Synthesis of SMP-797: A new potent ACAT inhibitor

Article abstract of DOI:10.1016/j.tet.2005.08.009

A potent ACAT (acyl-CoA: cholesterol acyltransferase) inhibitor SMP-797 was effectively synthesized by the urea formation of 3-amino-4-aryl-1,8- naphthyridin-2(1H)-one and 4-amino-2,6-diisopropylamine. The synthesis of the former compound involved the Suzuki coupling reaction as a key step, and the latter was prepared by the 4-selective nitration of 2,6-diisopropylaniline using 2,3,5,6-tetrabromo-4-methyl-4-nitro-2,5-cyclohexadienone.

Full text of DOI:10.1016/j.tet.2005.08.009

Tetrahedron 61 (2005) 10081–10092
Synthesis of SMP-797: a new potent ACAT inhibitor
*
Hitoshi Ban, Masami Muraoka and Naohito Ohashi
Research Division, Sumitomo Pharmaceuticals Co. Ltd, 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka 554-0022, Japan
Received 11 July 2005; revised 3 August 2005; accepted 3 August 2005
Available online 19 August 2005
Abstract—A potent ACAT (acyl-CoA: cholesterol acyltransferase) inhibitor SMP-797 was effectively synthesized by the urea formation of
3-amino-4-aryl-1,8-naphthyridin-2(1H)-one and 4-amino-2,6-diisopropylamine. The synthesis of the former compound involved the Suzuki
coupling reaction as a key step, and the latter was prepared by the 4-selective nitration of 2,6-diisopropylaniline using 2,3,5,6-tetrabromo-4-
methyl-4-nitro-2,5-cyclohexadienone.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
SMP-797 was synthesized by the urea coupling reaction of
3-amino-4-phenylnaphthyridine 4 and 4-amino-2,6-diiso-
propylaniline 8.7 Initial preparation of 4 and 8, however,
employed relatively long synthetic methods. The compound
4 was obtained according to the synthesis of SM-32504,6
which involved benzoylation of 20-aminopyridine 1 via
An enzyme acyl-CoA: cholesterol acyltransferase (ACAT),
which catalyzes the intracellular cholesterol esterification,1
plays important roles in several physiological processes: (1)
absorption of dietary and biliary cholesterol in the intestines;2
(2) determination of cholesteryl ester content and the secretion
of hepatic very low density lipoprotein (VLDL);3 (3)
accumulation of cholesteryl esters in macrophage in the
arterial wall.4 Inhibition of ACAT, therefore, is expected to
reduce plasma lipid levels by inhibiting intestinal cholesterol
absorption and hepatic VLDL secretion, and to prevent
progression of atherosclerotic lesions by inhibiting the
accumulation of cholesteryl esters in macrophage. For this
reason, ACAT inhibitor is an attractive target for the treatment
of hypercholesterolemia and atherosclerosis.5
¨
directed ortho-metalation and the Friedlander reaction of
2-amino-3-(3-methoxybenzoyl)pyridine 3. The synthesis
required 10 steps from commercially available 1. Use of
expensive BuLi reagent in the synthesis of 2 and one carbon
removal from 3 using the Crutius reaction were other
drawbacks.
The other unit 8 of SMP-797 was obtained by nitration of
protected 2,6-diisopropylaniline 5 followed by functional
manipulation, which resulted in a five-step synthesis from
commercially available 5.7,9 In addition, 8 was gradually
oxidized in air, and was not easy to handle. An improved
synthesis of 4 and 8, therefore, was required for the effective
preparation of SM-797 (Scheme 1).
It was previously found in our group that urea derivatives
derived from 3-amimo-4-aryl-1,8-naphthyridin-2(1H)-one
and anilines, in paticular, SM-32504 exhibited potent
ACAT inhibitory activity.6 However, this compound was
poorly absorpted by oral absorption due to its low aqueous
solubility. Extensive studies then lead to the development of
SMP-797, which possesses 4-amino group on the aniline
and 3-hydroxypropoxy group on the 4-phenyl group of the
naphthyridinone moiety (Fig. 1).7 SMP-797 decreased the
serum total cholesterol level by 53% compared with control
at the dosage of 1.0 mg/kg/day orally for 3 weeks in a rabbit
model fed a casein-rich diet. This effect can be compared
with atrovastatin, which decreased 54% by a dose of 10 mg/
kg/day orally for 6 weeks.8
In the improved synthesis of the naphthyridine unit, hydroxy
protecting group was changed from acetate to benzyl,
because we first examined naphthyridine construction in the
¨
synthesis of 16. The Skraup reaction and the Friedlander
¨
Keywords: Cyclization; Friedlander reaction; Suzuki coupling; 4-Selective
nitration; SMP-797.
*
Corresponding author. Tel.: C81 6 6466 5227; fax: C81 6 6466 5287;
e-mail: ban@sumitomopharm.co.jp
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.009

10082
H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
Scheme 1.
reaction are classical methods to prepare 1,8-naphthyridin-
2(1H)-ones.10 The former is the condensation reaction of
2-aminopyridine with a three-carbon unit such as b-ketoester.
The latter is the condensation of a 2-amino-3-carbonylpyridine
with a two-carbon unit typically enolizable carbonyl
compounds. Preparation of 4-arylated 1,8-naphtyhyridin-
2(1H)-ones by these methods, however, has been rare:
condensation reaction of 6-amino-4-phenylpyridin-2(1H)-
ones and b-ketoesters11,12 (Skraup reaction); condensation
of 2-amino-3-benzoylpyridine and activated methyl-
enes11,13 (Friedlander reaction); cyclization of 2-[(2,2-
¨
dimethyl-1-oxopropyl)amino]-b-hydroxy-b-phenyl-3 pyridi-
nepropanoic acids.14 We, therefore, explored a new method
for the synthesis of 4-aryl-1,8-naphthyridin-2(1H)-ones:15 It
was planned that aryl group was introduced by the Suzuki
coupling reaction. Only two precedents of the Suzuki
coupling were reported for naphthyridines.16,17 In spite of
few precedents, the organometallic method appeared to be
effective for a preparation of naphthyridine derivatives. As a
result of the present study, a synthesis involving shorter than
the original method, and overcoming the drawbacks noted
above was developed: (1) condensation of 2-chloro-3-
carboxypyridine 10 with primary amine giving 2-amino-3-
carboxypyridine; (2) construction of 1,8-naphthyridin-
¨
2(1H)-one nuclei by the modified Friedlander reaction
using acetic anhydride. Such cyclization of 2-aminobenzoic
acid with acetic anhydride has been used only to synthesize
quinolines;18 (3) nitration at the 3-position; (4) the Suzuki
coupling19 of 4-halo-1,8-naphthyridin-2(1H)-ones 13
(Scheme 2).
Scheme 2.

H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
10083
2. Results and discussion
Heating neat 2-chloronicotinic acid 10 and butylamine
under reflux for 2 days or benzylamine at 90 8C for 10 h
gave 2-aminonicotinic acids 11a and 11b, respectively.20,21
The reaction of 11a or 11b with acetic anhydride in boiling
acetic acid for 2 h gave the cyclized products 4-acetoxy-1,8-
naphthyridines 12a and 12b in good yields. Thus, the 1,8-
naphthyridine structure could be constructed in two-steps
from commercially available 10 using inexpensive reagents.
It may be likely that the intramoleculer C–C bond formation
takes place via the Claisen condensation of acetamide and
mixed anhydride formed from pyridinecarboxylate and
acetic anhydride.
The compounds 17a and 17b obtained by deacetylation of
12a and 12b, respectively, were converted to 4-chloro-
naphthyridines 18a and 18b by reacting with POCl3.
Treatment of 17a with POBr3 gave a bromide 18d.
N-Phenyl derivative 11c obtained according to the
literature22 was converted analogously to 18c without
isolating the intermediates 12c and 17c. Although the
yield of 18c was low due to the formation of various by-
products in the cyclizaion step, the method provided a
sufficient amount of 18c for our study. It should be noted
that these syntheses provide 1-alkyl- or 1-aryl-3-halo-
naphthyridin-2(1H)-ones lacking the 3-substituent, which
have not appeared in literature. 4-Halo-3-nitronaphthyridine
18e23 and 18f were obtained from 12a by nitration and
halogenation (Scheme 3).
Organometallic 4-arylation was examined using 4-halo-1,8-
naphthyridin-2-ones. 4-Bromo-3-nitro-1,8-naphthyridine
18f was initially reacted with zinc or Grignard reagent
prepared from 3-bromoanisole in the presence of metal
catalysts such as CuI, Pd(PPh3)4, PdCl2(dppf), Ni(PPh3)4,
NiCl2(PPh3)2, NiCl2(dppp).24 Immediate decomposition of
18f, however, took place, and no desired coupling product
20 was obtained. We, therefore, focused our attention to the
palladium catalyzed Suzuki coupling of 18f and 3-methoxy-
phenylboronic acid (Table 1).
Scheme 3. Reagents and conditions: (a) butylamine, reflux, 2 days; (b)
benzylamine, 90 8C, 10 h; (c) Ac2O, AcOH, reflux, 2 h; (d) K2CO3,
H2O–MeOH, rt, 3 h; (e) POCl3, 90 8C, 0.5–2 h; (f) POBr3, 100 8C, 30 min;
(g) concd HNO3, concd H2SO4, rt, overnight; (h) POCl3, 90 8C, 45 min; (i)
POBr3, 100 8C, 30 min.
Table 1. The Suzuki coupling reaction of 4-halo-3-nitronaphthyridines 18f with 3-methoxyphenylboronic acid
Entry
Solvent
Base
Time (h)
Yield (%)
Recovered SM (%)
1
2
3
4
5
6
7
8
9
DME–H2O
DME
Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
iPr2NEt
Cs2CO3
Cs2CO3
Cs2CO3
4
4
4
4
4
4
8
8
4
52
5
11
42
87
0
83
62
12
—
77
63
33
—
—
5
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
DME
DME
27
—

