Syntheses and antibacterial activity of a series of 3-(pyridine-3-yl)-2- oxazolidinone

Article abstract of DOI:10.1016/j.ejmech.2004.10.012

The syntheses of substituted piperazinyl pyridyl oxazolidinones 8-16 are described. Their in vitro activities against Gram-positive organisms such as Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus and enterococcus were evaluated by minim

Full text of DOI:10.1016/j.ejmech.2004.10.012

European Journal of Medicinal Chemistry 40 (2005) 209–214
www.elsevier.com/locate/ejmech
Short communication
Syntheses and antibacterial activity of a series
of 3-(pyridine-3-yl)-2-oxazolidinone
Yingjie Cui a,b,*,Yaxian Dang b,YusheYang b,*, Shuhua Zhang c, Ruyun Ji b
a Laboratoire de Pharmacochimie Moléculaire et Systèmes Membranaires, Université Paris 7-Denis Diderot, 75251 Paris cedex 05, France
b Shanghai Institute of Materia Medica, Shanghai Institute for Biological Science, Chinese Academy of Sciences, Shanghai 201203, China
c Sichuan Industrial Institute of Antibiotics, Chengdu 610051, China
Received 21 August 2004; received in revised form 17 October 2004; accepted 26 October 2004
Available online 19 January 2005
Abstract
The syntheses of substituted piperazinyl pyridyl oxazolidinones 8–16 are described. Their in vitro activities against Gram-positive organ-
isms such as Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus and enterococcus were evaluated by minimum inhibitory
concentration (MIC) determination. Compound 8 and 10 were found to be superior to linezolid.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Oxazolidinone; Linezolid; Antibacterial activity; Gram-positive organism
1. Introduction
focused on substituted phenyl oxazolidinones. Eperezolid
(Fig. 2) and AZD2563 (Fig. 3) have been the main structural
feature for modification [9–11]. We consider to link pyridine
as isoster of phenyl to oxazolidinone ring in order to study
the antibacterial activity. To our knowledge, there are some
investigations on pyridyl and pyrryl oxazolidinone [12,13].
In the present communication we wish to report the synthesis
Oxazolidinones, a new class of synthetic antibacterial
agents, exhibit activity against a large number of Gram-
positive organisms including methicillin-resistant Staphylo-
coccus aureus (MRSA), Staphylococcus epidermidis
(MRSE), penicillin- and cephalosporinresistant Streptococ-
cus and vancomycin-resistant enterococcus (VRE) [1,2]. Their
mode of action has been shown to inhibit protein synthesis at
the initial phase by binding to the 50S ribosomal subunit to
prevent formation of 70S initiation complex [3]. Due to the
unique action mechanism of oxazolidinones, it is believed
that oxazolidinones are not cross resistant with other types of
antibiotics. Linezolid (Fig. 1), the only oxazolidinone ap-
proved by FDA, has already taken it place in the clinic for
treatment of Gram-positive infections [4].
Fig. 1
.
After a few years of introducing linezolid, there are already
reports on linezolid-resistance Enterococci [5,6] and linezolid-
resistance S. aureus [7,8].
Fig. 2
.
Therefore, it is necessary to develop more effective oxazo-
lidinones antibacterial agent. At present most efforts are
* Corresponding authors. Tel.: +33-1-44-27-60-50; fax:
+33-1-44-27-56-41.
E-mail addresses: yingjie.cui@paris7.jussieu.fr (Y. Cui),
ysyang@mail.shcnc.ac.cn (Y.Yang).
Fig. 3
.
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.10.012

210
Y. Cui et al. / European Journal of Medicinal Chemistry 40 (2005) 209–214
and antibacterial activity of 3-(pyridine-3-yl)-2-
oxazolidinones derivatives.
3. Biological activities
The in vitro antibacterial activity of compounds 8–16
against Gram-positive pathogens clinically isolated was tested
with Linezolid as reference compound. Linezolid was pre-
pared according to literature method [1]. Minimum inhibi-
tory concentration (MIC) values were determined usingAgar
dilution methodology according to NCCLS standards [14].
