Synthesis of new 4(3H)-quinazolinone derivatives by reaction of 3-amino-2(1H)-thioxo-4(3H)-quinazolinone with selected chloroformates: Ammonolysis of 3-ethoxycarbonylamino-2-ethoxycarbonylthio-4(3h)-quinazolinone, part 21

Article abstract of DOI:10.1080/10426500802105233

A series of N- and S-alkylated 4(3H)-quinazolinone derivatives (2-6) have been synthesized by the reaction of 3-amino-2(1H)-thioxo-4(3H)-quinazolinone (1) with selected chloroformates. 3-Ethoxycarbonylamino-2-ethoxycarbonylthio-4(3H)- quinazolinone (3) wa

Full text of DOI:10.1080/10426500802105233

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Phosphorus, Sulfur, and Silicon
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Synthesis of New 4(3H)-
Quinazolinone Derivatives by
Reaction of 3-Amino-2(1H)-
thioxo-4(3H)-quinazolinone
with Selected Chloroformates:
Ammonolysis of 3-
Ethoxycarbonylamino-2-
ethoxycarbonylthio-4(3h)-
quinazolinone, Part 21
Wanda P. Nawrocka a
a Wroclaw Medical University, Wroclaw, Poland
Version of record first published: 03 Feb 2009.
To cite this article: Wanda P. Nawrocka (2009): Synthesis of New 4(3H)-Quinazolinone
Derivatives by Reaction of 3-Amino-2(1H)-thioxo-4(3H)-quinazolinone with Selected
Chloroformates: Ammonolysis of 3-Ethoxycarbonylamino-2-ethoxycarbonylthio-4(3h)-
quinazolinone, Part 21 , Phosphorus, Sulfur, and Silicon and the Related Elements,
184:2, 261-274
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Phosphorus, Sulfur, and Silicon, 184:261–274, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802105233
Synthesis of New 4(3H )-Quinazolinone Derivatives by
Reaction of 3-Amino-2(1H )-thioxo-4(3H )-quinazolinone
with Selected Chloroformates: Ammonolysis of
3-Ethoxycarbonylamino-2-ethoxycarbonylthio-4(3h)-
quinazolinone, Part 21
Wanda P. Nawrocka
Wroclaw Medical University, Wroclaw, Poland
A series of N- and S-alkylated 4(3H)-quinazolinone derivatives (2–6) have
been synthesized by the reaction of 3-amino-2(1H)-thioxo-4(3H)-quinazolinone (1)
with selected chloroformates. 3-Ethoxycarbonylamino-2-ethoxycarbonylthio-4(3H)-
quinazolinone (3) was ammonolysed using ammonia, primary or secondary amines.
Depending on the kind of substrates and conditions of ammonolysis, products of
various chemical structures were obtained. The products %2–17 were identified by
the results of elemental analysis and by their IR, 1H NMR, and mass spectra.
Keywords 3-Amino-2(1H)-thioxo-4(3H)-quinazolinone derivatives; ammonolysis; 2,3-
dialkoxycarbonyl-4(3H)-quinazolinone; IR, 1H NMR; mass spectra; synthesis
INTRODUCTION
Numerous derivatives of 4(3H)-quinazoline exhibiting various biologi-
cal and pharmacological activities have been obtained and studied in
the last few years. They include compounds obtained synthetically and
compounds isolated from natural materials.2–6 4(3H)-Quinazolinones
showing anticancer activity are of special interest.7–9a–c Interest
in this class of compounds increased after introduction of the so-
called thymidylate synthetase inhibitors to therapeutic practice.7,10,11
TomudexTM from Astra Zeneca is used mainly in chemotherapy of col-
orectal cancer,12 and ThymitaqTM from Zarix is used in lung cancer
therapy.13,14 The literature also presents 4(3H)-quinazolinones as hav-
ing other mechanisms of anticancer action; for example, 8-hydroxy-2-
methyl-4(3H)-quinazolinone (Nu 1025) is a PARP enzyme blocker and
Received 26 January 2008; accepted 5 April 2008.
Address correspondence to Wanda P. Nawrocka, Department of Technology of
Drugs, Wroclaw Medical University, 50-140 Wroclaw, Nankier Sq. 1, Poland. E-mail:
paulina@ktl.am.wroc.pl
261

