Parallel solution phase synthesis of 3,6,7-4(3 H)-Quinazolinones and evaluation of their antitumor activities against human cancer

Article abstract of DOI:10.1021/cc900173s

Three diversity points of 4(3H)-quinazolinone are introduced at the 3-, 6-, and 7-positions with an efficient parallel solution-phase synthetic method. A one-pot synthesis was developed that gave the key intermediate in high yield. Five hit compounds exhibit preferable activities against a panel of human tumor cell lines, which pointed out preliminary structure-activity relationships.

Full text of DOI:10.1021/cc900173s

346
J. Comb. Chem. 2010, 12, 346–355
Parallel Solution Phase Synthesis of 3,6,7-4(3H)-Quinazolinones and
Evaluation of Their Antitumor Activities against Human Cancer
Hao Wu, Xilei Xie, and Gang Liu*
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College,
2 Nanwei Road, Xuanwu District, Beijing 100050, P. R. China
ReceiVed NoVember 4, 2009
Three diversity points of 4(3H)-quinazolinone are introduced at the 3-, 6-, and 7-positions with an efficient
parallel solution-phase synthetic method. A one-pot synthesis was developed that gave the key intermediate
in high yield. Five hit compounds exhibit preferable activities against a panel of human tumor cell lines,
which pointed out preliminary structure-activity relationships.
Introduction
achieved in both high yield and purity by reflux in water.
The chlorine atom was also quantitatively replaced by
secondary amines catalyzed by organic base, such as
diisopropylethylamine (DIPEA), triethylamine (TEA) or
N-methylmorpholine (NMM). However, substitutions of
chlorine atom with alcohols [2{6} and 2{7}, Figure 2]
were difficult that required the assistant of quaternary
ammonium salt as phase-transfer catalyst and KOH as
base.
The 4(3H)-quinazolinone core is well-known as a “privi-
leged structure”1 for drug design, which is defined as a class
of molecules that are capable of binding to multiple receptors
with high affinity.2 The potential therapeutic applications of
4(3H)-quinazolinones include antiviral,3 antihypertensive,4
cardiotonic,5 antiulcerative,6 anticoccidia,7 antineoplastic,8
5-HT3 antagonist,9and antiemetic10activities. Two of its
derivatives have been clinically used as a muscle relaxant
(afloqualone I11) or as an antifolate (raltiterxed II12) for the
first-line palliative treatment of advanced colorectal cancer.
Some others, exhibiting activities of calcium channel an-
tagonist III,13 5-hydroxytryptamine release inhibitor IV,14
antiulcer V,15 and antifungal activity VI,16 have been studied
in preclinic or clinical trials (Figure 1).
A standard procedure in literature for synthesis of 4(3H)-
quinazolinones is the condensation of a C1-source with
2-aminobenzonitrile,17 2-aminobenzoic acid,18 or 2-ami-
nobenzamide19 (Scheme 1). The relevant methods are well
documented in a recent review.20 In this article, we report a
one-pot synthetic route to synthesize 4(3H)-quinazolinones
to further extend our “scaffold-directed” strategy by using a
raw material of 5-chloro-2,4-dinitrobenzoic acid (CDBC,
1)19,21 instead of 1,5-difluoro-2,4-dinitrobenzene (DFDNB).22
This method not only afforded 4(3H)-quinazolinones skeleton
from o-nitrobenzamides in one-pot but also introduced three
diversity points at 3-, 6-, 7-positions.
Benzamide 6, as a key intermediate, was readily gained
by amidation of compound 4 with primary amines 5 (R2NH2,
Figure 3). Noticeably, the phenoxyl moieties (R1) were able
to be replaced by excess primary amines 5 (R2NH2) under
amidation condition so that equal molar primary amine
should be added. In fact, it was unnecessary to further purify
the crude product (6) for the next step synthesis as a result
of high yield.
A one-pot synthetic procedure is anticipated to prepare
9 from 6 directly because the intermidiate 7 is unstable
when it is exposed to the air. Many methods are well
documented for quantitative reduction of the aromatic nitro
group into aniline under an acid condition,23a–d a neutral
condition,23e,f or a basic condition.23g HCO2H as an acid
resource was selected in this paper to provide a carbon
atom to simultaneously construct quinazolinone 9 through
intermolecular cyclization of 7 in one pot. After several
explorations of correspounding synthetic methods, Fe/
HCO2H reductant gave the satisfied results although it
provided 7-formylated byproduct 8 in high yield. Indeed,
the formyl group of 8 is easily removed by using
concentrated HCl in ethyl alcohol. Thus, this method is
fairly beneficial to construct the quinazolinone ring in one-
pot avoiding the oxidation of 7 exposured into air. To
modify the 7-aromatic amino group of 9, chloroacetylation
(10) and chloroformylation (13) were carried out that
subsequently gave 12 and 14 (Table 1) through the
nucleophilic substitutions. These reactions resulted in a
urea functional group for 14 and an amide compound 12
at 7-position by secondary amines [11{1-10}, Figure 4],
respectively. In addition, a direct acylation by acyl
Results and Discussion
The new synthetic route for the synthesis of 3,6,7-
trisubstituted 4(3H)-quinazolinones (12, 14, and 15) is
depicted in Scheme 2. Starting from 1, three types of
nucleophilic reagents (secondary amines, phenols, and
alcohols) were used for the introduction of the first
diversity element at 6-position of 4(3H)-quinazolinone
(R1H, Figure 2). Nucleophilic substitutions of chlorine
atom with phenols in the presence of NaHCO3 were
* To whom correspondence should be addressed. Phone: +86-10-
63167165. Fax: +86-10-63165246. E-mail: gliu@imm.ac.cn.
10.1021/cc900173s  2010 American Chemical Society
Published on Web 03/02/2010

3,6,7-4(3H)-Quinazolinones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 347
Figure 1. 4(3H)-Quinazolinones entered into preclinical or clinical trials.
Scheme 1. Literature Methods for Synthesis of 4(3H)-Quinazolinones
chlorides [16(1-6), Figure 4] was also performed to yield
15 without an additional N-atom introduction at 7-position
(Table 1).
was performed at the last reaction step to obtain 19 that
was completely acylated to gain the aimed compound 20
(Table 2).
To overcome the difficulty of direct introduction of more
alcohols at 6-position, an alternative synthetic route of
4(3H)-quinazolinone was developed (Scheme 3). The
6-position was first protected through benzoxylation (3,
R1 ) BnO, Scheme 2), which smoothly generated 8 as
above-described method (Scheme 2). Attempt to convert
6 (R1 ) BnO) into 17 in one pot (debenzylation and ring
closure steps) by using Pd/C+HCO2H was unsuccessful
because of the fairly low yield of intermidiate 17 under
this condation. Considering that acylations occur at the
last reaction step to vary the diversities at 6- and
7-positions, respectively, in a parallel manner, the benzyl
protected group of 6-position was then removed from 8
(R1 ) BnO) by hydrogenation or transfer hydrogenation
method that offered the 17 in good yield (Scheme 3).