Compounds were dissolved in 20% water in DMSO to pre-
pare stock solution in which concentration of compound is
1920 µg/ml. Serial two fold dilutions were prepared from
stock solution in sterile water or Mueller–Hinton (MH) agar
medium to provide the concentration of 128, 64, 32, 16, 8, 4,
2, 1, 0.5, 0.25, 0.125, 0.06, 0.03 mg/l. The test organism was
grown in MH broth medium at 35 °C for 16–18 h, the broths
were adjusted to the turbidity of 0.5McFarland standard; then
the bacterial suspensions were inoculated onto the drug-
supplemented MH agar plates at 35 °C for 18–20 h. The MIC
was defined as the lowest concentration of drug that com-
pletely inhibited growth of the organism. At the end of each
series of tests, one plate was inoculated without antimicro-
bial agent; it was used as a control for growth comparison.
2. Chemistry
The syntheses of derivatives 8–16 are outlined in Scheme 1.
2-Chloro-5-nitropyridine as starting material on conden-
sation with anhydrous piperazine in acetonitrile at room tem-
perature (r.t.) gave 1-(5-nitro-2-pyridinyl) piperazine 4.
Hydrogenation of compound 4 with 10% Pd–C/H2 was
followed by condensation with benzyl chloroformate to afford
protected pyridine 5. Conversion of compound 5 to oxazoli-
dinone 6 was accomplished by use of n-butyl lithium and
(R)-glycidyl butyrate in dry THF at –78 °C. Compound 6 was
reacted with methanesulfonyl chloride, followed by treat-
ment with sodium azide to yield azide 7. Reduction and acy-
lation of compound 7 by thioacetic acid gave acetamide
derivative 8 and subsequent hydrogenation provided pipera-
zine acetamide 9. Derivatives 10–12 were obtained by con-
densation of compound 9 with chloroformate. Acylation of
compound 9 yielded derivative 13. The reaction of com-
pound 9 with 4-nitrophenyl sulfonyl chloride furnished deriva-
tive 14. Hydrogenation of compound 14 with 10% Pd–C/H2
gave derivative 15.Acylation of compound 15 yielded deriva-
tives 16.
4. Results and discussion
Compounds 8, 9 and 13–16 were firstly synthesized and
screened during our work (Table 1). Compound 8 containing
Scheme 1. Reagents and conditions: (a) piperazine, CH3CN, r.t.; (b) 10% Pd/C, H2, THF; (c) CBZ-Cl, Na2CO3, acetone: H2O = 2:1, 0 °C to r.t.; (d) (i) n-BuLi,
dry THF, –78 °C, (ii) (R)-glycidyl butyrate, –78 °C to r.t.; (e) MsCl, Et3N, CH2Cl2; (f) NaN3, DMF, 70–80 °C; (g) CH3COSH, r.t.; (h) H2, 10% Pd/C,
CH3OH/CH2Cl2; (i) RSO2Cl, Et3N, 0 °C to r.t.; (j) Ac2O, Py, 0 °C to r.t.; (k) ClCOOR, Et3N, THF, 0 °C to r.t.; (l) H2, 10% Pd/C, CH3OH/CH2Cl2; (m) Ac2O,
Py, 0 °C to r.t.

Y. Cui et al. / European Journal of Medicinal Chemistry 40 (2005) 209–214
211
Table 1
MIC (µg/ml) values of oxazolidinone derivatives against 20 bacterial strains
Compounds
Microorganism
S.e.c (three strains)
<0.004
S.a.a (five strains)
0.015–0.06
32–64
S.a.b (four strains)
0.06–0.125
16–32
S.e.d (five strain)
<0.004–0.015
32–128
>128
Str.A (three strains)
<0.004–0.008
16
8
9
16–64
13
14
15
16
LZ
>128
>128
>128
>128
8–128
16–32
<0.004–0.5
1–8
0.5–1
<0.004–1
0.5–2
8–16
8–16
2–4
>128
>128
2–128
>128
0.008–4
1–2
1–2
0.25
0.5–2
0.125–2
LZ = linezolid, Str.A = Streptococcus A.
a S.a. = MSSA.
b S.a. = MRSA.
c S.e. = MSSE.
d S.e. = MRSE.