262
W. P. Nawrocka
increases the activity of alkylating drugs.15 In vitro studies showed that
6-chloro-2-ethyl-3-(3-phenylisoxazol-5-yl)-4(3H)-quinazolinone was ac-
tive towards neoplastic cells of human leukemia, human lymphoma,
and Burkitt’s lymphoma.163-Phenyl-6-iodo-4(3H)-quinazolinone was
active towards Ehrich ascites tumor.17 2,2ꢀ-Thiobis[3-amino-4(3H)-
quinazolinone]9a,b exhibited the highest activity in vitro against
melanoma cells. 3-Amino-2-methylthio-4(3H)-quinazolinone showed an
antituberculostatic and antiproliferative activity in vitro towards hu-
man neoplastic cells CCRF/CEM (leukemia), SW707 (colorectal cancer),
and Du145 (prostate cancer).9c In our latest article, we described the
synthesis of new derivatives by the reaction of 3-amino-2(1H)-thioxo-
4(3H)-quinazolinone (1) with selected substituted cinnamic acids and
with halogenoketones.[1] The aim of this study was to synthesize new
derivatives of 4(3H)-quinazolinone 1 by reaction with selected chloro-
formates. The presence of two chemically active groups, 3-amino and
2-thiocarbonyl, in the molecule of 4(3H)-quinazolinone 1, allows us to
obtain products of various chemical structures: S−, N−, S−, and N−
substituted or tricyclic products derived from 3H-1,3,4-thiadiazol[2,3-
b]quinazolin-2,5-dione. In the case of the substituted products obtained,
their behavior towards nitrogen nucleophilic agents, such as ammonia
and primary and secondary amines, was tested.
In our previous studies, we found that the presence of alkoxycar-
bonyl groups in 1,5-benzodiazepines is usually connected with high
psychotropic activity.18 The presence of such groups in pyrido[2,3-b]-
[1,4]diazepine results in high antiproliferative activity in vitro against
human neoplastic cells HL-60 (leukemia) and HCV29T (urinary blad-
der cancer) when cis-platinum is used as a reference.19
RESULTS AND DISCUSSION
3-Amino-2(1H)-thioxo-4(3H)-quinazolinone20 (1) was added to selected
chloroformates in a stoichiometric ratio. The reactions were carried
out in boiling toluene in the presence of triethylamine (Scheme 1).
Thin-layer chromatography (TLC) confirmed the presence of unreacted
substrate—4(3H)-quinazolinone20 1—in the solution, and the reaction
products were obtained in the form of a precipitate. Prolonged heating
did not cause any significant increase in the quantity of the products.
The precipitate was collected by filtration and analyzed after recrystal-
lization from ethanol. The results of elemental analysis and the mass
spectra confirmed the formation of disubstituted derivatives. The reac-
tions were repeated using 2.2-fold excess of the chlorofomates, giving
the derivatives 2–6 with adequately higher yield. The same products

Synthesis of New 4(3H)-Quinazolinone Derivatives
263
SCHEME 1

264
W. P. Nawrocka
2–6 were obtained with similar yields, when the reactions were carried
out using the sodium salt of 4(3H)-quinazolinone20 1a in anhydrous
boiling tetrahydrofurane with a 2.2-fold excess of the respective chlo-
roformate.
Peaks of the molecular ions are present in the mass spectra of the
products 2–5, but they are not the base ions. In the mass spectrum of
compound 6 there is no molecular ion peak, while a fragment ion peak
is observed indicating the elimination of the benzyloxycarbonyl group.
In the case of compounds 2 and 3, the base ions are the quinazolinone
cations, m/z = 146 (100), and in the case of compounds 4–6 the base
ions are the cations propyl (m/z = 43), isobutyl (m/z = 57), and benzyl
(m/z = 91), respectively. The further fragmentation of the compounds
2–6 is typical for 4(3H)-quinazolinones.21 As a result, the cyclopropenyl
ion m/z = 39 is present in the spectra, formed as the final product of
the degradation of both aliphatic substituents and phenyl rings.
A single band at ∼ 3340 cm−1 was observed in the IR spectra of
compounds 2–6, and it was attributed to the stretching vibration of
N-H belonging to the NHCO groups. In the region of 1760–1732 cm−1
,
there are two absorption bands corresponding to the stretching vibra-
tion of C O groups. Bands present in the region of ∼ 1760 cm−1 were
attributed to C O groups belonging to SCOOR moieties, and bands
present at lower wave numbers ∼ 1740 cm−1 were attributed to C O
groups of NHCOOR fragments.
Interpretation of the 1H NMR spectra of compounds 2–6 is based on
1
the comparison with the H NMR spectrum of 3-amino-2(1H)-thioxo-
4(3H)-quinazolinone (1). The most characteristic features for compound
1 are the chemical shifts of the protons in the NH2 and NH-C=S groups.
They are present as two- and one-proton singlets at δ ∼ 6.30 ppm and
δ ∼ 14.50 ppm, respectively. Signals of these protons are absent in
1
the H NMR spectra of the synthesized compounds 2–6. The lack of
signals for the NHC S proton indicates that substitution took place
also at the position 2. However, the presence of one-proton singlet at
δ ∼ 9.50 ppm was observed for the compounds 2–5, and in the case
of the benzyl derivative 6, this signal was observed at δ ∼ 10.16 ppm.
The signals were attributed to the NH proton of the NHCO group,
present in the 3 position. Signals of the protons of the substituent
connected with heteroatoms at positions 2 and 3 are clearly separated,
and, therefore, can be identified. At lower δ values (shielding effect), the
1H NMR signals of the alkoxy and benzyloxycarbonyl groups connected
with nitrogen are observed, while the signals of groups attached to
the sulphur atom appear at higher δ values (deshielding effect). For
example, in the case of the compound 2, the signals of the protons in

