Concise route to the key intermediate for divergent synthesis of C7-substituted fluoroquinolone derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.11.077

A concise route to ethyl 7-bromo-1-cyclopropyl-6,8-difluoro-4-quinolone-3-carboxylate has been developed. This compound is a key intermediate for divergent synthesis of various C7-substituted fluoroquinolones, a group of potent topoisomerase II inhibitors

Full text of DOI:10.1016/j.tetlet.2009.11.077

Tetrahedron Letters 51 (2010) 600–601
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise route to the key intermediate for divergent synthesis of C7-substituted
fluoroquinolone derivatives
*
Xin Zhang, Feng Mu, Bobby Robinson, Pengfei Wang
Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise route to ethyl 7-bromo-1-cyclopropyl-6,8-difluoro-4-quinolone-3-carboxylate has been devel-
oped. This compound is a key intermediate for divergent synthesis of various C7-substituted fluoroquin-
olones, a group of potent topoisomerase II inhibitors with promising clinical applications.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 October 2009
Revised 11 November 2009
Accepted 16 November 2009
Available online 20 November 2009
Keyword:
Fluorquinolone
Topoisomerase II inhibitor
Antibiotics
Cancer drug
DNA topoisomerase II belongs to a class of enzymes that control
the topological conformation of DNA, affecting virtually every as-
pect of nucleic acid physiology. It is crucial to DNA replication
and is also involved in transcription, DNA repair, and recombina-
tion.1 All type II topoisomerases are structurally and phylogeneti-
cally related. Eukaryotic topoisomerase II is the primary cellular
target of a variety of clinically established antitumor agents, while
prokaryotic topoisomerase II (DNA gyrase) is the target of antibiot-
ics in treating infections of a wide range of microbial pathogens.2
Fluoroquinolone antibiotics are known topoisomerase inhibi-
tors,3 and hinder bacterial DNA replication through targeting
DNA gyrase. As topoisomerase II inhibitors, they also show poten-
tial as anticancer agents via stimulating double strand cleavage of
DNA. Recently, there has been growing interest of developing quin-
olone-based ligands for the CB2 cannabinoid receptors. These li-
gands can be potentially useful in treating alleviating pain,
inflammation, cough, dermatitis, and cancers of different origins.4
The broad spectrum of fluoroquinolones’ activity as topoiso-
merase II inhibitors in treating bacterial infections, cancers, and
other diseases has motivated considerable efforts from the scien-
tific community. Various fluoroquinolone derivatives have been
synthesized for structure-activity relationship studies.3c,e,4a,b,5
Most fluoroqinolones with anticancer activity possess aryl moiety
at the C-7 position. Extensive studies focusing on the effect of
the substituent group at C7 on activity have been carried out.
Ethyl 7-bromo-1-cyclopropyl-6,8-difluoro-4-quinolone-3-car-
boxylate (1) is the key intermediate for the divergent synthesis
of various C7-substituted fluoroquinolone derivatives via conve-
nient Suzuki coupling with different boronic acid compounds
(Scheme 1). This compound has previously been synthesized in
eight steps from 2,3,4,5-tetrafluorobenzoic acid via the intermedi-
ate ethyl 1-cyclopropyl-6,7,8-trifluoro-4-quinolone-3-carboxyl-
ate.5e Herein, we report our alternative access to compound 1 in
six steps under simple reaction conditions. We also exemplify
our divergent approach to C7-substituted fluoroquinolone deriva-
tives with the synthesis of CP-115,953 1-cyclopropyl-6,8-di-
* Corresponding author. Tel.: +1 205 9965625; fax: +1 205 9342543.
E-mail address: wangp@uab.edu (P. Wang).
Scheme 1. Divergent synthesis of fluoroquinolones.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.077

X. Zhang et al. / Tetrahedron Letters 51 (2010) 600–601
601
of the C3 ethyl ester moiety in dilute hydrochloric acid.8
(Scheme 2)
In summary, the intermediate 1, crucial for divergent synthesis
of various C7-substituted fluoroquinolone compounds for
extensive SAR studies, has been synthesized in six steps with a
14% overall yield. Although the overall yield is lower than that of
the eight-step sequence in the literature (i.e., 31%),5e this synthesis
provides a convenient and simple alternative access to the target
compound.
Acknowledgment
We thank the University of Alabama at Birmingham for support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.077.
References and notes
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