Table 2
MIC (µg/ml) values of oxazolidinone derivatives against 40 bacterial strains
Microorganism
Compounds
8
1
10
11
4
12
1
LZ
S.a.a (one strain)
S.a.b (eight strains)
S.a.c (six strains)
S.e.d (14 strains)
S.e.e (two strains)
Str.p. (four strains)
E.f. (five strains)
0.5
0.5
<0.008–1
0.015–0.125
0.03–1
<0.008–0.125
0.5–1
N.T.f
0.5–8
4–8
0.03–2
4
2–8
0.25–1
1–2
N.T.f
8
0.015–0.25
N.T.f
0.125–4
0.015–1
1
8
0.25–0.5
0.25–0.5
2–4
2–4
1
0.5
0.25
1–2
0.25–0.5
LZ = linezolid, Str.p. = Streptococcus pneumoniae, E.f. = enterococcus sensitive.
a S.a. = Staphylococcus aureus, ATCC 29213.
b S.a. = MSSA.
c S.a. = MRSA.
d S.e. = MSSE.
e S.e. = MRSE.
f N.T. = no tested.
carbobenzoxy group exhibits more potent antibacterial activ-
ity than linezolid. When removal of carbobenzoxy group from
8 yields compound 9, it is almost inactive. This suggests that
carbobenzoxy group is favorable for antibacterial activity.
Derivative 13 resulting from acylation of compound 9 com-
pletely loses activity. None of compounds 14, 15 and 16 con-
taining sulphonyl groups show good activities. From the
results, introduction of carboalkoxy group to piperazinyl
pyridyl oxazolidinone appears to be the best choice compar-
ing with introduction of acyl and sulphonyl groups. Further,
three compounds 10–12 containing carboalkoxy group were
prepared. We selected compounds 8, 10, 11 and 12 for fur-
ther screening in more Gram-position strains (Table 2). All
four compounds show potent antibacterial activity.
Compounds 8 and 10 show more potent antibacterial activ-
ity than linezolid. Compounds 11 and 12 were found to be
inferior to linezolid. With increasing bulk from methoxy,
ethoxy to tert-butoxy in compounds 10, 11 and 12, their activi-
ties decrease. The electron donating effect of phenyl in com-
pound 8 maybe enhances interaction between compound 8
and receptor.
5. Conclusion
A series of substituted piperazinyl pyridyl oxazolidinones
was synthesized and evaluated for microbiological activity
against Gram-positive organisms in vitro comparable to lin-
ezolid. The carboalkoxy piperazinyl pyridyl oxazolidinones
exhibits potent antibacterial activity. Compounds 8 and 10
were found to be superior to linezolid and this type of com-
pound is worth further study.
6. Experimental protocol
Melting points (m.p.) were determined on a MEL-TEMP
m.p. apparatus and were uncorrected. 1H NMR spectral data
were recorded using a Bruker AM-400 spectrometer. Chemi-
cal shifts are reported in units (ppm). Coupling contants (J)
are reported in hertz (Hz). Mass spectra were recorded on a
MAT-711. Elemental analysis were recorded on an Elemen-
tal vario 1106. Optical rotations were measured with a PERKI-
NELMER 241.

212
Y. Cui et al. / European Journal of Medicinal Chemistry 40 (2005) 209–214
6.1. 1-(5-Nitro-2-pyridinyl)piperazine (4)
(m, 3H), 3.75 (dd, J = 12.8 Hz, J = 3.9 Hz, 1H), 3.60–3.65
(m, 4H), 3.50–3.58 (m, 4H); EI-MS (m/z): 412 (M+); Calc.
for C21H24N4O5·H2O: C 58.60, H 6.04, N 13.02. Found: C
58.99, H 6.17, N 13.09.
A solution of 2-chloro-5-nitropyridine (1.61 g, 10.0 mmol)
in CH3CN (20 ml) was treated with piperazine (2.61 g,
25.2 mmol) at r.t. After 2.5 h, TLC showed that the reaction
completed. The mixture was filtered and filtrate was concen-
trated in vacuo. The residue was dissolved in AcOEt and it
was washed with H2O, dried over Na2SO4, then concentrated
in vacuo to afford 4 (1.76 g, 84.6%) as yellow solid; m.p.