Intermediate 17 was efficiently diversified on its free
phenol group of 6-position to obtain 18 through a
Mitsunobu reaction from various commercially available
alcohols. Quantitative removal of the formyl group of 18
The synthesized compounds were partially tested after
diversity selection by the developmental therapeutics program
(DTP) of drug discovery at the National Cancer Institute
(NCI) for antitumor activity evaluation. Five compounds are
giving the 50% growth inhibitory activities (GI50) at 0.11
µM-3.38 µM of level range to the specific tumor cell lines
(Table 3). The most potent compound is 12{6,3,5} that is
particularly active to a non-small tumor cell line (HOP-92)
of lung cancer at 0.11 µM of GI50 value. After comparison
of 15{4,3,4} and 12{6,3,5} that share the same 1-phenyl-
ethanamine at 3-position, the modification at 6- and 7-posi-
tions is concluded for significantly improving the antitumor
activity. Further consideration of the similarity of 12{6,3,5}
and 15{4,3,4}, 15{4,3,4}, and 15{1,5,4} in structure, 7-posi-
tion replacement by [2-(4-methylpiperiazin-1-yl)acetamide]
is the key feature for the activity improvement. In addition,
introducing R,ꢀ-unsaturated moiety at 7-position (15{1,5,4}

348 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Wu et al.
Scheme 2. Synthetic Route to 3,6,7-Trisubstituted 4(3H)-Quinazolinones (12, 14, 15)
and 15{4,3,4}) did not further increase the potency indicating
that Michael acceptor fragment could not contribute its
antitumor activity significantly.
spindle protein),24 poly(ADP-ribose)polymerase25 (ADP,
adenosine diphosphate), and targeting the Hedgehog path-
way, 26 etc. It is not clear yet for our compounds to target a
certain tumor cell growth life cycle. The continuous outline
of structure-activity relationships (SARs) through the
4(3H)-Quinazolinones exhibit multiple inhibitory mech-
anisms against tumors, such as inhibition of KSP (kinesin
Figure 2. Reagents for the introduction of the first diversity element at 6-position of 4(3H)-quinazolinone (2, R1H).
Figure 3. Primary amines for the introduction of the second diversity element at 3-position of 4(3H)-quinazolinone (5, R2NH2).
Table 1. Characterization of the Representative Substituted 4(3H)-Quinazolinones 12{R1,R2,R4NR5}, 14{R1,R2,R4NR5}, and
15{R1,R2,R3}
entry
compound
puritya (%)
yieldb(%)
entry
compound
puritya (%)
yieldb(%)
1
2
3
4
5
6
7
8
12{3,1,2}
12{3,1,3}
12{3,1,7}
12{3,1,1}
12{3,1,8}
12{5,6,4}
12{5,6,10}
12{5,6,6}
12{7,6,5}
12{7,4,9}
12{6,3,5}
12{5,6,5}
12{3,7,10}
14{7,4,8}
14{7,4,9}
100.0
100.0
97.6
100.0
97.1
96.2
95.2
99.4
95.3
100.0
99.6
96.4
100.0
99.3
95.4
52.0
50.5
54.0
51.2
51.5
52.1
51.5
58.1
60.9
59.0
69.3
51.0
54.6
46.8
54.4
16
17
18
19
20
21
22
23
24
25
26
27
28
29
14{4,3,5}
15{3,6,3}
15{3,6,1}
15{7,4,3}
15{5,6,5}
15{1,5,5}
15{1,5,3}
15{7,4,6}
15{6,4,4}
15{4,3,2}
15{2,2,4}
15{1,5,4}
15{4,3,4}
15{3,7,3}
100.0
100.0
98.0
100.0
95.6
99.5
94.4
100.0
96.7
99.7
99.6
94.9
98.2
99.4
45.6
61.9
54.1
50.5
54.4
55.9
40.5
44.0
50.3
59.9
56.9
40.1
30.8
64.2
9
10
11
12
13
14
15
a Purity based on the integration area of the HPLC peaks (the detection wavelength was 254 nm). b Isolated yield.

3,6,7-4(3H)-Quinazolinones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 349
Figure 4. Secondary amines (11) and acyl chlorides (16) as building blocks at 7-position of 4(3H)-quinazolinones.
Scheme 3. Alternative Synthetic Route of 3,6-Disubstituted-4(3H)-Quinazolinones
Table 2. Characterization of the Representative Substituted
4(3H)-Quinazolinones 20{R4NR5,R2}
Parallel synthesis was carried out on an H + P Labortechnik
parallel synthesizer. The detailed HPLC equipment and
procedures are available in the Supporting Information.
Preparation of 1 (5-Chloro-2,4-dintrobenzoic Acid). 3-Chlo-
robenzoic acid (10 g, 63.8 mmol) was dissolved in 120 mL
of concentrated sulfuric acid with stirring at room temper-
ature. Potassium nitrate (16.5 g, 163.2 mmol) was added in
portions over 15 min. The reaction mixture was then warmed
to 80 °C and held at this temperature for 30 min. After it
was warmed to 110 °C, the reaction was allowed to continue
for an additional 2 h at 110 °C and at 120 °C for 2 more
hours. The reaction mixture was continuously cooled down
to the room temperature and poured into 660 g of ice to
precipitate an off-white solid. This solid was collected by
filtration and washed with water. The resultant crude product
was purified by recrystallization from the mixed solvent of
40 mL of ethanol/200 mL of H2O to afford 6.74 g of a faintly
yellow solid in 42.7% yield. ESI-MS m/z: 245 (M - H)-.1H
NMR (300 MHz, DMSO-d6): δ 8.29 (s, 1H), 8.85 (s, 1H).
General Procedure for the Synthesis of 3. Method 1. A
mixture of 1 (3 g, 12 mmol), NaHCO3 (2.16 g, 25.68 mmol),
and phenol (2(3), 12.78 mmol) in water (18 mL) was heated
under reflux for 2 h. The reaction mixture was cooled to
room temperature; 30 mL of methylene chloride and 30 mL
of water were added. After separation of the organic layer,
the aqueous layer was acidified with concentrated HCl and
extracted with methylene chloride (2 × 50 mL). The organic
extract was washed with water and dried over anhydrous
Na2SO4, then concentrated under reduced pressure to give
the desired 3. For 2,4-dinitro-5-phenoxybenzoic acid, as an
example compound, 3.2 g of yellow solid was obtained in
86.5% yield with an HPLC purity >98% that was directly
entry
compound
puritya (%)
yieldb(%)
1
2
3
4
20{4,3}
20{2,3}
20{3,3}
20{4,4}
96.1
98.9
99.3
99.1
51.3
62.6
65.4
50.9
a Purity based on the integration area of the HPLC peaks (the
detection wavelength was 254 nm). b Isolated yield.
construction of sublibrary is underway based on these
preliminary observations.
Conclusion
An efficient solution-phase method was described in this
paper for the synthesis of 3,6,7-position diverse 4(3H)-
quinazolinones. A one-pot synthesis was developed that gave
the key intermediate 9 in high yield and good purity. A
library of 4(3H)-quinazolinone was synthesized and evaluated
for their anti tumor activity. Five hit compounds exhibit good
activities against a panel of human tumor cell lines, which
pointed out preliminary structure-activity relationships.
Experimental Section
All chemical reagents were purchased from Acros Organ-
ics (Geel, Belgium) and were used without further purifica-
tion. Tetrahydrofuran (THF) was dried over molecular sieves
and redistilled from sodium before usage. Acetone was
treated with anhydrous K2CO3. N,N-dimethylformamide
(DMF) was treated with anhydrous MgSO4. All NMR
experiments were carried out on a Varian Mercury 300 MHz
NMR spectrometer using DMSO-d6 or CDCl3 as the solvent.

350 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Wu et al.
