Fenofibric acid

Article abstract of DOI:10.1107/S0108270104032573

Unlike the related fenofibrate molecule [Henry, Zhang, Gao & Bruckner (2003). Acta Cryst. E59, o699-o700], fenofibric acid {systematic name: 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid}, C₁₇H ₁₅ClO₄, contains a carboxylic acid moiety instead of an ester moiety. This polar moiety plays an important role in the formation of a rare acid-to-ketone hydrogen-bond-type packing interaction. The lack of an isopropyl group in fenofibric acid aligns the carboxyl group on the same side as the ketone carbonyl group; this conformation may play an important role in discrimination between the acid and the fenofibrate molecule in molecular recognition.

Full text of DOI:10.1107/S0108270104032573

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
feno®bric acid is not commercially available, we have
prepared it in our laboratory by alkaline hydrolysis following
modi®ed conditions for biochemical studies. In this article, we
describe the synthesis, crystallization and structural char-
acterization of feno®bric acid. This is the ®rst crystal structure
report of feno®bric acid.
ISSN 0108-2701
Fenofibric acid
Nigam P. Rath,a Wahajul Haqb and Ganesaratnam K.
Balendiranc*
aDepartment of Chemistry and Biochemistry, University of Missouri±St Louis,
MO 63121, USA, bMedicinal Chemistry Division, Central Drug Research Institute,
Lucknow 226 001, India, and cDivision of Immunology, Beckman Research Institute
and City of Hope National Medical Center, 1450 E. Duarte Road, Duarte, CA 91010,
USA
Correspondence e-mail: gbalendiran@coh.org
Received 4 November 2004
Accepted 9 December 2004
Online 15 January 2005
The CÐO bond distances in the carboxyl group of feno-
®bric acid indicate that it is in the acid form [C15 O3 =
Ê
Ê
1.2014 (19) A and C15ÐO4 = 1.3248 (19) A; Table 1] rather
than the carboxylate form. This observation is further
con®rmed by the location and re®nement of the acidic H
atom. The molecules form strong hydrogen-bonded dimers as
a result of the presence of the carboxyl OH group (Table 2).
The two molecules in the dimer (Fig. 2) are related by an
inversion center. The dimer is formed by hydrogen bonding
between the carbonyl O atom of the ketone moiety in one
feno®bric acid molecule and the carboxyl OH group of the
second molecule, rather than by the more usual hydrogen-
bonding interaction between two carboxylic acid groups. The
crystal packing, viewed down the a axis, shows that the dimers
form layers that stack in the b direction and form a zigzag
pattern in the bc plane (Fig. 3). By contrast, feno®brate, which
is the isopropyl ester of feno®bric acid, does not have the
hydroxy H atom required for the formation of the hydrogen-
bonding interaction and so packs in a completely different way
(Henry et al., 2003).
Unlike the related feno®brate molecule [Henry, Zhang, Gao
& Bruckner (2003). Acta Cryst. E59, o699±o700], feno®bric
acid {systematic name: 2-[4-(4-chlorobenzoyl)phenoxy]-2-
methylpropanoic acid}, C17H15ClO4, contains a carboxylic
acid moiety instead of an ester moiety. This polar moiety plays
an important role in the formation of a rare acid-to-ketone
hydrogen-bond-type packing interaction. The lack of an iso-
propyl group in feno®bric acid aligns the carboxyl group on
the same side as the ketone carbonyl group; this conformation
may play an important role in discrimination between the acid
and the feno®brate molecule in molecular recognition.
Comment
Fibrates, such as beza®brate, clo®bric acid and feno®brate,
which are ligands for the nuclear receptor PPARꢀ (peroxi-
some proliferator-activated receptor ꢀ), are used as thera-
peutic agents in the treatment of hyperlipidemia, heart disease
and diabetic complications (Throp, 1962; Miller & Spence,
1998; Forcheron et al., 2002). Feno®brate (TRICOR) is a lipid-
regulating agent available as tablets for oral administration
(Adkins & Faulds, 1997; Guay, 1999; Keating & Ormrod,
2002). Feno®brate treatment also reduces the angiographic
progression of coronary-artery disease in type 2 diabetes
(Taniguchi et al., 2001). Following oral administration, feno-
®brate is rapidly hydrolyzed by esterases to its active meta-
bolite, viz. feno®bric acid, (I). Unchanged feno®brate has
been reported to be undetectable in plasma samples following
an oral dose (Streel et al., 2000). The mechanism of action of
feno®brate and its metabolites is not fully understood. Feno-
®bric acid is also an activator of PPARꢀ, which ultimately
results in the reduction of triglycerides, total cholesterol and
low-density lipoprotein cholesterol (LDL-C), as well as an
increase in high-density lipoprotein cholesterol (HDL-C)
(Adkins & Faulds, 1997; Guay, 1999; Keating & Ormrod,
2002). Our lead optimization effort indicates that feno®bric
acid may have improved potency over beza®brate. Since
Feno®bric acid utilizes a rare hydrogen-bonding pattern to
form intermolecular dimers, rather than the acid-to-acid
hydrogen-bonding dimerization that is most common in
carboxylic acids. Ketocarboxylic acid-type compounds, such as
feno®bric acid, contain only one acidic donor H atom and two
possible acceptors, namely the O atoms in the ketone carbonyl
and carboxyl moieties of the organic acid. Studies have
Figure 1
A view of the molecule of (I). Non-H atoms are shown with 50%
probability displacement ellipsoids.
Acta Cryst. (2005). C61, o81±o84
DOI: 10.1107/S0108270104032573
# 2005 International Union of Crystallography o81

organic compounds
Ê
atoms are more than 6.8 A in feno®bric acid. This distance is
established that ketocarboxylic acids exhibit ®ve hydrogen-
bonding modes or patterns (Newman et al., 2002), viz. acid-to-
acid dimer (Barcon et al., 2002), acid-to-ketone catemer
too long to allow the formation of intramolecular hydrogen-
bonding interactions and may explain why feno®bric acid does
not form an intramolecular hydrogen-bonding interaction.
Alignment of the sp2 ketone moiety (the C4/C7/O1/C8
plane) of feno®bric acid and the corresponding plane in the
feno®brate molecule reveals that the carboxyl moiety is
positioned almost on the same side as the ketone carbonyl
group in feno®bric acid (Fig. 4). This conformation may
facilitate the formation of intermolecular CÐOÁ Á ÁHÐO
hydrogen bonding over the carboxyl OH dimer. However, the
carboxyl moiety of the feno®brate molecule is located away
from the ketone carbonyl group, at the back of the molecule.
Â
(Barcon et al., 2002), intramolecular or internal (Cote et al.,
1996), acid-to-acid catemer (Lalancette et al., 1998), and acid-
to-ketone dimer (Newman et al., 2002). Analysis of the
structural entries in the Cambridge Structural Database (CSD;
Allen, 2002) reveals that acid-to-acid dimerization and acid-
to-ketone catemer hydrogen-bonding patterns are the most
common (Leiserowitz, 1976; Lalancette et al., 1998), while
intramolecular, acid-to-acid catemer and acid-to-ketone dimer
Â
hydrogen-bonding patterns are rare (Cote et al., 1996). We
have identi®ed six compounds in the CSD that form acid-to-
ketone hydrogen-bonding patterns out of 92 compounds in the
literature. These six compounds are BOZTUF (Peters et al.,
1983), FAZGAO (Nuhrich et al., 1986), JIKDEM (Abell et al.,
1991), TEVGIK (Kosela et al., 1995), EFANEE (Newman et
al., 2002) and MOZZOQ (Armstrong et al., 2002). Thus,
feno®bric acid is the seventh compound to join a very small
number of examples in the CSD that form acid-to-ketone
hydrogen-bonding dimers.
The intramolecular hydrogen-bonding pattern involving a
carbonyl O atom and a carboxyl OH group has been found in
only a few organic acids. Formation of the intramolecular
hydrogen-bonding pattern requires mostly a seven-membered
hydrogen-bonded ring arrangement (Griffe et al., 1972; Shel-
drick & Trowitzsch, 1983; Halfpenny, 1990; Abell et al., 1990).
The distances between carbonyl atom O1 and the carboxyl O
Figure 3
A packing diagram of feno®bric acid, in the orthorhombic space group
Pbca, viewed along the a axis.
Figure 4
A view down the C4/C7/O1/C8 plane along the C O double-bond
direction of the ketone moiety. Feno®bric acid and feno®brate are
superimposed with black and grey, respectively. Feno®bric acid atom
labels O1, O3 and O4 are shown, while the corresponding carboxyl atoms
of feno®brate are denoted by O labels.
Figure 2
A dimer of feno®bric acid, showing the rare acid-to-ketone hydrogen-
bonding pattern. The symmetry operator ( x, y, 1 z) was used to
generate atoms labeled with the suf®x A.
ꢀ
o82 Nigam P. Rath et al.
C17H15ClO4
Acta Cryst. (2005). C61, o81±o84

