Carboxylic Acids as Antitumor Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 25 5571
under ice-cooling. The reaction mixture was heated at 50 °C
for 2 h and diluted with ice-water. The resulting precipitates
were collected by filtration, washed with water, and dried to
give 2.0 g (63%) of 4 (R1 ) 2-thiazolyl).
Eth yl 7-(3-Am in o-1-p yr r olid in yl)-6-flu or o-1,4-d ih yd r o-
4-oxo-1-(2-th ia zolyl)-1,8-n a p h th yr id in e-3-ca r boxyla te (5,
R1 ) 2-Th ia zolyl, R2R3N ) 3-Am in o-1-p yr r olid in yl). To a
suspension of 50 g (0.14 mol) of 4 (R1 ) 2-thiazolyl) in 1 L of
CH3CN was added 36.5 g (0.42 mol) of 3-aminopyrrolidine. The
reaction mixture was stirred at room temperature for 1 h. After
ice-cooling, the resulting precipitates were collected by filtra-
tion, washed with CH3CN and a mixture of CH3CN and EtOH,
and extracted with CHCl3. The organic layer was dried over
Na2SO4 and concentrated to dryness to afford a crude product,
which was chromatographed on silica gel with CHCl3/MeOH
(50:1) to give 3.3 g (59%) of ethyl 7-ethanesulfonyl-6-fluoro-
1,4-dihydro-4-oxo-1-(2-thiazolyl)methyl-1,8-naphthyridine-3-
carboxylate.
A mixture composed of 1.15 g (2.7 mmol) of the above
compound and 0.70 g (8.1 mmol) of 3-aminopyrrolidine in 30
mL of CH3CN was heated to reflux for 15 min. The reaction
mixture was concentrated under reduced pressure, and the
obtained residue was diluted with water and extracted with
CHCl3. The organic layer was dried over Na2SO4 and concen-
trated to dryness to afford a crude product, which was
recrystallized from CH3CN to give 1.1 g (96%) of ethyl 7-(3-
amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1-(2-thi-
azolyl)methyl-1,8-naphthyridine-3-carboxylate, mp 165-166
°C. MS (m/z): 418 (MH+). IR (KBr) cm-1: 1718, 1631. 1H NMR
(CDCl3) δ: 1.39 (t, 3 H, J ) 7 Hz), 1.70-1.90 (m, 1 H), 2.08-
2.26 (m, 1 H), 3.45-3.58 (m, 1 H), 3.70-4.05 (m, 4 H), 4.39 (q,
2 H, J ) 7 Hz), 5.73 (s, 2 H), 7.30 (d, 1 H, J ) 3 Hz), 7.76 (d,
1 H, J ) 3 Hz), 8.07 (d, 1 H, J ) 13 Hz), 8.59 (s, 1 H).
A suspension of 1.1 g (2.6 mmol) of the above compound in
9 mL of 10% HCl and 1 mL of EtOH was heated to reflux for
1 h. The reaction mixture was concentrated under reduced
pressure and triturated with EtOH. The resulting precipitates
were collected by filtration, washed with EtOH, and dried to
give 0.69 g (60%) of 15, mp 268-269 °C. MS (m/z): 390 (MH+).
IR (KBr) cm-1: 1716, 1630.
successively, and dried to give 55.4 g (98%) of 5 (R1
)
2-thiazolyl, R2R3N ) 3-amino-1-pyrrolidinyl), mp 218-220 °C
(dec). IR (KBr) cm-1: 1728, 1638. 1H NMR (DMSO-d6) δ: 1.31
(t, 3 H, J ) 7.0 Hz), 1.40-2.40 (m, 2 H), 3.40-4.00 (m, 5 H),
4.80 (q, 2 H, J ) 7.0 Hz), 7.68 (d, 1 H, J ) 3.5 Hz), 7.76 (d, 1
H, J ) 3.5 Hz), 7.83 (d, 1 H, J ) 13 Hz), 9.54 (s, 1H).
