Synthesis of novel 3-amino-2-(1H)-thioxo-4(3H)-quinazolinone derivatives. Part 3

Article abstract of DOI:10.1080/10426507.2011.582055

The synthesis of novel derivatives containing the quinazolinone-4 moiety is described. 3-Amino-2(1H)-tioxo-4(3H)-quinazolinone (1) forms a sodium salt 2, which was subjected to reaction with dicarboxylic acid chlorides such as chloroformyl ethyl formate and malonyl chloride, leading to the corresponding ester 3 and acid 4, respectively. 3-Amino-2-ethoxycarbonylmethylthio-4(3H)- quinazolinone (5) was acylated or ammonolyzed and products of various chemical structure were obtained. The chemical structures 3, 4, 6-12, and 14-18 were identified by the results of elemental analysis and their IR, ¹H NMR, and mass spectra. Copyright Taylor and Francis Group, LLC.

Full text of DOI:10.1080/10426507.2011.582055

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Synthesis of Novel 3-Amino-2-(1H)-
Thioxo-4(3H)-Quinazolinone Derivatives.
Part 3
Wanda Nawrocka a , Anna Wojcicka a & Anna Nowicka a
a Department of Drugs Technology , Wroclaw Medical University ,
Wroclaw , Poland
Published online: 06 Dec 2011.
To cite this article: Wanda Nawrocka , Anna Wojcicka & Anna Nowicka (2012) Synthesis of Novel 3-
Amino-2-(1H)-Thioxo-4(3H)-Quinazolinone Derivatives. Part 3 , Phosphorus, Sulfur, and Silicon and the
Related Elements, 187:1, 79-87, DOI: 10.1080/10426507.2011.582055
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Phosphorus, Sulfur, and Silicon, 187:79–87, 2012
Copyright ꢀC 2011 Wroclaw Medical University
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.582055
SYNTHESIS OF NOVEL 3-AMINO-
2-(1H)-THIOXO-4(3H)-QUINAZOLINONE
DERIVATIVES. PART 3
Wanda Nawrocka, Anna Wojcicka, and Anna Nowicka
Department of Drugs Technology, Wroclaw Medical University, Wroclaw, Poland
GRAPHICAL ABSTRACT
Abstract The synthesis of novel derivatives containing the quinazolinone-4 moiety is de-
scribed. 3-Amino-2(1H)-tioxo-4(3H)-quinazolinone (1) forms a sodium salt 2, which was sub-
jected to reaction with dicarboxylic acid chlorides such as chloroformyl ethyl formate and
malonyl chloride, leading to the corresponding ester 3 and acid 4, respectively. 3-Amino-2-
ethoxycarbonylmethylthio-4(3H)-quinazolinone (5) was acylated or ammonolyzed and prod-
ucts of various chemical structure were obtained. The chemical structures 3, 4, 6–12, and
14–18 were identified by the results of elemental analysis and their IR, 1H NMR, and mass
spectra.
Keywords Acylation; ammonolysis; 3-amino-2(1H)-thioxo-4(3H)-quinazolinone; 3-amino-
2-ethoxy-carbo-nylmethylthio-4(3H)-quinazolinone derivatives; synthesis
INTRODUCTION
Quinazolinone-4 derivatives have been found to be biologically and pharmacolog-
ically versatile compounds, having antimalarial, hypnotic, anticonvulsant, antitubercular,
Received 27 December 2010; accepted 12 April 2011.
Address correspondence to Wanda P. Nawrocka, Department of Drugs Technology, Wroclaw Medical
University, Nankiera 1 Sq, 50-140 Wroclaw, Poland. E-mail: paulina@ktl.am.wroc.pl
79

