Syntheses of quinolone hydrochloride enantiomers from synthons (R)- and (S)-2-methylpiperazine

Article abstract of DOI:10.1016/j.bmc.2005.01.032

A series of R and S enantiomers of 7-(3-methylpiperazin-1-yl) quinolone derivatives were synthesized from (R)- and (S)-tert-butyl 2-methylpiperazine-1- carboxylate and tested for their antibacterial activities on 14 kinds of bacteria. Although no distinct

Full text of DOI:10.1016/j.bmc.2005.01.032

Bioorganic & Medicinal Chemistry 13 (2005) 2451–2458
Syntheses of quinolone hydrochloride enantiomers from
synthons (R)- and (S)-2-methylpiperazine
Bo Liu,a,ꢀ Chun-Hao Yang,a,ꢀ Guang-Yu Xu,a Yong-Hong Zhu,b Jing-Rong Cui,b
Xi-Han Wua,* and Yu-Yuan Xiea,*
aState Key Laboratory of Drug Research, Shanghai Institute of Meteria Medica, SIBS, Chinese Academy of Sciences,
Graduate School of the CAS, 555 Zuchongzhi Road, Shanghai 201203, PR China
bState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, PR China
Received 21 December 2004; revised 20 January 2005; accepted 21 January 2005
Abstract—A series of R and S enantiomers of 7-(3-methylpiperazin-1-yl) quinolone derivatives were synthesized from (R)- and (S)-
tert-butyl 2-methylpiperazine-1-carboxylate and tested for their antibacterial activities on 14 kinds of bacteria. Although no distinct
difference in in vitro antibacterial activities was observed, 2–64-fold difference between R and S enantiomers was observed in
approximately 52% of cases.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
(Chart 1). They are racemate having a chiral center at
C3 of the 7-piperazin-1-yl group. In 1991, Daniel
T.W.C. and his colleagues reported the synthesis and
properties of the enantiomers of temafloxacin hydro-
chloride. To their conclusion, no difference in in vitro
antibacterial activities but a minor difference in in vivo
antibacterial activities was observed. However, ((R)-
pyrrolidin-2-yl)methanol,4 (S)-3-aminopyrrolidine5 and
(S)-7-amino-5-azaspiro[2.4]heptane6 are known to be
more potent than their antipodes of some but not all
quinolone derivatives in terms of antibacterial activity
and pharmacokinetic profiles. These limited data
Piperazine derivatives are particularly important to
medicinal chemist. They were found to be used as sub-
stituents to impart the desired pharmacological and
pharmacokinetic properties to quinolone antibiotics.
In recent years, many evidence proved that 7-(substi-
tuted-piperazin-1-yl)quinolone derivatives has the lower
CNS toxicity than 7-(piperazin-1-yl)quinolone antibio-
tics.1 So many clinical quinolone antibacterials contain
the 3-methylpiperazin-1-yl group at C7. Examples can
be found in the Gatifloxacin 12 and Temafloxacin 23
O
O
O
N
O
F
F
F
OH
OH
H3C
H3C
N
N
OCH3
N
*
*
HN
HN
1
F
2
Chart 1.
Keywords: Quinolone; Synthon; Methylpiperazine; Antibacterial activity.
*
Corresponding authors. Tel.: +86 021 5080 6600 3515; fax: +86 021 5080 6770; e-mail: doctliu@263.net
ꢀ The two authors made the same contribution.
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.01.032

2452
B. Liu et al. / Bioorg. Med. Chem. 13 (2005) 2451–2458
Table 1. The structure of quinolone nuclear parents
prompted us to explore further if there exists steric influ-
ence on biological activities in quinolone series of com-
pounds. In this paper, we report the synthesis and in
vitro activities of a series of (R)- and -(S)-7-(3-methyl-
piperazin-1-yl)quinolone compounds.
Compound
R8
R1
(S)-OCH2CH(CH3)
(R)-OCH2CH(CH3)
8
9
10
11
12
13
14
H
F
F
F
F
c-C3H5
c-C3H5
C6H3F2-2,4
C6H3F2-3,4
C6H4F-3
2. Chemistry
The general method used for the preparation of quino-
lone derivatives involving an intermolecular nucleophilic
displacement ammonification reaction has been previ-
ously described.7 However, the displacement of the
quinolone parent nucleus by chiral 2-methylpiperazine
provided the target compound in low yield.3 And the chi-
ral 2-methylpiperazine was not easy to store because of
its hygroscopicity. In order to improve the selectivity of
amino-group in 2-methylpiperazine and the synthetic
yield, we used the enantiomerically pure tert-butyl 2-
methylpiperazine-1-carboxylate 3a and 3b (Chart 2) as
synthons for the chiral 2-methylpiperazinesꢁ analogs.
Next, we used the general method to prepare a series of
9-fluoro or 7-fluoro quinolone parent nucleus (Table 1),
for the reason that the fluorine atom is the preferred
leaving group. The synthesis of compound 8,9 9,9 10,10
11,11 1212 have been reported, and compound 13, 14
were synthesized according to Scheme 2.
Finally, we connected the quinolone parent nucleus (8 to
14) with 3a and 3b to get the N-tert-butoxycarbonyl pro-
tected quinolone compounds13 (17a,b to 23a,b), fol-
lowed by deprotection in acid medium to get the
quinolone hydrochlorides. The general route to synthe-
size the target compounds was described in Scheme 3
and the compounds synthesized were listed in Table 2.
In our previous work, we have reported a novel and fac-
ile method to synthesize 3a and 3b.8 The synthetic route
was depicted in Scheme 1. Comparing to other works,
we used cheaper material and reagent to get the enantio-
merically pure 1-protected 2-methylpiperazine in higher
yield. Moreover, the operation process was facile and
suitable for large scale production.
3. Results and discussion
From Table 2, we can see that 8-fluoro parent nucleus
led to better results than S- and R-ofloxacin parent nu-
cleus. This is due to the ꢀI effect and ꢀC effect of 8-sub-
stituent on the aromatic ring. As the ꢀI effect of fluoro
atom is more powerful than ꢀC effect, the 8-fluoro
group reduces the electron density of Meisenheimer
and makes the SN2 nucleophilic substitution reaction
easier and faster. Just on the contrary, the alkoxy group
increases the electron density of transition complex and
makes the reaction more difficult and slower. However,
even in the reaction of S- and R-ofloxacin parent nu-
cleus, the yield is higher than the synthesis of Temaflox-
acin 2.
H
H
N
N
N
N
CO2tBu
CO2tBu
3a
3b
Chart 2.