Table 3. Activity of 4(3H)-Quinazolinones against Human Cancer Cell Linesa
GI50 values (µM) in cell linesb
panel/cell line
15{7,4,3}
15{1,5,4}
15{4,3,4}
12{6,3,5}
12{5,6,5}
CCRF-CEM
SR
HOP-92
COLO 205
HT 29
3.18
2.26
1.87
1.58
1.98
1.82
0.17
1.53
2.63
2.77
3.38
2.07
1.97
1.50
1.92
1.65
1.79
1.85
2.87
0.86
0.11
0.88
0.79
0.93
2.01
1.97
1.70
1.90
1.98
1.83
SK-MEL-28
a Determined by MTT assay. b Cancer cell line origin: CCRF-CEM (leukemia), SR (leukemia), HOP-92 (nonsmall cell lung), COLO 205 (colon),
HT 29 (colon), and SK-MEL-28 (melanoma).
1
used for the next reaction without further purification. H
NMR (300 MHz, DMSO-d6): δ 7.20 (s, 1H), 7.28 (d, 1H, J
) 7.8 Hz), 7.36 (t, 2H, J ) 7.8 Hz), 7.53 (t, 2H, J ) 7.8
Hz), 8.82 (s, 1H).
5-(Methoxy)-2,4-dinitrobenzoic Acid. 1H NMR (300 MHz,
DMSO-d6): δ 4.09 (s, 3H),7.69 (s, 1H), 8.70 (s, 1H). ESI-
MS m/z: 241 (M - H)-.
General Procedure for the Synthesis of 6. Method 1.
Compound 3 (1.84 mmol) was suspended or dissolved in 5
mL of thionyl chloride containing 2 drops of DMF under
stirring. The suspension or solution was heated to reflux for
2 h. Thionyl chloride was evaporated under reduced pressure.
After the mixture was cooled to room temperature, 5 mL of
toluene was added, and the solution was evaporated under
reduced pressure. The solid or liquid 4 was dissolved in 3
mL of methylene chloride (or acetone) and added dropwise
to a cooled solution (0 °C) of 2 equiv of primary amine 5
(or 1 equiv of primary amine 5 and 1 equiv of Et3N) in 5
mL of methylene chloride over 5 min. Stirring was continued
for 1 h. The reaction mixture was diluted with 50 mL of
methylene chloride and washed subsequently with 2%
aqueous HCl, water, saturated NaHCO3, and water. The
organic phase was dried and concentrated to yield 6.
Method 2. Compound 3 (6.28 mmol) was dissolved in
40 mL of methylene chloride containing 4 drops of DMF
under stirring. Oxalyl chloride (1.9 mL) was added dropwise.
The reaction mixture was heated to reflux for 2 h. The
reaction mixture was evaporated to dryness under reduced
pressure to give the compound 4. Forty milliliters of
methylene chloride was added, and resultant solution was
added dropwise to a cooled solution (0 °C) of 1 equiv of
primary amine 5 and 1 equiv of triethyl amine in 40 mL of
methylene chloride over 5 min. Stirring was continued for
an additional hour. The reaction mixture was diluted with
50 mL of methylene chloride and washed successively with
2% aqueous HCl, water, saturated NaHCO3, and water. The
organic phase was dried and concentrated to yield 6.
For N-(3,4-dimethoxyphenethyl)-5-(3,5-dimethylphenoxy)-
2,4-dinitrobenz amide, as an example compound, a brown
solid was obtained in 96.6% yield, with an HPLC purity
1
5-(4-Fluorophenoxy)-2,4-dinitrobenzoic Acid. H NMR
(500 MHz, DMSO-d6): δ 7.21 (d, 1H, J ) 1.0 Hz), 7.36
(brs, 2H), 7.38 (brs, 2H), 8.82 (d, 1H, J ) 1.0 Hz).
5-(3,5-Dimethylphenoxy)-2,4-dinitrobenzoic Acid. 1H NMR
(300 MHz, DMSO-d6): δ 2.29 (s, 6H), 6.89 (s, 2H), 6.98 (s,
1H), 7.15 (s, 1H), 8.77 (s, 1H).
Method 2. A mixture of 1 (1 g, 4 mmol) and triethyl amine
(1.224 mL, 8.8 mmol) in THF (6 mL) was stirred at room
temperature. Secondary amine (2(1), 6 mmol) was added
dropwise. The reaction was monitored by LC-MS analysis.
After 12 h, the reaction mixture was acidified with concen-
trated HCl. The resulting precipitate was collected by
filtration and washed with water, then dried in vacuo to gain
the desired 3. For 5-morpholino-2,4-dinitrobenzoic acid, as
an example compound, 0.97 g of yellow solid was obtained
in 80.3% yield with an HPLC purity >98% that was directly
used for the next reaction without further purification. ESI-
MS m/z: 296 (M - H)-. 1H NMR (300 MHz, DMSO-d6): δ
3.29 (m, 4H), 3.69 (m, 4H), 7.48 (s, 1H), 8.56 (s, 1H).
2,4-Dinitro-5-(pyrrolidin-1-yl)benzoic Acid. 1H NMR (300
MHz, DMSO-d6): δ 1.93 (m, 4H), 3.28 (m, 4H), 7.14 (s,
1H), 8.54 (s, 1H).
Method 3. A mixture of 1 (3 g, 12.2 mmol) and KOH
(1.62 g, 28.9 mmol) in alcohol (2(6), 40 mL) was stirred at
room temperature. (n-Bu)4NBr (100 mg) was added. Stirring
was continued for 12 h. Methylene chloride (150 mL) was
added. The resulting precipitate was collected by filtration
and washed with methylene chloride and then dissolved in
200 mL water. The mixture was acidified with concentrated
HCl, and the desired 3 was obtained by filtration and dried.
For 5-(benzyloxy)-2,4-dinitrobenzoic acid, as an example
compound, 2.8 g of white solid was obtained in 72.2% yield,
with an HPLC purity >98%. ESI-MS m/z: 317 (M - H)-.
1H NMR (300 MHz, DMSO-d6): δ 5.50 (s, 2H), 7.42 (m,
5H), 7.81 (s, 1H), 8.72 (s, 1H).
1
>98%. ESI-MS m/z: 496 (M + H)+. H NMR (300 MHz,
DMSO-d6): δ 2.30 (s, 6H), 2.68 (t, 2H, J ) 7.2 Hz), 3.37
(m, 2H), 3.67 (s, 3H), 3.69 (s, 3H), 6.21-6.71 (m, 2H), 6.80

3,6,7-4(3H)-Quinazolinones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 351
(brs, 1H), 6.87 (brs, 2H), 6.96 (s, 1H), 7.00 (brs, 1H), 8.77
(t, 1H, J ) 5.4 Hz), 8.81 (s, 1H).
7-Amino-6-(4-fluorophenoxy)-3-(1-phenylethyl)quinazo-
lin-4(3H)-one. H NMR (300 MHz, DMSO-d6): δ 1.75 (d,
1
3H, J ) 7.2 Hz), 5.99 (q, 1H, J ) 7.2 Hz), 6.14 (brs, 2H,
N-H), 6.85 (s, 1H), 7.08-7.34 (m, 10H), 8.16 (s, 1H). ESI-
MS m/z: 376 (M + H)+.
5-(Benzyloxy)-2,4-dinitro-N-(pyridin-2-ylmethyl)benzam-
ide. 1H NMR (300 MHz, DMSO-d6): δ 4.57 (d, 2H, J ) 6.0
Hz), 5.50 (s, 2H), 7.29-7.48 (m, 7H), 7.72 (s, 1H), 7.83 (t,
1H, J ) 8.1 Hz), 8.53 (d, 1H, J ) 4.2 Hz), 8.74 (s, 1H),
9.30 (t, 1H, J ) 6.0 Hz). ESI-MS (m/z): 409 [M + H]+.
