Practical synthesis of fenbufen ethanolamide

Article abstract of DOI:10.1002/ardp.200400888

The ongoing interest in ethanolamide derivatives of anti-inflammatory drugs as potential synthetic cannabinoids and mechanistic tools for the study of cannabinoid and vanilloid receptors prompted us to develop a practical gram scale synthesis for the hith

Full text of DOI:10.1002/ardp.200400888

546 Link et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 546−548
Vida Zohrabi-Kalantari,
Andreas Link
Practical Synthesis of Fenbufen Ethanolamide
The ongoing interest in ethanolamide derivatives of anti-inflammatory drugs as
potential synthetic cannabinoids and mechanistic tools for the study of canna-
binoid and vanilloid receptors prompted us to develop a practical gram scale
synthesis for the hitherto unknown ethanolamide of fenbufen. Dehydration of
fenbufen leads to intramolecular ring closure yielding bright pink crystals of the
intramolecular enol ester. Reaction of this activated but stable intermediate with
ethanolamine leads to the title compound in good yield and purity without the
necessity to remove coupling reagents or residual activating groups, such as
N,N-dialkyl ureas and fluorinated phenols.
Institute of Pharmaceutical
Chemistry, Philipps-Universität,
Marburg, Germany
Keywords: Anandamide; Enol ester; Fenbufen; Acylation
Received: March 25, 2004; Accepted: July 30, 2004 [FP888]
DOI 10.1002/ardp.200400888
Results and discussion
Introduction
Recently, it was revealed that AM404 (1) interacts with
The recently discovered role of AM404, N-(4-hydroxy-
phenyl)-5,8,11,14-eicosatetraenamide, 1 as an active
metabolite of paracetamol/acetaminophen sheds new
light on the question whether amide conjugates of
other known pain-relieving drugs contribute to the
mechanism of action of these agents, too [1]. Paraceta-
mol differs from most NSAIDs in that it is a weak anti-
inflammatory agent that does not generate the typical
side effects related to COX-1 inhibition. Although ex-
tensively used as antipyretic and analgesic for more
than a century, its mechanism of action is still widely
unsolved [2]. Selective inhibition of prostaglandin syn-
thesis in brain, consistent with a central site of action,
has been proposed. However, evidence is weak: para-
cetamol is no potent inhibitor of isolated COX-1 and
COX-2. The postulated target COX-3 does not seem
to be present in the human brain in sufficient
amounts [3].
vanilloid and cannabinoid receptors, and it might be
strongly anticipated today that interaction with these
receptors might help to understand hitherto obscure
clinical effects of other analgesic drugs such as
fenbufen (4). Conjugation of fenbufen (4) with ethanol-
amine might be a prerequisite for a probable contri-
bution to the mode of action of these analgesic drugs
[6].
Looking at the structure of the active metabolite
AM404 (1) formed after ingestion of paracetamol, an-
andamide (2) and the novel fenbufen ethanolamide 3
(see Figure 1), it seems rewarding to develop a high
yielding synthesis for this hitherto unknown fenbufen
derivative.
The synthesis of the title compound started from com-
mercially available fenbufen (4)(Scheme 1). In order
to avoid toxic and costly coupling reagents such as
N,N-dialkyl carbodiimides, acylated succinic imides or
pentafluoro phenol esters, fenbufen was dehydrated
by means of acetic anhydride. The resulting intramol-
ecular enol ester (5) could effortlessly be purified by
crystallization.
The endogenous fatty acid anandamide (arachidonoyl-
ethanolamide) 2 is hydrolyzed to arachidonic acid and
ethanolamine by fatty acid amide hydrolase (FAAH)
and, vice versa, ethanolamine and arachidonic acid
are reacted to form anandamide [4,5]. It is now hypo-
thesized that paracetamol, following deacetylation to
4-amino phenol, is similarly conjugated with arachi-
donic acid to form AM404 (1) in the CNS [1]. The
possible role of FAAH in formation of conjugates of
ethanolamine to xenobiotic acids is yet to be explored.
The beautifully glossy, bright pink crystals of com-
pound 5 are shelf-stable at room temperature and can
easily be obtained in multi-gram quantities. This is an
advantage in comparison to the possible preparation
of acid chloride derivatives of the starting material fen-
bufen. Ring-opening of the enol ester (5) by chemose-
lective reaction with ethanolamine (6) as N-nucleo-
phile in dry toluene yielded the desired target compound
in good yield and purity (Scheme 2). The development
of N-selective acylation procedures that allow for the
evasion of protecting groups operations represents a
Correspondence: Andreas Link, Institute of Pharma-
ceutical
Chemistry,
Philipps-Universität
Marburg,
Marbacher Weg 6, D-35037 Marburg, Germany. Phone:
+49 6421 282-5900, Fax: +49 6421 282-5901, e-mail:
link@mailer.uni-marburg.de.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 546−548
Practical Synthesis of Fenbufen Ethanolamide 547
Scheme 1. Preparation of the enol ester 5; i: a) tolu-
ene, reflux, b) acetic acid anhydride, reflux 6 h.
Figure 1. Structural comparison of AM-404 (1), anand-
amide (2), and amide 3.
general concern in the synthesis of natural product-
like compounds that are often decorated with reactive
primary alcoholic functions. Such approaches have
been explored by our group in detail [7Ϫ13]. In this
case, the absence of the tendency to form esters is
a benefit of the moderate reactivity of compound 5.
Comparable to the use of pentafluoro phenol esters
for the synthesis of ethanolamides, attack by O-nucle-
ophiles is negligible, the desired amides are the single
products, even under forcing conditions.
In comparison to standard procedures for the syn-
thesis of amides using activated esters as coupling re-
agents or in situ formed anhydrides, the lack of
sources for impurities using the inner ester 5 is a
strong advantage. Since neither formation of diisopro-
pyl urea nor liberation of pentafluoro phenol or pyrrol-
idine-2,5-dione occur, work-up of the reaction mixture
is straightforward. The crude reaction product is al-
ready pure and a single crystallization from a standard
Scheme 2. Preparation of fenbufen ethanolamide (3);
i: toluene, room temp.
solvents yields analytically pure material, as proven by
combustion analysis and HPLC.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