Synthesis of New 4(3H)-Quinazolinone Derivatives
265
the methoxy groups NHCOOCH3 and SCOOCH3 appear at δ= 3.69
ppm and at δ= 4.02 ppm, respectively. Signals present in the range of
δ 7.13–8.24 ppm confirm the presence of aromatic protons, and their
number is consistent with the structures 2–6.
The reactivity of 3-ethoxycarbonylamino-2-ethoxycarbonylthio-
4(3H)-quinazolinone (3) towards an excess (2.2 mol) of a concentrated
aqueous solution of ammonia, as well as towards primary and sec-
ondary amines under various conditions, was studied (Scheme 1).
The reactions yielded tricyclic products derived from quinazolin[2,3-
b][1,3,5,6]-thiatriazepin-2,4,7-trione, by ammonolysis at the position 2
or 3 or simultaneously at both positions 2 and 3. A long-lasting (1 week)
reaction of compound 3 with concentrated aq. ammonia solution at
room temperature resulted in the formation of 3-ethoxycarbonylamino-
2-aminocarbonylthio-4(3H)-quinazolinone (7) (Scheme 1). Only the
ethoxy group at position 2 underwent ammonolysis. In the IR spec-
trum of the compound 7, there is no band of a carbonyl group at ∼
1752 cm−1 indicating the presence of a –SCONH2 moiety, while the
band of the second C O group, originating from –NHCOOR, at ∼ 1738
cm−1 remained. The 1H NMR spectrum provides good evidence for the
product 7. The spectrum contains the proton signals of a single ethyl
group, and their chemical shifts at δ= 1.25 ppm (t, 3H) and δ= 4.15 ppm
(q, 2H) confirm that they belong to a substituent NHCOOCH2CH3 at
position 3.
Heating compound 3 with benzylamine or morpholine in ethanol
yielded compounds 10 and 11, while heating boiling 3 in toluene with
an excess of benzylamine for 5 h gave 3-ethoxycarbonylamino-2(1H)-
thioxo-4(3H)-quinazolinone (9)—a product of dealkylation at position 2.
Long-term heating of the substrates led also to dealkylation at position
3, yielding 3-amino-2(1H)-thioxo-4(3H)-quinazolinone20 (1). In a sim-
ilar, long-term reaction of compound 3 with morpholine, compound 8
was obtained—a product of dealkylation at position 2 and ammonolysis
at position 3.
3-Ethoxycarbonylamino-2-ethoxycarbonylthio-4(3H)-quinazolinone
(3) was also ammonolysed with selected primary amines ethylamine,
p-methoxyaniline, and aminomorpholine, as well as with secondary
amines diisopropylamine, piperidine, and 4-methylpiperazine, in
boiling ethanol (Scheme 2). Products of these reactions were the
derivatives 12–17 having structures analogous to those of the
ammonolysis products 10 and 11 obtained with benzylamine or
morpholine in ethanol.
The same type of fragmentation and elimination is observed in the
mass spectra of compounds 7, 10–17; molecular ions are not present.

266
W. P. Nawrocka
SCHEME 2
The ion with the highest mass observed is a fragment ion with m/z
= 265 [3-ethoxycarbonylamino-2(1H)-thioxo-4(3H)-quinazolinone]. It is
formed from the parent molecules by elimination of carbamoyl groups
of the substituent at position 2. Base ions for the majority of the com-
pounds are quinazolinone ions with m/z = 146 (100), and for the com-
pound 11 the morpholine ion with m/z = 87.
Depending on the kind of substrates and conditions of ammonolysis
of compound 3, products of various chemical structure were obtained,
which are of interest for biological studies or which can be substrates
for further syntheses.
EXPERIMENTAL
Melting points (uncorrected) were measured with a Boethius melting
point apparatus. Analyses were performed with a Perkin Elmer 2400

Synthesis of New 4(3H)-Quinazolinone Derivatives
267
analyzer, and satisfactory results within 0.4% of the calculated values
were obtained for all new compounds. IR spectra (in KBr) were recorded
with an IR 75 spectrophotometer. 1H NMR spectra were obtained with a
Bruker AVANCE DRX 300 and AVANCE 500 instrument using DMSO-
d6 as solvent at room temperature, and chemical shifts are referred to
the residual solvent signal at δ 2.50 ppm. Mass spectra were obtained
with a GCMS–LK 82091 spectrometer at ionization energy of 15 or 70
eV. The course of the reactions and the purity of the products were
checked by TLC (Kieselgel G, Merck) in diethyl ether:ethanol = 5:1 as
eluent.
3-Amino-2(1H)-thioxo-4(3H)-quinazolinone (1)
The compounds 1 and 1a were prepared exactly as described
previously.20
General Procedure for the Synthesis of Compounds 2–6
To a mixture of compound 1 (1.93 g, 0.01 mol) and NEt3 (3 mL) in
anhydrous toluene (50 mL), methyl (2), ethyl (3), propyl (4), isobutyl
(5), or benzyl (6) chloroformate (0.022 mol) was added dropwise with
mechanical stirring. The mixture was refluxed for 10–15 h (TLC). The
product was filtered off, washed with Et2O (20 mL), 5% aq. NaHCO3
solution (10 mL) and water (50 mL), dried and recrystallized from
ethanol. The compounds 2–6 were obtained with similar yields from
the reaction of the sodium salt 1a with the respective chloroformate in
boiling THF.
3-Methoxycarbonylamino-2-methoxycarbonylthio-4(3H)-
quinazolinone (2)
Yield: 2.00 g (65%); white solid; m.p. 183–185◦C. IR (KBr): ν (cm−1)=
3340 (NHCO), 2960 (CH3), 1756 (S-COOR), 1732 (NHCOOR), 1620
1
(NHCO), 1548 ( NH, C N), 1480 (C N ring), 770 (arom.). H NMR
(DMSO-d6, 300 MHz): δ = 3.69 (s, 3H), 4.02 (s, 3H), 7.29 (m, 1H), 7.65
(t, J ∼ 8.1 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H),
9.50 (s, 1H). MS (70 eV) m/z = 311 (3), 310 (6), 309 (61), 217 (17), 193
(39), 178 (27), 147 (12), 146 (100), 91 (7), 90 (28), 59 (31), 39 (4). Analysis
for C12H11N3O5S (309.30): Calcd. C, 46.60; H, 3.58; N, 13.59%. Found:
C, 46.66; H, 3.49; N, 13.70%.

268
W. P. Nawrocka
3-Ethoxycarbonylamino-2-ethoxycarbonylthio-4(3H)-
quinazolinone (3)
Yield: 2.32 g (69%); white solid; m.p. 175–178◦C. IR (KBr): ν (cm−1)=
3336 (NHCO), 2984 (CH3), 2912 (-CH2-), 1752 (S-COOR), 1734
(NHCOOR), 1658 (NHCO), 1446 (-CH2-), 775 (arom.). 1H NMR (DMSO-
d6, 300 MHz): δ = 1.25 (t, J = 5.8 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H), 4.14
(q, J = 5.8 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 7.13 (m, 1H), 7.65 (m, 1H),
7.77 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H ), 9.57 (s, 1H). MS (70
eV) m/z = 339 (3), 338 (7), 337 (35), 293 (9), 147 (18), 146 (100), 145
(7), 120 (22), 119 (16), 92 (10), 91 (8), 90 (22), 77 (8), 69 (24), 44 (22),
43 (18), 39 (8). Analysis for C14H15N3O5S (337.35): Calcd. C, 49.85; H,
4.48; N, 12.46. Found: C, 49.93; H, 4.46; N, 12.23%.
3-Propyloxycarbonylamino-2-propyloxycarbonylthio-4(3H)-
quinazolinone (4)
Yield: 2.00 g (55%); white solid; m.p.132–133◦C. IR (KBr): ν (cm−1)=
3336 (NHCO), 2964 (CH3), 2912 (-CH2-), 1752 (S-COOR), 1738
(NHCOOR), 1620 (NHCO), 1542 (N H and C N), 1448 (-CH2-), 760
(arom.). 1H NMR (DMSO-d6, 300 MHz): δ= 0.92 (t, J= 5.9 Hz, 3H), 1.01
(t, J= 6.2 Hz, 3H), 1.64 (m, 2H), 1.75 (m, 2H), 4.06 (t, J= 6.8 Hz, 2H),
4.36 (m, 2H), 7.29 (t, J ∼ 7.7 Hz, 1H), 7.65 (m, 1H), 7.87 (d, J= 7.9 Hz,
1H), 7.94 (d, J= 8.3 Hz, 1H), 9.49 (s, 1H). MS (70 eV) m/z = 367 (2),
366 (4), 365 (21), 281 (2), 280 (3), 279 (15), 220 (4), 206 (18), 164 (45),
146 (75), 120 (12), 66 (12), 57 (26), 55 (22), 43 (100), 39 (10). Analysis
for C16H19N3O5S (365.40): Calcd. C, 52.59; H, 5.24; N, 11.50. Found: C,
52.50; H, 5.29, N, 11.70%.
3-Isobutyloxycarbonylamino-2-isobutyloxycarbonylthio-4(3H)-
quinazolinone (5)
Yield: 1.90 g (48%); white solid; 129–133 ◦C. IR (KBr): ν (cm−1)=
3332 (NHCO), 3052 (CH), 2960 (CH3), 2888 (CH), 1756 (S-COOR),
1740 (NHCOOR), 1620 (NHCO), 1612 (ring), 1536 (N H, C N), 1168
(C(CH3)2), 760 (arom.). 1H NMR (DMSO-d6, 300 MHz): δ= 0.92 (d, J =
6.5 Hz, 6H), 1.00 (d, J= 6.7 Hz, 6H), 1.90 (m, 1H), 2.07 (m, 1H), 3.89
(d, J= 6.4 Hz, 2H), 4.22 (d, J= 6.7 Hz, 2H), 7.28 (m, 1H), 7.64 (m, 1H),
7.78 (d, J= 7.9 Hz, 1H), 8.11 (d, J= 8.1 Hz, 1H), 9.47 (s, 1H). MS (70
eV) m/z = 395 (1), 394 (2), 393 (11), 293 (10), 228 (5), 227 (18), 194 (4),
193 (19), 177 (16), 165 (5), 164 (74), 146 (74), 145(2), 91 (2), 90 (6), 57

Synthesis of New 4(3H)-Quinazolinone Derivatives
269
(100), 56 (4), 41 (57), 39 (6). Analysis for C18H23N3O5S (393.46): Calcd.
C, 54.95; H, 5.89; N, 10.69. Found: C, 54.63; H, 5.68; N, 10.49%.
3-Benzyloxycarbonylamino-2-benzyloxycarbonylthio-4(3H)-
quinazolinone (6)
◦
Yield: 2.80 g (61%); white solid; m.p. 89–93 C. IR (KBr): ν (cm−1)=
3340 (NHCO), 3030 (CH), 1750 (S-COOR), 1732 (NHCOOR), 1656, 1552
1
(N H, C N), 1484 (-CH2-), 1424 (N C S N), 772 (arom.). H NMR
(DMSO-d6, 300 MHz): δ= 4.58 (s, 2H), 5.20 (s, 2H), 7.35 (m, 11H), 7.59
(m, 1H), 7.84 (d, J= 7.5 Hz, 1H), 8.24 (d, J= 8.4 Hz, 1H), 10.16 (s, 1H).
MS (70 eV) m/z = 326 (3), 266 (2), 194 (2), 193 (8), 147 (10), 146 (9),
132 (8), 120 (7), 92 (17), 91 (100), 77 (6), 65 (14), 57 (4), 39 (7). Analysis
for C24H19N3O5S (461.49): Calcd. C, 62.46; H, 4.15; N, 9.11. Found: C,
62.80; H, 4.17; N, 9.23%.
General Procedure for the Synthesis of Compounds 7–17
To compound 3 (3.37 g, 0.01 mol) in ethanol (50 mL) the following
reactants were added:
r
25% aq. ammonia (0.022 mol), and the reaction mixture was left at
room temperature for 1 week (7).
Primary amines: benzylamine (10), ethylamine (12), 4-
aminomorpholine (13), 4-methoxyaniline (14), or secondary
amines: morpholine (11), piperidine (15), diisopropylamine (16),
4-methylpiperazine (17), and the reaction mixture was refluxed for
ca. 10 h (TLC).
r
To compound 3 in toluene (50 mL), benzylamine (0.022 mol) or mor-
pholine (0.022 mol) was added, and the reaction mixture was refluxed
for 5 h (9)–15 h (8, 1).
At the end of the reaction, the solvent was partially evaporated un-
der reduced pressure. The residue was left for crystallization, and the
precipitate was filtered, washed with Et2O (10 mL), and recrystallized
from ethanol.
3-Ethoxycarbonylamino-2-carbamoylthio-4(3H)-
quinazolinone (7)
Yield: 1.37 g (45%); white solid; m.p. 200–202◦C. IR (KBr): ν (cm−1)=
3388, 3348 (CONH2), 3124 (NHCO), 2952 (CH3), 1738 (NHCOOR), 1700