3-(3,4-Dimethoxyphenethyl)-7-amino-6-(3,5-dimethylphe-
1
noxy)quinazolin-4(3H)-one. H NMR (300 MHz, DMSO-
1
2,4-Dinitro-5-phenoxybenzamide. H NMR (300 MHz,
d6): δ 2.29 (s, 6H), 2.85 (t, 2H, J ) 6.9 Hz), 3.64 (s, 3H),
3.69 (s, 3H), 4.05 (t, 2H, J ) 6.9 Hz), 6.03 (brs, 2H, N-H),
6.65 (m, 3H), 6.74 (brs, 1H), 6.82 (m, 3H), 7.20(s, 1H), 7.85
(s, 1H). ESI-MS m/z: 446 (M + H)+.
DMSO-d6): δ 7.01 (s, 1H), 7.26 (d, 2H, J ) 7.8 Hz), 7.36
(t, 1H, J ) 7.8 Hz), 7.53 (t, 2H, J ) 7.8 Hz), 7.85 (s, 1H),
8.18 (s, 1H), 8.81 (s, 1H).
General Procedure for the Synthesis of 8. Compound 6
(2.94 mmol) was dissolved in 40 mL of HCOOH (98%)
under stirring at room temperature. Five grams of Fe powder
was added. The reaction mixture was heated to reflux for
8 h; 100 mL of ethyl acetate was added. The solid was
removed by filtration. The filtrate was evaporated to dryness.
The residue was treated with 50 mL methylene chloride and
50 mL of water. The organic phase was washed with water
and then evaporated under reduced pressure to give crude
8. If necessary, simple column chromatography or recrys-
tallization was used to further purify the crude 8. For N-(6-
(4-fluorophenoxy)-4-oxo-3-(1-phenylethyl)-3,4-dihydroquinazo-
lin-7-yl)formamide, as an example compound, 0.61 g of
white solid was obtained in 51.5% yield after column
chromatography eluting with ethyl acetate/petroleum (1:1.5)
and an HPLC purity >98%. ESI-MS m/z: 404 (M + H)+.1H
NMR (300 MHz, DMSO-d6): δ 1.80 (d, 3H, J ) 7.2 Hz),
6.00 (q, 1H, J ) 7.2 Hz), 7.27-7.36 (m, 10H), 8.36 (s, 1H),
8.46 (s, 1H), 8.65 (s, 1H), 10.50 (s, 1H).
Derivatization of 9 on 7-Aromatic Amino Group. Method
1 (Compound 12). To an ice-cooled and stirred suspension
of 9 hydrochloride (1.2 mmol) in 20 mL of anhydrous
methylene chloride, 0.7 mL of triethyl amine (5.04 mmol)
was added. After 5 min, 0.42 mL of chloroacetic chloride
(4.88 mmol) was subsequently added dropwise. Stirring was
continued for an additional hour. Fifty milliliters of meth-
ylene chloride was added. The organic layer was washed
with saturated NaHCO3 and further washed with water (2
× 50 mL), dried, and concentrated to yield 10 which was
directly used without further purification for the next reaction.
For N-(3-(benzo[d][1,3]dioxol-5-ylmethyl)-6-morpholino-4-
oxo-3,4-dihydroquinazolin-7-yl)-2-chloroacetamide, as an
example compound, 0.49 g of brown solid was obtained in
89.42% yield with an HPLC purity >95%. ESI-MS m/z: 457
1
(M + H)+. H NMR (300 MHz, DMSO-d6): δ 2.89 (brs,
4H), 3.81 (brs, 4H), 4.52 (s, 2H), 5.06 (s, 2H), 5.97 (s, 2H),
6.85 (brs, 2H), 7.00 (s, 1H), 7.84 (s, 1H), 8.39 (s, 1H), 8.50
(s, 1H), 9.73 (s, 1H). To a mixture of 10 (50 mg) and KI
(10-20 mg) in 2 mL of anhydrous ethanol and 1.5 mL of
anhydrous methylene chloride, 5 equiv of secondary amine
11 was added. The reaction mixture was stirred mechanically
on an H + P Labortechnik parallel synthesizer at 40 °C until
completion of the reaction. The solvent was evaporated in
vacuo to obtain the crude product 12. The final products were
characterized after chromatographic purification on silica gel.
The yields ranged from 50%-65%, a major loss of yields
was due to column chromatography because of adsorption
or solubility. For N-(3-(3,4-dimethoxyphenethyl)-6-methoxy-
4-oxo-3,4-dihydroquinazolin-7-yl)-2-(4-methylpi-perazin-1-
yl)acet amide, as an example compound, 35 mg of brown
solid was obtained in 60.9% yield with an HPLC purity
>95%.
N-(3-(3,4-Dimethoxyphenethyl)-6-methoxy-4-oxo-3,4-di-
hydroquinazolin-7-yl)formamide. 1H NMR (300 MHz, DM-
SO-d6): δ 2.92 (t, 2H, J ) 6.9 Hz), 3.65 (s, 3H), 3.69 (s,
3H), 3.98 (s, 3H), 4.17 (t, 2H, J ) 6.9 Hz), 6.64 (d, 1H, J
) 8.1 Hz), 6.78-6.83 (m, 3H), 7.57 (s, 1H), 7.97 (s, 1H),
8.42 (s, 1H), 8.50 (s, 1H), 10.13 (s, 1H). ESI-MS m/z: 384
(M + H)+. Eluting agent: petroleum/ethyl acetate (5: 1).
N-(3-(2-Methoxyethyl)-4-oxo-6-(pyrrolidin-1-yl)-3,4-dihy-
droquinazolin-7-yl)formamide. 1H NMR (300 MHz, DMSO-
d6): δ 1.92 (brs, 4H), 3.12 (brs, 4H), 3.23 (s, 3H), 3.58 (t,
2H, J ) 5.1 Hz), 4.11 (t, 2H, J ) 5.1 Hz), 7.63 (s, 1H),
8.12 (s, 1H), 8.29 (s, 1H), 8.45 (s, 1H), 9.75 (s, 1H). ESI-
MS m/z: 317 (M + H)+. Eluting agent: ethyl acetate.
General Procedure for the Synthesis of 9. Compound 8
(4.69 mmol) was suspended into 20 mL of anhydrous ethanol
under stirring at room temperature. Two milliliters of
concentrated hydrochloric acid (36%) was added. Stirring
was continued for 12 h. Fifty milliliters of anhydrous diethyl
ether was added. The resulted solid was collected by filtration
and washed with 20 mL of anhydrous diethyl ether and then
dried to afford 9 as hydrochloride salt. For 3-(3,4-dimethoxy-
phenethyl)-7-amino-6-methoxyquinazolin-4(3H)-one hydro-
chloride, as an example compound, 1.5 g of yellow solid
was obtained in 81.5% yield with an HPLC purity >95%.
N-(4-Oxo-6-phenoxy-3,4-dihydroquinazolin-7-yl)-2-(pyr-
rolidin-1-yl)acetamide 12{3,1,2}. 1H NMR (300 MHz, DMSO-
d6): δ 1.59 (m, 4H), 2.51 (m, 4H), 3.31 (s, 2H), 7.12 (m,
2H), 7.24 (m, 1H), 7.43-7.49 (m, 3H), 8.04 (s, 1H), 8.64
(s, 1H), 10.08 (s, 1H), 12.20 (brs, 1H). HRESIMS obsd m/z
365.1601, calcd for 365.1608.