548 Link et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 546−548
ded. The reaction mixture was stirred at room temperature
and monitored by TLC. Quantitative conversion was ob-
served after 4 h. The suspension was filtered and the residual
solid crystallized from ethanol to yield 429 mg (76%) of yel-
Conclusion
The rapidly growing understanding of the cannabinoid
system as an important endogenous regulator of
neuronal, cardiac, reproductive, and immune functions
demands molecular tools to study specific ligand-
receptor interactions, especially, as compounds are
currently developed for medical intervention. The
convenient, high yielding and practical synthesis of
fenbufen ethanolamide 3 is useful for the production
of this novel compound in gram scale and shall contri-
bute to investigations concerning the role of etha-
nolamide conjugation of fenbufen and to evaluate
biological activities of this novel fatty acid amide anal-
ogue.
1
lowish crystals. H NMR (500 MHz, DMSO-d6): δ (ppm) 8.05
(d, 2H, J = 8.7 Hz), 7.88 (t, 1H, J = 5.4 Hz), 7.83 (d, 2H, J =
8.7 Hz), 7.75 (d, 2H, J = 7.1 Hz), 7.51 (m, 2H), 7.43 (m, 1H),
4.63 (t, 1H, J = 5.5 Hz), 3.41 (q, 2H, J = 6.0 Hz), 3.26 (t, 2H,
J = 6.7 Hz), 3.13 (q, 2H, J = 6.0 Hz), 2.51 (d, 2H, J = 6.6 Hz
overlapping with DMSO signal.). 13C NMR (126 MHz, DMSO-
d6): δ (ppm) 198.40, 171.18, 144.32, 138.86, 135.40, 128.97,
128.47, 128.23, 126.85, 126.74, 59.87, 41.49, 33.38, 29.23.
IR (cmϪ1): 3298, 1685, 1638, 1560, 759. Combustion analy-
sis:% [C] 72.87 (calc. 72.71),% [H] 6.14 (calc. 6.44),% [N]
4.76 (calc. 4.71). Relative purity as determined by HPLC:
94%. Melting point: 157°C.
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Acknowledgments
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Funding by the Fonds der Chemischen Industrie is
gratefully acknowledged.
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Experimental
Structures were assigned by NMR spectroscopy. NMR spec-
tra were recorded on a JEOL ECLIPSE+500 spectrometer
(JEOL, Tokyo, Japan), using tetramethylsilane as internal
standard. IR spectra were recorded on a Nicolet 510P FT-
IR-spectrometer (Nicolet, Madison, MI, USA). TLC reaction
control was performed on Macherey-Nagel Polygram Sil G/
UV254 precoated microplates (Macherey-Nagel, Düren, Ger-
many). Spots were visualized under UV-illumination at 254
nm. Microanalyses were obtained from a Hewlett-Packard
CHN-analyzer type 185 (Hewlett-Packard, Palo Alto, CA,
USA).
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To a boiling solution of fenbufen (2.54 g, 9.98 mmol) in dry
toluene (40 mL), acetic acid anhydride was added dropwise
until all of the solid was dissolved and a bright red homogen-
ous liquid was obtained. The reaction was monitored by TLC.
Quantitative conversion was observed after 6 h of heating.
The reaction mixture was allowed to cool to room tempera-
ture and the product precipitated as glossy pink crystals. The
resulting suspension was filtered. The solid was recrystallized
from ethanol to yield 2.05 g (87%) of analytically pure mate-
rial. Analytical data were identical to those reported [14].
[9] A. Golisade, J. Wiesner, C. Herforth, H. Jomaa, A. Link,
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4-Biphenyl-4-yl-N-(2-hydroxy-ethyl)-4-oxo-butyramide (3)
Bioorg. Med. Chem. 2002, 10, 159Ϫ165.
To a solution of compound 5 (450 mg, 1.90 mmol) in dry tolu-
ene (20 mL) ethanolamine (114.70 µL, 1.90 mmol) was ad-
[14] B. Meseguer, T. Geller, H.-C. Militzer, DE 10157533,
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 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim