1912 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Kuramoto et al.
Eth yl 1-(3-ter t-Bu toxyca r bon yla m in o-4-flu or op h en yl)-
7-ch lor o-6-flu or o-4-oxo-1,4-d ih yd r o-1,8-n a p h th yr id in e-3-
ca r boxyla te (9c). Colorless powder (71% yield); mp 214-215
8.2 Hz), 8.33 (1H, s), 7.06 (1H, dd, J ) 10.5, 8.9 Hz), 6.80 (1H,
brs), 4.39 (2H, q, J ) 7.3 Hz), 1.51 (9H, s), 1.39 (3H, t, J ) 7.3
Hz). 13C NMR (CDCl3): δ 171.9 (s), 164.2 (s), 152.3 (dd, J )
241, 12 Hz), 152.0 (s), 151.8 (s), 151.7 (dd, J ) 252, 10 Hz),
151.1 (dd, J ) 255, 17 Hz), 148.6 (dd, J ) 254, 14 Hz), 133.9
(s), 126.4 (dd, J ) 14, 5 Hz), 126.2 (d, J ) 3 Hz), 124.7 (dd, J
) 11, 3 Hz), 119.0 (s), 113.8 (d, J ) 12 Hz), 112.2 (d, J ) 19
Hz), 111.9 (s), 104.5 (dt, J ) 24, 3 Hz), 82.2 (s), 61.4 (s), 28.2
1
°C. H NMR (CDCl3): δ 8.63 (1H, s), 8.48 (1H, d, J ) 7.3 Hz),
8.28 (1H, brs), 7.26 (1H, dd, J ) 11.1, 8.7 Hz), 7.00 (1H, ddd,
J ) 8.7, 4.5, 2.8 Hz), 6.90 (1H, s), 4.40 (2H, q, J ) 7.3 Hz),
1.52 (9H, s), 1.41 (3H, t, J ) 7.3 Hz). 13C NMR (CDCl3): δ
173.3 (s), 164.3 (s), 152.6 (d, J ) 262 Hz), 151.9 (s), 151.5 (d,
J ) 246 Hz), 149.4 (s), 145.2 (s), 142.5 (d, J ) 22 Hz), 135.9
(d, J ) 3 Hz), 128.5 (d, J ) 12 Hz), 123.4 (d, J ) 2 Hz), 123.1
(dd, J ) 21, 2 Hz), 121.4 (d, J ) 8 Hz), 118.5 (s), 115.6 (d, J )
21 Hz), 112.7 (s), 81.9 (s), 61.3 (s), 28.2 (s), 14.3 (s). IR: 3254,
1728, 1612, 1539, 1406, 1159 cm-1. MS m/z: 480 and 482 for
Cl isotopic peaks of (M + H)+.
(s), 14.3 (s). IR: 3250, 1739, 1712, 1612, 1529, 1172, 1070 cm-1
.
MS m/z: 515 and 517 for Cl isotopic peaks of (M + H)+.
Eth yl 8-Br om o-1-(5-ter t-bu toxyca r bon yla m in o-2,4-d i-
flu or op h en yl)-6,7-d iflu or o-4-oxo-1,4-d ih yd r oqu in olin e-3-
ca r boxyla te (12d ). Colorless solid (44% yield); mp 202-203
1
°C. H NMR (CDCl3): δ 8.39 (1H, t, J ) 9.4 Hz), 8.37 (1H, s),
Ethyl 1-(5-tert-Butoxycarbonylamino-2,3,4-trifluorophen-
yl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
ca r boxyla te (9d ). Colorless needles (92% yield); mp 208-
8.32 (1H, s), 7.06 (1H, t, J ) 9.7 Hz), 6.78 (1H, brs), 4.38 (2H,
q, J ) 7.3 Hz), 1.51 (9H, s), 1.39 (3H, t, J ) 7.3 Hz). 13C NMR
(CDCl3): δ 172.0 (s), 164.2 (s), 152.4 (dd, J ) 251, 12 Hz), 152.2
(s), 151.9 (dd, J ) 253, 16 Hz), 151.8 (s), 151.8 (dd, J ) 251,
10 Hz), 148.4 (dd, J ) 256, 16 Hz), 135.0 (s), 126.8 (d, J ) 3
Hz), 126.0 (dd, J ) 14, 4 Hz), 124.9 (dd, J ) 11, 4 Hz), 119.4
(s), 114.7 (d, J ) 19 Hz), 111.9 (s), 104.6 (dt, J ) 24, 3 Hz),
99.9 (d, J ) 12 Hz), 82.2 (s), 61.4 (s), 28.1 (s), 14.3 (s). IR: 3219,
1738, 1714, 1610, 1527, 1167 cm-1. MS m/z: 559 and 561 for
Br isotopic peaks of (M + H)+.
1
209 °C. H NMR (CDCl3): δ 8.54 (1H, s), 8.48 (1H, d, J ) 6.8
Hz), 8.16 (1H, brs), 6.82 (1H, s), 4.41 (2H, q, J ) 7.4 Hz), 1.52
(9H, s), 1.41 (3H, t, J ) 7.4 Hz). 13C NMR (DMSO-d6): δ 172.6
(s), 163.2 (s), 152.6 (s), 152.0 (d, J ) 258 Hz), 149.4 (s), 144.7
(s), 143.6 (dd, J ) 253, 10 Hz), 142.8 (dd, J ) 251, 12 Hz),
140.9 (d, J ) 22 Hz), 139.4 (dt, J ) 259, 13 Hz), 124.4 (d, J )
9 Hz), 123.5 (d, J ) 21 Hz), 123.2 (d, J ) 11 Hz), 122.8 (d, J
) 3 Hz), 118.1 (s), 112.8 (s), 80.3 (s), 60.4 (s), 27.8 (s), 14.1 (s).
IR: 3304, 1738, 1726, 1608, 1548, 1471, 1163 cm-1. MS m/z:
516 and 518 for Cl isotopic peaks of (M + H)+.
Eth yl 1-(3-ter t-Bu toxycar bon ylam in o-2,4-diflu or oph en -
yl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
ca r boxyla te (9e). Colorless solid (67% yield); mp 128-131
°C. 1H NMR (DMSO-d6): δ 9.16 (1H, brs), 8.75 (1H, s), 8.56
(1H, d, J ) 7.8 Hz), 7.68 (1H, ddd, J ) 8.2, 5.5, 2.7 Hz), 7.40
(1H, t, J ) 9.2 Hz), 4.24 (2H, q, J ) 7.4 Hz), 1.43 (9H, s), 1.28
(3H, t, J ) 7.4 Hz). 13C NMR (DMSO-d6): δ 172.6 (s), 163.1
(s), 158.0 (d, J ) 249 Hz), 153.3 (dd, J ) 249, 6 Hz), 152.7 (s),
151.9 (d, J ) 258 Hz), 149.4 (s), 144.9 (s), 141.0 (d, J ) 22
Hz), 127.3 (d, J ) 10 Hz), 123.7 (d, J ) 13 Hz), 123.4 (d, J )
20 Hz), 122.8 (d, J ) 3 Hz), 116.1 (t, J ) 17 Hz), 112.8 (s),
112.0 (d, J ) 22 Hz), 79.8 (s), 60.4 (s), 27.8 (s), 14.1 (s). IR:
3304, 1730, 1612, 1527, 1406, 1178 cm-1. MS m/z: 498 and
500 for Cl isotopic peaks of (M + H)+.
