Organic Process Research & Development 2002, 6, 184−186
An Efficient and Cost-Effective Synthesis of
3
-Ethoxy-4-ethoxycarbonyl-phenylacetic Acid: A Key Acid Synthon of
†
Repaglinide
Mohammad Salman,* Suresh J. Babu, Purna C. Ray, Sujoy Biswas, and Naresh Kumar
Chemical Research DiVision, Ranbaxy Research Laboratories, Gurgaon, Haryana - 122001, India
5
Abstract:
and with an overall yield of about 30% of theory. We
undertook development of an alternate and more efficient
synthetic strategy to prepare 1.
This report describes an efficient and commercially viable
synthesis of 3-ethoxy-4-ethoxy-carbonyl-phenylacetic acid (1),
a key intermediate for the preparation of repaglinide, an oral
hypoglycemic agent, from 2-hydroxy-4-methylbenzoic acid in
two steps. Thus, 2-hydroxy-4-methylbenzoic acid was first
alkylated with ethyl bromide in a polar aprotic solvent and in
the presence of an inorganic base to afford ethyl 2-ethoxy-4-
methylbenzoate; deprotonation with lithium diisopropylamide
Results and Discussion
5
There is a literature report for the preparation of the target
compound, 2-ethoxy-3-ethoxycarbonylphenylacetic acid (1),
starting from ethyl 2-ethoxy-4-methylbenzoate (4) through
substitution of benzylic proton. This method, however, is
relatively lengthy and, more importantly, uses several toxic
and potentially hazardous reagents. Thus, to accomplish
substitution of the carboxy group in 4, the literature procedure
(LDA) and quenching the resulting carbanion with carbon
dioxide provided the desired compound with improved yield
and excellent purity. This procedure is significantly better than
a previously published synthesis which involves five steps and
requires use of expensive and hazardous reagents.
(
Scheme 1) involved bromination of benzylic methyl (using
NBS in carbon tetrachloride in the presence of AIBN),
substitution of bromide with nitrile (using sodium cyanide
in the presence of N-benzyl-tri-n-butylammonium chloride),
conversion of nitrile to the corresponding ethyl ester (using
ethanol and HCl gas), and finally selective ester hydrolysis.
Furthermore, the literature procedure required maintaining
very high temperature (150 °C) for 30 h to accomplish
O-alkylation of 2-hydroxy-4-methyl benzoic acid (3) with
ethyl bromide to produce 4. Our aim was to develop a short
and easy-to-scale-up process with improved overall yield and
quality of the desired compound 1.
We conceptualized that it should be possible to depro-
tonate the benzylic proton in 4 (keeping the temperature low)
and quench the resulting carbanion with carbon dioxide to
generate the desired acid (1) in a one-step process. Indeed,
deprotonation (Scheme 2) of 4 with LDA and subsequent
reaction of the resulting carbanion with carbon dioxide
afforded the desired acid in good yields and excellent purity,
obviating the use of a lengthy sequence, as reported. Thus,
Introduction
Repaglinide (2) is first member of a new class of oral
hypoglycemic agents (meglitinides) for type-II non-insulin-
dependent diabetes mellitus (NIDDM). It stimulates the
secretion of insulin from pancreatic beta cells, acting via
calcium channels. Hypoglycemic events are fewer after the
administration of repaglinide as compared with those after
the administration of other antidiabetic agents, and repaglin-
ide offers a significantly better biological profile as compared
with that of the sulphonyl urea class of hypoglycemic
agents.1
-3
4
was reacted with LDA in a mixture of anhydrous THF
and dimethylpropylene urea (DMPU) at -75 °C; the
resulting carbanion was then quenched by bubbling carbon
dioxide gas. Use of a cosolvent was found to be necessary
to get optimum yields of the desired acid (1).
We next turned our focus on the optimization of reaction
conditions for O-alkylation of 2-hydroxy-4-methylbenzoic
acid to generate 4. The literature procedure requires an
autoclave and high temperature (150 °C) for long periods
of time (30 h) for this transformation. Substituting acetone
Synthesis of repaglinide involves condensation of an
appropriately substituted and chirally pure benzylamine
derivative with an appropriately substituted phenylacetic acid
derivative 1 followed by saponification. The literature
reports preparation of the key intermediate 1 in five steps
4
*
Author for correspondence. E-mail: msalman@ranbaxy.co.in. Telephone
(
91-124) 634-2001-10. Fax (91-124) 634 2017, 634 3545.
†
A patent application (WO 2001035900 A2) incorporating parts of this report
(as used in the literature report) with anhydrous DMSO
has been filed.
(
(
(
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2) Fr o¨ kjaer-Jensen, J.; Kotod, H.; Godtfredsen, S. E. Diabetologia 1992, 35
(4) Grell, W.; Hurnaus, R.; Griss, G.; Sauter, R.; Reiffen, M., Ruprecht, E.
(Dr. Karl Thomae GmbH). U.S. Patent 5,312,924, 1994.
(5) Grell, W.; Hurnaus, R.; Griss, G.; Sauter, R.; Ruprecht, E.; Mark, M.; Luger,
P.; Nar, H.; Wittneben, H.; M u¨ ller, P. J. Med. Chem. 1998, 41, 5219.
(
suppl. 1), Abst. 447.
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1
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Vol. 6, No. 2, 2002 / Organic Process Research & Development
10.1021/op015513k CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/26/2002