10084
H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
In the presence of 5 mol% Pd(PPh3)4, 18f and 3-methoxy-
phenylboronic acid were reacted in the presence of Na2CO3
in DME/H2O 4:1 at reflux for 4 h, and 20 was obtained in
52% yield (entry 1). The moderate yield of 20 was due to
hydrolysis of 4-bromonaphthyridine 18f to 4-hydroxy-
naphthyridine 19. Anhydrous conditions in DME or
1,4-dioxane prevented the hydrolysis, although yield
lowered (entries 2 and 3). Then, several bases were
examined, and Cs2CO3 turned out to give satisfactory
results (entries 3–6). As for solvent, 1,4-dioxane and toluene
gave better results than DME and DMF. Considerable
decomposition of 18f took place in DMF (entries 7–9).
or bromide 18f (entry 5). As indicated by the reactions of
18a, 18b, and 18c, 1-substituent did not affect the yield
(entries 1–3). Fortunately 3-nitro group of 18e, which is
essential for the synthesis of SM-32504, did not interfere
with the reaction (entries 5, 7, 9, 11, 13, 15, 17, 19, and 21)
(Table 2). A variety of arylboronic acids possessing either
electron-donating or electron-withdrawing substituent
underwent the Suzuki coupling, although the reaction of
3-acetyl and 3-cyanophenylboronic acid required slightly
prolonged reaction time (entries 18–21). The Suzuki
coupling method facilitated the synthesis of various
4-aryl-1,8-naphthyridin-2(1H)-one derivatives.15
Based on the studies, the Suzuki coupling reaction of 18
with several arylboronic acids (1.2 equiv) was conducted
under 1,4-dioxane reflux using 5 mol% Pd(PPh3)4 in the
presence of cesium carbonate (1.8 equiv), and 4-aryl-1,8-
naphthyridin-2(1H)-ones were obtained in high yields. The
coupling reaction proceeded equally well using chloride 18e
Then, this new synthetic method was applied to the
preparation of 16, an intermediate for SMP-797. Boronic
acid 14 was obtained from m-bromophenol 22 by
O-alkylation and organometallic boronic acid formation.
The key Suzuki coupling of 4-chloro-3-nitronaphthyridine
18e with 14 proceeded smoothly in 86% yield giving 15.
Reduction of the nitro group of 15 with zinc dust in AcOH
and MeOH provided 1-alkyl-3-amino-4-aryl-1,8-naphthyr-
idin-2(1H)-one 16 (Scheme 4). Thus, the improved
synthesis provided 16 in six-steps from commercially
available 10.
Table 2. The Suzuki coupling reaction of 4-halonaphthyridines 18 with
substituted aryl boronic acid
The next study was directed to the preparation of the aniline
part 26 of SMP-797. Previous synthesis of 26 involved
Entry
Ar
18
Time (h) Yield
(%)
1
2
3
4
5
18a
18b
18c
18d
18e
4
4
4
3
5
90
91
88
95
82
6
7
18a
18e
4
5
91
80
8
9
18a
18e
4
5
86
83
10
11
18a
18e
4
5
80
79
12
13
18a
18e
4
5
92
79
14
15
18a
18e
4
5
98
82
16
17
18a
18e
4
5
86
73
18
19
18a
18e
5
7
85
82
Scheme 4. Reagents and conditions: (a) benzyl 3-bromopropyl ether
(1.1 equiv), K2CO3 (3.0 equiv), DMF, 60 8C, 3 h; (b) Mg (1.1 equiv), cat I2,
B(OMe)3 (1.0 equiv), THF, rt, overnight; (c) Zn (10 equiv), AcOH
(2.5 equiv), MeOH, reflux, 1.5 h.
20
21
18a
18e
10
12
83
75

H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
Table 3. The nitration of 5 by using nitrating reagent 24
10085
N-protection of 2,6-diisopropylaniline 5.7,9 In the present
study, direct 4-selective nitration of 2,6-diisopropylaniline 5
was examined, although such reaction was not known in
literature. Nitration of aniline under strong acid conditions
is known to take place at the 3-position because of the
protonation of the amino group.25 In accordance, 2,6-
diisopropyl-3-nitroaniline was obtained as the only product
by the nitration of 2,6-diisopropylaniline 5 with concd
HNO3 in concd H2SO4.7 In order to direct the reaction at the
4-position, it was considered that bulky and neutral nitrating
reagent would be suitable, and reactions of N-nitropyrid-
inium salts26 and nitrocyclohexadienones27 were examined.
Entry
Solvent
Yield (%)
1
2
3
4
5
AcOH
CF3CO2H
MeOH
EtOH
Trace
Dec
50
68
43
When 2,6-diisoproylaniline 5 was treated with 24 in acetic
acid at rt, a very small amount of 4-nitro-2,6-diisopropylani-
line 25, starting material 5, and unknown by products were
obtained. Use of strong acid trifluoroacetic acid as solvent
resultedinthe complex mixture. The low yield was considered
to be due to nitration of amino group activated by dialkyl
group. In order to decrease the reactivity of 24, use of less
acidic alcohol solvents were examined, which considerably
improvedtheyieldof25.27 Thereactioninethanolgavehigher
yield of 68% than in methanol and 2-propanol (Table 3). The
nitration using 2,4,6-trimethyl-1-nitropyridinium tetrafluoro-
borate or 2,6-dimethyl-1-nitropyridinium tetrafluoroborate
did not proceed under various conditions.
iPrOH
monoprotected phenylenediamine 26 was obtained from 5
in two-steps.
The final urea formation from 16 and 26 was conducted as
follows. Urea 27 was prepared from 16 in a high yield via
the phenyl carbamate formation followed by teratment with
26 in the presence of DMAP in DMF. Then, 27 was
transformed into SMP-797 by hydrogenolysis of the benzyl
group, and the removal of the Boc group with 10%
methanolic HCl (Scheme 6).
Pd/C-catalyzed hydrogenation of 25 in MeOH followed by
treatment with (Boc)2O in situ gave stable key intermediate
26 in a high yield. These procedures avoided isolation of
unstable 4-amino-2,6-diisopropylaniline (Scheme 5). Thus,
3. Conclusion
In summary, we developed an efficient method to synthesize
potent ACAT inhibitor SMP-797 using novel syntheses of
4-aryl-3-animo-1,8-naphthyridin-2(1H)-one via modified
¨
Friedlander reaction and the Suzuki coupling reaction. An
efficient preparative method of 2,6-diisopropyl-4-amino-
aniline via direct nitration of 2,6-diisopropylamine was also
developed.
Scheme 5. Reagents and conditions: H2, cat Pd/C, MeOH, rt, 5 h and then
(Boc)2O (1.1 equiv), 2 h.
Scheme 6. Reagents and conditions: (a) phenyl chloroformate (2.0 equiv), THF, rt, overnight; (b) 26 (1.2 equiv), DMAP (3.0 equiv), DMF, rt, overnight;
(c) H2, cat Pd/C, MeOH, rt, 5 h; (d) 10% HCl/MeOH, rt, overnight.