270
W. P. Nawrocka
(SCONH2), 1642 (CON=, CONH2), 1570 (C N, N H), 1470 (-CH2-), 770
(arom.). 1H NMR (DMSO-d6, 300 MHz): δ= 1.25 (t, J= 5.8 Hz, 3H), 4.15
(q, J= 5.8 Hz, 2H), 7.18 (m, 3H), 7.49 (m, 1H), 7.73 (d, J= 6.9 Hz, 1H),
8.16 (d, J= 8.3 Hz, 1H), 10.20 (s, 1H). MS (70 eV) m/z = 265 (61), 220
(3), 205 (10), 147 (7), 146 (100), 120 (9), 92 (7), 91 (5), 90 (10), 77 (8), 65
(3), 39 (2). Analysis for C12H12N4O4S (308.31): Calcd. C, 46.75; H, 3.92;
N, 18.17. Found: C, 46.63; H, 4.07; N, 18.43%.
3-Morpholinocarbonylamino-2(1H)-thioxo-4(3H)-
quinazolinone (8)
Yield: 2.39 g (78%); white solid; m.p. 287–289◦C. IR (KBr): ν (cm−1)=
3308 (NHCO), 3076 (CH), 1680 (NHCON), 1620 (=NCO), 1528 (C N,
NH), 1476 (CH2), 768 (arom.). 1H NMR (DMSO-d6, 300 MHz): δ= 3.69
(m, 4H), 3.89 (m, 4H), 7.24 (m, 2H), 7.71 (t, J= 7.6 Hz, 1H), 7.94 (d,
J= 7.8 Hz, 1H), 12.14 (br, 2H). MS (70 eV) m/z = 307 (1), 306 (7), 163
(31), 162 (100), 146 (29), 145 (6), 144 (22), 130 (17), 119 (98), 92 (42), 91
(11), 86 (69), 57 (20), 56 (12), 39 (8). Analysis for C13H14N4O3S (306.34):
Calcd. C, 50.97; H, 4.61; N, 18.29. Found: C, 50.72; H, 4.39; N, 18.27%.
3-Ethoxycarbonylamino-2(1H)-thioxo-4(3H)-quinazolinone (9)
Yield: 0.95 g (36%); white solid; m.p. 193–195 ◦C. IR (KBr): ν (cm−1)=
3280 (NHCO), 3060 (CH), 2900 (CH2), 1740 (NHCOOR), 1660 (NHCO),
1450 (-CH2-), 1350 (N CS N), 1200 (NH CS), 760 (arom.), 708 (C S).
1H NMR (DMSO-d6, 300 MHz): δ= 1.24 (t, J= 5.9 Hz, 3H), 4.14 (q, J=
5.9 Hz, 2H), 7.26 (m, 1H), 7.59 (t, J= 7.7 Hz, 1H), 7.76 (d, J= 7.9 Hz,
1H), 7.98 (d, J= 8.4 Hz, 1H), 9.45 (s, 1H), 12.79 (s, 1H). MS (70 eV) m/z
= 267 (3), 266 (7), 265 (73), 220 (6), 193 (12), 146 (100), 120 (12), 118
(12), 107 (28), 106 (55), 91 (34), 90 (14), 77 (20), 57 (12), 44 (9), 39 (11).
Analysis for C11H11N3O3S (265.29): Calcd. C, 49.80; H, 4.18; N, 15.84.
Found: C, 49.63; H, 4.39; N, 15.97%.
3-Ethoxycarbonylamino-2-benzylcarbamoylthio-4(3H)-
quinazolinone (10)
Yield: 3.10 g (79%); white solid; m.p. 167–171 ◦C. IR (KBr): ν (cm−1)=
3240 (NHCO), 2976 (CH3), 1730 (NHCOOR), 1658 (NHCO), 1620
(=NCO), 1570 (-NH, C-N), 1476 (-CH2-), 758 (arom.). 1H NMR (DMSO-
d6, 500 MHz): δ= 1.27 (t, J= 5.8 Hz, 3H), 4.05 (d, J= 5.4 Hz, 2H), 4.18
(q, J= 5.8 Hz, 2H), 7.13 (m, 2H), 7.41 (m, 5H), 7.70 (d, J= 8.1 Hz, 1H),
8.15 (br, 1H), 8.33 (d, J= 8.4 Hz, 1H), 10.89 (s, 1H). MS (70 eV) m/z =
267 (3), 266 (3), 265 (62), 220 (4), 205 (13), 147 (7), 146 (100), 145 (3),
104 (10), 91 (12), 77 (11), 39 (6). Analysis for C19H18N3O4S (384.43):
Calcd. C, 59.36; H, 4.72; N, 10.93. Found: C, 58.98; H, 4.77; N, 10.60%.