The comparative in vitro antibacterial activity of the
enantiomers of quinolone hydrochlorides against 14 rep-
resentatives of Gram-negative and Gram-positive
organisms was shown in Tables 3 and 4. Data for S-
ofloxacin hydrochloride (S-1) and ciprofloxacin hydro-
chloride (S-2) are provided for comparison. The in vitro
antibacterial activities are reported as minimum inhibi-
tory concentration (MIC) in micromole per liter. The
MICꢁs were determined by the 2-fold agar dilution in
the MUELLER–HINTON substrate by using standard
microtitration techniques.14
Ph
Cl
N
O
Y
CO2H
CO2CH3
Y
X
b
a
Y
H2N
O
N
H
O
N
H
X
X
4a,4b
5a,5b
Ph
Ph
X
c
e
d
N
N
3a,3b
X
Y
N
N
H
Y
In the total 98 groups of R and S enantiomers listed in
Tables 3 and 4, 2–512-fold difference between enantio-
mers was observed in 51 groups. And this is more dis-
tinct in drug resistant strains, most remarkable
examples can be observed in the row of S. epidermidis
69. Among the 51 groups, in some case S enantiomers
are better than their antipodes, but in other cases R
enantiomers seem better. So there is no regularity to fol-
CO2tBu
a
X=H Y=CH3
b Y=CH3 X=H
6a,6b
7a,7b
Scheme 1. Reagents and conditions: (a) (1) SOCl2, CH3OH, rt,
overnight; (2) ClCH2COCl, NaHCO3, H2O/C6H6, rt, 3 h; (b)
benzylamine, TEA, CH3OH, reflux, 24 h; (c) LAH, THF, 0 °C–rt,
36 h; (d) (BOC)2O, TEA, CH2Cl2, overnight; (e) 10% Pd/C, H2,
CH3OH, rt, overnight.

B. Liu et al. / Bioorg. Med. Chem. 13 (2005) 2451–2458
2453
O
F
F
COCH2COOC2H5
F
F
F
COOC2H5
CHNH
a
F
R1
F
F
O
O
N
F
F
COOC2H5
F
F
COOH
b
c
N
R1
F
F
R1
15 R1=3,4-C6H3F2
16 R1=3-C6H4F
13 R1=3,4-C6H3F2
14 R1=3-C6H4F
Scheme 2. Reagents and conditions: (a) (1) CH(OC2H5)3/Ac2O; (2) NH2–R1/CH2Cl2; (b) K2CO3/DMF; (c) HCl/AcOH.
O
O
O
O
F
F
F
OH
a
OH
X
Y
N
N
N
N
R8 R1
R8 R1
ButO2C
17a, 17b to 23a, 23b
8 to 14
O
O
F
OH
.HCl
b
X
Y
N
N
HN
R8 R1
a
b
X=H Y=CH3
Y=CH3 X=H
24a, 24b to 30a, 30b
Scheme 3. Reagents and conditions: (a) 3a or 3b, N-methylmorpholine/DMSO; (b) 3 NHCl/EtOH.
Table 2. The structure of products 24a–30b and yields via Scheme 3
Product R8
R1
Side chain
Material Intermediate Yield of step a Yield of step b Overall yield
(%)
(%)
(%)
24a
24b
25a
25b
26a
26b
27a
27b
28a
28b
29a
29b
30a
30b
(S)-OCH2CH(CH3)
(S)-OCH2CH(CH3)
(R)-OCH2CH(CH3)
(R)-OCH2CH(CH3)
S-3-Methylpiperazin-1-yl
R-3-Methylpiperazin-1-yl
S-3-Methylpiperazin-1-yl
R-3-Methylpiperazin-1-yl
S-3-Methylpiperazin-1-yl
8
8
17a
17b
18a
18b
19a
19b
20a
20b
21a
21b
22a
22b
23a
23b
84.1
83.6
78.4
82.7
71.4
69.5
98.6
95.7
96.8
95.9
94.6
96.1
90.3
89.7
80.5
81.2
81.3
77.8
79.2
80.5
80.7
81.4
80.5
84.1
89.7
89.6
90.1
87.2
67.7
67.9
63.7
64.3
56.5
55.9
79.6
77.9
77.9
80.6
84.6
86.1
81.4
78.2
9
9
10
H
H
F
F
F
F
F
F
F
F
c-C3H5
c-C3H5
c-C3H5
c-C3H5
R-3-Methylpiperazin-1-yl 10
S-3-Methylpiperazin-1-yl 11
R-3-Methylpiperazin-1-yl 11
12
C6H3F2-2,4 R-3-Methylpiperazin-1-yl 12
C6H3F2-3,4 S-3-Methylpiperazin-1-yl 13
C6H3F2-3,4 R-3-Methylpiperazin-1-yl 13
C6H3F2-2,4 S-3-Methylpiperazin-1-yl
C6H4F-3
C6H4F-3
S-3-Methylpiperazin-1-yl 14
R-3-Methylpiperazin-1-yl 14
low, though a regular pattern can be found in 24a versus
24b, 25a versus 25b, and 26a versus 26b.
27a, 27b, 28a, 28b, 29a, and 29b showed no less activity
than S-1 versus P. aerug 10211, 26a and 27a demon-
strated 8-fold activity than S-2 and 2-fold activity than
S-1 versus P. aerug 10211. Furthermore, 24a, 24b, 26a,
26b, 27a, 27b, 28a, and 28b have excellent data in all
In comparison with S-ofloxacin hydrochloride (S-1) and
ciprofloxacin hydrochloride (S-2), 24a, 24b, 26a, 26b,

2454
B. Liu et al. / Bioorg. Med. Chem. 13 (2005) 2451–2458
Table 3. Biological testing results from Gram-negative organisms (MIC lmol/L)
Compd E. coli 46117 E. coli 323* K. pneum 25922 K. pneum 440* S. typh 50097 P. aerug 10211 P. aerug 322* Sh. flexneri 51573
24a
24b
25a
25b
26a
26b
27a
27b
28a
28b
29a
29b
30a
30b
S-1
S-2
0.125
0.25
16
16
>128
>128
4
0.25
0.5
128
128
>128
>128
128
128
64
0.125
0.25
8
4
8
8
16
>128
128
2
0.5
0.5
2
16
8
128
128
1
32
128
0.125
1
4
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.25
0.125
0.125
0.125
0.125
0.25
0.25
0.25
1
0.125
0.125
0.125
0.125
0.125
0.125
0.25
0.25
0.5
8
4
4
0.25
0.125
0.125
0.5
4
1
2
2
16
4
4
32
16
64
64
128
64
4
128
128
>128
>128
128
64
8
16
16
32
32
64
64
2
4
0.5
8
64
8
1
32
4
2
32
64
8
0.25
0.125
0.125
2
1
0.125
0.125
32
128
0.125
0.125
0.125
0.125
4
2
2
The strain tagged by * is the clinical drug resistance strain.
Table 4. Biological testing results from Gram-positive organisms (MIC lmol/L)
Compd
S. aureus 25923
S. aureus 22*
S. epidermidis 26069
S. epidermidis 69*
Streptococcus 32210
Streptococcus 27*
24a
24b
25a
25b
26a
26b
27a
27b
28a
28b
29a
29b
30a
30b
S-1
S-2
1
2
4
4
1
1
2
0
2
.5
0.25
2
1
128
64
0.5
0.5
0.5
0.5
1
>128
>128
2
128
64
0.5
1
64
128
128
4
32
16
0.125
0.25
1
0.125
0.25
0.125
0.125
2
4
4
1
0.5
0.5
2
0.25
0.5
1
2
1
32
4
16
8
1
4
128
2
128
16
128
64
64
2
0.5
1
4
64
32
64
32
1
4
1
4
0.25
8
2
8
16
16
0.5
0.5
4
8
0.125
0.125
0.25
4
0.5
1
0.125
0.125
2
0.5
The strain tagged by * is the clinical drug resistance strain.
tests. Especially, 27a showed better results than S-1 and
S-2 in all tested strains.
out on a Leco CHN-2000 elemental analyzer and the
IR spectra were determined using Nicolet-FTIR-750.
The optical rotation value [a]D was determined with
PerkinElmer-341 (589 nm).
4. Conclusion
5.1.1. Synthesis of the quinolone nuclear parents 13and
14
A series of R and S enantiomers of 7-(3-methylpiper-
azin-1-yl)quinolone derivatives were synthesized and
tested against 14 representative Gram-negative and
Gram-positive organisms. It was found that steric influ-
ences do exist in this series though not very significant.
5.1.1.1. Ethyl 6,7,8-trifluoro-1-(3,4-difluorophenyl)-
1,4-dihydro-4-oxoquinoline-3-carboxylate (15). A solu-
tion of ethyl 3-(2,3,4,5-tetrafluorophenyl)-3-oxopropan-
oate (9.03 g, 34.1 mmol) in triethylorthoformate
(8.5 mL, 51.2 mmol) and acetic anhydride (21.3 mL,
153 mmol) was heated at 130 °C for 2 h with removal
of the ethyl acetate formed during the reaction. The
solution was evaporated under reduced pressure to a
mobile oil that was dissolved in methylene chloride
(50mL). 3,4-Difluoroaniline (5.28 g, 40.9 mmol) was
added to the solution. After 1 h, the solution was evap-
orated to a residue that was dissolved in anhydrous
DMF (50mL). Anhydrous K 2CO3 (14 g, 101.4 mmol)
was added to the solution. After heating at 110 °C for
10h, the solution was poured into ice/water (200mL)
and stirred for 0.5 h. The suspension was filtered and
5. Experimental
5.1. General
1
The H NMR spectra were recorded on a Varian Mer-
cury-400 High Performance Digital FT-NMR with
TMS as internal standard, and the mass spectra were
determined using Finnigan MAT 95, EI: 70eV. Melting
points were obtained at a Buchi 510melting point appa-
¨
ratus and are uncorrected. Microanalyses were carried

B. Liu et al. / Bioorg. Med. Chem. 13 (2005) 2451–2458
2455
washed by water (40mL) three times to get crude prod-
uct. Crystallization from 1,4-dioxane (150mL) gave 7.96
g (60.9%) of 15 as a white solid. Mp 268–269 °C; H
NMR (CDCl3): d 1.39 (3H, t, J = 7.1 Hz), 4.38 (2H, q,
J = 7.1 Hz), 7.24–7.26 (1H, m), 7.33–7.42 (2H, m),
8.14-8.19 (1H, m), 8.34 (1H, s). MS(EI), m/z (%) 383
(M+, 8), 338 (25), 311 (100).
7.58 (1H, d, J = 12.1 Hz), 8.96 (1H, s), 15.11 (1H, br).
MS(EI), m/z (%) 461 (M+, 52), 404 (60), 361 (100), 305
21
D
1
(76), 261 (96). ½aꢁ ꢀ40( c 0.1, CHCl3).
5.1.2.2. Method B: 7-((S)-4-(tert-butoxycarbonyl)-3-
methylpiperazin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-
dihydro-4-oxoquinoline-3-carboxylic acid (20a). To N-
methyl-morpholine (0.1 mL, 0.9 mmol) and (S)-tert-bu-
tyl 2-methylpiperazine-1-carboxylate (3a) (120mg,
0.6 mmol) in DMSO (3 mL) was added 1-cyclopropyl-
6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic
acid (11) (113 mg, 0.4 mmol). The mixture was heated at
120 °C for 24 h and cooled slowly. The mixture was fil-
tered. The pale yellow solid was washed with ethyl ace-
tate (5 mL) three times and dried under vacuum,
yielding 116 mg of 20a. The mother liquor was diluted
with ethyl acetate (55 mL) and washed with water
(10mL) twice and brine (10mL) twice. It was dried with
Na2SO4 and concentrated. Crystallization from ethanol
gave further 66.7 mg of 20a. The total yield was 98.6%.
Mp 234–235 °C. 1H NMR (DMSO-d6): d 1.15–1.22 (4H,
m), 1.26 (3H, d, J = 6.8 Hz), 1.43 (9H, s), 3.18–3.45 (5H,
m), 3.83 (1H, m), 4.13 (1H, m), 4.23 (1H, m), 7.85 (1H,
d, J = 11.9 Hz), 8.69 (1H, m), 14.81 (1H, br). MS(EI), m/
5.1.1.2. Ethyl 6,7,8-trifluoro-1-(3-fluorophenyl)-1,4-
dihydro-4-oxoquinoline-3-carboxylate (16). This com-
pound was prepared in 53.9% yield from 3-fluoroaniline
as a white solid according to the procedure described
above. Mp 228–229 °C; 1H NMR (CDCl3): d 1.38
(3H, t, J = 7.2 Hz), 4.38 (2H, q, J = 7.2 Hz), 7.19–7.22
(1H, m), 7.25–7.31 (2H, m), 7.53–7.57 (1H, m), 8.17
(1H, m), 8.37 (1H, s). MS(EI), m/z (%) 365 (M+, 6.5),
320 (23), 293 (100).
5.1.1.3.
6,7,8-Trifluoro-1-(3,4-difluorophenyl)-1,4-
dihydro-4-oxoquinoline-3-carboxylic acid (13). Com-
pound 15 (1.53 g, 4 mmol) was dissolved in hot acetic
acid (20mL) and a half volume of 3 NHCl was added
over 2 h at 100 °C. The mixture was stirred an addi-
tional 2 h at this temperature and cooled slowly. The
white solids formed were filtered and washed with cold
water, 2-propanol, and ether to give 1.24 g (87.5%) of
z (%) 463 (M+, 14), 363 (96), 307 (100), 263 (92) 57 (87).
20
D
½aꢁ +43 (c 0.12, CH3OH).
1
13. Mp 260–261 °C. H NMR (DMSO-d6): d 7.67–7.71
(2H, m), 7.99–8.03 (1H, m), 8.20–8.25 (1H, m), 8.69
(1H, s), 14.05 (1H, br). MS(EI), m/z (%) 355 (M+, 6),
311 (100), 294 (32).