Eth yl
1-(5-ter t-Bu toxyca r bon yla m in o-2,4-d iflu or o-
phenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-
ca r boxyla te (12e). Slightly yellow solid (59% yield); mp 191-
192 °C. 1H NMR (CDCl3): δ 8.34 (1H, s), 8.32 (1H, s), 8.24
(1H, t, J ) 9.6 Hz), 7.10 (1H, dd, J ) 10.4, 8.7 Hz), 6.79 (1H,
brs), 4.40 (2H, q, J ) 7.3 Hz), 1.82 (3H, d, J ) 2.7 Hz), 1.52
(9H, s), 1.41 (3H, t, J ) 7.3 Hz). 13C NMR (CDCl3): δ 172.7
(s), 164.7 (s), 158.3 (dd, J ) 258, 12 Hz), 155.4 (dd, J ) 256,
12 Hz), 153.7 (s), 152.6 (dd, J ) 242, 15 Hz), 151.5 (s), 148.9
(dd, J ) 252, 16 Hz), 136.2 (d, J ) 4 Hz), 129.3 (d, J ) 16 Hz),
128.8 (s), 127.4 (dd, J ) 14, 4 Hz), 126.3 (d, J ) 3 Hz), 116.5
(d, J ) 19 Hz), 112.7 (d, J ) 19 Hz), 111.7 (s), 106.1 (dt, J )
26, 3 Hz), 81.6 (s), 61.3 (s), 28.1 (s), 14.3 (s), 11.5 (d, J ) 7
Hz). IR: 3049, 1736, 1714, 1616, 1520, 1159 cm-1. MS m/z:
495 (M + H)+.
1-(5-Am in o-2,4-diflu or oph en yl)-7-ch lor o-6-flu or o-4-oxo-
1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r boxylic a cid (10a ).
The naphthyridine-3-carboxylate derivative 9a (1.9 g, 3.82
mmol) was added to a mixture of acetic acid (10 mL) and
aqueous 6 M HCl (5 mL). The reaction mixture was heated to
reflux for 6 h, and then, H2O (50 mL) was added. After it was
cooled, the precipitate was collected by filtration and washed
with H2O, EtOH, and Et2O to give 10a as yellow needles (1.17
g, 84%); mp >270 °C. 1H NMR (DMSO-d6): δ 8.98 (1H, s), 8.76
(1H, d, J ) 7.4 Hz), 7.43 (1H, t, J ) 10.6 Hz), 7.02 (1H, dd, J
) 8.8, 7.7 Hz), 5.46 (2H, s). 13C NMR (DMSO-d6): δ 177.4 (s),
164.4 (s), 152.2 (d, J ) 259 Hz), 150.6 (s), 150.0 (dd, J ) 244,
11 Hz), 147.1 (dd, J ) 240, 11 Hz), 144.9 (s), 142.7 (d, J ) 23
Hz), 134.0 (d, J ) 15 Hz), 123.0 (d, J ) 20 Hz), 122.5 (dd, J )
15, 4 Hz), 121.4 (d, J ) 3 Hz), 114.7 (s), 110.3 (s), 104.5 (t, J
Eth yl
1-(5-ter t-Bu toxyca r bon yla m in o-2,4-d iflu or o-
p h en yl)-6,7-d iflu or o-4-oxo-1,4-d ih yd r oq u in olin e-3-ca r -
boxyla te (12a ). Colorless solid (76% yield); mp 235-236 °C.
1H NMR (DMSO-d6): δ 9.42 (1H, brs), 8.59 (1H, s), 8.14 (1H,
dd, J ) 10.1, 8.7 Hz), 8.10 (1H, t, J ) 8.0 Hz), 7.71 (1H, t, J )
10.1 Hz), 7.22 (1H, dd, J ) 11.2, 6.2 Hz), 4.22 (2H, q, J ) 7.3
Hz), 1.45 (9H, s), 1.27 (3H, t, J ) 7.3 Hz). 13C NMR (DMSO-
d6): δ 171.5 (s), 163.6 (s), 154.2 (dd, J ) 250, 8 Hz), 152.9 (dd,
J ) 249, 13 Hz), 152.8 (s), 152.5 (dd, J ) 254, 15 Hz), 149.3
(s), 147.7 (dd, J ) 248, 14 Hz), 137.5 (d, J ) 10 Hz), 124.6 (d,
J ) 3 Hz), 124.5 (d, J ) 20 Hz), 124.4 (d, J ) 16 Hz), 122.6
(dd, J ) 15, 4 Hz), 113.9 (d, J ) 18 Hz), 111.3 (s), 106.9 (d, J
) 21 Hz), 106.0 (t, J ) 26 Hz), 79.9 (s), 60.1 (s), 27.9 (s), 14.1
(s). IR: 3269, 1722, 1616, 1533, 1163 cm-1. MS m/z: 481 (M
+ H)+.