organic compounds
Re®nement
This conformation may be due to steric effects and packing
interactions, which are caused by the presence of the isopropyl
group. This phenomenon may play a signi®cant role in
distinguishing feno®bric acid as an activator of PPARꢀ over
feno®brate. In general, if polar groups, such as the carbonyl
and carboxyl groups in feno®brate and feno®bric acid, are
involved in the formation of speci®c interactions with their
target molecules, the orientation of these moieties will alter
the binding af®nities. Alternatively, these O atoms may change
the binding orientation with a given target molecule.
Re®nement on F2
R[F2 > 2ꢃ(F2)] = 0.042
wR(F2) = 0.099
S = 1.11
3497 re¯ections
w = 1/[ꢃ2(F2o) + (0.0404P)2
+ 1.7773P]
where P = (F2o + 2Fc2)/3
(Á/ꢃ)max < 0.001
3
Ê
Áꢄmax = 0.32 e A
3
Ê
0.29 e A
259 parameters
All H-atom parameters re®ned
Áꢄmin
=
Table 1
Selected geometric parameters (A, ).
ꢂ
Ê
O1ÐC7
O2ÐC11
O2ÐC14
1.2353 (18)
1.3689 (17)
1.4430 (17)
O3ÐC15
O4ÐC15
1.2014 (19)
1.3248 (19)
Experimental
Feno®bric acid was prepared by alkaline hydrolysis of feno®brate
under mild conditions, according to the procedures described below.
Feno®brate (300 mg) was suspended in methanol (10 ml), and a 2 N
NaOH solution (1 ml) was added to the reaction mixture. Stirring was
continued for several hours at room temperature. Thin-layer chro-
matography (TLC) was used to monitor the progress of the reaction.
The reaction mixture contained approximately 10% hydrolyzed
material and 90% starting material as the intact ester form. The
hydrolysis did not proceed further, even after 15±16 h of stirring, and
a major amount of starting material was recovered after work-up. In a
second experiment, feno®brate (300 mg) was suspended in methanol
(10 ml), 2 N NaOH (2.5 ml) was added, and the resulting suspension
was stirred at 343 K for 4 h. The reaction mixture became a clear
solution during this period (quantitative conversion as per TLC). The
solvent was removed under reduced pressure and water (5 ml) was
added to the residue. This solution was acidi®ed to an approximate
pH of 2 by adding 2 N hydrochloric acid. At a pH of ꢁ2, a thick
precipitate formed. The precipitate was extracted in ethyl acetate
(25 ml), and the organic layer was washed three times with brine,
dried over sodium sulfate and concentrated to a solid residue. The
residue was crystallized from ethyl acetate/hexane to obtain feno-
®bric acid as a white powder (>97% pure, high-performance liquid
chromatography) in excellent yield (>85%). To obtain single crystals,
feno®bric acid (5.0 mg) was dissolved in high-purity absolute ethanol
(225 ml) and heated at 313 K in a water bath. To this solution was
added deionized water (25 ml) and the tube was shaken under vortex
for 2 min. The clear solution was allowed to cool slowly to room
temperature and was left overnight. After several hours, colorless
plate-like crystals started to form in the tube; these were preserved by
sealing the tube and were stored for structural characterization and
future studies.
C11ÐO2ÐC14
O3ÐC15ÐO4
122.62 (11)
124.54 (15)
O3ÐC15ÐC14
O4ÐC15ÐC14
124.35 (14)
111.05 (13)
C4ÐC7ÐC8ÐC9
C11ÐO2ÐC14ÐC15
30.5 (2)
68.90 (17)
O2ÐC14ÐC15ÐO3
18.6 (2)
Table 2
Hydrogen-bonding geometry (A, ).
ꢂ
Ê
DÐHÁ Á ÁA
O4ÐH4Á Á ÁO1i
DÐH
HÁ Á ÁA
1.72 (3)
DÁ Á ÁA
DÐHÁ Á ÁA
0.91 (3)
2.6264 (17)
170 (3)
Symmetry code: (i) x; y; 1 z.
All H atoms were located in difference Fourier maps and were
re®ned freely using isotropic displacement parameters [OÐH =
Ê
0.91 (3) A and CÐH = 0.936 (18)±0.986 (14) A].
Ê
Data collection: SMART (Bruker, 2003); cell re®nement: SMART;
data reduction: SAINT (Bruker, 2003); program(s) used to solve
structure: SHELXTL (Sheldrick, 2003); program(s) used to re®ne
structure: SHELXTL; molecular graphics: SHELXTL; software used
to prepare material for publication: SHELXTL.
This work was supported by funding from the American
Diabetes Association and the Beckman Research Institute of
the City of Hope. Funding for the X-ray diffractometer was
provided by the National Science Foundation.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SQ1185). Services for accessing these data are
described at the back of the journal.
Crystal data
3
C17H15ClO4
Mr = 318.74
Orthorhombic, Pbca
Dm = no Mg m
Mo Kꢀ radiation
Cell parameters from 8481
re¯ections
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Ê
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C17H15ClO4
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