5.1.2.3. (S)-10-((R)-4-(tert-Butoxycarbonyl)-3-meth-
ylpiperazin-1-yl)-9-fluoro-3,7-dihydro-3-methyl-7-oxo-
2H-[1,4]oxa-zino[2,3,4-ij]quinoline-6-carboxylic
acid
(17b). This compound was prepared in 83.6% yield from
3b and 8 as a yellow solid according to method A. Mp
250–251 °C. 1H NMR (DMSO-d6): d 1.24 (3H, d,
J = 6.73 Hz), 1.43 (9H, s), 1.46 (3H, d, J = 6.74 Hz),
3.17–3.36 (5H, m), 3.79 (1H, d, J = 11.41 Hz), 4.19
(1H, m), 4.38 (1H, dd, J1 = 2.4 Hz, J2 = 11.4 Hz), 4.57
(1H, dd, J1 = 1.9 Hz, J2 = 11.4 Hz), 4.90(1H, m), 7.60
(1H, d, J = 12.24 Hz), 8.94 (1H, s), 15.13 (1H, br).
5.1.1.4. 6,7,8-Trifluoro-1-(3-fluorophenyl)-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid (14). This compound
was prepared in 93.4% yield from 16 as a white solid
according to the procedure described above. Mp 270–
271 °C. 1H NMR (DMSO-d6): d 7.51–7.55 (1H, m),
7.63–7.72 (2H, m), 7.76–7.79 (1H, m), 8.24–8.29 (1H,
m), 8.66 (1H, s), 14.25 (1H, br). MS(EI), m/z (%) 337
(M+, 6), 293 (100), 276 (31).
MS(EI), m/z (%) 461 (M+, 34), 404 (38), 361 (71), 305
21
D
(90), 261 (100). ½aꢁ ꢀ155 (c 0.12, CHCl3).
5.1.2. General procedure for the preparation of the N-tert-
butoxycarbonyl protected quinolone compounds 17a,b to
23a,b
5.1.2.4. (R)-10-((S)-4-(tert-Butoxycarbonyl)-3-meth-
ylpiperazin-1-yl)-9-fluoro-3,7-dihydro-3-methyl-7-oxo-
5.1.2.1. Method A: (S)-10-((S)-4-(tert-butoxycar-
bonyl)-3-methylpiperazin-1-yl)-9-fluoro-3,7-dihydro-3-
methyl-7-oxo-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carb-
oxylic acid (17a). To N-methylmorpholine (0.1 mL,
0.9 mmol) and (S)-tert-butyl 2-methylpiperazine-1-car-
boxylate (3a) (120mg, 0.6 mmol) in DMSO (3 mL) was
2H-[1,4]oxa-zino[2,3,4-ij]quinoline-6-carboxylic
acid
(18a). This compound was prepared in 78.4% yield from
3a and 9 as a yellow solid according to method A. Mp
247–248 °C. 1H NMR (DMSO-d6): d 1.24 (3H, d,
J = 6.59 Hz), 1.40(9H, s), 1.43 (3H, d, J = 6.87 Hz),
3.13-3.29 (5H, m), 3.76 (1H, d, J = 10.99 Hz), 4.17
(1H, m), 4.35 (1H, dd, J1 = 2.2 Hz, J2 = 11.35 Hz),
4.56 (1H, dd, J1 = 1.92 Hz, J2 = 11.55 Hz), 4.90(1H,
m), 7.59 (1H, d, J = 12.1 Hz), 8.96 (1H, s), 15.11 (1H,
added
(S)-9,10-difluoro-3,7-dihydro-3-methyl-7-oxo-
2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (8)
(112 mg, 0.4 mmol). The mixture was heated at 120 °C
for 24 h and cooled slowly. The solution was diluted by
ethyl acetate (70mL) and washed by water (10mL) twice
and brine (10mL) twice, dried with Na 2SO4, and concen-
trated to a yellow solid. Ethanol (2 mL) was added to di-
gest it at boiling for 1 h. The mixture was cooled and
filtered, yielding 155.2 mg (84.1%) of 17a as a yellow so-
lid. Mp 250–251 °C. 1H NMR (DMSO-d6): d 1.24 (3H, d,
J = 6.59 Hz), 1.40(9H, s), 1.42 (3H, d, J = 6.87 Hz),
3.11–3.28 (5H, m), 3.76 (1H, d, J = 10.44 Hz), 4.17
(1H, m), 4.36 (1H, dd, J1 = 2.2 Hz, J2 = 11.35 Hz), 4.55
(1H, dd, J1 = 1.92 Hz, J2 = 11.55 Hz), 4.90(1H, m),
br). MS(EI), m/z (%) 461 (M+, 30), 404 (36), 361 (68),
21
D
305 (84), 261 (100). ½aꢁ +148 (c 0.1, CHCl3).
5.1.2.5. (R)-10-((R)-4-(tert-Butoxycarbonyl)-3-meth-
ylpiperazin-1-yl)-9-fluoro-3,7-dihydro-3-methyl-7-oxo-
2H-[1,4]oxa-zino[2,3,4-ij]quinoline-6-carboxylic
(18b). This compound was prepared in 82.7% yield from
3b and 9 as a yellow solid according to method A. Mp
245–246 °C. 1H NMR (DMSO-d6): d 1.25 (3H, d,
J = 6.58 Hz), 1.42 (9H, s), 1.44 (3H, d, J = 6.86 Hz),
3.12–3.27 (5H, m), 3.78 (1H, d, J = 10.43 Hz), 4.18
acid

2456
B. Liu et al. / Bioorg. Med. Chem. 13 (2005) 2451–2458
(1H, m), 4.38 (1H, dd, J1 = 2.16 Hz, J2 = 11.34 Hz), 4.57
(1H, dd, J1 = 1.93 Hz, J2 = 11.53 Hz), 4.92 (1H, m), 7.60
(1H, d, J = 12.35 Hz), 8.98 (1H, s), 15.17 (1H, br).
J = 6.6 Hz), 1.37 (9H, s), 3.05–3.33 (5H, m), 3.72 (1H,
m), 4.09–4.18 (1H, m), 7.33 (1H, m), 7.62 (1H, m),
7.95 (1H, d, J = 12.4 Hz), 7.94–7.98 (1H, m), 8.69 (1H,
MS(EI), m/z (%) 461 (M+, 26), 404 (32), 361 (64), 305
m), 14.45 (1H, br). MS(EI), m/z (%) 535 (M+, 4), 478
23
D
21
D
(81), 261 (100). ½aꢁ +40( c 0.1, CHCl3).
(12), 435 (33), 379 (100), 335 (88), 57 (74). ½aꢁ ꢀ40( c
0.07, CH3OH).
5.1.2.6.
7-((S)-4-(tert-Butoxycarbonyl)-3-methylpi-
perazin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
quinoline-3-carboxylic acid (19a). This compound was
prepared in 71.4% yield from 3a and 10 as a yellow solid
according to method A. Mp 240–242 °C. 1H NMR
5.1.2.11. 7-((S)-4-(tert-Butoxycarbonyl)-3-methylpi-
perazin-1-yl)-6,8-difluoro-1-(3,4-difluorophenyl)-1,4-dihy-
dro-4-oxoquinoline-3-carboxylic
compound was prepared in 94.6% overall yield from
acid
(22a).