) 24 Hz). IR: 3472, 1741, 1612, 1525, 1406, 1255, 1147 cm-1
MS m/z: 370 (M + H)+. Anal. (C15H7ClF3N3O3) C, H, N.
.
E t h yl
1-(5-ter t-Bu t oxyca r b on yla m in o-2,4-d iflu or o-
1-(5-Am in o-2-flu or op h en yl)-7-ch lor o-6-flu or o-4-oxo-
1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r boxylic Acid (10b).
Yellow solid (82% yield); mp >290 °C. 1H NMR (DMSO-d6): δ
8.91 (1H, s), 8.75 (1H, d, J ) 7.8 Hz), 7.19 (1H, t, J ) 9.6 Hz),
6.81-6.79 (2H, m), 5.57 (2H, s). 13C NMR (DMSO-d6): δ 177.4
(s), 164.4 (s), 152.2 (d, J ) 260 Hz), 150.4 (s), 144.9 (s), 143.8
(d, J ) 255 Hz), 142.7 (d, J ) 22 Hz), 126.6 (d, J ) 14 Hz),
123.0 (d, J ) 20 Hz), 121.4 (d, J ) 4 Hz), 116.6 (d, J ) 21 Hz),
116.5 (d, J ) 20 Hz), 114.4 (s), 113.9 (s), 110.3 (s). IR: 3474,
1743, 1618, 1518, 1404, 1251, 1049 cm-1. MS m/z: 352 (M +
H)+. Anal. (C15H8ClF2N3O3) C, H, N.
1-(3-Am in o-4-flu or op h en yl)-7-ch lor o-6-flu or o-4-oxo-
1,4-d ih yd r o-1,8-n a p h th yr id in e-3-ca r boxylic Acid (10c).
Yellow solid (94% yield); mp >270 °C. 1H NMR (DMSO-d6): δ
8.79 (1H, s), 8.76 (1H, d, J ) 7.4 Hz), 7.22 (1H, dd, J ) 11.0,
8.7 Hz), 6.95 (1H, dd, J ) 7.8, 2.7 Hz), 6.74 (1H, ddd, J ) 8.7,
4.1, 2.7 Hz), 5.62 (2H, s). 13C NMR (DMSO-d6): δ 177.5 (s),
164.6 (s), 152.0 (d, J ) 260 Hz), 150.6 (d, J ) 241 Hz), 150.2
p h en yl)-4-oxo-6,7,8-tr iflu or o-1,4-d ih yd r oqu in olin e-3-ca r -
boxyla te (12b). Colorless powder (50% yield); mp 181-183
1
°C. H NMR (CDCl3): δ 8.44 (1H, brs), 8.31 (1H, s), 8.17 (1H,
t, J ) 10.1 Hz), 7.09 (1H, dd, J ) 10.5, 8.9 Hz), 6.80 (1H, brs),
4.39 (2H, q, J ) 7.3 Hz), 1.52 (9H, s), 1.39 (3H, t, J ) 7.3 Hz).
13C NMR (CDCl3): δ 171.4 (s), 164.3 (s), 151.9 (s), 151.5 (dd,
J ) 250, 10 Hz), 150.8 (s), 148.6 (dd, J ) 254, 11 Hz), 143.5
(dd, J ) 269, 16 Hz),143.2 (dd, J ) 259, 15 Hz), 141.4 (dd, J
) 256, 15 Hz), 126.9 (s), 126.2 (d, J ) 14 Hz), 124.7 (dd, J )
11, 3 Hz), 124.5 (d, J ) 4 Hz), 118.4 (s), 111.7 (s), 109.6 (d, J
) 19 Hz), 104.5 (dt, J ) 24, 3 Hz), 82.2 (s), 61.4 (s), 28.2 (s),
14.3 (s). IR: 1722, 1608, 1533, 1161 cm-1. MS m/z: 499 (M +
H)+.
Eth yl
1-(5-ter t-Bu toxyca r bon yla m in o-2,4-d iflu or o-
phenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-
ca r boxyla te (12c). Colorless solid (67% yield); mp 185-187
1
°C. H NMR (CDCl3): δ 8.35 (1H, s), 8.34 (1H, dd, J ) 10.1,