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C. Hubschwerlen et al. / Bioorg. Med. Chem. 11 (2003) 2313–2319
tered and the solid was chromatographed (CH2Cl2-
MeOH 9:1). The fractions were collected and evapo-
rated. The residue was crystallized from MeCN to
afford 3b (0.154 g; 0.27 mmol; 77%) as a pale yellow
solid. NMR: 1.11 (m, 2H), 1.21 (m, 2H), 1.83 (s,
3H), 3.17 (m, 4H), 3.41 (t, J=5.8, 3H), 3.71 (m, 2H),
4.01–4.11 (m, 5H), 4.71 (m, 1H), 7.11 (t, J=8, 1H),
7.18 (dd, J=7 and 2, 1H), 7.51 (dd, J=8 and 2,
1H), 8.05 (d, J=13, 1H), 8.24 (t, J=6, 1H), 8.59 (s,
1H), 15.1 (s, 1H). MS: 583.3 (M+H)+, 581.6 (M+H)À
Method ESI+, ESIÀ. Anal. calcd for C28H28F2N6O6: C,
56.94; H, 4.93; N, 14.23. Found: C, 57.01; H, 4.97; N,
14.04, H2O, 1.38.
6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-car-
boxylic acid (3e). A solution of 12 (0.044 g; 0.32 mmol)
in a mixture of 37% aq. HCl (1mL) and AcOH (1 mL)
was heated to 80 ꢀC for 20h. The solvents were eva-
porated. The residue was dissolved in a MeOH–
CH2Cl2 (1:1; 5 mL) mixture and treated with Et3N (0.5
mL). After evaporation to dryness, the residue was
taken up in AcOH (1 mL) and treated with Ac2O (1
mL). The reaction was left to proceed for 20h, and the
solvents were evaporated in vacuo. The residue was
purified by preparative HPLC (H2O–MeCN gradient)
to provide 3e (0.009 g; 0.06 mmol; 21%) as an off-white
solid. NMR: 1.84 (s, 3H), 3.02 (s, 3H), 3.11 (m, 4H),
3.50(m, 4H), 3.7 (dd, J=8 and 8.6, 1H), 4.09 (t, J=8,
1H), 4.71 (m, 1H), 5.3 (b, 1H), 7.13 (t, J=8, 1H), 7.20
(dd, J=7 and 2, 1H), 7.51 (dd, J=8 and 2, 1H), 7.63 (d,
J=13, 1H), 8.25 (t, J=6, 1H), 8.78 (s, 1H), 15.1 (s, 1H).
MS: 599.2 (M+H)+, 597.7 (MÀH)À, Method ESI+,
ESIÀ.
7-(4-{5-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-
3-yl]-pyridin-2-yl}-1-piperazin-1-yl)-1-cyclopropyl-6-
fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
acid (3c). This compound was prepared according to
the procedure reported for 3b starting from 4c and 5b.
NMR: 1.2-1.4 (m, 4H), 1.85 (s, 3H), 3.45 (m, 6H), 3.61
(m, 6H), 3.71 (m, 1H), 4.1 (t, J=8, 1H), 4.67 (m, 1H),
7.00 (d, J=9, 1H), 7.63 (d, J=8, 1H), 7.83 (d, J=9,
1H), 7.93 (d, J=14, 1H), 8.25 (s, 2H), 8.67 (s, 1H), 15.1
(s, 1H). MS: 565.8 (M+H)+ Method ESI+. Anal. calcd
for C28H28F2N6O6 (0.5 H2O): C, 56.44; H, 5.09; N,
17.06; H2O, 1.56. Found: C, 56.59; H, 5.08; N, 16.89,
H2O, 1.56.
7-(3-{4-[5(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-
3-yl]-2-fluoro-phenylamino}-azetidin-1-yl)-1-cyclopropyl-
6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-car-
boxylic acid (3f). This compound was prepared accord-
ing to the procedure reported for 3b starting from 4f
and 5b. NMR: 1.11–1.24 (m, 4H), 1.87 (s, 3H), 3.44 (t,
J=5, 2H), 3.68–3.76 (m, 2H), 4.09 (t, J=8, 1H), 4.32 (b,
2H), 4.51–4.57 (m, 1H), 4.67–4.77 (m, 3H), 6.24 (d,
J=7, 1H), 6.74 (t, J=9, 1H), 7.14 (d, J=9, 1H), 7.50
1-Cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5S)-5-(meth-
oxythiocarbonylamino-methyl)-2-oxo-oxazolidin-3-yl]-
phenyl}-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]-naphthyri-
dine-3-carboxylic acid (3d). This compound was pre-
pared according to the procedure reported for 3b
starting from 4d and 5b. NMR: 1.11–1.27 (m, 5H), 3.22
(m, 4H), 3.80(m, 4H), 3.91 (s, 3H), 4.1 (m, 4H), 4.95
(m, 1H), 7.13–7.24 (m, 2H), 7.56 (dd, J=15 and 3,
1H), 8.12 (d, J=15, 1H), 8.66 (s, 1H), 9.54 (t, J=6,
1H), 15.23 (s, 1H). MS: 615.2 (M+H)+ Method ESI+.