N-(4-Oxo-6-phenoxy-3,4-dihydroquinazolin-7-yl)-2-(pip-
eridin-1-yl)acetamide 12{3,1,3}. 1H NMR (300 MHz, DMSO-
d6): δ 1.40 (brs, 6H), 2.44 (brs, 4H), 3.13 (s, 2H), 7.17 (d,
2H, J ) 7.8 Hz), 7.27 (t, 1H, J ) 7.8 Hz), 7.38 (s, 1H),
7.48 (t, 2H, J ) 7.8 Hz), 8.04 (s, 1H), 8.66 (s, 1H), 10.32
(s, 1H), 12.19 (brs, 1H). HRESIMS obsd m/z 379.1770, calcd
for 379.1764.
1
ESI-MS m/z: 356 (M + H)+. H NMR (300 MHz, DMSO-
d6): δ 2.89 (t, 2H, J ) 7.2 Hz), 3.64 (s, 3H), 3.69 (s, 3H),
3.87 (s, 3H), 4.10 (t, 2H, J ) 7.2 Hz), 5.82 (brs, 2H, N-H),
6.63-6.68 (m, 2H), 6.74 (brs, 1H), 6.81 (d, 1H, J ) 8.1
Hz), 7.32 (s, 1H), 7.79 (s, 1H).

352 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Wu et al.
Ethyl 1-(2-Oxo-2-(4-oxo-6-phenoxy-3,4-dihydroquinazo-
lin-7-ylamino)ethyl)piperidine-4-carboxylate 12{3,1,7}. H
6.94 (d, 1H, J ) 8.1 Hz), 7.07 (t, 1H, J ) 8.1 Hz), 7.26 (t,
1H, J ) 7.2 Hz), 7.38 (d, 1H, J ) 7.8 Hz), 7.54 (s, 1H),
7.78 (t, 1H, J ) 7.8 Hz), 8.40 (s, 1H), 8.45 (d, 1H, J ) 4.2
Hz), 8.58 (s, 1H), 10.22 (s, 1H). HRESIMS obsd m/z
513.2610, calcd for 513.2608.
1
NMR (300 MHz, DMSO-d6): δ 1.12 (t, 3H, J ) 6.9 Hz),
1.38 (m, 2H), 1.70 (m, 2H), 2.23 (m, 3H), 2.36 (m, 2H),
3.17 (s, 2H), 4.01 (q, 2H, J ) 6.9 Hz), 7.13 (d, 2H, J ) 7.5
Hz), 7.23 (t, 1H, J ) 7.5 Hz), 7.41 (s, 1H), 7.45 (t, 2H, J )
7.5 Hz), 8.04 (s, 1H), 8.65 (s, 1H), 10.25 (s, 1H), 12.20 (brs,
1H). HRESIMS obsd m/z 451.1969, calcd for 451.1981.
2-(Dipropylamino)-N-(4-oxo-6-phenoxy-3,4-dihydroquinazo-
N-(6-(Benzyloxy)-4-oxo-3-(1-phenylethyl)-3,4-dihydro-
quinazolin-7-yl)-2-(4-methylpiperazin-1-yl)acetamide 12{6,
1
3,5}. H NMR (300 MHz, DMSO-d6): δ 1.83 (d, 3H, J )
6.9 Hz), 2.49 (brs, 4H), 2.59 (s, 3H), 2.95 (brs, 4H), 3.31 (s,
2H), 5.35 (s, 2H), 6.09 (q, 1H, J ) 6.9 Hz), 7.29-7.58 (m,
10H), 7.72 (s, 1H), 8.34 (s, 1H), 8.55 (s, 1H), 9.82 (s, 1H).
HRESIMS obsd m/z 512.2645, calcd for 512.2656.
1
lin-7-yl)acetamide 12{3,1,1}. H NMR (300 MHz, DMSO-
d6): δ 0.77 (t, 6H, J ) 6.9 Hz), 1.33 (sex, 4H, J ) 7.2 Hz),
2.40 (t, 4H, J ) 6.9 Hz), 3.21 (s, 2H), 7.12 (d, 2H, J ) 7.5
Hz), 7.24 (t, 1H, J ) 7.5 Hz), 7.32 (s, 1H), 7.49 (t, 2H, J )
7.5 Hz), 8.02 (d, 1H, J ) 3.3 Hz), 8.70 (s, 1H), 10.32 (s,
1H), 12.18 (s, 1H). HRESIMS obsd m/z 395.2087, calcd for
395.2077.
N-(3-(3,4-Dimethoxyphenethyl)-6-(3,5-dimethylphenoxy)-
4-oxo-3,4-dihydroquinazolin-7-yl)-2-(4-methylpiperazin-1-
1
yl)acetamide 12{5,6,5}. H NMR (300 MHz, DMSO-d6): δ
2.28 (s, 9H), 2.71 (s, 8H), 2.89 (t, 2H, J ) 6.9 Hz), 3.24 (s,
2H), 3.65 (s, 3H), 3.69 (s, 3H), 4.11 (t, 2H, J ) 6.9 Hz),
6.65 (d, 1H, J ) 7.8 Hz), 6.76 (m, 3H), 6.82 (d, 1H, J ) 7.8
Hz), 6.89 (s, 1H), 7.48 (s, 1H), 8.07 (s, 1H), 8.59 (s, 1H),
10.10 (brs, 1H). HRESIMS obsd m/z 586.3024, calcd for
586.3029.
2-(Methyl(2-(pyridin-2-yl)ethyl)amino)-N-(4-oxo-6-phenoxy-
1
3,4-dihydroquinazolin-7-yl) acetamide 12{3,1,8}. H NMR
(300 MHz, DMSO-d6): δ 2.21 (s, 3H), 2.83 (brs, 4H), 3.25
(s, 2H), 7.08-7.26 (m, 5H), 7.36 (s, 1H), 7.45 (t, 2H, J )
7.8 Hz), 7.57 (t, 1 H, J ) 7.8 Hz), 8.03 (s, 1H), 8.39 (d, 1H,
J ) 4.2 Hz), 8.64 (s, 1H), 9.95 (s, 1H), 12.19 (s, 1H).
HRESIMS obsd m/z 452.1927, calcd for 452.1934.
2-(4-(4-Fluorophenyl)piperazin-1-yl)-N-(4-oxo-6-phenoxy-
3-phenyl-3,4-dihydroquinazolin-7-yl) acetamide 12{3,7,10}.
1H NMR (300 MHz, DMSO-d6): δ 2.66 (brs, 4H), 2.89 (brs,
4H), 3.30 (s, 2H), 6.83 (m, 2H), 7.02 (t, 2H, J ) 9 Hz),
7.12-7.22 (m, 3H), 7.40 (t, 2H, J ) 7.5 Hz), 7.50-7.57
(m, 6H), 8.31 (s, 1H), 8.74 (s, 1H), 10.32 (s, 1H). HRESIMS
obsd m/z 550.2252, calcd for 550.2254.