This
(DMSO-d6):
d
1.11–1.18 (2H, m), 1.24 (3H, d,
3a and 13 as a pale yellow solid according to method
1
J = 6.87 Hz), 1.27–1.32 (2H, m), 1.41 (9H, s), 2.91–
3.09 (3H, m), 3.53–3.65 (2H, m), 3.75–3.92 (2H, m),
4.26 (1H, m), 7.55 (1H, d, J = 7.70Hz), 7.91 (1H, d,
B. Mp 257–258 °C. H NMR (DMSO-d6): d 1.14 (3H,
d, J = 6.5 Hz), 1.40(9H, s), 3.50–3.39 (5H, m), 3.75
(1H, m), 4.11–4.19 (1H, m), 7.64–7.73 (2H, m), 7.95
(1H, d, J = 12.5 Hz), 7.99–8.05 (1H, m), 8.59 (1H, m).
J = 12.92 Hz), 8.65 (1H, s). MS(EI), m/z (%) 445 (M+,
21
D
28), 401 (36), 345 (100), 289 (57), 245 (68). ½aꢁ ꢀ36 (c
MS(EI), m/z (%) 535 (M+, 17), 478 (76), 435 (100), 379
20
D
0.055, CHCl3).
(78), 335 (73), 57 (72). ½aꢁ +36 (c 0.055, CH3OH).
5.1.2.7.
7-((R)-4-(tert-Butoxycarbonyl)-3-methylpi-
5.1.2.12. 7-((R)-4-(tert-Butoxycarbonyl)-3-methylpi-
perazin-1-yl)-6,8-difluoro-1-(3,4-difluorophenyl)-1,4-dihy-
perazin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
quinoline-3-carboxylic acid (19b). This compound was
prepared in 69.5% yield from 3b and 10 as a yellow solid
according to method A. Mp 241–242 °C. 1H NMR
dro-4-oxoquinoline-3-carboxylic
compound was prepared in 96.1% overall yield from
acid
(22b).
This
3b and 13 as a pale yellow solid according to method
1
(DMSO-d6):
d
1.11–1.18 (2H, m), 1.24 (3H, d,
B. Mp 257–258 °C. H NMR (DMSO-d6): d 1.17 (3H,
J = 6.87 Hz), 1.27–1.32 (2H, m), 1.41 (9H, s), 2.91–
3.09 (3H, m), 3.53–3.65 (2H, m), 3.75–3.92 (2H, m),
4.26 (1H, m), 7.55 (1H, d, J = 7.70Hz), 7.91 (1H, d,
d, J = 6.7 Hz), 1.43 (9H, s), 3.08–3.41 (5H, m), 3.77
(1H, m), 4.13–4.21 (1H, m), 7.66–7.75 (2H, m), 7.97
(1H, d, J = 11.75 Hz), 8.03–8.07 (1H, m), 8.61 (1H,
J = 12.92 Hz), 8.65 (1H, s). MS(EI), m/z (%) 445 (M+,
m). MS(EI), m/z (%) 535 (M+, 12), 478 (40), 435 (58),
21
D
20
D
28), 401 (36), 345 (100), 289 (57), 245 (68). ½aꢁ +32 (c
379 (73), 335 (71), 57 (100). ½aꢁ ꢀ31 (c 0.065, CH3OH).
0.13, CHCl3).
5.1.2.13. 7-((S)-4-(tert-Butoxycarbonyl)-3-methylpi-
perazin-1-yl)-6,8-difluoro-1-(3-fluorophenyl)-1,4-dihy-
5.1.2.8.
7-((R)-4-(tert-Butoxycarbonyl)-3-methylpi-
perazin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-
oxoquinoline-3-carboxylic acid (20b). This compound
was prepared in 95.7% overall yield from 3b and 11 as
a pale yellow solid according to method B. Mp 234–
235 °C. 1H NMR (DMSO-d6): d 1.16–1.23 (4H, m),
1.25 (3H, d, J = 6.6 Hz), 1.43 (9H, s), 3.18–3.45 (5H,
m), 3.82 (1H, m), 4.12 (1H, m), 4.22 (1H, m), 7.84
(1H, d, J = 11.9 Hz), 8.68 (1H, m), 14.81 (1H, br).
dro-4-oxoquinoline-3-carboxylic acid (23a). This
compound was prepared in 90.3% overall yield from
3a and 14 as a yellow solid according to method B.
1
Mp 252–253 °C. H NMR (DMSO-d6): d 1.13 (3H, d,
J = 6.7 Hz), 1.38 (9H, s), 3.04–3.31 (5H, m), 3.72–3.74
(1H, m), 4.13 (1H, m), 7.45–7.49 (1H, m), 7.57–7.66
(2H, m), 7.73 (1H, m), 7.94 (1H, d, J = 11.80Hz), 8.53
(1H, s). MS(EI), m/z (%) 517 (M+, 36), 460(84), 417
21
D
MS(EI), m/z (%) 463 (M+, 14), 363 (96), 307 (100), 263
(100), 361 (65), 317 (46), 57 (51). ½aꢁ +40( c 0.07,
20
D
(92), 57 (87). ½aꢁ ꢀ45 (c 0.11, CH3OH).
CH3OH).
5.1.2.9.
perazin-1-yl)-6,8-difluoro-1-(2,4-difluorophenyl)-1,4-dihy-
dro-4-oxoquinoline-3-carboxylic acid (21a). This
7-((S)-4-(tert-Butoxycarbonyl)-3-methylpi-
5.1.2.14. 7-((R)-4-(tert-Butoxycarbonyl)-3-methylpi-
perazin-1-yl)-6,8-difluoro-1-(3-fluorophenyl)-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid (23b). This compound
was prepared in 90.3% overall yield from 3b and 14 as
a yellow solid according to method B. Mp 253–254 °C.
1H NMR (DMSO-d6): d 1.12 (3H, d, J = 6.6 Hz), 1.37
(9H, s), 3.03–3.30 (5H, m), 3.70–3.72 (1H, m), 4.14
(1H, m), 7.43–7.48 (1H, m), 7.56–7.65 (2H, m), 7.71–
7.73 (1H, m), 7.93 (1H, d, J = 11.82 Hz), 8.51 (1H, s),
compound was prepared in 96.8% overall yield from
3a and 12 as a yellow solid according to method
1
B. Mp 244–245 °C. H NMR (DMSO-d6): d 1.12 (3H,
d, J = 6.7 Hz), 1.36 (9H, s), 3.05–3.33 (5H, m), 3.72
(1H, m), 4.09–4.18 (1H, m), 7.34 (1H, m), 7.62 (1H,
m), 7.95 (1H, d, J = 12.4 Hz), 7.94–7.98 (1H, m), 8.69
(1H, m), 14.45 (1H, br). MS(EI), m/z (%) 535 (M+,
14.59 (1H, br). MS(EI), m/z (%) 517 (M+, 16), 460
21
D
13), 478 (34), 435 (44), 379 (34.5), 335 (34), 63 (100),
(45), 417 (74), 361 (71), 317 (100), 57 (57). ½aꢁ ꢀ40( c
21
D
57 (47). ½aꢁ +39 (c 0.065, CH3OH).
