Organic Process Research & Development 2004, 8, 291−292
A Simple Procedure for the Isolation of γ-Oxobenzenebutanoic Acid
Derivatives: Application to the Synthesis of Fenbufen†
Ch. Srinivas, C. M. Haricharan Raju, and Palle V. R. Acharyulu*
Technology DeVelopment Centre, Custom Chemical SerVices, Dr. Reddy’s Laboratories, Bollaram Road,
Miyapur, Hyderabad 500 050, India
Abstract:
procedures for such a Friedel-Crafts reaction generally
A simple, convenient, and industrially viable process for the
isolation of 4-oxobutanoic acid derivatives resulting from
Friedel-Crafts acylation products of aromatic hydrocarbons
with succinic anhydride is reported. The isolation procedure
involves simple quenching of the reaction mixture followed by
filtration of the product in good yield and with excellent purity.
The generality of the procedure has been demonstrated with
representative examples of aromatic hydrocarbon precursors
and has also been applied to the isolation of fenbufen. The
quantity of aluminum chloride used in the reaction has also
been optimized to reduce the load on effluent.
involve high molar equivalents of aluminum chloride and
tedious isolation techniques. Herein, we report a simple and
general procedure for the isolation of γ-oxobenzenebutanoic
acid derivatives in good yields and high purity. The quantity
of aluminum chloride required for the reaction has also been
lowered to reduce the load on effluent.
Although Friedel-Crafts reaction of succinic anhydride
with toluene using Lewis acid reagents such as aluminum
chloride is known in the literature,4 the procedure has its
own disadvantages. The literature procedure involves the use
of high molar equivalents of aluminum chloride and tedious
workup and isolation procedures, which are difficult to
operate on large scale. Recrystallization of the crude material
is often recommended to achieve pure product to be able to
use in the subsequent synthetic transformations. The literature
procedures use aluminum chloride in excess of the required
quantities (2.2 equiv wrt to succinic anhydride) and carci-
nogenic solvents such as benzene. The isolation of the
material is also cumbersome and involves azeotropic distil-
lation, charcoal treatment, and high-temperature operations.
The material is generally isolated in low yields and also
requires multiple extractions with organic solvents.
Introduction
The structural moiety, γ-oxobenzenebutanoic acid, with
suitable substitution on benzene nucleus and side chain is a
useful structural moiety in the synthesis of several biologi-
cally active compounds such as fenbufen,1 bucloxic acid,2
menbutone,3 trepibutone,4 florantyrone,5 etc., as shown in
Chart 1. The same moiety, γ-oxobenzenebutanoic acid, is
also an important precursor for the preparation of aromatic
lactones in organic synthesis.6
Among the γ-oxobenzenebutanoic acid analogues, fen-
bufen occupies a special place due to its biological activity.
Fenbufen is a non-steroidal antiinflammatory drug (NSAID),
used to relieve the pain, stiffness, and inflammation that may
accompany a number of disorders.1 It is similar to aspirin in
the way it works in that it acts as an analgesic as well as an
antiinflammatory and is effective therapy for the symptoms
of rheumatoid arthritis, osteoarthritis, and gout.2 It also
relieves pain following surgery and from soft-tissue injuries.
γ-Oxobenzenebutanoic acid analogues are generally pre-
pared using Friedel-Crafts acylation of the corresponding
aromatic hydrocarbon with succinic anhydride. Literature
Results and Discussion
As a continuation to the ongoing program, we needed to
prepare some analogues of γ-oxobenzenebutanoic acid. To
address the above difficulties involved in the preparation of
γ-oxobenzenebutanoic acid, better isolation protocols coupled
with replacement of carcinogenic solvents, such as benzene,
became the twin objectives of our approach. As a first step
towards the process optimization, the carcinogenic solvent,
benzene, was replaced with ethylene dichloride. Later, the
quantity of aluminum chloride was reduced from 2.2 to1.3
equiv with respect to succinic anhydride. Reduction of the
quantity of aluminum chloride not only made isolation of
the product more simple but also decreased the waste stream.
After the completion of the reaction, the reaction mixture
was poured into chilled aqueous HCl under stirring to
precipitate the product directly. Although the material was
isolated in two crops initially, after adjusting the quantities
of ethylene dichloride, it was possible to isolate the product
in single crop with good recovery and purity. The purity was
checked by HPLC7 technique.
* To whom correspondence should be addressed. E-mail: raghupv@
drreddys.com. Fax: 91-40-23044044.
† DRL Publication No: 357.
(1) Hey, D. H.; Wilkinson, R. J. Chem. Soc. 1940, 1030; cf. Weizmann, M. et
al. Chem. Ind. 1940, 402; Reppe, W. et al. Ann. 1955, 223, 596; Tomcufcik,
A. S.; Child, R. G.; Sloboda, A. E. (American Cyanamid). German Patent
2,147,111 corresponding to U.S. Patent 3,784,701, 1972, 1974.
(2) Krausz, B. German Patent DE 2021445, Br. Patent 1,315,542; Krausz, B.
et al. Arzneim.- Forsch. 1974, 24, 1360 and 1364.
(3) Murata, T.; Nohara, A.; Sugihara, H.; Sanno, Y. (Takeda). German Patent
2,244,324 corresponding to U.S. Patent 3,943,169, 1973, 1976.
(4) Ruzicka, Waldman, HelV. Chim. Acta 1932, 15, 907; Fieser, Hershberg, J.
Am. Chem. Soc. 1936, 58, 2314; Burtner, R. R. U.S. Patent 2,623,065.
(5) Burtner, R. R. (Searle). U.S. Patent 2,773,091, 1956. See also: Fancher,
O. E. (Miles Labs). U.S. Patent 2,560,425, 1951.
(7) HPLC conditions: Column: Symmetry shield (150 mm × 4.6 mm). Flow
rate: 1.0 mL/min. Mobile phase: 0.01 M KH2PO4 (pH ) 3.5):CH3CN
(55:45). UV ) 250 nm. Run time: 60 min.
(6) McGahey, L. J. Chem. Edu. 1986, 63, 1101.
10.1021/op034173v CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/18/2004
Vol. 8, No. 2, 2004 / Organic Process Research & Development
•
291