2-(Dipropylamino)-N-(4-oxo-6-phenoxy-3,4-dihydroquinazo-
1
lin-7-yl)acetamide 12{5,6,4}. H NMR (300 MHz, DMSO-
d6): δ 0.77 (t, 6H, J ) 6.9 Hz), 1.33 (m, 4H), 2.40 (t, 4H, J
) 6.9 Hz), 3.21 (s, 2H), 7.12 (d, 2H, J ) 7.5 Hz), 7.24 (t,
1H, J ) 7.5 Hz), 7.32 (s, 1H), 7.49 (t, 2H, J ) 7.5 Hz),
8.02 (d, 1H, J ) 3.3 Hz), 8.70 (s, 1H), 10.32 (s, 1H), 12.18
(s, 1H). HRESIMS obsd m/z 573.2706, calcd for 573.2713.
Ethyl 4-(2-Oxo-2-(4-oxo-6-phenoxy-3,4-dihydroquinazo-
lin-7-ylamino)ethyl)piperazine-1-carboxylate 12{5,6,10}. 1H
NMR (300 MHz, DMSO-d6): δ 1.16 (t, 3H, J ) 6.9 Hz),
2.45 (brs, 4H), 3.18 (brs, 4H), 3.24 (s, 2H), 4.01 (q, 2H, J
) 6.9 Hz), 7.18 (d, 2H, J ) 7.8 Hz), 7.26 (t, 1H, J ) 7.8
Hz), 7.38 (s, 1H), 7.47 (t, 2H, J ) 7.8 Hz), 8.04 (d, 1H, J )
3.9 Hz, 8.61 (s, 1H), 10.15 (s, 1H), 12.20 (s, 1H). HRESIMS
obsd m/z 666.3100, calcd for 666.3092.
N-(3-(3,4-Dimethoxyphenethyl)-6-(3,5-dimethylphenoxy)-
4-oxo-3,4-dihydroquinazolin-7-yl)-2-(cyclohexyl(methyl)ami-
no)acetamide 12{5,6,6}. 1H NMR (300 MHz, DMSO-d6): δ
1.20 (m, 6H), 1.62 (m, 4H), 2.16 (s, 3H), 2.26 (s, 6H), 2.45
(m, 1H), 2.90 (t, 2H, J ) 7.2 Hz), 3.18 (s, 2H), 3.65 (s,
3H), 3.69 (s, 3H), 4.13 (t, 2H, J ) 7.2 Hz), 6.64-6.88 (m,
6H), 7.48 (s, 1H), 8.06 (s, 1H), 8.63 (s, 1H), 10.29 (s, 1H).
HRESIMS obsd m/z 599.3239, calcd for 599.3233.
N-(3-(3,4-Dimethoxyphenethyl)-6-(3,5-dimethylphenoxy)-
4-oxo-3,4-dihydroquinazolin-7-yl)-2-(4-(4-fluorophenyl)pip-
erazin-1-yl)acetamide 12{7,6,5}. 1H NMR (300 MHz, DMSO-
d6): δ 2.19 (s, 6H), 2.63 (brs, 4H), 2.89 (m, 6H), 3.26 (s, 2
H), 3.65 (s, 3H), 3.69 (s, 3H), 4.13 (t, 2H, J ) 6.9 Hz), 6.65
(m, 3H), 6.77-6.86 (m, 5H), 7.03 (t, 2H, J ) 7.8 Hz), 7.54
(s, 1H), 8.09 (s, 1H), 8.64 (s, 1H), 10.24 (s, 1H). HRESIMS
obsd m/z 496.2536, calcd for 496.2560.
2-(4-(2,3-Dimethylphenyl)piperazin-1-yl)-N-(6-methoxy-4-
oxo-3-(pyridin-2-ylmethyl)-3,4-dihydroquinazolin-7-yl)acet-
amide 12{7,4,9}. 1H NMR (300 MHz, DMSO-d6): δ 2.16 (s,
3H), 2.20 (s, 3H), 2.75 (brs, 4H), 2.89 (brs, 4H), 3.31 (s,
2H), 4.00(s, 3H), 5.28 (s, 2H), 6.88 (d, 1H, J ) 7.2 Hz),
Method 2 (compound 14). To an ice-cooled and stirred
suspension of 9 hydrochloride (50 mg) in 5 mL of anhydrous
methylene chloride, 5 equiv of triethylamine was added,
followed by addition of 10 equiv of triphosgene. Stirring
was continued for 1 h. The solvent was evaporated in vacuo
to dryness. The residue 13 was dissolved in 2 mL of
anhydrous methylene chloride and added to a solution of 3
equiv of secondary amine 11 in 3 mL of anhydrous
methylene chloride. After 1 h, the solvent was evaporated
under the reduced pressure to yield the crude compound 14.
The crude compound 14 was purified on silica gel and
1
characterized by H NMR.
Ethyl 4-((6-Methoxy-4-oxo-3-(pyridin-2-ylmethyl)-3,4-di-
hydroquinazolin-7-yl)carbamoyl) piperazine-1-carboxylate
14{7,4,8}. 1H NMR (300 MHz, DMSO-d6): δ 1.19 (t, 3H, J
) 6.9 Hz), 3.44 (brs, 4H), 3.46 (brs, 4H), 3.94 (s, 3H), 4.05
(q, 2H, J ) 6.9 Hz), 5.27 (s, 2H), 7.28 (t, 1H, J ) 6.3 Hz),
7.36 (d, 1H, J ) 7.8 Hz), 7.47 (s, 1H), 7.78 (t, 1H, J ) 7.5
Hz), 8.08 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.45 (d, 1H, J
) 4.2 Hz). HRESIMS obsd m/z 467.2045, calcd for
467.2037.
4-(2,3-Dimethylphenyl)-N-(6-methoxy-4-oxo-3-(pyridin-2-
ylmethyl)-3,4-dihydroquinazolin-7-yl) piperazine-1-carbox-
amide 14{7,4,9}. 1H NMR (300 MHz, DMSO-d6): δ 2.19 (s,
3H), 2.21 (s, 3H), 2.83 (brs, 4H), 3.62 (brs, 4H), 3.95 (s,
3H), 5.27 (s, 2H), 6.89 (d, 2H, J ) 7.5 Hz), 7.05 (t, 1H, J
) 7.5 Hz), 7.28 (t, 1H, J ) 6.9 Hz), 7.36 (d, 1H, J ) 7.5
Hz), 7.48 (s, 1H), 7.77 (t, 1H, J ) 7.8 Hz), 8.08 (s, 1H),
8.27 (s, 1H), 8.37 (s, 1H), 8.45 (d, 1H, J ) 4.2 Hz).
HRESIMS obsd m/z 499.2451, calcd for 499.2452.

3,6,7-4(3H)-Quinazolinones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 353
N-(6-(4-Fluorophenoxy)-4-oxo-3-(1-phenylethyl)-3,4-dihy-
droquinazolin-7-yl)-4-methylpiperazine-1-carboxamide 14{4,
3,5}. H NMR (300 MHz, CDCl3): δ 1.81 (d, 3H, J ) 6.9
N-(3-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-morpholino-4-
oxo-3,4-dihydroquinazolin-7-yl)-2-(benzyloxy)acetamide 15
1
1
{1,5,3}. H NMR (300 MHz, DMSO-d6): δ 2.79 (brs, 4H),
3.48 (brs, 4H), 4.24 (s, 2H), 4.68 (s, 2H), 5.05 (s, 2H), 5.97
(s, 2H), 6.86 (m, 2H), 6.99 (s, 1H), 7.35-7.46 (m, 5H), 7.82
(s, 1H), 8.49 (s, 1H), 8.56 (s, 1H), 9.70 (s, 1H). HRESIMS
obsd m/z 529.2096, calcd for 529.2088.
