Microwave assisted amination of quinolone carboxylic acids: An expeditious synthesis of fluoroquinolone antibacterials

Article abstract of DOI:10.1016/S0040-4039(01)01385-5

A facile amination of quinolone carboxylic acids to fluoroquinolone antibacterials under microwave irradiation is described.

Full text of DOI:10.1016/S0040-4039(01)01385-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6775–6777
Microwave assisted amination of quinolone carboxylic acids:
an expeditious synthesis of fluoroquinolone antibacterials
P. Ganapati Reddy and S. Baskaran*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
Received 1 June 2001; revised 18 July 2001; accepted 27 July 2001
Abstract—A facile amination of quinolone carboxylic acids to fluoroquinolone antibacterials under microwave irradiation is
described. © 2001 Elsevier Science Ltd. All rights reserved.
The fluoroquinolones such as ciprofloxacin, norfloxacin
and sporfloxacin are totally synthetic antibacterial
agents that have gained wide acceptance for use in the
Fluoroquinolone antibacterials are conveniently pre-
pared by the direct amination of 7-halo-6-
fluoroquinolone-3-carboxylic acids with piperazine or
pyrrolidine derivatives under thermal conditions.
Unlike piperazine derivatives, pyrrolidine derivatives
are less reactive towards the quinolone nucleus and in
fact (3R,4R)-3,4-diaminopyrrolidine derivatives do not
undergo direct amination with quinolone carboxylic
1
treatment of various bacterial infections. Their mode
of action is believed to involve inhibition of bacterial
DNA gyrase, an enzyme essential for DNA replica-
2
tion. Moreover, recent studies have identified some
quinolones which also inhibit mammalian topoiso-
merase-II as potential lead compounds in the develop-
6
acids. However, we could overcome this problem by
3
ment of anticancer drugs. In addition, very recently, it
converting the quinolone carboxylic acid to the corre-
7
has been reported that fluoroquinolone antibacterials
having the pyridone carboxylic acid skeleton at the N-1
sponding, more reactive, borate ester (Scheme 2).
Hence, the ideal approach would be the direct amina-
tion of quinolone carboxylic acids under mild reaction
conditions which would allow us to generate diverse
4
position, show anti-HIV activity. In general, piper-
azine or 3-aminopyrrolidine derivatives at the C-7 posi-
tion of the quinolone nucleus have significant biological
activity (Scheme 1). Knowing of the increasing inci-
dence of bacterial resistance to a large number of
8
chemical libraries for biological screening. In this com-
munication we report a facile and general method for
the direct amination of quinolone carboxylic acids with
5
9
antibacterial agents coupled with the desire to make
less reactive amines under microwave conditions.
more potent broad spectrum quinolone antibacterials,
we embarked on the synthesis of chemically modified
Microwave assisted synthesis of fluoroquinonolone
antibacterials involves irradiation of a mixture of the
7-halo-6-fluoroquinolone carboxylic acid 1 and an
excess of the amine 2 in DMSO using an unmodified
quinolones
and
subsequently
reported
novel
10
fluoroquinolone antibacterials having chiral 63,4-
diaminopyrrolidine derivatives at the C-7 position.
O
N
O
O
O
O
O
F
F
F
OH
OH
OH
N
N
N
N
N
HN
N
O
H C
3
CH3
H N
2
Ciprofloxacin
Clinofloxacin
Ofloxacin
Scheme 1.
Keywords: fluoroquinolone; antibacterial; amination; microwave.
*
Corresponding author. Fax: 0091-44-235 2545; e-mail: sbhaskar@iitm.ac.in
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01385-5