10086
H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
4. Experimental
Mp 73–74 8C (Et2O/hexane). IR (film): n 1762, 1662,
1581 cmK1; 1H NMR (DMSO-d6, 300 MHz), d (ppm) 0.91
(3H, t, JZ7.3 Hz), 1.33 (2H, qt, JZ7.3, 7.3 Hz), 1.60 (2H,
tt, JZ7.3, 7.3 Hz), 2.42 (3H, s), 4.36 (2H, t, JZ7.3 Hz),
6.61 (1H, s), 7.34 (1H, dd, JZ4.8, 8.1 Hz), 8.20 (1H, dd,
JZ1.7, 8.1 Hz), 8.71 (1H, dd, JZ1.7, 4.8 Hz). Anal. Calcd
for C18H18N2O: C, 64.41; H, 6.09; N, 10.61. Found: C,
64.60; H, 6.20; N, 10.76.
4.1. General
Melting points were determined on a Thomas-Hoover
melting point apparatus without correction. 1H NMR
spectra were recorded on a JEOL JNM-LA300 spectrometer
in the stated solvents using tetramethylsilane as an internal
standard. IR spectra were obtained on a JEOL JIR-SPX60 or
a Perkin-Elmer 1600 FT-IR spectrometer. Elemental
analyses and high resolution mass spectra were conducted
at Sumitomo Analytical Center Inc. Thin layer chromato-
graphy and flash column chromatography were performed
on silica gel glass-backed plates (5719, Merck&Co.) and
silica gel 60 (230–400 or 70–230 mesh, Merck&Co.),
respectively. Unless otherwise noted, all the materials were
obtained from commercial suppliers, and were used without
further purification. All solvents were commercially
available grade. All reactions were carried out under
nitrogen atmosphere unless otherwise mentioned.
4.1.4. 1-Benzyl-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl
acetate (12b). 2-(Benzylamino)nicotinic acid 11b (2.00 g,
8.76 mmol) was suspended in a mixture of acetic anhydride
(25 mL) and acetic acid (17 mL), and the mixture was
stirred under reflux for 2 h. After cooled, volatile materials
were evaporated in vacuo, and the residue was purified by
silica gel chromatography to give 12b (1.62 g, 63%) as pale
brown crystals.
Mp 133–134 8C (Et2O/hexane). IR (film): n 1770,
1651 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
2.44 (3H, s), 5.60 (2H, s), 6.70 (1H, s), 7.20–7.30 (5H, m),
7.37 (1H, dd, JZ4.6, 7.9 Hz), 7.26 (1H, dd, JZ1.7, 7.9 Hz),
8.68 (1H, dd, JZ1.7, 4.6 Hz). Anal. Calcd for C17H14N2O3:
C, 69.38; H, 4.79; N, 9.52. Found: C, 69.53; H, 4.65; N,
9.63.
4.1.1. 2-(Butylamino)nicotinic acid (11a). A mixture of
2-chloronicotinic acid 10 (10.0 g, 63.5 mmol) and butyl-
amine (20 mL) was heated at reflux for 2 days. The reaction
mixture was concentrated in vacuo, and the residue was
diluted with Et2O. The organic materials were extracted
twice with 1 M NaOH, and the combined aqueous layers
were acidified to pH 3 by adding concd HCl. The resulting
crystals were collected by filtration, washed with AcOEt,
and dried in vacuo to give 11a (10.5 g, 85%) as colorless
crystals.
4.1.5. 1-Butyl-4-hydroxy-1,8-naphthyridin-2(1H)-one
(17a). To a solution of 12a (200 mg, 0.768 mmol) in
MeOH (8 mL) was added a solution of K2CO3 (106 mg,
1.15 mmol) in water (2 mL). The mixture was stirred at rt
for 3 h. Volatile materials were evaporated in vacuo, and to
the residue was added 3 M HCl. The resulting crystals were
collected by filtration, washed with AcOEt, and dried in
vacuo to give 17a (162 mg, 97%) as white crystals.
Mp 160–161 8C, lit.20 mp 157 8C (benzene); 1H NMR
(DMSO-d6, 300 MHz), d (ppm) 0.91 (3H, t, JZ7.3 Hz),
1.35 (2H, qt, JZ7.3, 7.3 Hz), 1.55 (2H, tt, JZ7.3, 7.3 Hz),
3.44 (2H, t, JZ7.3 Hz), 6.57 (1H, dd, JZ4.8, 7.7 Hz), 8.05
(1H, dd, JZ2.0, 7.7 Hz), 8.11 (1H, br), 8.24 (1H, dd, JZ
2.0, 4.8 Hz), 13.0 (1H, br).
1
Mp 210–211 8C. IR (film): n 1554, 1508 cmK1; H NMR
(DMSO-d6, 300 MHz), d (ppm) 0.89 (3H, t, JZ7.3 Hz),
1.30 (2H, qt, JZ7.3, 7.3 Hz), 1.55 (2H, tt, JZ7.3, 7.3 Hz),
4.29 (2H, t, JZ7.3 Hz), 5.87 (1H, s), 7.26 (1H, dd, JZ4.7,
7.9 Hz), 8.21 (1H, dd, JZ1.8, 7.9 Hz), 8.63 (1H, dd, JZ1.8,
4.7 Hz), 11.6 (1H, s). Anal. Calcd for C18H18N2O: C, 66.04;
H, 6.47; N, 12.84. Found: C, 65.82; H, 6.44; N, 12.70.
4.1.2. 2-(Benzylamino)nicotinic acid (11b). A mixture of
2-chloronicotinic acid 10 (5.00 g, 31.7 mmol) and benzyl-
amine (17 mL) was stirred at 90 8C for 10 h. NaOH (2 M)
and Et2O were added, and the aqueous layer was separated.
The organic layer was extracted twice with 2 M NaOH. The
combined aqueous layers were acidified by concd HCl to pH
3. The resulting crystals were collected by filtration, washed
with AcOEt, and dried in vacuo to give 11b (5.14 g, 71%) as
colorless crystals.
4.1.6. 1-Benzyl-4-hydroxy-1,8-naphthyridin-2(1H)-one
(17b). To a solution of 12b (1.10 g, 3.74 mmol) in MeOH
(40 mL) was added a solution of K2CO3 (775 mg,
5.61 mmol) in water (10 mL). The mixture was stirred at
rt for 3 h. Volatile materials were evaporated in vacuo, and
to the residue was added 3 M HCl. The resulting crystals
were collected by filtration, washed with AcOEt and dried in
vacuo to give 17b (940 mg, quant.) as white crystals.
1
Mp 230–231 8C, lit.21 mp 238–240 8C (EtOH); H NMR
(DMSO-d6, 300 MHz), d (ppm) 4.68 (2H, d, JZ4.8 Hz),
6.61 (1H, dd, JZ4.7, 7.7 Hz), 7.19–7.31 (5H, m), 8.08 (1H,
dd, JZ1.8, 7.7 Hz), 8.23 (1H, dd, JZ1.8, 4.7 Hz), 8.47 (1H,
br), 13.1 (1H, br).
1
Mp 258–259 8C. IR (film): n 1558, 1523 cmK1; H NMR
(DMSO-d6, 300 MHz), d (ppm) 5.53 (3H, s), 5.95 (1H, s),
7.15–7.30 (6H, m), 8.25 (1H, dd, JZ1.8, 7.9 Hz), 8.59 (1H,
dd, JZ1.8, 4.8 Hz), 11.2 (1H, s). Anal. Calcd for
C17H14N2O3$H2O: C, 71.16; H, 4.82; N, 11.06. Found: C,
71.08; H, 4.74; N, 10.93.
4.1.3. 1-Butyl-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl
acetate (12a). 2-(Butylamino)nicotinic acid 11a (2.80 g,
14.4 mmol) was suspended in a mixture of acetic anhydride
(35 mL) and acetic acid (18 mL), and the mixture was
stirred under reflux for 2 h. After cooled, volatile materials
were evaporated in vacuo, and the residue was purified by
silica gel chromatography to give 12a (2.48 g, 66%) as
colorless crystals.
4.1.7. 1-Butyl-4-chloro-1,8-naphthyridin-2(1H)-one
(18a). A mixture of 17a (200 mg, 0.916 mmol) and POCl3
(0.342 mL, 3.67 mmol) was stirred at 100 8C for 2 h. The
reaction mixture was neutralized by adding saturated