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W. NAWROCKA ET AL.
bronchodilator, immunotropic, anticancer, anti-inflammatory, analgesic and COX-2 in-
hibitor, and other diverse activities.1–10 In our review papers, we have described the syn-
theses of various bioactive derivatives of quinazolinone-4,11 of quinazolinone-4 derivatives
occurring in alkaloids and fungi,12 as well as of quinazolinone-4 derivatives showing an-
tibacterial13 and anticancer activity, together with novel mechanisms of action and strategies
for their discovering.14 3-Amino-2(1H)-thioxo-4(3H)-quinazolinone (1)15 is a universal
substrate for syntheses of quinazolinone-4 derivatives. The reaction of 3-amino-2(1H)-
thioxo-4(3H)-quinazolinone (1) with carbonyl compounds,9 acetic acid derivatives,15
cyanogen bromide,16 halogenocinnamic acids, and halogenoketones,17 as well as with
selected chloroformates18 has been described previously. The substituted derivatives or tri-
cyclic compounds thus prepared show in vitro high antiproliferative,19,20 antitubercular,19,20
and immunotropic9 activity. This study is a continuation of our previous investigations with
the aim to synthesize new derivatives of 3-amino-2(1H)-thioxo-4(3H)-quinazolinone (1) for
biological testing. The new compounds were obtained from the reactions of quinazolinone
1 with dicarboxylic acid chlorides, and also by modification of the chemical structure of
previously obtained 3-amino-2-ethoxycarbonylmethylthio-4(3H)-quinazolinone (5). The
presence of oxalyl ( COCO ) or malonyl ( COCH2CO ) groups in heterocyclic com-
pounds belonging to various chemical families is known to be related to psychotropic,
antiaggregation, anti-inflammatory, anti-HIV, and antiproliferative activity of these com-
pounds.21–26 It is reasonable to assume that the presence of analogous units in derivatives
of quinazolinone 1 yields bioactive compounds as well. Similar situation is assumed for
the presence of pharmacophor substituents in the ester 5.
RESULTS AND DISCUSSION
The sodium salt 2 of 3-amino-2(1H)-thioxo-4(3H)-quinazolinone (1) reacts with
dicarboxylic acid chlorides, chloroformyl ethyl formate, and malonyl chloride (Scheme 1)
to form substitution products or tricyclic compounds.
Most probably, in the first step of the reaction, acylation at the position 2 of the
quinazolinone takes place, which is followed by acylation of the NH2 group at the position
3 combined with cyclization. The reactions were carried out in boiling anhydrous THF.
Homogenous products were obtained. Elemental analysis and analysis of the MS, IR, and
1H NMR spectra confirmed the formation of monosubstituted derivatives and showed that
substitution in the positions 2 or 3 had occurred. Substitution at the position 3 is confirmed
by the IR spectra, where the 2 bands characteristic for the NH2 group in compound 1 are
missing.15 There are bands at 3340 cm−1 characteristic for NHCO and bands characteristic
1
for C O groups. Correspondingly, in the H NMR spectra, the singlet for the 2 protons
of the NH2 group at δ = 6.30 ppm, which is present in the spectrum of compound 1, is
missing.15 Instead, singlets corresponding to one proton are observed at δ = 11.16 ppm
(NHCO) and at δ = 14.73 ppm (NHC S) for compound 3, and at δ = 10.09, 11.54, and
14.82 ppm for compound 4. In the last case they are attributed to the protons of COOH,
NHCO, and NHCS, respectively. In the mass spectra of compounds 3 and 4, peaks for the
molecular ions at m/z = 293 and m/z = 279 as well as base peaks at m/z = 220 (M+ −
COOEt) and m/z = 146 (quinazolinone ion), respectively, are observed.
In the next stage of our study, 3-amino-2-ethoxycarbonylmethylthio-4(3H)-
quinazolinone (5) was allowed to react with selected acid chlorides like acetyl-,
chloroacetyl-, ethyl chloroformyl formate, benzoyl-, crotonoyl-, cinnamoyl-, and p-
nitrocinnamoyl chloride. Acylation reactions were carried out in boiling anhydrous THF,