6
776
P. G. Reddy, S. Baskaran / Tetrahedron Letters 42 (2001) 6775–6777
O
O
X=Cl or F
R=H or alkyl
F
CO R X=F
F
CO R
2
2
No
R= BF
2
Reaction
Amine 2z
BOCHN
BOCHN
N
N
X
N
Amine 2z
R2 R1
R2 R1
Scheme 2.
1
1
6
domestic microwave oven (Scheme 3). A beaker of
water was kept near the reaction vessel to serve as a
tartaric acid, reacted readily with 6,7-difluoroquino-
lone-3-carboxylic acids 1b–d, however the reaction of 2z
with the 7-chloro-6-fluoroquinolone-3-carboxylic acid
1a was found to be very slow and resulted in the
isolation of impure product.
‘
heat sink’ to provide fine control of the temperature of
12
the reaction mixture. The reaction mixtures were con-
tinuously exposed to microwave irradiation for no
more than 10 min. In the case of reactions requiring
longer time, after regular intervals they were exposed
again to microwave irradiation. Unlike conventional
Typical experimental procedure: A mixture of 1-ethyl-
,7,8-trifluoro-4-oxo-1,4-dihydro quinoline-3-carboxylic
6
1
3
methods, these reactions are very facile (8–35 min),
the isolation procedure is very simple and the product
does not require any further purification. After comple-
tion of the reaction, the mixture was cooled to room
temperature and then triturated with water. The tritu-
rated mixture was allowed to stand at 0°C for 1 h to
complete the separation of product and then filtered to
give the pure fluoroquinolone 3 in very good yields. In
the case of entries 1, 4 and 7, better yields were
obtained by removing DMSO under vacuum followed
by triturating the residue with aqueous isopropanol.
The purity of the isolated product was found to be very
acid 1c (100 mg, 0.37 mmol) and (3R,4R)-3,4-diamino
pyrrolidine 2z (212 mg, 0.78 mmol) in DMSO (1.5 mL)
was irradiated in an unmodified domestic microwave
11
oven at power setting 2 for 20 min (2×10 min pulse).
The reaction mixture was cooled to room temperature,
triturated with water (3 mL), allowed to stand at 0°C
for 1 h and then filtered. The solid was washed with
water (2 mL) and dried under high vacuum to afford
6
pure fluoroquinolone 3cz (165 mg, 85%) as an off
white solid, mp 254–256°C.
1
4
In conclusion, we have developed a facile and general
synthesis of fluoroquinolone antibacterial agents by
direct amination of 7-halo-6-fluoroquinolone-3-car-
boxylic acids in excellent yields, under microwave con-
ditions. We are confident this methodology will allow
us to develop chemical libraries of fluoroquinolone
analogues at the fraction of the normal cost and time
for biological testing.
high by HPLC (>92%). The reaction times and yields
are shown in Table 1. Although, both piperazine 2x
and pyrrolidine 2y underwent facile aromatic nucle-
ophilic substitution with 7-fluoro- as well as 7-chloro-
quinolone-3-carboxylic acids 1a–d under microwave
conditions, the rate of reaction of piperazine 2x was
found to be faster than pyrrolidine 2y. Chiral (3R,4R)-
3
,4-diaminopyrrolidine derivative 2z, derived from (+)-
L
O
O
O
N
O
F
F
OH
OH
DMSO, MWI
R3
X
N
1
3
R H
R2
R
R2
1
R
1
2
3
3
1
2
3
1
2
2x R =piperazinyl
3ax R =cyclopropyl, R =H, R =piperazinyl
1
1
1
1
a X=Cl, R =cyclopropyl, R =H
3
1
2
3
1
2
2y R =pyrrolidinyl
3ay R =cyclopropyl, R =H, R =pyrrolidinyl
b X=F, R =cyclopropyl, R =H
2
1
NHBOC
c X=R =F, R =ethyl
NHBOC
2z R3=
1
2
3
N
1
2
3bz R =cyclopropyl, R =H, R =
d X=F, R & R = -CH(CH3)CH2O-
N
NHBOC
NHBOC
1
2
3
3
cx R =ethyl, R =F, R =piperazinyl
1
2
3
3
cy R =ethyl, R =F, R =pyrrolidinyl
NHBOC
1
2
3
3
cz R =ethyl, R =F, R =
N
NHBOC
1
2
3
3
dx R & R = -CH(CH3)CH2O-, R =piperazinyl
1
2
3
3
dy R & R = -CH(CH3)CH2O-, R =pyrrolidinyl
NHBOC
NHBOC
1
2
3
3
dz R & R = -CH(CH3)CH2O-, R =
N
Scheme 3.

P. G. Reddy, S. Baskaran / Tetrahedron Letters 42 (2001) 6775–6777
Table 1. Microwave assisted synthesis of fluoroquinolones
6777
Producta
Yieldb (%)
Purity (%) (HPLC)
c
Entry
Substrate
Amine (equiv.)
Time (min)
1
2
3
4
5
6
7
8
9
1a
1a
1b
1c
1c
1c
1d
1d
1d
2x (3.5)
2y (3.0)
2z (2.5)
2x (3.5)
2y (5.0)
2z (2.1)
2x (3.5)
2y (5.0)
2z (2.1)
10+10
10+10+10+5
10+10+10+5
8
3ax
3ay
3bz
3cx
3cy
3cz
3dx
3dy
3dz
84
78
83
81
82
85
75
99.84
98.95
92.74
96.54
96.85
99.47
98.79
96.98
92.08
d
8
10+10
10+5
10+5
e
87
e
10+10+10+5
94
a
All the products gave satisfactory spectral data.
Isolated yields.
For HPLC conditions see Ref. 14.
b
c
d
e
Reaction was carried out in presence of 3 equiv. of Hunig base.
Reaction mixture was extracted with CH Cl after adding water.
2
2
Acknowledgements
Chemtech 1997, 27, 18; (d) Galema, S. A. Chem. Soc.
Rev. 1997, 26, 233; (e) Loupy, A.; Petit, A.; Hamelin, J.;
Texier-Boullet, F.; Francoise, P.; Mathe, D. Synthesis
1998, 1213.
We thank Dr. B. P. S. Reddy, C. M. D., Hetero Drugs
Ltd, Hyderabad for providing the spectral data and
Professor K. K. Balasubramanian and Professor D. V.
Ramana for allowing us to use their facilities. We thank
DST, New Delhi for financial support and PGR (SRF)
thanks CSIR, New Delhi for a research fellowship.
10. (a) Domagala, J. M.; Heifetz, C. L.; Hutt, M. P.; Mich,
T. F.; Nichols, J. B.; Solomon, M.; Worth, D. F. J. Med.
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Hagen, S. E.; Heifetz, C. L.; Hutt, M. P.; Nichols, J. B.;
Trehan, A. K. J. Med. Chem. 1988, 31, 983; (c) Ledous-
sal, B.; Bouzard, D.; Coroneos, E. J. Med. Chem. 1992,
35, 198.
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1
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mm, 5m (GL sciences); flow rate: 1.0 mL/min; tempera-
ture: 35°C; mobile phase: 45% buffer solution (to a
solution of 0.05 M sodium lauryl sulfate was added 0.1%
triethylamine and the pH of the solution was adjusted to
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