0.075, CH3OH).
5.1.2.10. 7-((R)-4-(tert-Butoxycarbonyl)-3-methylpi-
perazin-1-yl)-6,8-difluoro-1-(2,4-difluorophenyl)-1,4-dihy-
5.1.3. General procedure for the preparation of the
quinolone hydrochlorides 24a,b to 30a,b
dro-4-oxoquinoline-3-carboxylic
compound was prepared in 95.9% overall yield from
acid
(21b).
This
5.1.3.1. (S)-9-Fluoro-3,7-dihydro-3-methyl-10-((S)-3-
methylpiperazin-1-yl)-7-oxo-2H-[1,4]oxazino[2,3,4-ij]-
quinoline-6-carboxylic acid hydrochloride (24a). To 17a
(92 mg, 0.20 mmol) in ethanol (4 mL) was added
3b and 12 as a yellow solid according to method B.
1
Mp 243–244 °C. H NMR (DMSO-d6): d 1.12 (3H, d,

B. Liu et al. / Bioorg. Med. Chem. 13 (2005) 2451–2458
2457
3 NHCl (2 mL). The mixture was heated at boiling for
10h and concentrated under reduced pressure to dry-
ness. The residue was crystallized from ethanol–water
to yield 65.9 mg (80.5%) of 24a as a white solid. Mp
>290 °C. H NMR (D2O): d 1.32 (3H, d, J = 6.46 Hz),
1.51 (3H, d, J = 6.60Hz), 3.29–3.58 (7H, m), 4.40(1H,
d, J = 11.14 Hz), 4.54 (1H, d, J = 11.14 Hz), 4.70(1H,
m), 7.22 (1H, d, J = 12.23 Hz), 8.65 (1H, s). IR (KBr)
1H NMR (D2O): d 1.23–1.35 (4H, m), 1.42 (3H, d,
J = 6.67 Hz), 3.17–3.53 (7H, m), 4.21 (1H, m), 7.38
(1H, d, J = 7.60Hz), 7.76 (1H, d, J = 12.43 Hz), 8.78
(1H, s). IR (KBr) m 3437.6, 2950.4, 2703.7, 1725.6,
1
1620.4, 1363.2, 1046.8, 805.9 cmꢀ1. MS(EI), m/z (%)
21
D
345 (M+, 31), 289 (100), 245 (88). ½aꢁ +24 (c 0.12,
H2O). Anal. Calcd for C18H20FN3O3ÆHClÆH2O: C,
54.07; H, 5.80; N, 10.51. Found: C, 53.92; H, 5.93; N,
10.72.
m
3473.2, 2950.6, 2767.4, 1708.6, 1621.9, 1053.0,
804.2 cmꢀ1. MS(EI), m/z (%) 361 (M+, 31), 305 (100),
22
D
261 (91). ½aꢁ ꢀ82 (c 0.13, H2O). Anal. Calcd for
5.1.3.6. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-((R)-3-
methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid
hydrochloride (26b). This compound was prepared in
C18H20FN3O4ÆHClÆ1.1H2O: C, 51.76; H, 5.60; N,
10.06. Found: C, 51.48; H, 5.45; N, 9.94.
1
80.5% yield from 19b as a white solid. Mp >290 °C. H
5.1.3.2. (S)-9-Fluoro-3,7-dihydro-3-methyl-10-((R)-3-
methylpiperazin-1-yl)-7-oxo-2H-[1,4]oxazino[2,3,4-ij]-
quinoline-6-carboxylic acid hydrochloride (24b). This
compound was prepared in 81.2% yield from 17b as a
NMR (D2O): d 1.23–1.35 (4H, m), 1.42 (3H, d,
J = 6.67 Hz), 3.17–3.53 (7H, m), 4.21 (1H, m), 7.38 (1H,
d, J = 7.60Hz), 7.76 (1H, d, J = 12.43 Hz), 8.78 (1H, s).
IR (KBr) m 3442.5, 2941.2, 2704.8, 1726.8, 1620.4,
1
white solid. Mp >290 °C. H NMR (D2O): d 1.43 (3H,
1362.7, 1045.6, 805.9 cmꢀ1. MS(EI), m/z (%) 345 (M+,
21
D
d, J = 6.38 Hz), 1.63 (3H, d, J = 6.55 Hz), 3.38–3.46
(2H, m), 3.54–3.72 (5H, m), 4.52 (1H, d, J =
11.75 Hz), 4.66 (1H, d, J = 12.09 Hz), 4.70 (1H, m),
7.46 (1H, d, J = 11.92 Hz), 8.81 (1H, s). IR (KBr) m
3419.2, 2939.0, 2775.1, 1708.6, 1621.9, 1054.9,
31), 289 (100), 245 (88). ½aꢁ ꢀ25 (c 0.09, H2O). Anal.
Calcd for C18H20FN3O3ÆHClÆ0.8H2O: C, 54.56; H, 5.75;
N, 10.60. Found: C, 54.38; H, 5.86; N, 10.47.
5.1.3.7. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-((S)-
3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid
hydrochloride (27a). This compound was prepared in
80.7% yield from 20a as a white solid. Mp >290 °C.
1H NMR (D2O): d 1.27–1.36 (4H, m), 1.44 (3H, d,
J = 6.60Hz), 3.44–3.78 (7H, m), 4.18 (1H, m), 7.70
(1H, d, J = 11.41 Hz), 8.82 (1H, s). IR (KBr) m
3430.8, 2937.1, 2699.9, 1727.9, 1625.7, 1475.3, 1324.9,
804.2 cmꢀ1. MS(EI), m/z (%) 361 (M+, 28), 305 (98),
22
D
261 (100). ½aꢁ ꢀ25 (c 0.115, H2O). Anal. Calcd for
C18H20FN3O4ÆHClÆH2O: C, 51.99; H, 5.57; N, 10.10.
Found: C, 51.95; H, 5.83; N, 10.33.
5.1.3.3. (R)-9-Fluoro-3,7-dihydro-3-methyl-10-((S)-3-
methylpiperazin-1-yl)-7-oxo-2H-[1,4]oxazino[2,3,4-
ij]quinoline-6-carboxylic acid hydrochloride (25a). This
compound was prepared in 81.3% yield from 18a as a
1033.7, 806.1, 551.6 cmꢀ1. MS(EI), m/z (%) 363 (M+,
20
D
27), 307 (100), 263 (60). ½aꢁ ꢀ26 (c 0.233, H2O).