Synthesis of New 4(3H)-Quinazolinone Derivatives
271
3-Ethoxycarbonylamino-2-morpholinocarbonylthio-4(3H)-
quinazolinone (11)
Yield: 2.20 g (58%); white solid; m.p. 170–173◦C. IR (KBr): ν
(cm−1)= 3255 (NHCO), 2980 (CH2), 2880 (CH3), 2730 (=NCH2), 1730
(NHCOOEt), 1615 (=NCO), 1560 (C=N), 1540 (C O ), 1470 (=N CH2,
CH), 775 (arom.). 1H NMR (DMSO-d6, 500 MHz): δ= 1.27 (t, J= 5.9 Hz,
3H), 3.13 (m, 4H), 3.77 (m, 4H), 4.18 (q, J= 5.9 Hz, 2H), 7.14 (m, 1H),
7.42 (m, 1H), 7.71 (d, J= 7.8 Hz, 1H), 8.32 (d, J= 8.4 Hz, 1H), 10.88 (s,
1H). MS (70 eV): m/z = 267 (4), 266 (8), 265 (59), 146 (62), 119 (11), 118
(11), 91 (6), 90 (9), 87 (100), 86 (59), 57 (84), 56 (75), 39 (8). Analysis
for C16H18N4O5S (378.40): Calcd. C, 50.79; H, 4.79; N, 14.81. Found: C,
50.93; H, 5.11; N, 14.70%.
3-Ethoxycarbonylamino-2-ethoxycarbamoylthio-4(3H)-
quinazolinone (12)
Yield: 1.78 g (53%); white solid; m.p. 146–150◦C with benzene.
IR (KBr): ν (cm−1)= 3400 (NHCO), 2984 (CH3), 2845 (CH2), 1740
(NHCOOR), 1700, 1658 (NHCO), 1570 (C N, NH), 1464 (-CH2-), 760
1
(arom.). H NMR (300 MHz, DMSO-d6,): δ= 1.23 (t, J= 5.9 Hz, 3H),
1.27 (t, J= 5.7 Hz, 3H), 2.84 (q, J= 5.9 Hz, 2H), 4.18 (q, J= 5.7 Hz,
2H), 7.13 (m, 1H), 7.42 (m, 1H), 7.71 (d, J= 7.9 Hz, 1H), 7.79 (br,
1H), 8.32 (d, J= 8.3, 1H), 10.89 (s, 1H). MS (70 eV) m/z = 267 (2), 266
(5), 265 (43), 220 (3), 219 (13), 148 (4), 147 (5), 146 (85), 107 (100), 106
(99), 104 (10), 91 (21), 90 (12), 79 (57), 78 (18), 77 (30), 76(5), 51(20),
39 (13). Analysis for C14H16N4O4S (336.37): Calcd. C, 49.99; H, 4.79; N,
16.66. Found: C, 49.73; H, 4.92; N, 16.63%.
3-Ethoxycarbonylamino-2-morpholincarbamoylthio-4(3H)-
quinazolinone (13)
Yield: 2.60 g (66%); white solid; m.p. 159–163◦C. IR (KBr): ν (cm−1)=
3248 (NHCO), 2980 (CH3), 2852 (-CH2-), 1732 (NHCOOR), 1656
(NH CO NH), 1636 (NHCO), 1570 (C N ring), 1470 (-CH2-), 756
1
(arom.). H NMR (DMSO-d6, 300 MHz): δ= 1.26 (t, J= 5.7 Hz, 3H),
3.13 (m, 4H), 3.76 (m, 4H), 4.16 (q, J= 5.7 Hz, 2H), 7.14 (m, 1H), 7.43
(t, J= 7.9 Hz, 1H), 7.79 (d, J= 7.8 Hz, 1H), 8.32 (d, J= 8.4 Hz, 1H), 8.77
(s, 1H), 10.81 (s, 1H). MS (70 eV) m/z = 266 (4), 265 (33), 220 (4), 219
(23), 177 (5), 163 (4), 162 (36), 147 (8), 146 (100), 120 (12), 119 (40), 92
(23), 91 (11), 90 (18), 87 (23), 86 (9), 77 (10), 76 (16), 39 (10). Analysis
for C16H19N5O5S (393.42): Calcd. C, 48.84; H, 4.89; N, 17.80. Found: C,
48.89; H, 4.62%; N, 17.98%.