7-(3-Am in o-1-p yr r olid in yl)-6-flu or o-1,4-d ih yd r o-4-oxo-
1-(2-th ia zolyl)-1,8-n a p h th yr id in e-3-ca r boxylic Acid Hy-
d r och lor id e (1). A suspension of 27.0 g (67.0 mmol) of 5 in
540 mL of 20% HCl was heated to reflux for 6 h. After ice-
cooling, the resulting precipitates were collected by filtration,
washed with 0.5 N HCl and EtOH successively, and dried to
give 25.2 g (91%) of 1, mp 286-288 °C (dec). MS (m/z): 376
(MH+). IR (KBr) cm-1: 1727, 1635. 1H NMR (NaOD/D2O) δ:
1.30-3.8 (m, 7 H), 6.99 (d, 1 H, J ) 3.5 Hz), 7.23 (d, 1 H, J )
13 Hz), 7.30 (d, 1 H, J ) 3.5 Hz), 8.90 (s, 1H).
7-(3-Am in o-1-p yr r olid in yl)-6-flu or o-1,4-d ih yd r o-4-oxo-
1-p h en yl-1,8-n a p h t h yr id in e-3-ca r b oxylic Acid H yd r o-
ch lor id e (6). Compound 6 was prepared from 2 and aniline.
3-Acetamidopyrrolidine and NaHCO3 were used instead of
3-aminopyrrolidine in the coupling reaction at C-7, mp 292-
295 °C (dec). IR (KBr) cm-1: 1720, 1625.
7-(3-Am in o-1-p yr r olid in yl)-6-flu or o-1,4-d ih yd r o-1-(3-
m eth yl-5-isoxa zolyl)-4-oxo-1,8-n a p h th yr id in e-3-ca r box-
ylic Acid Hyd r och lor id e (12). Compound 12 was prepared
from 2 and 5-amino-3-methylisoxazole. Et3N was added in the
coupling reaction at C-7, mp 253-255 °C (dec). MS (m/z): 390
(MH+). IR (KBr) cm-1: 1636, 1458.
According to the similar procedure for 1, 6, and 12, com-
pounds 7, 8, 10, 11, 13, 14, and 16-24 were prepared.
7-(3-Am in o-1-p yr r olid in yl)-1-cyclop r op yl-6-flu or o-1,4-
d ih yd r o-4-oxo-1,8-n a p h th yr id in e-3-ca r boxylic Acid Hy-
d r och lor id e (9). Compound 9 was prepared by a coupling
reaction of 3-aminopyrrolidine and 7-chloro-1-cyclopropyl-6-
fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
which was derived from 4 (R1 ) cyclopropyl), mp 280-285 °C
(dec).
7-(3-Am in o-1-p yr r olid in yl)-6-flu or o-1,4-d ih yd r o-4-oxo-
1-(2-th iazolyl)m eth yl-1,8-n aph th yr idin e-3-car boxylic Acid
Hyd r och lor id e (15). To a solution composed of 4.0 g (13.5
mmol) of ethyl 7-ethylthio-6-fluoro-1,4-dihydro-4-oxo-1,8-naph-
thyridine-3-carboxylate, 5.3 g (20.2 mmol) of PPh3, 3.2 g (16.5
mmol) of diethyl azodicarboxylate (90%), and 80 mL of THF
was added a THF (2 mL) solution of 1.7 g (14.9 mmol) of
2-hydroxymethylthiazole. The reaction mixture was stirred at
room temperature for 1 h and concentrated under reduced
pressure. The obtained residue was diluted with water and
extracted with CHCl3. The organic layer was dried over Na2-
SO4 and concentrated to dryness to afford a crude product,
which was chromatographed on silica gel with CHCl3/MeOH
(19:1) and recrystallized from AcOEt to give 5.2 g (98%) of ethyl
7-ethylthio-6-fluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)methyl-
1,8-naphthyridine-3-carboxylate, mp 148-149 °C. MS (m/z):
394 (MH+). IR (KBr) cm-1: 1728, 1612. 1H NMR (CDCl3) δ:
1.35 (t, 3 H, J ) 7 Hz), 1.40 (t, 3 H, J ) 7 Hz), 3.23 (q, 2 H, J
) 7 Hz), 4.40 (q, 2 H, J ) 7 Hz), 5.85 (s, 2 H), 7.33 (d, 1 H, J
) 3 Hz), 7.77 (d, 1 H, J ) 3 Hz), 8.19 (d, 1 H, J ) 9 Hz), 8.73
(s, 1 H).