Anal. calcd for C28H28F2N6O6S: C, 54.72; H, 4.59; N,
13.67; S, 5.22. Found: C, 54.41; H, 4.76; N, 13.33; S,
5.0.4.
(dd, J=14 and 2, 1H), 8.04 (d, J=11, 1H), 8.27 (t, J=6,
+
1H), 8.60(s, 1H), 15.41 (s, 1H). MS: 569.5 (M+H)
Method ESI+.
,
7-[(3R)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazoli-
din-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]-1cyclo-
propyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-1-carboxylic
acid (3g). A solution of 5a (0.204 g; 0.5 mmol), 4g (0.052
g; 0.75 mmol) and DABCO# (0.112 g; 1 mmol) in
DMSO (5 mL) was stirred for 50h at 120 ꢀC. After
evaporation under reduced pressure, the residue was
resuspended in EtOH (10mL), treated with Et N (0.1
3
mL) and further stirred at rt for 20h. The mixture was
diluted with H2O (20mL). The solid was collected by
filtration and crystallized in MeOH–EtOH–CH2Cl2 to
afford 3g (0.024 g; 0.027 mmol; 5.5%) as a beige pow-
der. NMR: 0.9 (t, J=8, 1H), 1.00 (m, 2H), 1.15 (d,
J=4, 1H), 1.6 (s, 3H), 1.96 (m, 1H), 2.15 (m, 1H), 3.15
(m, 1H), 3.22–3.68 (m, 6H), 3.9 (m, 1H), 4.15 (m, 1H),
4.5 (m, 1H), 5.3 (d, J=7, 1H), 6.73 (t, J=7, 1H), 6.95
(m, 2H), 7.15 (dd, J=15 and 2, 1H), 7.68 (d, J=15,
1H), 8.08 (t, J=6, 1 h), 8.42 (s, 1H). MS: 582.4
(M+H)+, Method ESI+.
9-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-
3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-
6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-car-
boxylic acid ethyl ester (12). A solution of 8,9-
difluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-
phenalene-5-carboxylic acid ethyl ester10 (0.1 g; 0.32
mmol) and 4a (0.216 g; 0.64 mmol) in a mixture of pyri-
dine (1 mL) and DMSO (1 mL) was heated to 120 ꢀC
for 20h. The solvents were evaporated under reduced
pressure and the residue was taken up in H2O. The solid
was collected by filtration and purified by chromato-
graphy (CH2Cl2–MeOH 9:1) to yield 12 (0.044 g; 0.07
mmol; 22%) as an off-white solid. NMR: 1.4 (t, J=8,
3H), 2.0(s, 3H), 3.15 (s, 3H), 326 (m, 4H), 3.30(d, J=6,
2H), 3.61 (m, 5H), 3.74 (dd, J=8 and 9, 1H), 5.2 (m,
2H), 5.38 (m, 2H), 5.65 (m, 1H), 7.23–7.40(m, 2H), 7.61
(d, J=15, 1H), 7.65 (d, J=15, 1H), 8.4 (t, J=6, 1H),
8.62 (s, 1H). MS: 627.7 (M+H)+, Method ESI+.
7-[(3R)-3-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazoli-
din-3-yl]-2-fluoro-phenylamino}-pyrrolidin-1-yl]-1-cyclo-
propyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]-naphthyridine-3-
carboxylic acid (3h). This compound was prepared
according to the procedure reported for 3g starting from
4g and 5b. NMR: 1.0–1.3 (m, 7H), 1.84 (s, 3H), 2.07 (m,
1H), 3.4 (t, J=5, 1H), 3.70(m, 1H), 3.8–4.0(m, 2H),
4.07 (t, J=9, 1H), 4.30–4.5 (m, 3H), 4.66 (m, 1H), 5.17
(d, J=6, 1H), 6.87 (t, J=12, 1H), 7.07 (d, J=8, 1H),
7.40(dd, J=14 and 2, 1H), 8.00 (d, J=14, 1H), 8.02 (t,
9-(4-{4-[(5S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-
3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-