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W. P. Nawrocka
3-Ethoxycarbonylamino-2-(p-
methoxyphenylene)carbamoylthio-4(3H)-quinazolinone (14)
Yield: 1.41 g (34%); white solid; m.p. 155–159◦C. IR (KBr): ν (cm−1)=
3256 (NHCO), 2880 (Ar OCH3), 1738 (NHCOOR), 1656 (NHCO), 1616
(C N ring), 768 (arom.). 1H NMR (DMSO-d6, 300 MHz): δ= 1.27 (t, J=
5.8 Hz, 3H), 3.75 (s, 3H), 4.18 (q, J= 5.8 Hz, 2H), 6.97 (d, J= 8.5 Hz,
2H), 7.13 (t, J= 7.7 Hz, 1H), 7.45 (m, 3H), 7.71 (d, J= 7.7 Hz, 1H), 8.03
(br, 1H), 8.74 (d, J= 8.4 Hz, 1H), 10.89 (s, 1H). MS (70 eV) m/z = 267 (2),
266 (6), 265 (54), 192 (2), 146 (82), 138 (7), 137 (100), 136 (99), 122 (11),
121 (87), 120 (21), 109 (42), 108 (12), 106 (56), 94 (24), 93 (14), 92 (10),
91 (14), 90 (11), 65 (14), 39 (18). Analysis for C19H18N4O5S (414.44):
Calcd. C, 55.06; H, 4.38; N, 13.52. Found: C, 55.41; H, 4.73; N, 13.80%.
3-Ethoxycarbonylamino-2-piperidinocarbonylthio-4(3H)-
quinazolinone (15)
Yield: 2.69 g (63%); white solid; m.p. 130–135◦C. IR (KBr): ν (cm−1)=
3248 (NHCO), 2956 (CH3), 2880 (CH2), 1738 (NHCOOR), 1656 (NHCO),
1602 (C=N ring), 1570 (C-N, NH), 1480 (-CH2-), 756 (arom.). 1H NMR
(DMSO-d6, 500 MHz): δ= 1.27 (t, J= 5.8 Hz, 3H), 1.62 (m, 6H), 3.02 (m,
4H), 4.18 (q, J= 5.8 Hz, 2H), 7.13 (m, 1H), 7.42 (m, 1H), 7.70 (d, J= 7.9
Hz, 1H), 8.33 (d, J= 8.4 Hz, 1H), 10.89 (s, 1H). MS (70 eV) m/z = 267
(3), 266 (7), 265 (57), 205 (13), 193 (5), 162 (4), 147 (7), 146 (100), 145
(4), 120 (11), 119 (8), 118 (10), 104 (6), 91 (13), 77 (11), 39 (11). Analysis
for C17H20N4O4S (376.43): Calcd. C, 54.24; H, 5.36; N, 14.88. Found: C,
54.26; H, 5.39; N, 14.97%.
3-Ethoxycarbonylamino-2-diisopropylcarbamoylthio-4(3H)-
quinazolinone (16)
Yield: 1.70 g (43%); white solid; m.p. 161–165 ◦C. IR (KBr): ν (cm−1)=
3240 (NHCO), 2984 (CH3), 2844 (CH2), 1730 (NHCOOR), 1656 (NHCO),
1600 (C N ring), 1570 (C N, N H), 1474 (-CH2-), 758 (arom.). 1H NMR
(DMSO-d6, 500 MHz): δ = 1.20 (d, J = 6.5 Hz, 12H), 1.27 (t, J = 5.9 Hz,
3H), 3.36 (m, 2H), 4.18 (q, J = 5.9 Hz, 2H), 7.14 (m, 1H), 7.42 (m, 1H),
7.70 (d, J = 7.2 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 10.89 (s, 1H). MS (70
eV): m/z = 267 (3), 266 (7), 265 (64), 220 (3), 205 (14), 193 (4), 192 (3),
146 (100), 120 (10), 104 (12), 91 (5), 39 (6). Analysis for C18H24N4O4S
(392.47): Calcd. C, 55.09; H, 6.16; N, 14.28. Found: C, 55.38; H, 6.43; N,
14.26%.

Synthesis of New 4(3H)-Quinazolinone Derivatives
273
3-Ethoxycarbonylamino-2-(4-methylpiperazinyl)carbonylthio-
4(3H)-quinazolinone (17)
Yield: 2.00 g (51%); cream solid; m.p. 173–176 ◦C. IR (KBr): ν (cm−1)=
3252 (NHCO), 2976 (CH3), 2880 (CH2), 1736 (NHCOOR), 1656 (CON),
1616 (C N ring), 1570 ( NH, C N), 1480 (-CH2-), 756 (arom.). 1H NMR
(DMSO-d6, 500 MHz): δ = 1.27 (t, J = 5.9 Hz, 3H), 2.21 (s, 3H), 2.50
(m, 4H), 3.06 (m, 4H), 4.18 (q, J= 5.9 Hz, 2H), 7.14 (m, 1H), 7.42 (m,
1H), 7.71 (d, J = 7.9 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 10,87 (s, 1H). MS
(70 eV) m/z = 267 (3), 266 (7), 265 (65), 205 (12), 165 (1), 147 (7), 146
(100), 104 (9), 100 (23), 91 (5), 90 (13), 77 (10), 58 (9), 51 (6), 44 (11), 43
(30), 42 (19), 41 (4), 39 (6). Analysis for C17H21N5O4S (391.44): Calcd.
C, 52.16; H, 5.41; N, 17.89. Found: C, 52.24; H, 5.33%; N, 17.72%.
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