124–127 °C; 1H NMR (400 MHz, CDCl3): 9.02 (d,
J = 2.57 Hz, 1H), 8.20 (dd, J = 9.5 Hz, J = 2.6 Hz, 1H), 7.55
(d, J = 9.5 Hz, 1H), 3.75 (m, 4H), 3.95 (m, 4H).
6.4. (R)-(N-3-(4-(N-carbobenzoxypiperazinyl)-pyridine-3-
yl)-2-oxo-5-oxazolidinyl)methyl azide (7)
To a cooled (0 °C) solution of compound 6 (0.16 g,
0.39 mmol) and Et3N (0.16 ml, 1.0 mmol) in CH2Cl2 (10 ml)
was added dropwise MeSO2Cl with stirring, the reaction mix-
ture was allowed to warm to r.t. overnight. The mixture was
washed with H2O and extracted with CH2Cl2. Combined
extract was dried over Na2SO4, and then concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CH2Cl2/CH3OH = 50:1) to give mesylate (0.146 g,
76%) as pale red solid, still contaminated with impurity. The
6.2. 2-(N-carbobenzoxypiperazinyl)-5-(carbobenzoxyami-
no)pyridine (5)
A mixture of compound 4 (1.76 g, 8.46 mmol) and 5%
Pd/C (0.166 g) in THF (420 ml) was stirred at r.t. under a H2
atmosphere (1 atm) overnight. The resulting mixture was fil-
tered and concentrated in vacuo to give the amine as red oil,
which was used for the next reaction without further purifi-
cation.
1
mesylate was used in next reaction. H NMR (400 MHz,
CDCl3): 8.12 (d, J = 2.8 Hz, 1H), 7.95 (dd, J = 9.1 Hz,
J = 2.6 Hz, 1H), 7.30–7.40 (m, 4H), 6.70 (d, J = 9.2 Hz, 1H),
5.16 (s, 2H), 4.70–4.85 (m, 1H), 4.50 (dd, J = 11.5 Hz,
J = 3.5 Hz, 1H), 4.45 (dd, J = 11.7 Hz, J = 4.0 Hz, 1H), 4.12
(t, J = 9.2 Hz, 1H), 3.92 (m, 1H), 3.60–3.65 (m, 4H), 3.50–
3.60 (m, 4H), 3.10 (s, 3H).
To a cooled solution of crude amine in acetone (60 ml)
and H2O (30 ml) was added Na2CO3 (2.12 g, 20.0 mmol) and
then benzyl chloroformate (3.0 ml, 90% W/W, 19 mmol) over
10 min via syringe. The mixture was allowed to warm to r.t.
and stirred overnight. The mixture was filtered, and precipi-
tate was purified by silica gel column chromatography
(CH2Cl2/CH3OH = 50:1) and then recrystallized from DMF
and H2O to give 5 (3.23 g, 86.7%) as pale red solid; m.p.
157-158 °C; 1H NMR (400 MHz, CDCl3): 8.10 (s, 1H), 7.82
(brs, 1H), 7.30–7.40 (m, 8H), 6.65 (d, J = 9.2 Hz, 1H), 5.19
(s, 2H), 5.16 (s, 2H), 3.62 (m, 4H), 3.50 (m, 4H); EI-MS
(m/z): 446 (M+); Calc. for C25H26N4O4: C 67.26, H 5.83, N
12.56. Found: C 67.29, H 5.78, N 12.40.
A mixture of mesylate (1.67 g, 3.40 mmol) and NaN3
(0.88 g, 13.5 mmol) in DMF (50 ml) was heated at 70-80 °C
for 5 h. The mixture was poured into H2O and filtered, the
precipitate was air dried to give 7 (1.1 g, 73%) as white solid;
m.p. 117–119 °C; [␣]D20 –100.43° (C 0.42, DMSO); 1H NMR
(400 MHz, CDCl3): 8.10 (d, J = 2.8 Hz, 1H), 8.00 (dd,
J = 9.1 Hz, J = 2.5 Hz, 1H), 7.30–7.40 (m, 4H), 6.70 (d,
J = 9.2 Hz, 1H), 5.17 (s, 2H), 4.80 (m, 1H), 4.05 (t, J = 8.8 Hz,
1H), 4.45 (dd, J = 11.7 Hz, J = 4.0 Hz, 1H), 3.92 (m, 1H),
3.50–3.85 (m, 10H); EI-MS (m/z): 437 (M+); Calc. for
C21H23N7O4: C 57.66, H 5.26, N 22.42. Found: C 57.99, H
5.36, N 22.04.
6.3. (R)-(N-3-(4-(N-carbobenzoxypiperazinyl)-pyridine-3-
yl)-2-oxo-5-oxazolidinyl)methanol (6)
6.5. (S)-(N-3-(4-(N-carbobenzoxypiperazinyl)-pyridine-3-
yl)-2-oxo-5-oxazolidinyl)acetamide (8)
To a stirred solution of compound 5 (2.04 g, 4.57 mmol)
in dry THF (30 ml) at –78 °C under Ar was added dropwise
1.6 M n-butylithium-hexane (2.90 ml, 4.64 mmol).After 3.5 h,
(R)-glycidyl butyrate (0.70 ml, 93% W/W, 4.6 mmol) was
added and stirred at –78 °C for 2 h. Then the mixture was
allowed to warm to r.t. overnight. AcOEt (50 ml) was added
to the mixture, the mixture was washed with H2O and brine,
respectively, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatogra-
phy (CH2Cl2/CH3OH = 25:1) and then recrystallized from
AcOEt and petroleum to give 6 (1.30 g, 69.1%) as white solid;
m.p. 136–138 °C; [␣]D20 –30.53° (C 0.83, DMSO); 1H NMR
(400 MHz, CDCl3): 8.10 (d, J = 2.8 Hz, 1H), 8.00 (dd,
J = 9.2 Hz, J = 2.8 Hz, 1H), 7.30–7.40 (m, 4H), 6.70 (d,
J = 9.2 Hz, 1H), 5.16 (s, 2H), 4.75–4.80 (m, 1H), 3.95–4.02
A solution of compound 7 (1.1 g, 2.5 mmol) in CH3COSH
(10 ml) was stirred at r.t. for 36 h. The mixture was diluted
with CH2Cl2 (20 ml) and washed with saturated NaHCO3,
H2O and brine, respectively, dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (CH2Cl2/CH3OH = 25:1) and then recrys-
tallized fromAcOEt and petroleum to give 8 (0.70 g, 57%) as
20
white solid; m.p. 151–153 °C; [␣]D –20.86° (C 0.52,
DMSO); 1H NMR (400 MHz, CDCl3): 8.12 (d, J = 2.5 Hz,
1H), 7.95 (d, J = 8.0 Hz, 1H), 7.30–7.40 (m, 4H), 6.70 (d,
J = 9.2 Hz, 1H), 5.17 (s, 2H), 4.80 (m, 1H), 4.02 (t, J = 8.7 Hz,
1H), 3.70–3.80 (m, 2H), 3.50–3.70 (m, 10H), 2.03 (s, 3H);
EI-MS (m/z): 453 (M+); Calc. for C23H27N5O5: C 60.93, H
5.96, N 15.45. Found: C 61.30, H 6.08, N 15.52.

Y. Cui et al. / European Journal of Medicinal Chemistry 40 (2005) 209–214
213
6.6. (S)-(N-3-(4-(N-piperazinyl)-pyridine-3-yl)-2-oxo-5-
oxazolidinyl)acetamide, hydrochloride (9)
(400 MHz, CDCl3): 8.12 (d, J = 2.7 Hz, 1H), 7.85 (dd,
J = 9.2 Hz, J = 2.9 Hz, 1H), 6.65 (d, J = 9.2 Hz, 1H), 6.36 (t,
J = 6.2 Hz, 1H), 4.78 (m, 1H), 4.02 (t, J = 8.9 Hz, 1H), 3.65–
3.78 (m, 2H), 3.45–3.55 (m, 9H), 2.02 (s, 3H), 1.47 (s, 9H).
EI-MS (m/z): 419 (M+). Calc. for C20H29N5O5: C 57.28, H
6.92, N 16.71. Found: C 57.16, H 6.84, N 16.43.
A mixture of compound 8 (0.70 g, 1.4 mmol) and 10%
Pd/C (0.090 g) in CH3OH (35 ml) and CH2Cl2 (10 ml) was
stirred at r.t. under a H2 atmosphere (1 atm) overnight. The
resulting mixture was filtered and filtrate was concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CH3OH) to give 9 (0.425 g, 93.2%) as white solid;
m.p. 194–198 °C; [␣]D20 –18.17° (C 0.125, DMSO); 1H NMR
(400 MHz, CDCl3): 8.82 (brs, 1H), 8.22 (d, J = 2.9 Hz, 2H),
7.82 (dd, J = 9.2 Hz, J = 2.7 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H),
4.70 (m, 1H), 4.05 (m, 1H), 3.60–3.70 (m, 5H), 3.15–3.20
(m, 5H), 1.82 (s, 3H). EI-MS (m/z): 319 (M+); Calc. for
C15H21N5O3·2HCl: C 45.92, H 5.87, N 17.86. Found: C 46.27,
H 5.74, N 17.60.
6.10. (S)-(N-3-(4-(N-acetylpiperazinyl)-pyridine-3-yl)-2-
oxo-5-oxazolidinyl)acetamide (13)
To a cooled mixture of compound 9 (0.050 g, 0.18 mmol)
in pyridine (5 ml) was added Ac2O (1 ml) with stirring, the
reaction mixture was allowed to warm to r.t. overnight. The
mixture was diluted with CH2Cl2 (20 ml) and washed with
H2O and brine, dried over Na2SO4, then concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CH2Cl2/CH3OH = 15:1) and then recrystallized
from EtOAc to give 13 (0.020 g, 34%) as white solid; m.p.
6.7. (S)-(N-3-(4-(N-carbomethoxypiperazinyl)-pyridine-3-
yl)-2-oxo-5-oxazolidinyl)acetamide (10)
20
1
125–127 °C; [␣]D –25.14 (C 0.125, DMSO); H NMR
(400 MHz, CDCl3): 8.15 (d, J = 2.9 Hz, 1H), 7.88 (m, 1H),
6.69 (d, J = 9.2 Hz, 1H), 4.80 (m, 1H), 4.00 (t, J = 8.8 Hz,
1H), 3.82–3.85 (m, 1H), 3.60 (m, 4H), 3.45 (m, 2H), 2.14 (s,
3H), 2.02 (s, 3H). 13C NMR (100 MHz, CDCl3): 171.3, 169.3,
156.2, 155.0, 138.7, 129.7, 126.1, 107.2, 72.3, 47.7, 45.8, 45.4,
45.3, 42.0, 40.9, 23.0, 21.4. HRMS Calc. for C17H23N5O4
(M+) 361.1750. Found: 361.1751.
To a cooled mixture of compound 9 (0.058 g, 0.18 mmol)
and Et3N (0.5 ml) in THF (5 ml) was added dropwise methyl
chloroformate with stirring, the reaction mixture was allowed
to warm to r.t. overnight. The mixture was diluted with CH2Cl2
(20 ml) and washed with H2O and brine, dried over Na2SO4,
then concentrated in vacuo. The residue was purified by silica
gel column chromatography (CH2Cl2/CH3OH = 10:1) to give
20
10 (0.053 g, 78%) as white solid; m.p. 130–132 °C; [␣]D
6.11. (S)-(N-3-(4-(N-(4-nitrophenylsulfonyl) piperazinyl)-
pyridine-3-yl)-2-oxo-5-oxazolidinyl)acetamide (14)
–30.86 (C 0.20, DMSO); 1H NMR (400 MHz, CDCl3): 8.14
(d, J = 2.6 Hz, 1H), 7.90 (dd, J = 9.2 Hz, J = 2.8 Hz, 1H), 6.78
(d, J = 9.4 Hz, 1H), 6.17 (t, J = 6.0 Hz, 1H), 4.78 (m, 1H),
4.03 (t, J = 9.0 Hz, 1H), 3.65–3.78 (m, 5H), 3.45–3.62 (m,
9H), 2.02 (s, 3H). EI-MS (m/z): 377 (M+); Calc. for
C17H23N5O5·CH3OH: C 52.81, H 6.60, N 17.11. Found: C
53.01, H 6.06, N 17.01.