NOVEL 3-AMINO-2-(1H)-THIOXO-4(3H)-QUINAZOLINONE DERIVATIVES
81
Scheme 1
yielding the products 6–12. The IR spectra of compounds 6–12 do not contain 2 absorption
bands characteristic for NH2 groups, present in compound 5.15 Bands characteristic for
CONH groups at approximately 3300 cm−1 are present, however. The IR spectra of
derivatives 10–12 contain also bands for CH CH groups at 3100–3080 cm−1 as
1
well as bands at 1660–1635 cm−1 and at approximately 1620 cm−1. In the H NMR
spectra of derivatives 6–12, signals for NH2 protons are missing; the signals at δ = 10.32–
11.92 ppm are attributed to NHCO protons. In the case of the derivatives 10–12, the signal
of the proton next to the carbonyl group CH CH C O is observed as a doublet at δ =
6.14, 6.89, and 7.12 ppm, respectively. The 3JHH coupling constants of 15–16 Hz indicate a
trans configuration of the protons in the vinylic fragment. The signal of vinylic proton next
to methyl, CH3 CH , or to aryl, Ar CH , appears among the signals of the aromatic
protons. The mass spectra of the compounds 6–12 display the peaks of the molecular
ions. The peaks of the base ions for compounds 6–8 result from the fragmentation and
elimination of an acetyl (CH3CO), a chloromethyl (CH2Cl), and an ethoxycarbonyl

82
W. NAWROCKA ET AL.
(COOEt) group, respectively. In the case of derivatives 9 and 10 the peaks of the base
ions correspond to the benzoyl ion, m/z = 105 (100), and the crotonoyl ion, m/z = 69
(100), respectively. The base ions for derivatives 11 and 12 result from the elimination
from the position 2 of ethoxycarbonylmethyl and ethoxy-carbonylomethylthio groups,
respectively.
The other possibility for a chemical modification of ester 5 is the ammonolysis with
equimolar amounts of p-fluoro-, p-chloro-, and o-chlorobenzylamine in boiling toluene.
The reaction yields the products 14–16. Two sharp bands characteristic for NH2 groups
are observed in the IR spectra of compounds 14–16. Bands at approximately 3440 cm−1
correspond to NH vibrations of NHCO groups. In the 1H NMR spectra of amides 14–16,
1
there are no signals for the protons of ethoxy groups, which are present in the H NMR
spectrum of ester 5. However, singlets corresponding to two protons at δ = 4.16, 4.19, and
4.20 ppm for SCH2CO, and as doublets at δ = 4.29, 4.33, and 4.38 ppm for CONHCH2Ar,
respectively, were observed. A broad signal for the NH proton of the CONHCH2Ar unit is
found at δ = 8.87, 8.87, and 8.85 ppm, respectively. The signal for the protons of the NH2
group appears along with aromatic protons at δ = 6.64, 6.42, and 6.65 ppm, respectively.
The number of signals for the aromatic protons in the 1H NMR spectra of compounds 14–16
is in good agreement with their structures. For compound 14 the peak for the molecular ion
was observed at m/z = 358. Mass spectra of compounds 15 and 16 display peaks of the
molecular ions at m/z = 374 and the isotope ions at m/z = 376. They additionally confirm
the presence of chlorine in the parent molecules. For the ortho-derivative 16 elimination of
Cl radical from the molecular ion is observed, which results in the formation of an ion with
m/z = 339 (27). One of the observed routes of fragmentation of the compounds 14–16 is the
elimination of the groups ArCH2NHCOCH2 from position 2. Peaks of ortho-iminobenzoyl
ions are formed as base ions at m/z = 120 after fragmentation and degradation of the
quinazolinone system.9
In the next stage, the previously obtained 3-amino-2-benzylcarbamylomethylthio-
4(3H)-quinazolinone (13)15 was subjected to acylation with cinnamoyl (17) and p-
nitrocinamoyl (18) chloride. The reactions were carried out in a way similar to the synthesis
of amides 6–12 yielding the corresponding 3-N-acyl derivatives.
Fourteen new compounds assigned for biological studies were obtained from the
syntheses described here. These derivatives may also be used as starting materials for
further syntheses.
EXPERIMENTAL
Melting points (uncorrected) were measured with a Boethius melting point apparatus.
Analyses were performed with a Perkin Elmer 2400 analyzer and satisfactory results within
0.4% of the calculated values were obtained for all new compounds. IR spectra (in KBr)
1
were recorded with an IR 75 spectrophotometer. H 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. Compounds 1 and
2 were prepared as described previously.15 2-Amino-3-ethoxycarbonylmethylthio-4(3H)-
quinazo-linone (5) was prepared as described.15