Eth yl 3-(4-Ch lor o-2-m eth ylth iop yr im id in -5-yl)-3-oxo-
p r op ion a te (31). To a solution of 12.3 g (92.8 mmol) of ethyl
hydrogen malonate in 80 mL of THF was added dropwise 64
mL (192 mmol) of 3 M MeMgBr in Et2O under ice-cooling.
After the mixture was stirred for 20 min, THF (100 mL)
solution of 8.6 g (38.3 mmol) of 3010 was added dropwise. After
being stirred at room temperature for 2 h, the reaction mixture
was poured into ice-water and acidified to pH 5-6 with
concentrated HCl and extracted with AcOEt. The organic layer
was dried over Na2SO4 and concentrated to dryness to afford
a crude product, which was chromatographed on silica gel with
CHCl3 to give 8.0 g (76%) of 31. MS (m/z): 275 (MH+). IR (neat)
cm-1: 1743.
Eth yl 5,8-Dih yd r o-2-m eth ylth io-5-oxo-8-(2-th ia zolyl)-
p yr id o[2,3-d ]p yr im id in e-6-ca r boxyla te (32). A mixture
composed of 7.95 g (30 mmol) of 31, 6.8 g (45.9 mmol) of CH-
(OEt)3, and 7.76 g (76.0 mmol) of Ac2O was heated to reflux
at 130 °C for 1 h, during which period the resulting AcOEt
was distilled off under atmospheric pressure. After concentra-
tion under reduced pressure, the obtained residue was diluted
with 50 mL of i-Pr2O, and 3.28 g (32.8 mmol) of 2-aminothia-
zole was added. After the mixture was stirred at room
temperature overnight, the resulting precipitates were col-
lected by filtration and washed with i-Pr2O to give 6.4 g (55%)
of ethyl 2-[(4-chloro-2-methylthiopyrimidin-5-yl)carbonyl]-3-(2-
thiazolylamino)acryrate. To a solution of 6.4 g (18.2 mmol) of
the above compound in 70 mL of dioxane was added 2.72 g
(19.7 mmol) of K2CO3 under ice-cooling. After being stirred for
5 h, the reaction mixture was diluted with 100 mL of ice-
water and neutralized with 10% HCl. The resulting precipi-
tates were collected by filtration, washed with water, dioxane,
and i-Pr2O successively, and dried to give 6.0 g (95%) of 32,
mp 183-184 °C. MS (m/z): 349 (MH+). IR (KBr) cm-1: 1736.
E t h yl 5,8-Dih yd r o-2-m et h a n esu lfon yl-5-oxo-8-(2-t h i-
a zolyl)p yr id o[2,3-d ]p yr im id in e-6-ca r boxyla te (33). To a
solution of 5.99 g (17.2 mmol) of 32 in 450 mL of CH2Cl2 was
added 9.30 g (43.1 mmol) of 80% MCPBA under ice-cooling.
After being stirred for 15 h at room temperature, the reaction
mixture was washed with aqueous Na2S2O3 and aqueous
NaHCO3 successively. The organic layer was dried over Na2-
SO4 and concentrated to dryness to afford a crude product,
which was recrystallized from a mixture of AcOEt and i-Pr2O
to give 4.48 g (69%) of 33, mp 185-187 °C. MS (m/z): 381
(MH+). IR (KBr) cm-1: 1741.
To a solution of 5.2 g (13.2 mmol) of the above compound in
210 mL of CH2Cl2 was added 6.8 g (27.6 mmol) of 3-chloro-
peroxybenzoic acid (MCPBA, 70%). The reaction mixture was
stirred at room temperature overnight, then diluted with water
Eth yl 2-(3-Am in o-1-p yr r olid in yl)-5,8-d ih yd r o-5-oxo-8-
(2-th ia zolyl)p yr id o[2,3-d ]p yr im id in e-6-ca r boxyla te (34).