H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
10087
aqueous NaHCO3 under ice-cooling, and the organic
materials were extracted with AcOEt. The organic layer
was washed with saturated aqueous NaHCO3, dried over
MgSO4, and concentrated in vacuo. The residue was
purified by silica gel chromatography to give 18a
(218 mg, quant.) as a colorless oil.
HRMS (ESI) (MCH)C calcd for C14H10ClN2O 257.0482,
found 257.0427.
4.1.10. 4-Bromo-1-butyl-1,8-naphthyridin-2(1H)-one
(18d). A mixture of 17a (300 mg, 1.37 mmol) and POBr3
(1.18 g, 4.12 mmol) was stirred at 100 8C for 30 min. Then,
the reaction was quenched by adding saturated aqueous
NaHCO3 under ice-cooling, and the organic materials were
extracted with AcOEt. The combined organic layers were
washed with saturated aqueous NaHCO3, dried over
MgSO4, and concentrated in vacuo. The residue was
purified by silica gel chromatography to give 18d
(351 mg, 91%) as a colorless oil.
1
IR (film): n 1645, 1577, 1550 cmK1; H NMR (DMSO-d6,
300 MHz), d (ppm) 0.89 (3H, t, JZ7.3 Hz), 1.32 (2H, qt,
JZ7.3, 7.3 Hz), 1.58 (2H, tt, JZ7.3, 7.3 Hz), 4.34 (2H, t,
JZ7.3 Hz), 7.01 (1H, s), 7.42 (1H, dd, JZ4.6, 7.9 Hz), 8.30
(1H, dd, JZ1.1, 7.9 Hz), 8.73 (1H, dd, JZ1.1, 4.6 Hz).
Anal. Calcd for C12H13ClN2O$H2O: C, 60.43; H, 5.58; N,
11.84. Found: C, 60.25; H, 5.41; N, 11.62.
1
IR (film): n 1647, 1578, 1547 cmK1; H NMR (DMSO-d6,
300 MHz), d (ppm) 0.90 (3H, t, JZ7.5 Hz), 1.32 (2H, qt,
JZ7.5, 7.5 Hz), 1.60 (2H, tt, JZ7.5, 7.5 Hz), 4.35 (2H, t,
JZ7.5 Hz), 7.23 (1H, s), 7.43 (1H, dd, JZ4.6, 7.9 Hz), 8.27
(1H, dd, JZ1.8, 7.9 Hz), 8.72 (1H, dd, JZ1.8, 4.6 Hz).
Anal. Calcd for C12H13BrN2O: C, 51.26; H, 4.66; Br, 28.42;
N, 9.96. Found: C, 51.25; H, 4.67; Br, 28.56; N, 9.96.
4.1.8. 1-Benzyl-4-chloro-1,8-naphthyridin-2(1H)-one
(18b). A mixture of 17b (640 mg, 2.54 mmol) and POCl3
(0.946 mL, 10.1 mmol) was stirred at 90 8C for 30 min. The
reaction mixture was neutralized by adding saturated
aqueous NaHCO3 under ice-cooling, and the organic
materials were extracted with AcOEt. The organic layer
was washed with saturated NaHCO3 solution, dried over
MgSO4, and concentrated in vacuo. The residue was
purified by silica gel chromatography to give 18b
(580 mg, 84%) as pale green crystals.
4.1.11. 1-Butyl-4-hydroxy-3-nitro-1,8-naphthyridin-
2(1H)-one (19). To
a solution of 12a (500 mg,
1.92 mmol) in concd H2SO4 (5 mL) was added concd
HNO3 (0.130 mL, 2.11 mmol) at 0 8C. The mixture was
stirred at rt overnight, and was poured into ice-water. The
resulting crystals were collected by filtration, and dried to
give 19 (467 mg, 92%) as pale yellow crystals.
Mp 131–132 8C (Et2O/hexane). IR (film): n 1650,
1573 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
5.60 (2H, s), 7.12 (1H, s), 7.19–7.29 (5H, m), 7.44 (1H, dd,
JZ4.6, 7.9 Hz), 8.36 (1H, dd, JZ1.5, 7.9 Hz), 8.71 (1H, dd,
JZ1.5, 4.6 Hz); HRMS (ESI) (MCH)C calcd for
C15H12ClN2O 271.0638, found 271.0631.
1
Mp 110 8C, lit.28 mp 106–109 8C (iPrOH/H2O); H NMR
(DMSO-d6, 300 MHz), d (ppm) 0.91 (3H, t, JZ7.3 Hz),
1.33 (2H, qt, JZ7.3, 7.3 Hz), 1.57 (2H, tt, JZ7.3, 7.3 Hz),
4.31 (2H, t, JZ7.3 Hz), 7.32 (1H, dd, JZ4.6, 7.9 Hz), 8.44
(1H, dd, JZ1.8, 7.9 Hz), 8.69 (1H, dd, JZ1.8, 4.6 Hz).
4.1.9. 4-Chloro-1-phenyl-1,8-naphthyridin-2(1H)-one
(18c). 2-(Phenylamino)nicotinic acid 11c (200 mg,
0.934 mmol) was suspended in a mixture of acetic
anhydride (20 mL) and acetic acid (2 mL), and the mixture
was stirred under reflux for 8 h. After cooled, volatile
materials were evaporated in vacuo, and the residue was
purified by short silica gel chromatography. The product
was dissolved in MeOH (15 mL), and a solution of K2CO3
(645 mg, 4.67 mmol) in water (5 mL) was added. The
mixture was stirred at rt for 2 h, and concentrated in vacuo.
The residue was diluted with AcOEt, and the organic
materials were extracted twice with 2 M NaOH. The
combined aqueous layers were acidified by adding concd
HCl, and the organic materials were extracted three times
with CHCl3. The combined organic layers were dried over
MgSO4, and concentrated in vacuo. To the residue was
added POCl3 (1.5 mL), and the mixture was heated at reflux
for 1.5 h. The reaction mixture was neutralized by adding
saturated aqueous NaHCO3 under ice-cooling, and the
organic materials were extracted with AcOEt. The organic
layer was washed with saturated aqueous NaHCO3, dried
over MgSO4, and concentrated in vacuo. The residue was
purified by silica gel chromatography to give 18c (28.2 mg,
12% for three-steps) as colorless crystals.
4.1.12.
1-Butyl-4-chloro-3-nitro-1,8-naphthyridin-
2(1H)-one23 (18e) A mixture of 19 (800 mg, 3.04 mmol)
and POCl3 (3 mL) was stirred at 100 8C for 45 min. The
mixture was poured into ice-water, and was neutralized with
saturated aqueous NaHCO3 under ice-cooling. The organic
materials were extracted with AcOEt. The organic layer was
washed with saturated aqueous NaHCO3, dried over
MgSO4, and concentrated in vacuo. The residue was
purified by silica gel chromatography to give 8e (734 mg,
86%) as pale yellow crystals.
Mp 93–94 8C (Et2O/hexane). IR (neat): n 1660, 1535 cmK1
;
1H NMR (DMSO-d6, 300 MHz), d (ppm) 0.92 (3H, t, JZ
7.3 Hz), 1.37 (2H, qt, JZ7.3, 7.3 Hz), 1.67 (2H, tt, JZ7.3,
7.3 Hz), 4.44 (2H, t, JZ7.3 Hz), 7.60 (1H, dd, JZ4.6,
8.0 Hz), 8.54 (1H, dd, JZ1.7, 8.0 Hz), 8.92 (1H, dd, JZ1.7,
4.6 Hz). Anal. Calcd for C12H12ClN3O3: C, 51.16; H, 4.29;
N, 14.92. Found: C, 51.00; H, 4.27; N, 14.84.
4.1.13. 4-Bromo-1-butyl-3-nitro-1,8-naphthyridin-
2(1H)-one (18f). A mixture of 19 (200 mg, 0.759 mmol)
and POBr3 (1.00 g, 3.80 mmol) was stirred at 100 8C for
30 min. After diluted with toluene, the suspension was
poured into ice-water. The mixture was neutralized by
adding saturated aqueous NaHCO3 under ice-cooling. The
organic materials were extracted with toluene. The organic
layer was washed with saturated aqueous NaHCO3, dried
Mp 192–193 8C (Et2O/hexane). IR (film): n 1655,
1577 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
7.13 (1H, s), 7.27–7.29 (2H, m), 7.39–7.54 (4H, m), 8.37
(1H, dd, JZ1.3, 7.9 Hz), 8.50 (1H, dd, JZ1.3, 4.4 Hz);