To a cooled solution of compound 9 (0.10 g, 0.31 mmol)
and Et3N (2 ml) in CH2Cl2 (35 ml) was added
4-nitrobenzenesulfonyl chloride (0.136 g, 0.614 mmol) with
stirring, the reaction mixture was allowed to warm to r.t. over-
night. The mixture was washed with H2O and brine, dried
over Na2SO4, then concentrated in vacuo. The residue was
purified by silica gel column chromatography
(CH2Cl2/CH3OH = 10:1) to give 14 (0.15 g, 95%) as yellow
6.8. (S)-(N-3-(4-(N-carboethoxypiperazinyl)-pyridine-3-
yl)-2-oxo-5-oxazolidinyl)acetamide (11)
20
1
solid; m.p. >230 °C; [␣]D –13.29° (C 0.15, DMSO); H
NMR (400 MHz, CDCl3): 8.40 (d, J = 8.8 Hz, 1H), 8.07 (d,
J = 2.3 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 9.1 Hz,
1H), 6.65 (d, J = 9.1 Hz, 1H), 5.96 (m, 1H), 4.78 (m, 1H),
4.00 (t, J = 8.9 Hz, 1H), 3.55–3.75 (m, 7H), 3.19 (m, 4H),
2.00 (s, 3H). EI-MS (m/z): 504 (M+). Calc. for
C21H24N6O7S·0.5H2O: C 49.12, H 4.87, N 16.37. Found: C
49.34, H 5.02, N 16.07.
Compound 9 was treated by the same procedure as for the
derivative 10, giving 11 (0.057 g, 75%) as white solid; m.p.
20
1
154–157 °C; [a]D –17.72° (C 0.345, DMSO): H NMR
(400 MHz, CDCl3): 8.13 (d, J = 2.8 Hz, 1H), 7.89 (dd,
J = 9.1 Hz, J = 2.8 Hz, 1H), 6.68 (d, J = 9.2 Hz, 1H), 6.13 (t,
J = 5.9 Hz, 1H), 4.78 (m, 1H), 4.10–4.20 (m, 2H), 4.02 (t,
J = 9.0 Hz, 1H), 3.65–3.78 (m, 2H), 3.45–3.62 (m, 9H), 2.02
(s, 3H), 1.25 (t, J = 7.2 Hz, 3H). EI-MS (m/z): 391 (M+).
Calc. for C18H25N5O5: C 55.24, H 6.39, N 17.90. Found: C
55.19, H 6.40, N 17.10.
6.12. (S)-(N-3-(4-(N-(4-aminophenylsulfonyl) piperazinyl)-
pyridine-3-yl)-2-oxo-5-oxazolidinyl) acetamide (15)
6.9. (S)-(N-3-(4-(N-carbotertbutoxypiperazinyl)pyridine-3-
yl)-2-oxo-5-oxazolidinyl)acetamide (12)
A mixture of compound 14 (0.15 g, 0.30 mmol) and 10%
Pd/C (0.090 g) in CH3OH (30 ml) and CH2Cl2 (20 ml) was
stirred at r.t. under a H2 atmosphere (1 atm) overnight. The
resulting mixture was filtered and filtrate was concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CH2Cl2/CH3OH = 15:1) to give 15 (0.10 g, 70%)
Compound 9 was treated by the same procedure as for the
derivative 10, giving 12 (0.071 g, 68%) as white solid; m.p.
20
1
184–186 °C; [␣]D –17.63° (C 0.345, DMSO); H NMR

214
Y. Cui et al. / European Journal of Medicinal Chemistry 40 (2005) 209–214
20
[2] D.J. Diekema, R.N. Jones, Drugs 59 (2000) 7.
as white solid; m.p. >230 °C; [␣]D –13.83 (C 0.125,
DMSO); 1H NMR (400 MHz, CDCl3): 8.08 (d, J = 2.8 Hz,
1H), 7.85 (dd, J = 9.2 Hz, J = 2.9 Hz, 1H), 6.70 (dd, J = 6.7 Hz,
J = 1.9 Hz, 1H), 6.60 (d, J = 9.2 Hz, 1H), 5.98 (m, 1H), 4.78
(m, 1H), 4.13 (brs, 2H), 4.00 (t, J = 9.1 Hz, 1H), 3.65–3.75
(m, 2H), 3.55–3.62 (m, 5H), 3.05 (m, 4H), 2.00 (s, 3H). EI-MS
(m/z): 474 (M+). Calc. for C21H26N6O5S·1.5H2O: C 50.30,
H 5.79, N 16.77. Found: C 50.43, H 5.67, N 16.46.