NOVEL 3-AMINO-2-(1H)-THIOXO-4(3H)-QUINAZOLINONE DERIVATIVES
83
Synthesis of Compounds 3 and 4: General Procedure
Compound 2 (2.25 g, 0.01 mol) was suspended in anhydrous THF (50 mL) and
0.01 mol of the appropriate acid chloride (chloroformyl ethyl formate or malonyl chloride)
in THF (20 mL) was added dropwise with mechanical stirring at room temperature. The
mixture was refluxed for 10–20 h (TLC). The solid (NaCl + 1) was filtered off. The filtrate
was evaporated in vacuo, water was added (ca. 50 mL) and the mixture was neutralized
with 5% of aq. NaHCO3 (10 mL). The crude product was filtered off, washed with water
(30 mL), dried, and crystallized from an appropriate solvent.
3-Ethoxalylamino-2-(1H)-Thioxo-4(3H)-Quinazolinone (3). Yield: 1.76 g
(60%); yellow solid; mp 212 ◦C–214 ◦C, crystallized from ethanol. IR (KBr): ν (cm−1) =
3400 (NHCO), 3010 (CH), 2900 ( CH2 ), 1750, 1700 (C O), 1610, 1510 (arom.), 1360
(N CS N), 1260 (C S), 760 ( CH ). 1H NMR (DMSO-d6, 300 MHz): δ = 1.33 (t, J =
7.4 Hz, 3H), 4.32 (q, J = 7.4 Hz, 2H), 7.37 (m, 1H), 7.62 (m, 1H), 7.84 (d, J = 7.8 Hz,
1H), 8.36 (d, J = 8.4 Hz, 1H), 11.16 (s, 1H), 14.73 (br, s, 1H). Analysis for C12H11N3O4S
(293.3): Calcd. C, 49.14; H, 3.78; N, 14.33; Found: C, 49.17; H, 3.39; N, 14.27%. MS
(70 eV): m/z = 294 (5), 293 (41), 265 (40), 221 (9), 220 (100), 181 (7), 162 (19), 161 (15),
146 (40), 145 (12), 120 (17), 119 (61), 91 (6), 90 (17), 77 (10), 76 (6), 55 (11), 44 (16), 39
(9).
β-Oxo-3-[2(1H)-Thioxo 4(3H)-Oxo-Quinazolin-3-Ylamino]-Propionic Acid
(4). Yield: 0.78 g (28%); brown solid; mp 238 ◦C–240 ◦C crystallized from acetonitrile. IR
(KBr): ν (cm−1) = 3300 (NHCO), 3260 (OH), 3010 (CH), 2880 ( CH2 ), 1720 (COOH),
1670 (NHCO), 1540 (NH, C N), 1260 (C S), 940 (-OH), 790 (arom.). 1H NMR (DMSO-
d6, 500 MHz): δ = 4.12 (s, 2H), 7.35 (m, 1H), 7.53 (m, 1H), 7.83 (m, 1H), 8.14 (m, 1H),
10.09 (s, 1H), 11.54 (s, 1H), 14.82 (br s, 1H). Analysis for C11H9N3O4S1 (279.27): Calcd.
C, 47.31; H, 3.25; N, 15.05; Found: C, 47.59; H, 3.26; N, 15.00%. MS (70 eV): m/z = 279
(3), 234 (58), 192 (15), 160 (27), 146 (100), 133 (23), 133 (23), 115 (66), 96 (10), 91 (38),
65 (59), 43 (51), 42 (20), 41 (28), 39 (9).
Synthesis of Compounds 6–12, 17, and 18: General Procedure
To a mixture of compound 5 (2.51 g, 0.01 mol) or 13 (3.40 g, 0.01 mol) and NEt3
(2.5 mol) in anhydrous THF (50 mL), 0.01 mol of the respective acid chloride (acetyl
chloride for 6, chloroacetyl chloride for 7, chloroformyl ethyl formate for 8, benzoyl
chloride for 9, crotonoyl chloride for 10, cinnamoyl chloride for 11 and 17, p-nitrocinnamoyl
chloride for 12 and 18) in THF (20 [mL]) was added dropwise with mechanical stirring at
room temperature. The mixture was refluxed for 10–20 h (TLC). The solvent was evaporated
in vacuo and water was added (50 mL). The crude product was filtered off, washed with
water (30 mL), dried and crystallized from ethanol or n-butanol (for 10, 12).
3-Acetylamino-2-Ethoxycarbonylmethylthio-4(3H)-Quinazolinone (6).
Yield: 2.05 g (64%); white solid; mp 137 ◦C–139 ◦C. IR (KBr): ν (cm−1) = 3330 (NHCO),
2980 (CH3), 2940 (CH2), 1740, 1680, 1650 (C O), 1480 (CH2), 1305, 1260, 1195 (C O),
740 (C H arom.). 1H NMR (DMSO-d6, 300 MHz): δ = 1.20 (t, J = 7.20 Hz, 3H), 1.99
(s, 3H), 4.17 (q, J = 7.20 Hz, 2H), 4.31 (s, 2H), 7.29 (m, 1H), 7.59 (m, 1H), 7.87 (d,
J = 8.0 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 10.32 (s, 1H). Analysis for C14H15N3O4S
(321.36): Calcd. C, 52.33; H, 4.70; N, 13.08; Found: C, 52.37; H, 5.01, N, 13.38%. MS
(70 eV) m/z = 323 (3), 322 (6), 321 (34), 280 (13), 279 (100), 203 (5), 202 (40), 162 (20),
161 (3), 160 (18), 146 (11), 120 (85), 119 (11), 118 (45), 92 (16), 91 (8), 77 (7), 43 (49),
39 (5).