10088
H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
over MgSO4, and concentrated in vacuo. The residue was
purified by silica gel chromatography to give 18f (222 mg,
90%) as pale brown crystals.
0.94 (3H, t, JZ7.5 Hz), 1.40 (2H, qt, JZ7.5, 7.5 Hz), 1.71
(2H, tt, JZ7.5, 7.5 Hz), 4.50 (2H, t, JZ7.5 Hz), 7.38–7.45
(3H, m), 7.55–7.68 (4H, m), 8.81–8.84 (1H, m). Anal. Calcd
for C18H17N3O3: C, 66.86; H, 5.30; N, 13.00. Found: C,
66.68; H, 5.27; N, 12.90.
Mp 120–121 8C (Et2O/hexane). IR (film): n 1655,
1543 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
0.90 (3H, t, JZ7.3 Hz), 1.35 (2H, qt, JZ7.3, 7.3 Hz), 1.65
(2H, tt, JZ7.3, 7.3 Hz), 4.42 (2H, t, JZ7.3 Hz), 7.57 (1H,
dd, JZ4.6, 8.0 Hz), 8.46 (1H, dd, JZ1.7, 8.0 Hz), 8.86 (1H,
dd, JZ1.7, 4.6 Hz). Anal. Calcd for C12H12BrN3O3: C,
44.19; H, 3.71; N, 12.88. Found: C, 44.10; H, 3.63; N, 12.76.
4.2.5. 1-Butyl-4-(4-methoxyphenyl)-1,8-naphthyridin-
2(1H)-one. The title compound was prepared from
4-methoxyphenylboronic acid (70.0 mg, 0.461 mmol) and
18a (100 mg, 0.384 mmol), and was obtained as colorless
crystals (95.8 mg, 91%).
4.2. General procedure for the Suzuki coupling reaction
Mp 114–115 8C (Et2O/hexane). IR (film): n 1655,
1581 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
1-Alkyl-4-halo-1,8-naphthyridin-2(1H)-one (1.0 equiv),
arylboronic acid (1.2 equiv), Cs2CO3 (1.8 equiv), and
Pd(PPh3)4 (5 mol%) were suspended in 1,4-dioxane, and
the mixture was stirred under reflux. After cooling to rt,
water was added. The organic materials were extracted with
AcOEt, washed with brine, and dried over MgSO4. The
solvent was evaporated in vacuo, and the residue was
purified by silica gel chromatography to give 1-alkyl-4-aryl-
1,8-naphthyridin-2(1H)-one.
0.93 (3H, t, JZ7.5 Hz), 1.37 (2H, qt, JZ7.5, 7.5 Hz), 1.64
(2H, tt, JZ7.5, 7.5 Hz), 3.83 (3H, s), 4.42 (2H, t, JZ
7.5 Hz), 6.56 (1H, s), 7.10 (2H, d, JZ7.5 Hz), 7.28 (1H, dd,
JZ4.7, 8.0 Hz), 7.45 (1H, d, JZ7.5 Hz), 7.92 (1H, d, JZ
8.0 Hz), 7.67 (1H, d, JZ4.7 Hz). Anal. Calcd for
C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 73.32;
H, 6.49; N, 8.85.
4.2.6. 1-Butyl-4-(4-methoxyphenyl)-3-nitro-1,8-naph-
thyridin-2(1H)-one. The title compound was prepared
from 4-methoxyphenylboronic acid (56.0 mg, 0.368 mmol)
and 18e (86.5 mg, 0.307 mmol), and was obtained as pale
yellow crystals (87.2 mg, 80%).
4.2.1. 1-Butyl-4-phenyl-1,8-naphthyridin-2(1H)-one. The
title compound was prepared from phenylboronic acid
(56.2 mg, 0.461 mmol) and 18a (100 mg, 0.384 mmol), and
was obtained as colorless crystals (96.4 mg, 90%).
Mp 124–125 8C (Et2O/hexane). IR (film): n 1655,
Mp 96–97 8C (Et2O/hexane), lit.28 mp 96–97 8C (iPr2O); 1H
NMR (DMSO-d6, 300 MHz), d (ppm) 0.93 (3H, t, JZ
7.1 Hz), 1.37 (2H, qt, JZ7.1, 7.1 Hz), 1.64 (2H, tt, JZ7.1,
7.1 Hz), 4.42 (2H, t, JZ7.1 Hz), 6.60 (1H, s), 7.28 (1H, dd,
JZ4.6, 7.4 Hz), 7.50–7.54 (5H, m), 7.85 (1H, d, JZ
7.4 Hz), 8.67 (1H, d, JZ4.6 Hz).
1535 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
0.94 (3H, t, JZ7.5 Hz), 1.39 (2H, qt, JZ7.5, 7.5 Hz), 1.70
(2H, tt, JZ7.5, 7.5 Hz), 3.83 (3H, s), 4.49 (2H, t, JZ
7.5 Hz), 7.13 (2H, d, JZ8.8 Hz), 7.36 (2H, d, JZ8.8 Hz),
7.40 (1H, dd, JZ4.6, 8.1 Hz), 7.74 (1H, dd, JZ1.6, 8.1 Hz),
8.82 (1H, dd, JZ1.6, 4.6 Hz). Anal. Calcd for C19H19N3O4:
C, 64.58; H, 5.42; N, 11.89. Found: C, 64.29; H, 5.40; N,
11.78.
4.2.2. 1-Benzyl-4-phenyl-1,8-naphthyridin-2(1H)-one.
The title compound was prepared from phenylboronic acid
(43.9 mg, 0.360 mmol) and 18b (81.2 mg, 0.300 mmol),
and was obtained as pale yellow crystals (85.0 mg, 91%).
4.2.7. 1-Butyl-4-(3-methoxyphenyl)-1,8-naphthyridin-
2(1H)-one. The title compound was prepared from
3-methoxyphenylboronic acid (46.6 mg, 0.368 mmol) and
18a (79.9 mg, 0.307 mmol), and was obtained as a colorless
amorphous solid (81.6 mg, 86%).
Mp 150–152 8C (Et2O/hexane), lit.28 mp 154–155 8C
(iPr2O); 1H NMR (DMSO-d6, 300 MHz), d (ppm) 5.67
(2H, s), 6.68 (1H, s), 7.18–7.32 (6H, m), 7.51–7.55 (5H, m),
7.89 (1H, dd, JZ1.5, 7.9 Hz), 8.64 (1H, dd, JZ1.5, 4.6 Hz).
IR (film): n 1651, 1578 cmK1 1H NMR (DMSO-d6,
;
300 MHz), d (ppm) 0.93 (3H, t, JZ7.5 Hz), 1.37 (2H, qt,
JZ7.5, 7.5 Hz), 1.65 (2H, tt, JZ7.5, 7.5 Hz), 3.80 (3H, s),
4.43 (2H, t, JZ7.5 Hz), 6.62 (1H, s), 7.03–7.10 (3H, m),
7.28 (1H, dd, JZ4.6, 8.1 Hz), 7.46 (1H, dd, JZ7.3, 7.3 Hz),
7.89 (1H, d, JZ8.1 Hz), 8.67 (1H, d, JZ4.6 Hz); HRMS
(ESI) (MCH)C calcd for C19H22N2O2 309.1603, found
309.1612.
4.2.3. 1,4-Diphenyl-1,8-naphthyridin-2(1H)-one. The title
compound was prepared from phenylboronic acid (43.9 mg,
0.360 mmol) and 18c (77.0 mg, 0.300 mmol), and was
obtained as pale yellow crystals (79.2 mg, 88%).
Mp 203–204 8C (Et2O/hexane), lit.29 mp 210–212 8C
(AcOEt); H NMR (DMSO-d6, 300 MHz), d (ppm) 6.70
1
(1H, s), 7.26–7.32 (3H, m), 7.44–7.61 (8H, m), 7.90 (1H, dd,
JZ1.8, 8.0 Hz), 8.44 (1H, dd, JZ1.8, 4.6 Hz).
4.2.8. 1-Butyl-4-(3-methoxyphenyl)-3-nitro-1,8-naph-
thyridin-2(1H)-one (15). The title compound was prepared
from 3-methoxyphenylboronic acid (56.0 mg, 0.368 mmol)
and 18e (86.5 mg, 0.307 mmol), and was obtained as pale
yellow crystals (89.5 mg, 83%).
4.2.4. 1-Butyl-3-nitro-4-phenyl-1,8-naphthyridin-2(1H)-
one. The title compound was prepared from phenylboronic
acid (44.9 mg, 0.368 mmol) and 18e (86.5 mg, 0.307 mmol),
and was obtained as pale yellow crystals (81.6 mg, 82%).
Mp 124–125 8C (Et2O/hexane). IR (film): n 1662,
1535 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
Mp 149–150 8C (Et2O/hexane). IR (film): n 1662,
0.94 (3H, t, JZ7.5 Hz), 1.40 (2H, qt, JZ7.5, 7.5 Hz), 1.70
(2H, tt, JZ7.5, 7.5 Hz), 3.77 (3H, s), 4.50 (2H, t, JZ
1535 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;