Hz), 2.33 (s, 3H), 2.46 (brs, 4H), 3.55 (brs, 4H), 6.24 (q,
1H, J ) 6.9 Hz), 7.05 (m, 4H), 7.27-7.48 (m, 6H), 7.52 (s,
1H), 7.88 (s, 1H), 8.59 (s, 1H). HRESIMS obsd m/z
502.2261, calcd for 502.2249.
(E)-3-(2-Chlorophenyl)-N-(6-methoxy-4-oxo-3-(pyridin-2-
ylmethyl)-3,4-dihydroquinazolin-7-yl) acrylamide 15{7,4,6}.
1H NMR (300 MHz, DMSO-d6): δ 4.00 (s, 3H), 5.32 (s,
2H), 7.33-7.58 (m, 6H), 7.80-7.95 (m, 3H), 8.45 (s, 1H),
8.50 (d, 1H, J ) 4.2 Hz), 8.71 (s, 1H), 8.84 (s, 1H), 9.84 (s,
1H). HRESIMS obsd m/z 447.1226, calcd for 447.1218.
N-(6-(Benzyloxy)-4-oxo-3-(pyridin-2-ylmethyl)-3,4-dihy-
droquinazolin-7-yl)acrylamide 15{6,4,4}. 1H NMR (300
MHz, DMSO-d6): δ 5.25 (s, 2H), 5.39 (s, 2H), 5.82 (dd,
1H, J ) 2.1 Hz, 9.9 Hz), 6.32 (dd, 1H, J ) 2.1 Hz, 16.8
Hz), 6.81 (dd, 1H, J ) 9.9 Hz, 16.8 Hz), 7.25-7.40 (m,
5H), 7.51 (d, 2H, J ) 7.5 Hz), 7.55 (s, 1H), 7.79 (m, 1H),
8.38(s, 1H), 8.44 (m, 1H), 8.54 (s, 1H), 9.73 (s, 1H).
HRESIMS obsd m/z 413.1610, calcd for 413.1608.
N-(6-(4-Fluorophenoxy)-4-oxo-3-(1-phenylethyl)-3,4-dihy-
droquinazolin-7-yl)cyclopropane carboxamide 15{4,3,2}. 1H
NMR (300 MHz, DMSO-d6): δ 0.84 (m, 4H), 1.78 (d, 3H,
J ) 6.9 Hz), 2.24 (m, 1H), 6.00 (q, 1H, J ) 6.9 Hz),
7.25-7.35(m, 10H), 8.33 (s, 1H), 8.54 (s, 1H), 10.15 (s, 1H).
HRESIMS obsd m/z 444.1716, calcd for 444.1715.
N-(3-(2-Methoxyethyl)-4-oxo-6-(pyrrolidin-1-yl)-3,4-dihy-
droquinazolin-7-yl)acrylamide 15{2,2,4}. 1H NMR (300
MHz, DMSO-d6): δ 1.91 (brs, 4H), 3.19 (brs, 4H), 3.23 (s,
3H), 3.59 (t, 2H, J ) 5.1 Hz), 4.12(t, 2H, J ) 5.1 Hz), 5.78
(dd, 1H, J ) 1.8 Hz, J ) 9.9 Hz), 6.29 (dd, 1H, J ) 1.8 Hz,
J ) 16.8 Hz), 6.63 (dd, 1H, J ) 9.9 Hz, 16.8 Hz), 7.49 (s,
1H), 7.91 (s, 1H), 8.09 (s, 1H), 9.69 (s, 1H). HRESIMS obsd
m/z 343.1766, calcd for 343.1765.
Method 3 (Compound 15). To an ice-cooled and stirred
suspension of 9 hydrochloride (50 mg) in 5 mL of anhydrous
methylene chloride, 3.5 equiv of triethyl amine was added.
After 5 min, 2-4 equiv of acyl chloride 16 was added
dropwise. Stirring was continued for 1 h. 50 mL of methylene
chloride was added. The organic layer was washed with
saturated NaHCO3 and then washed with water (2 × 50 mL),
and concentrated to yield crude compound 15. Crude
compound 15 was purified on silica gel with the ethyl acetate/
petroleum ether system as an eluent.
N-(3-(3,4-Dimethoxyphenethyl)-4-oxo-6-phenoxy-3,4-dihy-
1
droquinazolin-7-yl)-2-(benzyloxy) acetamide 15{3,6,3}. H
NMR (300 MHz, DMSO-d6): δ 2.87 (t, 2H, J ) 6.9 Hz),
3.65 (s, 3H), 3.68 (s, 3H), 4.12 (t, 2H, J ) 6.9 Hz), 4.25 (s,
2H), 4.62 (s, 2H), 6.63 (dd, 1H, J ) 1.8 Hz, 7.8 Hz), 6.76
(d, 1H, J ) 1.8 Hz), 6.81 (d, 1H, J ) 7.8 Hz), 7.18-7.35
(m, 8H), 7.36 (s, 1H), 7.51 (t, 2H, J ) 7.8 Hz), 8.04 (s,
1H), 8.59 (s, 1H), 9.60 (s, 1H). HRESIMS obsd m/z
566.2286, calcd for 566.2291.
N-(3-(3,4-Dimethoxyphenethyl)-4-oxo-6-phenoxy-3,4-dihy-
droquinazolin-7-yl)acetamide 15{3,6,1}. 1H NMR (300 MHz,
DMSO-d6): δ 2.18 (s, 3H), 2.87 (t, 2H, J ) 6.9 Hz), 3.64
(s, 3H), 3.68 (s, 3H), 4.10 (t, 2H, J ) 6.9 Hz), 6.62 (dd, 1H,
J ) 2.1 Hz, 8.1 Hz), 6.75 (d, 1H, J ) 1.8 Hz), 6.81 (d, 1H,
J ) 8.1 Hz), 7.18 (d, 2H, J ) 7.5 Hz), 7.28 (t, 2H, J ) 7.5
Hz), 7.50 (t, 2H, J ) 7.5 Hz), 8.01 (s, 1H), 8.51 (s, 1H),
9.89 (s, 1H). HRESIMS obsd m/z 460.1870, calcd for
460.1872.
N-(3-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-morpholino-4-
oxo-3,4-dihydroquinazolin-7-yl)acrylamide 15{1,5,4}. 1H NMR
(300 MHz, DMSO-d6): δ 2.65 (brs, 4H), 3.83 (brs, 4H), 5.06
(s, 2H), 5.83 (d, 1H, J ) 9.9 Hz), 5.97 (s, 2H), 6.32 (d, 1H,
J ) 16.8 Hz), 6.75 (dd, 1H, J ) 9.9 Hz, J ) 16.8 Hz),6.87
(s, 2H), 6.99 (s, 1H), 7.78 (s, 1H), 8.42 (s, 1H), 8.48 (s,
1H), 9.40 (s, 1H). HRESIMS obsd m/z 435.1670, calcd for
435.1663.
2-(Benzyloxy)-N-(6-methoxy-4-oxo-3-(pyridin-2-ylmethyl)-
1
3,4-dihydroquinazolin-7-yl)acetamide 15{7,4,3}. H NMR
(300 MHz, DMSO-d6): δ 3.94 (s, 3H), 4.24 (s, 2H), 4.67 (s,
2H), 5.28 (s, 2H), 7.26-7.43 (m, 7H), 7.54 (s, 1H), 7.78
(m, 1H), 8.40 (s, 1H), 8.45 (m, 1H), 8.57 (s, 1H), 9.38 (s,
1H). HRESIMS obsd m/z 431.1716, calcd for 431.1719.