1
white solid. Mp >290 °C. H NMR (D2O): d 1.44 (3H,
Anal. Calcd for C18H19F2N3O3ÆHClÆ0.2H2O: C,
53.59; H, 5.10; N, 10.42. Found: C, 53.47; H, 5.24;
N, 10.37.
d, J = 6.33 Hz), 1.64 (3H, d, J = 6.73 Hz), 3.39–3.44
(2H, m), 3.55–3.72 (5H, m), 4.52 (1H, d, J =
11.00 Hz), 4.67 (1H, d, J = 10.26 Hz), 4.71 (1H, m),
7.44 (1H, d, J = 12.09 Hz), 8.82 (1H, s). IR (KBr) m
3423.1, 2941.0, 2807.9, 1706.7, 1621.9, 1054.9,
5.1.3.8. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-((R)-
3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid
hydrochloride (27b). This compound was prepared in
81.4% yield from 20b as a white solid. Mp >290 °C.
1H NMR (D2O): d 1.27–1.36 (4H, m), 1.44 (3H, d,
J = 6.60Hz), 3.44–3.78 (7H, m), 4.18 (1H, m), 7.70
(1H, d, J = 11.41 Hz), 8.82 (1H, s). IR (KBr) m 3453.9,
2931.3, 2699.9, 1727.9, 1618.0, 1479.2, 1326.8, 1035.6,
804.2 cmꢀ1. MS(EI), m/z (%) 361 (M+, 30), 305 (100),
21
D
261 (93). ½aꢁ +21 (c 0.12, H2O). Anal. Calcd for
C18H20FN3O4ÆHClÆH2O: C, 51.99; H, 5.57; N, 10.10.
Found: C, 51.85; H, 5.84; N, 10.23.
5.1.3.4. (R)-9-Fluoro-3,7-dihydro-3-methyl-10-((R)-3-
methylpiperazin-1-yl)-7-oxo-2H-[1,4]oxazino[2,3,4-
806.1, 551.6 cmꢀ1. MS(EI), m/z (%) 363 (M+, 25), 307
23
ij]quinoline-6-carboxylic acid hydrochloride (25b). This
compound was prepared in 77.8% yield from 18b as a
(100), 263 (66). ½aꢁ +34 (c 0.105, H2O). Anal. Calcd
for C18H19F2N3O3ÆDHClÆ0.3H2O: C, 53.35; H, 5.12; N,
10.37. Found: C, 53.53; H, 5.46; N, 10.64.
1
white solid. Mp >290 °C. H NMR (D2O): d 1.44 (3H,
d, J = 5.04 Hz), 1.63 (3H, d, J = 6.88 Hz), 3.42–3.47
(2H, m), 3.55–3.71 (5H, m), 4.52 (1H, d, J =
11.74 Hz), 4.66 (1H, d, J = 11.76 Hz), 4.70(1H, m),
5.1.3.9. 6,8-Difluoro-1-(2,4-difluorophenyl)-1,4-dihy-
dro-7-((S)-3-methylpiperazin-1-yl)-4-oxoquinoline-3-car-
boxylic acid hydrochloride (28a). This compound was
prepared in 80.5% yield from 21a as a white solid. Mp
7.43 (1H, d, J = 11.92 Hz), 8.80(1H, s). IR (KBr)
3471.3, 2950.6, 2769.3, 1708.6, 1621.9, 1477.2, 1053.0,
m
804.2 cmꢀ1. MS(EI), m/z (%) 361 (M+, 28), 305 (100),
>290 °C. H NMR (D2O): d 1.37 (3H, d, J = 6.6 Hz),
1
21
D
261 (70). ½aꢁ +75 (c 0.12, H2O). Anal. Calcd for
3.30–3.38 (2H, m), 3.48–3.66 (5H, m), 7.27–7.37 (2H,
m), 7.73–7.79 (1H, m), 7.99 (1H, d, J = 10.86 Hz), 8.80
(1H, s). IR (KBr) m 3446.2, 2939.0, 2709.5, 1731.8,
C18H20FN3O4ÆHClÆH2O: C, 51.99; H, 5.57; N, 10.10.
Found: C, 51.87; H, 5.80; N, 10.21.
1618.0, 1459.9, 1438.7, 1322.9, 806.1, 536.1 cmꢀ1
.
5.1.3.5. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-((S)-3-
methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid
hydrochloride (26a). This compound was prepared in
79.2% yield from 19a as a white solid. Mp >290 °C.
MS(EI), m/z (%) 435 (M+, 24), 379 (100), 335 (80).
21
D
½aꢁ
ꢀ27 (c 0.12, H2O). Anal. Calcd for
C21H17F4N3O3ÆHClÆH2O: C, 51.49; H, 4.12; N, 8.58.
Found: C, 51.36; H, 4.25; N, 8.76.

2458
B. Liu et al. / Bioorg. Med. Chem. 13 (2005) 2451–2458
5.1.3.10. 6,8-Difluoro-1-(2,4-difluorophenyl)-1,4-dihy-
5.1.3.14. 6,8-Difluoro-1-(3-fluorophenyl)-1,4-dihydro-
7-((R)-3-methylpiperazin-1-yl)-4-oxoquinoline-3-carbox-
ylic acid hydrochloride (30b). This compound was pre-
pared in 87.2% yield from 23b as a white solid. Mp
dro-7-((R)-3-methylpiperazin-1-yl)-4-oxoquinoline-3-car-
boxylic acid hydrochloride (28b). This compound was
prepared in 80.5% yield from 21b as a white solid. Mp
1
1
>290 °C. H NMR (D2O): d 1.35 (3H, d, J = 6.46 Hz),
>290 °C. H NMR (D2O): d 1.37 (3H, d, J = 6.46 Hz),
3.28–3.36 (2H, m), 3.46–3.64 (5H, m), 7.25–7.35 (2H,
m), 7.71–7.77 (1H, m), 7.96 (1H, d, J = 12.09 Hz), 8.79
(1H, s). IR (KBr) m 3446.2, 2939.0, 2738.5, 1731.8,
3.26–3.34 (2H, m), 3.45–3.63 (5H, m), 7.45–7.49 (3H,
m), 7.65–7.71 (1H, m), 7.95 (1H, d, J = 11.62 Hz), 8.79
(1H, s). IR (KBr) m 3444.3, 2929.4, 2701.8, 1735.6,
1619.9, 1596.8, 1477.2, 1446.4, 1322.9, 1027.9, 804.2,
1618.0, 1508.1, 1438.7, 1322.9, 806.1, 536.1 cmꢀ1
.
MS(EI), m/z (%) 435 (M+, 24), 379 (100), 335 (80).