H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
10089
7.5 Hz), 6.96–7.01 (2H, m), 7.15 (1H, dd, JZ2.8, 8.4 Hz),
7.40 (1H, dd, JZ4.2, 8.0 Hz), 7.49 (1H, dd, JZ7.9, 7.9 Hz),
7.72 (1H, dd, JZ1.5, 8.0 Hz), 8.82 (1H, dd, JZ1.5, 4.2 Hz).
Anal. Calcd for C19H19N3O4: C, 64.58; H, 5.42; N, 11.89.
Found: C, 64.33; H, 5.33; N, 11.76.
JZ0.93, 4.7 Hz). Anal. Calcd for C19H16F3N3O3: C, 58.31;
H, 4.12; N, 10.74. Found: C, 58.06; H, 4.09; N, 10.45.
4.2.13.
1-Butyl-4-[3-(trifluoromethyl)phenyl]-1,8-
naphthyridin-2(1H)-one. The title compound was prepared
from 3-(trifluoromethyl)phenylboronic acid (87.6 mg,
0.461 mmol) and 18a (100 mg, 0.384 mmol), and was
obtained as colorless crystals (131 mg, 98%).
4.2.9. 1-Butyl-4-(2-methoxyphenyl)-1,8-naphthyridin-
2(1H)-one. The title compound was prepared from
2-methoxyphenylboronic acid (70.0 mg, 0.461 mmol) and
18a (100 mg, 0.384 mmol), and was obtained as a colorless
amorphous solid (95.3 mg, 80%).
Mp 127–128 8C (Et2O/hexane). IR (film): n 1655,
1581 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
0.94 (3H, t, JZ7.3 Hz), 1.38 (2H, qt, JZ7.3, 7.3 Hz), 1.66
(2H, tt, JZ7.3, 7.3 Hz), 4.44 (2H, t, JZ7.3 Hz), 6.71 (1H,
s), 7.30 (1H, dd, JZ4.6, 7.9 Hz), 7.76–7.92 (5H, m), 8.68–
8.70 (1H, m). Anal. Calcd for C19H17F3N2O: C, 65.89; H,
4.95; N, 8.09. Found: C, 65.75; H, 4.91; N, 8.01.
IR (film): n 1650, 1581 cmK1 1H NMR (DMSO-d6,
;
300 MHz), d (ppm) 0.94 (3H, t, JZ7.5 Hz), 1.38 (2H, qt,
JZ7.5, 7.5 Hz), 1.65 (2H, tt, JZ7.5, 7.5 Hz), 3.68 (3H, s),
4.42 (2H, t, JZ7.5 Hz), 6.53 (1H, s), 7.01–7.12 (3H, m),
7.19–7.30 (1H, m), 7.19–7.30 (3H, m), 7.49–7.51 (2H, m),
8.64 (1H, d, JZ4.6 Hz); HRMS (ESI) (MCH)C calcd for
C19H22N2O2 309.1603, found 309.1590.
4.2.14. 1-Butyl-3-nitro-4-[3-(trifluoromethyl)phenyl]-1,
8-naphthyridin-2(1H)-one. The title compound was pre-
pared from 3-(trifluoromethyl)phenylboronic acid (58.3 mg,
0.368 mmol) and 18e (86.5 mg, 0.307 mmol), and was
obtained as pale yellow crystals (98.9 mg, 82%).
4.2.10.
1-Butyl-4-(2-methoxyphenyl)-3-nitro-1,8-
naphthyridin-2(1H)-one. The title compound was prepared
from 2-methoxyphenylboronic acid (56.0 mg, 0.368 mmol)
and 18e (86.5 mg, 0.307 mmol), and was obtained as pale
yellow crystals (85.4 mg, 79%).
Mp 130–131 8C (Et2O/hexane). IR (film): n 1659,
1527 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
0.95 (3H, t, JZ7.5 Hz), 1.41 (2H, qt, JZ7.5, 7.5 Hz), 1.71
(2H, tt, JZ7.5, 7.5 Hz), 4.52 (2H, t, JZ7.5 Hz), 7.41 (1H,
dd, JZ4.6, 8.4 Hz), 7.64 (1H, dd, JZ1.1, 8.4 Hz), 7.78–
7.86 (2H, m), 7.90 (1H, s), 7.98 (1H, d, JZ7.3 Hz), 8.84
(1H, dd, JZ1.1, 4.6 Hz). Anal. Calcd for C19H16F3N3O3: C,
58.31; H, 4.12; N, 10.74. Found: C, 58.17; H, 4.07; N, 10.77.
Mp 189–190 8C (Et2O/hexane). IR (film): n 1655,
1535 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
0.95 (3H, t, JZ7.1 Hz), 1.46 (2H, qt, JZ7.1, 7.1 Hz), 1.71
(2H, tt, JZ7.1, 7.1 Hz), 3.69 (3H, s), 4.49 (2H, t, JZ
7.1 Hz), 7.12 (1H, t, JZ7.5 Hz), 7.24–7.28 (2H, m), 7.37
(1H, dd, JZ4.6, 8.0 Hz), 7.54–7.60 (2H, m), 8.82 (1H, dd,
JZ1.7, 4.6 Hz). Anal. Calcd for C19H19N3O4: C, 64.58; H,
5.42; N, 11.89. Found: C, 64.23; H, 5.34; N, 11.64.
4.2.15. 1-Butyl-4-(3-fluorophenyl)-1,8-naphthyridin-
2(1H)-one. The title compound was prepared from
3-fluorophenylboronic acid (56.2 mg, 0.461 mmol) and
18a (100 mg, 0.384 mmol), and was obtained as colorless
crystals (98.0 mg, 86%).
4.2.11. 1-Butyl-4-[4-(trifluoromethyl)phenyl]-1,8-naph-
thyridin-2(1H)-one. The title compound was prepared
from 4-(trifluoromethyl)phenylboronic acid (87.6 mg,
0.461 mmol) and 18a (100 mg, 0.384 mmol), and was
obtained as colorless crystals (123 mg, 92%).
Mp 97–98 8C (Et2O/hexane). IR (film): n 1647, 1578 cmK1
;
1H NMR (DMSO-d6, 300 MHz), d (ppm) 0.93 (3H, t, JZ
7.3 Hz), 1.37 (2H, qt, JZ7.3, 7.3 Hz), 1.64 (2H, tt, JZ7.3,
7.3 Hz), 4.43 (2H, t, JZ7.3 Hz), 6.70 (1H, s), 7.29 (1H, dd,
JZ4.7, 6.8 Hz), 7.73–7.86 (3H, m), 8.00–8.02 (2H, m), 8.69
(1H, d, JZ4.7 Hz). Anal. Calcd for C18H17FN2O: C, 72.95;
H, 5.78; N, 9.45. Found: C, 72.85; H, 5.68; N, 9.27.
Mp 150–151 8C (Et2O/hexane). IR (film): n 1655,
1581 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
0.93 (3H, t, JZ7.1 Hz), 1.38 (2H, qt, JZ7.1, 7.1 Hz), 1.66
(2H, tt, JZ7.1, 7.1 Hz), 6.69 (1H, s), 7.28 (1H, dd, JZ4.7,
7.1 Hz), 7.74 (2H, d, JZ8.3 Hz), 7.81 (1H, d, JZ7.1 Hz),
7.92 (1H, d, JZ8.3 Hz), 8.69 (1H, d, JZ4.7 Hz). Anal.
Calcd for C19H17F3N2O: C, 65.89; H, 4.95; N, 8.09. Found:
C, 65.70; H, 4.92; N, 7.88.
4.2.16. 1-Butyl-4-(3-fluorophenyl)-3-nitro-1,8-naphthyr-
idin-2(1H)-one. The title compound was prepared from
3-fluorophenylboronic acid (51.5 mg, 0.368 mmol) and 18e
(86.5 mg, 0.307 mmol), and was obtained as pale yellow
crystals (76.5 mg, 73%).
4.2.12. 1-Butyl-3-nitro-4-[4-(trifluoromethyl)phenyl]-1,
8-naphthyridin-2(1H)-one. The title compound was pre-
pared from 4-(trifluoromethyl)phenylboronic acid (58.3 mg,
0.368 mmol) and 18e (86.3 mg, 0.307 mmol), and was
obtained as pale yellow crystals (95.1 mg, 79%).
Mp 172–173 8C (Et2O/hexane). IR (film): n 1666,
1539 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
0.95 (3H, t, JZ7.5 Hz), 1.40 (2H, qt, JZ7.5, 7.5 Hz), 1.71
(2H, tt, JZ7.5, 7.5 Hz), 4.51 (2H, t, JZ7.5 Hz), 7.29 (1H, d,
JZ7.7 Hz), 7.39–7.49 (3H, m), 7.60–7.72 (2H, m), 8.83
(1H, dd, JZ1.1, 4.0 Hz). Anal. Calcd for C18H16FN3O3: C,
63.34; H, 4.72; N, 12.31. Found: C, 63.05; H, 4.67; N, 12.01.
Mp 119–120 8C (Et2O/hexane). IR (film): n 1655,
1535 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
0.95 (3H, t, JZ7.5 Hz), 1.41 (2H, qt, JZ7.5, 7.5 Hz), 1.72
(2H, tt, JZ7.5, 7.5 Hz), 4.52 (2H, t, JZ7.5 Hz), 7.39 (1H,
dd, JZ4.7, 8.0 Hz), 7.66 (1H, dd, JZ0.93, 8.0 Hz), 7.71
(2H, d, JZ8.0 Hz), 7.98 (1H, d, JZ8.0 Hz), 8.84 (1H, dd,
4.2.17. 4-(3-Acethylphenyl)-1-butyl-1,8-naphthyridin-
2(1H)-one. The title compound was prepared from
3-acethylphenylboronic acid (75.6 mg, 0.461 mmol) and