[3] M.R. Barbachyn, C.W. Ford, Angew Chem. 42 (2003) 2010 Int. Ed.
[4] B. Bozdogan, P.C. Appelbaum, Int. J. Antimicrob. Agents 23 (2004)
113.
[5] A.P. Johnson, L. Tysall, M.W. Stockdale, N. Woodford, M.E. Kauf-
mann, M. Warner, D.M. Livermore, F. Asboth, F.J. Allerberger, Eur. J.
Clin. Microbial. Infect. Dis. 21 (2002) 751.
[6] C. Auckland, L. Teare, F. Cooke, M.E. Kaufmann, M. Warner,
G. Jones, K. Bamford, H. Ayles, A.P. Johnson, J. Antimicrob.
Chemother. 50 (2002) 743.
6.13. (S)-(N-3-(4-(N-(4-acetylaminophenylsulfonyl)pip-
erazinyl)-pyridine-3-yl)-2-oxo-5-oxazolidinyl)acetamide
(16)
[7] S. Tsiodras, H.S. Gold, G. Sakoulas, G.E. Eliopoulos, C. Wennersten,
L. Venkataraman, R.C.J. Moellering, M.J. Ferraro, Lancet 358 (2001)
207.
To a cooled mixture of compound 15 (0.10 g, 0.21 mmol)
in pyridine (7 ml) was added Ac2O (1 ml) with stirring, the
reaction mixture was allowed to warm to r.t. overnight. The
mixture was filtered and filtrate was concentrated in vacuo.
The residue was recrystallized from CH3OH to give 16
(0.75 g, 69%) as white solid; m.p. >230 °C; [␣]D20 –15.07°
(C 0.20, DMSO); 1H NMR (400 MHz, CDCl3): 10.36 (s, 1H),
8.20 (t, J = 5.9 Hz, 1H), 8.15 (d, J = 2.6 Hz, 1H), 7.70–7.80
(m, 3H), 7.60–7.70 (m, 2H), 6.85 (d, J = 9.2 Hz, 1H), 4.60–
4.70 (m, 1H), 4.00 (t, J = 8.8 Hz, 1H), 3.60–3.65 (m, 1H),
3.50–3.60 (m, 4H), 2.95 (m, 4H), 2.06 (s, 3H), 1.80 (s, 3H).
EI-MS (m/z): 516 (M+). Calc. for C23H28N6O6S: C 53.49, H
5.43, N 16.28. Found: C 53.58, H 5.53, N 15.88.
[8] P. Wilson, J.A. Andrews, R. Charlesworth, R. Walesby, M. Singer,
D.J. Farrell, M.J. Robbins, Antimicrob. Chemother. 51 (2003) 186.
[9] B.B. Lohray, V.B. Lohray, B.K. Srivastava, S. Gupta, M. Solanki,
P. Kapadnis,V. Takale, P. Pandya, Bioorg. Med. Chem. Lett. 14 (2004)
3139.
[10] S.Y. Jang, Y.H. Ha, S.W. Ko, W. Lee, J. Lee, S. Kim, Y.W. Kim,
W.K. Lee, H.J. Ha, Bioorg. Med. Chem. Lett. 14 (2004) 3881.
[11] B.K. Srivastava, P.B. Kapadnis, P. Pandya, V.B. Lohray, Eur. J. Med.
Chem. 39 (2004) 989.
[12] (a) R. Bernd, Chem. Abstr. 124 (1997) 289520 (EP 693,491); (b) R.
Bernd, Chem. Abstr. 124 (1997) 261021 (EP 694,543); (c) R. Bernd,
Chem. Abstr. 127 (1998) 205567 (DE 19604223).
[13] G. Sbardella, A. Mai, M. Artico, R. Loddo, M.G. Setzu, P. La Colla,
Bioorg. Med. Chem. Lett. 14 (2004) 1537.
References
[14] National Committee for Clinical and Laboratory Standards,Method
for dilution antimicrobial susceptibility test for bacteria that grow
aerobically, Approved Standard fourth ed, NCCLS USA, 1997,
M7-A4.
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