Expeditious solution phase synthesis of fluoroquinolone antibacterial agents using polymer supported reagents

Article abstract of DOI:10.1016/S0040-4039(00)02340-6

The first example of a library synthesis of novel quinolone antibacterial agents using a polymer supported base (Amberlite 900-Cl) is described.

Full text of DOI:10.1016/S0040-4039(00)02340-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1645–1646
Expeditious solution phase synthesis of fluoroquinolone
antibacterial agents using polymer supported reagents
Peter Hilty, Christian Hubschwerlen and Andrew W. Thomas*
F. Hoffmann-La Roche AG, Pharmaceuticals Division, Discovery Chemistry, CH 4070 Basel, Switzerland
Received 21 December 2000; accepted 27 December 2000
Abstract—The first example of a library synthesis of novel quinolone antibacterial agents using a polymer supported base
Amberlite 900-Cl) is described. © 2001 Elsevier Science Ltd. All rights reserved.
(
The use of polymer supported reagents and scavenging
reagent systems has become routine in organic syn-
thesis. These techniques are widely considered to be
reaching maturation, partly due to the recent demon-
stration that these reagent systems can be used in
multi-step synthesis and their development has resulted
in a dramatic impact in the creation of chemical
piperazine in various solvents (DCM, MeCN, toluene,
DMSO) with a range of polymer supported bases 1a–
4
d. Much to our delight it was shown that in each case
the product could be isolated in excellent purity (>95%
by HPLC and NMR analysis) after filtration and evap-
oration of the reaction mixture, and via this route it
was possible to isolate significant quantities (>20 mg) of
pure material, although in each case the yield of the
1
libraries.
5
product was disappointingly low (<10%).
With an aim towards the generation of new chemical
entities active against fluoroquinolone resistant antibac-
terial strains, we recently introduced a synthesis pro-
gramme towards the creation of chemical libraries of
novel fluoroquinolones (R =F, R =amines). Herein
we wish to report a straightforward method to realise
these goals using a polymer supported ion-exchange
base in a key nucleophilic displacement step.
Screening of commercially available ion-exchange bases
revealed that Amberlite 900-Cl (resin 1e, Table 1, entry
5) showed a dramatic improvement in the reaction, and
in the event, the desired product was isolated in quanti-
tative yield and excellent purity (>95%) under mild
1
2
2
6
conditions. Representative examples, from a library of
200 compounds prepared, are shown which were pre-
pared from a range of cyclic secondary amines that had
no functionality adjacent to the N-atom (Fig. 1). From
these examples it can be seen that the scope of the
In our initial experiments the N-cyclopropyl-6,7,8-trifl-
3
uoroquinolonecarboxylic acid was treated with excess
*
0
Corresponding author. Fax: +41-61-688 64 59; e-mail: andrew.thomas@roche.com
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02340-6