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H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
18a (100 mg, 0.384 mmol), and was obtained as a colorless
amorphous solid (105 mg, 85%).
AcOEt, washed with water, dried over MgSO4, and
concentrated in vacuo. The residue was purified by silica
gel chromatography to give 23 (4.71 g, 85%) as a colorless
oil.
IR (film): n 1651, 1581 cmK1 1H NMR (DMSO-d6,
;
300 MHz), d (ppm) 0.94 (3H, t, JZ7.1 Hz), 1.38 (2H, qt,
JZ7.1, 7.1 Hz), 1.66 (2H, tt, JZ7.1, 7.1 Hz), 2.63, (3H, s),
4.45 (2H, t, JZ7.5 Hz), 6.70 (1H, s), 7.29 (1H, dd, JZ4.7,
8.0 Hz), 7.68–7.85 (3H, m), 8.05–8.11 (2H, m), 8.70 (1H,
dd, JZ1.7, 4.6 Hz); HRMS (ESI) (MCH)C calcd for
C20H22N2O2 321.1603, found 321.1609.
IR (film): n 1589, 1466 cmK1 1H NMR (DMSO-d6,
;
300 MHz), d (ppm) 1.98 (2H, tt, JZ6.2, 6.2 Hz), 3.57
(2H, t, JZ6.2 Hz), 4.06 (2H, t, JZ6.2 Hz), 4.48 (2H, s),
6.92–6.96 (1H, m), 7.10–7.13 (2H, m), 7.21–7.36 (6H, m);
HRMS (ESI) (MCH)C calcd for C16H19BrO2 321.0490,
found 321.0512.
4.2.18.
4-(3-Acethylphenyl)-1-butyl-3-nitro-1,8-
naphthyridin-2(1H)-one. The title compound was prepared
from 3-acethylphenylboronic acid (60.3 mg, 0.368 mmol)
and 18e (86.5 mg, 0.307 mmol), and was obtained as pale
yellow crystals (80.2 mg, 82%).
4.2.22. {3-[3-(Benzyloxy)propoxy]phenyl}boronic acid
(14). To a suspension of Mg (2.50 g, 10.3 mmol) and a
catalytic amount of I2 in THF (15 mL), a solution of 23
(3.00 g, 9.34 mmol) in THF (3 mL) was added dropwise at
rt. The mixture was stirred for 1.5 h at reflux. After cooled to
K10 8C, B(OMe)3 (1.05 mL, 9.34 mmol) was added. The
mixture was warmed to rt, and stirred overnight. Then, 10%
H2SO4 (10 mL) was added, and the organic materials were
extracted with Et2O. The extracts were washed twice with
10% H2SO, dried over MgSO4, and concentrated in vacuo.
The residue was purified by silica gel chromatography to
give 14 (1.35 g, 51%) as a colorless amorphous solid.
Mp 151–152 8C (Et2O/hexane). IR (film): n 1662,
1531 cmK1 1H NMR (DMSO-d6, 300 MHz), d (ppm)
;
0.95 (3H, t, JZ7.5 Hz), 1.41 (2H, qt, JZ7.5, 7.5 Hz), 1.72
(2H, tt, JZ7.5, 7.5 Hz), 2.60 (3H, s), 4.52 (2H, t, JZ
7.5 Hz), 7.40 (1H, dd, JZ4.8, 8.1 Hz), 7.66 (1H, dd, JZ1.1,
8.1 Hz), 7.70–7.78 (2H, m), 8.02 (1H, s), 8.15–8.18 (1H, m),
8.84 (1H, dd, JZ1.1, 4.8 Hz). Anal. Calcd for C20H19N3O4:
C, 65.74; H, 5.24; N, 11.50. Found: C, 65.41; H, 5.17; N,
11.10.
IR (film): n 3267, 1346 cmK1 1H NMR (DMSO-d6,
;
300 MHz), d (ppm) 2.00 (2H, tt, JZ6.2, 6.2 Hz), 3.36
(1H, br d), 3.60 (2H, t, JZ6.2 Hz), 4.05 (2H, t, JZ6.2 Hz),
4.49 (2H, s), 6.93–6.96 (1H, m), 7.21–7.46 (8H, m), 8.03
(1H, br); HRMS (ESI) (MCH)C calcd for C16H21BO4
287.1457, found 287.1478.
4.2.19. 3-(1-Butyl-2-oxo-1,2-dihydro-1,8-naphthyridin-
4-yl)benzonitrile. The title compound was prepared from
3-cyanophenylboronic acid (67.7 mg, 0.461 mmol) and 18a
(100 mg, 0.384 mmol), and was obtained as colorless
crystals (97.1 mg, 83%).
4.2.23. 4-{3-[3-(Benzyloxy)propoxy]phenyl}-1-butyl-3-
nitro-1,8-naphthyridin-2(1H)-one (15). The compound
18e (100 mg, 0.355 mmol), 14 (122 mg, 0.426 mmol),
Cs2CO3 (208 mg, 0.640 mmol), and Pd(PPh3)4 (20.6 mg,
5 mol%) were suspended in 1,4-dioxane (10 mL), and the
mixture was stirred under reflux for 4 h. After cooling to rt,
water was added. The organic materials were extracted with
AcOEt, washed with brine, and dried over MgSO4. The
solvent was evaporated in vacuo, and the residue was
purified by silica gel chromatography to give 15 (148 mg,
86%) as a pale yellow oil.
Mp 144–145 8C (Et2O/hexane). IR (film): n 2233, 1651,
1581 cmK1; 1H NMR (DMSO-d6, 300 MHz), d (ppm) 0.93
(3H, t, JZ7.5 Hz), 1.37 (2H, qt, JZ7.5, 7.5 Hz), 1.64 (2H,
tt, JZ7.5, 7.5 Hz), 4.43 (2H, t, JZ7.5 Hz), 6.70 (1H, s),
7.29 (1H, dd, JZ4.6, 7.9 Hz), 7.72–7.86 (3H, m), 8.00–8.02
(2H, m), 8.69 (1H, d, JZ4.6 Hz). Anal. Calcd for
C19H17N3O: C, 75.23; H, 5.65; N, 13.85. Found: C, 74.92;
H, 5.65; N, 13.71.
4.2.20.
3-(1-Butyl-3-nitro-2-oxo-1,2-dihydro-1,8-
naphthyridin-4-yl)benzonitrile. The title compound was
prepared from 3-cyanophenylboronic acid (54.1 mg,
0.368 mmol) and 18e (86.5 mg, 0.307 mmol), and was
obtained as pale yellow crystals (80.3 mg, 75%).
1
IR (film): n 1662, 1587, 1539 cmK1; H NMR (DMSO-d6,
300 MHz), d (ppm) 0.96 (3H, t, JZ7.1 Hz), 1.41 (2H, qt,
JZ7.1, 7.1 Hz), 1.71 (2H, tt, JZ7.1, 7.1 Hz), 2.00 (2H, tt,
JZ6.2, 6.2 Hz), 3.58 (2H, t, JZ6.2 Hz), 4.04–4.12 (2H, m),
4.47 (2H, s), 4.51 (2H, t, JZ7.1 Hz), 6.97–7.02 (2H, m),
7.13–7.16 (1H, m), 7.23–7.33 (5H, m), 7.41 (1H, dd, JZ4.8,
8.1 Hz), 7.49 (1H, t, JZ8.3 Hz), 7.73 (1H, dd, JZ1.7,
8.1 Hz); HRMS (ESI) (MCH)C calcd for C28H31N3O5
488.2185, found 488.2204.
Mp 160–161 8C (Et2O/hexane). IR (film): n 2233, 1659,
1531 cmK1; 1H NMR (DMSO-d6, 300 MHz), d (ppm) 0.95
(3H, t, JZ7.5 Hz), 1.40 (2H, qt, JZ7.5, 7.5 Hz), 1.71 (2H,
tt, JZ7.5, 7.5 Hz), 4.52 (2H, t, JZ7.5 Hz), 7.41 (1H, dd,
JZ4.6, 8.1 Hz), 7.68 (1H, dd, JZ1.7, 8.1 Hz), 7.79–7.82
(2H, m), 8.02–8.03 (1H, m), 8.07–8.10 (1H, m), 8.85 (1H,
dd, JZ1.7, 4.6 Hz). Anal. Calcd for C19H16N4O3: C, 65.51;
H, 4.63; N, 16.08. Found: C, 65.43; H, 4.57; N, 15.84.
4.2.24. 3-Amino-4-{3-[3-(benzyloxy)propoxy]phenyl}-1-
butyl-1,8-naphthyridin-2(1H)-one (16). A suspension of
15 (156 mg, 0.320 mmol), Zn dust (209 mg, 3.20 mmol),
and AcOH (0.046 mL, 0.800 mmol) in MeOH (10 mL) was
heated at reflux for 1.5 h. The mixture was made basic with
saturated aqueous NaHCO3, and the precipitate was
removed by passing through Celite. The organic materials
were extracted with AcOEt, washed with saturated aqueous
NaHCO3, and dried over MgSO4. The solvents were
4.2.21. 1-[3-(Benzyloxy)propoxy]-3-bromobenzene (23).
To a suspension of 3-bromophenol (3.00 g, 17.3 mmol) and
K2CO3 (7.19 g, 52.0 mmol) in DMF (20 mL) was added
benzyl 3-bromopropyl ether (3.92 g, 19.1 mmol) at rt. The
mixture was stirred at 60 8C for 3 h. After cooling to rt,
water was added. The organic materials were extracted with

