONACyT for
the scholarship grant 228019 to carry out Master degree studies.
In Silico PASS Screening
References
An approach to computer-aided prediction of the general
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Results presented in Table 4 describe four biological
activities taken from PASS software: antidiabetic, anti-
inflammatory, hypolipemiant and anti-atherosclerosis
effects. Pa values estimated for all activities were ranging
between 0.74 and 0.91. These results indicated that com-
pound exhibited chemical levels of similarity to those of
known antidiabetic, anti-inflammatory and antidislipidemic
drugs, and are likely to reveal these activities in in vitro or
in vivo tests. The predictions include a specific target as
PPAR-a agonist.
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Supplementary Material
CCDC-737613 contains the supplementary crystallo-
graphic data for this paper. The data can be obtained free of
123