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P. Hilty et al. / Tetrahedron Letters 42 (2001) 1645–1646
Table 1.
Entry
Resin 1
Reaction conditions
Equiv. 1
Yield (%)
a
b
b
b
b
1
2
3
4
5
a
b
c
d
e
Piperazine (1.5–3.0 equiv.), MeCN, rt, 1 h
Piperazine (1.5–3.0 equiv.), MeCN, rt, 1 h
Piperazine (1.5–3.0 equiv.), MeCN, rt, 1 h
Piperazine (1.5–3.0 equiv.), MeCN, rt, 1 h
Piperazine (4.0 equiv.), MeCN, rt to 60°C, 2 h
1.1–3.0
1.1–3.0
1.1–3.0
1.1–3.0
2.0
10 (75)
a
6
9
(69)
(81)
(77)
a
a
a
8
98
a
Yield after filtration and evaporation to afford pure product.
Yield after acidification.
b
7
Figure 1. Selected examples (purity, yield based on HPLC, NMR spectroscopy).
reaction is wide and can tolerate other functionalities
primary amines and anilines, alcohols, ester, etc.) with-
out altering the outcome of the reaction.
product (overall yields approaching 90%) but unfortu-
nately this was met with a reduction in the purity (69–
81%) since the mixture included significant amounts of
unreacted starting material. Increasing the reaction tem-
perature resulted in no improvement in yield.
. Typical experimental conditions: The Amberlite 900-Cl
resin 1e was purchased from Fluka. For best results, prior
to use, the resin was washed with consecutive portions of
MeOH (×3), DCM (×3) and MeOH (×1) and dried
overnight under vacuum. To a mixture of the trifl-
uoroquinolone 2 (0.05 mmol) in acetonitrile (0.5 ml) was
added the amine (1.0–4.0 equiv.) followed by the resin 1e
(
In conclusion a new straightforward method for the
solution phase synthesis of a library of fluoroquinolone
anti-infective agents has been achieved. The reaction
proceeds under mild conditions using a basic resin
6
(
Amberlite 900-Cl) and no chromatography is necessary
in order to achieve high purity products in excellent
yield.
(
2.0 equiv.) and the resulting mixture heated at 60°C. Once
References
the reaction was complete (30 min to 2 h, as judged by
HPLC) the mixture was cooled to room temperature,
filtered and evaporated to afford the product used directly
for antibacterial testing.
. All new compounds gave satisfactory H, C NMR and
MS data. Selected H NMR spectroscopic data: 2a (300
MHz, DMSO-d ) l 14.51 (br s, 1H), 8.72 (s, 1H), 7.80 (d,
J 9, 1H), 7.52–7.32 (m, 5H), 5.11 (br s, 2H), 4.31 (m, 1H),
4
1
1
2
1
. (a) Parlow, J. J. Tetrahedron Lett. 1995, 36, 1395–1396; (b)
Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1
1
13
7
1
2000, 3815–4195.
6
2
. Previously two independent groups have reported the
library synthesis of potential anti-infective agents. (a)
Frank, K. E.; Jung, M.; Mitscher, L. A. Comb. Chem.
High Throughput Screening 1998, 1, 73–87. (b) MacDon-
ald, A. A.; DeWitt, S. H.; Hogan, E. M.; Ramage, R.
Tetrahedron Lett. 1996, 37, 4815–4818.
.22–3.21 (m, 6H), 1.33–1.24 (m, 4H); 2b l 12.21 (br s,
H), 8.81 (s, 1H), 7.96 (d, J 9, 1H), 6.87 (t, 1H), 6.64 (d,
H), 6.45 (d, 1H), 5.50 (br s, 2H), 4.11 (m, 1H), 3.66 (dt,
H), 3.31 (m, 4H), 2.82 (d, 2H), 1.43 (m, 4H); 2c l 13.01
(
4
br s, 1H), 8.74 (s, 1H), 7.94 (d, J 9, 1H), 7.43 (m, 5H),
.23 (m, 1H), 3.94 (d, 1H), 3.74 (s, 3H), 3.33–2.94 (m, 4H),
3
. Domagala, J. M.; Heifetz, C. L.; Hutt, M. P.; Mich, T. F.;
Nichols, J. B.; Solomon, M.; Worth, D. F. J. Med. Chem.
1
988, 31, 991–1001.
2.13 (dt, 1H), 1.94 (dt, 1H), 1.66 (dt, 1H), 1.44 (m, 4H); 2d
l 11.05 (br s, 1H), 8.84 (s, 1H), 7.80 (d, J 9, 1H), 7.60 (m,
1H), 7.31 (d, 1H), 7.08 (t, 1H), 6.73 (dd, 1H), 4.43 (br s,
1H), 4.22 (m, 1H), 3.72 (s, 3H), 2.82–2.62 (m, 4H), 2.11–
1.42 (m, 12H), 1.32 (m, 4H).
4
. The resins 1a–d were commercially available and were
purchased from Fluka.
. Treatment of the resin with dilute HCl followed by wash-
ing with DCM resulted in an improved recovery of the
5
.