H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
10091
evaporated in vacuo, and the residue was purified by silica
gel chromatography to give 16 (154 mg, quant.) as colorless
crystals.
concentrated in vacuo. The residue was purified by silica
gel chromatography to give 27 (456 mg, 90% for two-steps)
as a colorless amorphous solid.
IR (film): n 1637, 1603, 1581, 1157 cmK1 1H NMR
;
Mp 100–101 8C (AcOEt/hexane). IR (film): n 3446, 3344,
1585, 1571 cmK1; 1H NMR (DMSO-d6, 300 MHz), d (ppm)
0.95 (3H, t, JZ7.3 Hz), 1.39 (2H, qt, JZ7.3, 7.3 Hz), 1.69
(2H, tt, JZ7.3, 7.3 Hz), 2.00 (2H, tt, JZ6.2, 6.2 Hz), 3.59
(2H, t, JZ6.2 Hz), 4.09 (2H, t, JZ6.2 Hz), 4.47 (2H, s),
4.53 (2H, t, JZ7.3 Hz), 5.12 (2H, s), 6.86–6.89 (2H, m),
7.04 (1H, dd, JZ2.6, 9.7 Hz), 7.13 (1H, dd, JZ4.6, 7.9 Hz),
7.24–7.33 (6H, m), 7.48 (1H, t, JZ7.9 Hz), 8.34 (1H, dd,
JZ1.8, 4.6 Hz); HRMS (ESI) (MCH)C calcd for
C28H33N3O3 458.2444, found 458.2455.
(DMSO-d6, 300 MHz), d (ppm) 0.94–0.99 (15H, m), 1.42
(2H, qt, JZ7.1, 7.1 Hz), 1.45 (9H, s), 1.71 (2H, tt, JZ7.1,
7.1 Hz), 2.01 (2H, tt, JZ6.2, 6.2 Hz), 2.85 (2H, tt, JZ7.1,
7.1 Hz), 3.59 (2H, t, JZ6.2 Hz), 4.06 (2H, t, JZ6.2 Hz),
4.46 (2H, s), 4.52 (2H, t, JZ7.1 Hz), 6.88–6.91 (2H, m),
7.00–7.03 (1H, m), 7.15 (2H, s), 7.22–7.31 (6H, m), 7.39
(1H, t, JZ8.3 Hz), 7.59–7.61 (2H, m), 7.70 (1H, s), 8.61
(1H, dd, JZ1.8, 4.6 Hz), 9.09 (1H, s); HRMS (ESI) (MC
H)C calcd for C46H59N5O6 776.4387, found 776.4389.
4.2.25. 2,6-Diisopropyl-4-nitroaniline (25). To a solution
of 2,6-diisopropylaniline 5 (0.0940 mL, 0.500 mmol) in
EtOH (2.5 mL) was added, 2,3,5,6-tetrabromo-4-methyl-4-
nitro-2,5-cyclohexadienone 24 (234 mg, 0.500 mmol) at rt.
The mixture was stirred at rt for 3 h, and poured into water.
The organic materials were extracted with AcOEt, washed
twice with water, and dried over MgSO4. The solvents were
evaporated in vacuo, and the residue was purified by silica
gel chromatography to give 25 (75.6 mg, 68%) as yellow
crystals.
4.2.28. tert-Butyl (4-{[({1-butyl-4-[3-(3-hydroxypropoxy)
phenyl]-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl}-
amino)carbonyl]amino}-3,5-diisopropylphenyl)carba-
mate (28). A suspension of 27 (239 mg, 0.308 mmol), 10%
Pd/C (24 mg), and AcOH (0.0264 mL, 0.462 mmol) in
MeOH (20 mL) was stirred at rt for 5 h under a hydrogen
atmosphere. The catalyst was removed by passing through
Celite, and the solvent was evaporated in vacuo. The residue
was purified by silica gel chromatography to give 28
(211 mg, quant.) as a colorless amorphous solid.
Mp 125–126 8C (Et2O/hexane), lit.9 mp 105–108 8C
(CH2Cl2/petroleum ether); 1H NMR (DMSO-d6,
300 MHz), d (ppm) 1.18 (12H, d, JZ6.6 Hz), 3.05–3.14
(2H, m), 6.29 (2H, br), 7.80 (2H, s).
IR (film): n 3320, 1635, 1600, 1583, 1157 cmK1; 1H NMR
(DMSO-d6, 300 MHz), d (ppm) 0.85–0.99 (15H, m), 1.42
(2H, qt, JZ7.0, 7.0 Hz), 1.45 (9H, s), 1.71 (2H, tt, JZ7.0,
7.0 Hz), 1.88 (2H, tt, JZ6.2, 6.2 Hz), 2.86 (2H, tt, JZ7.0,
7.0 Hz), 3.56 (2H, t, JZ6.2 Hz), 4.04 (2H, t, JZ6.2 Hz),
4.52 (2H, t, JZ7.0 Hz), 6.88–6.90 (2H, m), 7.01 (1H, dd,
JZ2.2, 8.3 Hz), 7.15 (2H, s), 7.25 (1H, dd, JZ4.8, 8.3 Hz),
7.39 (1H, t, JZ7.9 Hz), 7.60–7.63 (2H, m), 7.69 (1H, s),
8.61 (1H, dd, JZ2.2, 4.8 Hz), 9.90 (1H, s); HRMS (ESI)
(MCH)C calcd for C39H53N5O6 686.3918, found 686.3930.
4.2.26. tert-Butyl (4-amino-3,5-diisopropylphenyl)carba-
mate (26). A suspension of 25 (275 mg, 1.24 mmol) and
10% Pd/C (20 mg) in MeOH (20 mL) was stirred at rt for
2 h under a hydrogen atmosphere. Hydrogen was replace
with nitrogen, and 2 M NaOH (0.310 mL, 0.620 mmol) was
added. The reaction mixture was stirred for 2 h. The catalyst
was removed by passing through Celite, and (Boc)2O
(0.313 mL, 1.36 mmol) was added to the solution. After the
mixture was stirred for 2 h at rt, the solvent was evaporated
in vacuo. Separated crystals were washed with hexane, and
dried in vacuo to give 26 (292 mg, 81%) as colorless
powder.
4.2.29. N-(4-amino-2,6-diisopropylphenyl)-N0-{1-butyl-
4-[3-(3-nydroxypropoxy)phenyl]-2-oxo-1,2-dihydro-1,8-
naphthyridin-3-yl}urea hydrochloride hydrate (SMP-
797). To a solution of 28 (3.00 g, 4.37 mmol) in MeOH
(7 mL) was added 10% HCl/MeOH (30 mL) at rt. The
mixture was stirred at rt overnight. Volatile materials was
evaporated, and the residue was dissolved in MeOH (5 mL)
by heating at 70 8C. Acetone (50 mL) was added to the
solution, and the mixture was stirred under reflux for 1 h.
After cooled, separated white crystals were filtered, and
dried to give SMP-797 (2.59 g, 95%), which was
recrystallized from MeOH giving colorless crystals.
Mp 158–159 8C. IR (film): n 3329, 1689, 1537, 1157 cmK1
;
1H NMR (DMSO-d6, 300 MHz), d (ppm) 1.11 (12H, d, JZ
6.8 Hz), 1.44 (9H, s), 2.94–3.03 (2H, m), 4.26 (2H, br), 6.99
(2H, br), 8.68 (1H, br d); HRMS (ESI) (MCH)C calcd for
C17H30N2O2 293.2229, found 293.2231.
4.2.27. tert-Butyl [4-({[(4-{3-[3-(benzyloxy)propoxy]phe-
nyl}-1-butyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)
amino]carbonyl}amino)-3,5-diisopropylphenyl]carba-
mate (27). To a solution of 16 (300 mg, 0.656 mmol) in
THF (15 mL) was added phenyl chloroformate (0.0905 mL,
0.721 mmol) at rt. The mixture was stirred at rt overnight.
Volatile materials was evaporated, and the residue was
dissolved by DMF (15 mL). To the solution, were added 26
(210 mg, 0.718 mmol) and DMAP (168 mg, 1.38 mmol) at
rt, and the mixture was stirred at rt overnight. Saturated
aqueous NH4Cl was added, and the organic materials were
extracted with AcOEt. The organic layer was washed with
saturated aqueous NaHCO3, dried over MgSO4, and
Mp 196–197 8C (MeOH).7 IR (KBr): n 2966, 1636, 1584,
1546 cmK1; 1H NMR (DMSO-d6, 300 MHz), d (ppm) 0.85–
0.99 (15H, m), 1.41 (2H, qt, JZ7.3, 7.3 Hz), 1.70 (2H, tt,
JZ7.3, 7.3 Hz), 1.87 (2H, tt, JZ6.1, 6.1 Hz), 2.95 (2H, tt,
JZ7.3, 7.3 Hz), 3.54 (2H, t, JZ6.1 Hz), 4.03 (2H, t, JZ
6.1 Hz), 4.50 (2H, t, JZ7.0 Hz), 6.88–6.89 (2H, m), 7.00–
7.03 (3H, m), 7.25 (1H, dd, JZ4.6, 7.9 Hz), 7.40 (1H, t, JZ
7.9 Hz), 7.60 (1H, dd, JZ1.5, 7.9 Hz), 7.79 (1H, s), 7.87
(1H, s), 8.61 (1H, dd, JZ1.5, 4.6 Hz), 9.88 (2H, br). Anal.
Calcd for C34H43N5O4$HCl$H2O: C, 63.79; H, 7.24; Cl,
5.54; N, 10.94. Found: C, 63.85; H, 7.21; Cl, 5.74; N, 10.96.

10092
H. Ban et al. / Tetrahedron 61 (2005) 10081–10092
15. A preliminary communication: Ban, H.; Muraoka, M.; Ohashi,
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