N-(3-(3,4-Dimethoxyphenethyl)-6-(3,5-dimethylphenoxy)-
4-oxo-3,4-dihydroquinazolin-7-yl)cinnamamide 15{5,6,5}. 1H
NMR (300 MHz, DMSO-d6): δ 2.36 (s, 6H), 2.88 (t, 2H, J
) 6.9 Hz), 3.65 (s, 3H), 3.69 (s, 3H), 4.12 (t, 2H, J ) 6.9
Hz), 6.64 (d, 1H, J ) 8.1 Hz), 6.80 (m, 4H), 6.94 (s, 1H),
7.30-7.44 (m, 5H), 7.66 (m, 3H), 8.03 (s, 1H), 8.72 (s, 1H),
10.03 (s, 1H). HRESIMS obsd m/z 576.2485, calcd for
576.2498.
N-(6-(4-Fluorophenoxy)-4-oxo-3-(1-phenylethyl)-3,4-dihy-
droquinazolin-7-yl)acrylamide 15{4,3,4}. 1H NMR (300
MHz, DMSO-d6, ppm): δ 1.79 (d, 3H, J ) 7.2 Hz), 5.80
(dd, 1H, J ) 2.1 Hz, 9.9 Hz), 6.01 (q, 1H, J ) 7.5 Hz), 6.36
(dd, 1H, J ) 2.1 Hz, 16.8 Hz), 6.86 (dd, 1H, J ) 9.9 Hz,
16.8 Hz), 7.23-7.35 (m,10H), 8.35 (s, 1H), 8.66 (s, 1H),
10.10 (s, 1H). HRESIMS obsd m/z 430.1567, calcd for
430.1567.
N-(3-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-morpholino-4-
oxo-3,4-dihydroquinazolin-7-yl)cinnamamide 15{1,5,5}. 1H
NMR (300 MHz, DMSO-d6): δ 2.90 (brs, 4H), 3.89 (brs,
4H), 5.06 (s, 2H), 5.98 (s, 2H), 6.85 (m, 2H), 7.00 (s, 1H),
7.25 (d, 1H, J ) 15.6 Hz), 7.46 (m, 3H), 7.64 (d, 1H, J )
15.9 Hz), 7.71-7.73 (m, 2H), 7.81 (s, 1H), 8.49 (s, 1H),
8.56 (s, 1H), 9.37 (s, 1H). HRESIMS obsd m/z 511.1983,
calcd for 511.1981.
2-(Benzyloxy)-N-(4-oxo-6-phenoxy-3-phenyl-3,4-dihydro-
quinazolin-7-yl)acetamide 15{3,7,3}. H NMR (300 MHz,
DMSO-d6, ppm): δ 4.27 (s, 2H), 4.63 (s, 2H), 7.18-7.36
(m, 8H), 7.41 (s, 1H), 7.46-7.56 (m, 7H), 8.29 (s, 1H), 8.71
(s, 1H), 9.65 (s, 1H). HRESIMS obsd m/z 478.1769, calcd
for 478.1767.
1
General Procedure for the Synthesis of 17. Method 1.
Compound 8 (R1 ) BnO) (0.7 g) was dissolved in 4.2 mL

354 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Wu et al.
of anhydrous THF (or DMF) under stirring at room tem-
perature; 0.3-0.7 g of Pd/C (10%) was added, and the
mixture was hydrogenated under the atmospheric pressure
for 3 h. Fifty milliliters of anhydrous THF (or DMF) was
added. Pd/C was removed by filtration. The filtrate was
evaporated to give 17. For N-(6-hydroxy-4-oxo-3-(pyridin-
2-ylmethyl)-3,4-dihydroquinazolin-7-yl)formamide, as an
example compound, 0.46 g of white solid was obtained in
85.8% yield with an HPLC purity >95%. ESI-MS (m/z): 297
[M + H]+. 1H NMR (300 MHz, DMSO-d6): δ 5.24 (s, 2H),
7.27 (m, 1H), 7.34 (d, 1H, J ) 7.8 Hz), 7.47 (s, 1H), 7.77
(m, 1H), 8.31 (s, 1H), 8.45 (m, 2H), 8.52 (s, 1H), 10.00 (s,
1H), 10.88 (brs, 1H).
Method 2. Compound 8 (R1 ) BnO, 0.5 g) was dissolved
in 5 mL of anhydrous THF (or DMF), and 5 mL of
anhydrous ethanol under stirring at room temperature;
0.25-0.5 g of Pd/C (10%) and 2 g of ammonium formate
were added. Stirring was continued for 3 h. Twenty milliliters
of THF (or DMF) was added. Pd/C was removed by
filtration. The filtrate was concentrated to yield crude 17.
Crude 17 was purified on silica gel with the ethyl acetate/
petroleum ether (or methylene chloride/methanol) system as
an eluent. For N-(6-hydroxy- 4-oxo-3-(1-phenylethyl)-3,4-
dihydroqui nazolin-7-yl)formamide, as an example com-
pound, 0.34 g of white solid, was obtained in 88% yield
with an HPLC purity >95%. ESI-MS (m/z): 310 [M + H]+.
1H NMR (300 MHz, DMSO-d6): δ 1.80 (d, 3H, J ) 7.2
Hz), 6.06 (q, 1H, J ) 7.2 Hz), 7.25-7.39 (m, 5H), 7.51 (s,
1H), 8.23 (s, 1H), 8.41 (d, 1H, J ) 1.5 Hz), 8.49 (s, 1H),
10.00 (s, 1H), 10.91 (s, 1H).
7.29-7.38 (m, 5H), 7.74 (s, 1H), 7.90 (s, 1H), 8.75 (brs, 1
H), 8.83 (s, 1H). HRESIMS obsd m/z 449.2183, calcd for
449.2183.
N-(4-Oxo-3-(1-phenylethyl)-6-(2-(piperidin-1-yl)ethoxy)-
3,4-dihydroquinazolin-7-yl)acrylamide 20{3,3}. 1H NMR
(300 MHz, CDCl3): δ 1.61 (brs, 2H), 1.83 (d, 3H, J ) 6.9
Hz), 1.89 (brs, 4H), 2.91 (brs, 4H), 3.22 (brs, 2H), 4.38 (t,
2H, J ) 5.4 Hz), 5.78 (d, 1H, J ) 9.9 Hz), 6.32 (q, 1H, J )
6.9 Hz), 6.48 (d, 1H, J ) 16.8 Hz), 6.93 (m, 1H), 7.37 (m,
5H), 7.67 (s, 1H), 7.90 (s, 1H), 8.87 (s, 1H), 9.49 (brs, 1H).
HRESIMS obsd m/z 447.2391, calcd for 447.2391.
Acknowledgment. This research was financially supported
by the National Natural Science Foundation of China (No.
90713045).
Supporting Information Available. Full NCI GI50 values
for compounds 15{7,4,3}, 15{1,5,4}, 15{4,3,4}, 12{6,3,5},
and 12{5,6,5} and additional experimental details. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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General Procedure for the Synthesis of 18. A solution of
17 (0.113 mmol) in 0.4 mL of anhydrous THF (or DMF)
was stirred at 0 °C. After addition of triphenylphosphine
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1
[M + H]+. H NMR (300 MHz, DMSO-d6): δ 1.39-1.62
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(m, 6H), 1.82 (d, 3H, J ) 7.2 Hz), 2.49 (brs, 4H), 2.81 (brs,
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1

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