684.6 cmꢀ1. MS(EI), m/z (%) 417 (M+, 24), 361 (100),
23
D
23
D
½aꢁ
+30(
c
0.10, H2O). Anal. Calcd for
317 (79). ½aꢁ +25 (c 0.099, H2O). Anal. Calcd for
C21H17F4N3O3ÆHClÆ0.6H2O: C, 52.26; H, 4.01; N,
8.71. Found: C, 52.45; H, 4.19; N, 8.98.
C21H18F3N3O3ÆHClÆ0.3H2O: C, 54.92; H, 4.30; N,
9.15. Found: C, 55.04; H, 4.33; N, 9.40.
5.1.3.11. 6,8-Difluoro-1-(3,4-difluorophenyl)-1,4-dihy-
dro-7-((S)-3-methylpiperazin-1-yl)-4-oxoquinoline-3-car-
boxylic acid hydrochloride (29a). This compound was
prepared in 89.7% yield from 22a as a white solid. Mp
References and notes
1
1. Kidwai, M.; Misra, P.; Kumar, R. Curr. Pharm. Des.
1998, 4, 101–118.
2. Sanchez, J. P.; Gogliotti, R. D.; Domagala, J. M.;
Gracheck, S. J.; Huband, M. D.; Sesnie, J. A.; Cohen,
M. A.; Shapiro, M. A. J. Med. Chem. 1995, 38, 4478–
4487.
3. Chu, D. T.; Nordeen, C. W.; Hardy, D. J.; Swanson, R.
N.; Giardina, W. J.; Pernet, A. G.; Plattner, J. J. J. Med.
Chem. 1991, 34, 168–174.
4. Rosen, T.; Chu, D. T.; Lico, I. M.; Fernandes, P. B.;
Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G. J. Med.
Chem. 1988, 31, 1598–1611.
>290 °C. H NMR (D2O): d 1.37 (3H, d, J = 6.46 Hz),
3.31–3.37 (2H, m), 3.47–3.65 (5H, m), 7.49 (1H, m),
7.54–7.61 (1H, m), 7.64–7.68 (1H, m), 8.00 (1H, d,
J = 11.55 Hz), 8.81 (1H, s). IR (KBr) m 3419.2, 2941.0,
2717.3, 1726.0, 1623.8, 1510.0, 1448.3, 1274.7, 802.3,
775.3, 563.1 cmꢀ1. MS(EI), m/z (%) 435 (M+, 24), 379
21
D
(100), 335 (77). ½aꢁ ꢀ29 (c 0.095, H2O). Anal. Calcd
for C21H17F4N3O3ÆHClÆH2O: C, 51.49; H, 4.12; N,
8.58. Found: C, 51.72; H, 4.13; N, 8.61.
5.1.3.12. 6,8-Difluoro-1-(3,4-difluorophenyl)-1,4-dihy-
dro-7-((R)-3-methylpiperazin-1-yl)-4-oxoquinoline-3-car-
boxylic acid hydrochloride (29b). This compound was
prepared in 89.6% yield from 22b as a white solid. Mp
5. Rosen, T.; Chu, D. T.; Lico, I. M.; Fernandes, P. B.; Shen,
L.; Borodkin, S.; Pernet, A. G. J. Med. Chem. 1988, 31,
1586–1590.
6. Kimura, Y.; Atarashi, S.; Kawakami, K.; Sato, K.;
Hayakawa, I. J. Med. Chem. 1994, 37, 3344–3352.
7. Domagala, J. M.; Bridges, A. J.; Culbertson, T. P.;
Gambino, L.; Hagen, S. E.; Karrick, G.; Porter, K.;
Sanchez, J. P.; Sesnie, J. A.; Spense, G.; Szotek, D.;
Wemple, J. J. Med. Chem. 1991, 34, 1142–1154.
8. Liu, B.; Xu, G. Y.; Yang, C. H.; Wu, X. H.; Xie, Y. Y.
Synth. Commun. 2004, 34, 4111–4118.
9. Mitscher, L. A.; Sharma, P. N.; Chu, D. T.; Shen, L. L.;
Pernet, A. G. J. Med. Chem. 1987, 30, 2283–2286.
10. Sanchez, J. P.; Domagala, J. M.; Hagen, S. E.; Heifetz, C.
L.; Hutt, M. P.; Nichols, J. B.; Trehan, A. K. J. Med.
Chem. 1988, 31, 983–991.
11. Domagala, J. M.; Heifetz, C. L.; Hutt, M. P.; Mich, T. F.;
Nichols, J. B.; Solomn, M.; Worth, D. F. J. Med. Chem.
1988, 31, 991–1001.
12. Chu, D. T.; Fernandes, P. B.; Maleczka, R. E.; Nordeen,
C. W.; Pernet, A. G. J. Med. Chem. 1987, 30, 504–509.
13. Gordeev, M. F.; Hackbarth, C.; Barbachyn, M. R.;
Baintt, L. S.; Gage, J. R.; Luehr, G. W.; Gomez, M.;
Trias, J.; Morin, S. E.; Zurenko, G. E.; Parker, C. N.;
Evans, J. M.; White, R. J.; Patel, D. V. Bioorg. Med.
Chem. Lett. 2003, 13, 4213–4216.
1
>290 °C. H NMR (D2O): d 1.35 (3H, d, J = 6.46 Hz),
3.27–3.35 (2H, m), 3.46–3.64 (5H, m), 7.48 (1H, m),
7.52–7.59 (1H, m), 7.63–7.66 (1H, m), 7.98 (1H, d,
J = 10.86 Hz), 8.79 (1H, s). IR (KBr) m 3423.1, 2935.2,
2736.5, 1726.0, 1623.8, 1510.0, 1452.2, 1274.7, 804.2,
775.3, 563.1 cmꢀ1. MS(EI), m/z (%) 435 (M+, 23), 379
23
D
(100), 335 (90). ½aꢁ +36 (c 0.105, H2O). Anal. Calcd
for C21H17F4N3O3ÆHClÆH2O: C, 51.49; H, 4.12; N,
8.58. Found: C, 51.60; H, 4.15; N, 8.65.
5.1.3.13. 6,8-Difluoro-1-(3-fluorophenyl)-1,4-dihydro-
7-((S)-3-methylpiperazin-1-yl)-4-oxoquinoline-3-carb-
oxylic acid hydrochloride (30a). This compound was pre-
pared in 90.1% yield from 23a as a white solid. Mp
1
>290 °C. H NMR (D2O): d 1.37 (3H, d, J = 6.47 Hz),
3.29–3.37 (2H, m), 3.48–3.66 (5H, m), 7.48–7.52 (3H,
m), 7.68–7.72 (1H, m), 7.93 (1H, d, J = 11.82 Hz), 8.80
(1H, s). IR (KBr) m 3434.7, 2933.2, 2713.4, 1735.6,
1619.9, 1596.8, 1484.9, 1446.4, 1322.9, 1027.9, 804.2,
684.6 cmꢀ1. MS(EI), m/z (%) 417 (M+, 14), 361 (96),
22
D
317 (100). ½aꢁ ꢀ29 (c 0.1, H2O). Anal. Calcd for
14. Cohen, M. A.; Griffin, T. J.; Bien, P. A.; Heifetz, C. L.;
Domagala, J. M. Antimicrob. Agents. Chemother. 1985, 28,
766.
C21H18F3N3O3ÆHClÆ0.1H2O: C, 55.36; H, 4.25; N,
9.22. Found: C, 55.23; H, 4.20; N, 9.15.