84
W. NAWROCKA ET AL.
3-Chloroacetylamino-2-Ethoxycarbonylmethylthio-4(3H)-Quinazolinone
◦
◦
(7). Yield: 1.88 g (53%); white solid; mp 139 C–140 C. IR (KBr): ν (cm−1) = 3300
(NHCO), 2950 (CH3), 2900 (CH2), 1730, 1710, 1680 (C O), 1470, 1440 (CH2), 1310,
1250, 1180 (C O), 750 (C H arom.). 1H NMR (DMSO-d6, 300 MHz): δ = 1.19 (t, J =
7.2 Hz, 3H), 4.16 (q, J = 7.2 Hz, 2H), 4.31 (s, 2H), 4.45 (s, 2H), 7.36 (m, 1H), 7.64
(m, 1H), 7.91 (d, J = 7,2 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 10.91 (s, 1H). Analysis for
C14H14N3O4SCl (355.80): Calcd. C, 47.26; H, 3.97; N, 11.81; Found: C, 47.18; H, 4.15;
N, 12.17%. MS (70 eV) m/z = 357 (11), 356 (5), 355 (30), 309 (2), 308 (11), 307 (100),
238 (9), 237 (5), 236 (30), 198 (9), 197 (3), 196 (44), 133 (9), 132 (11), 92 (15), 91 (22),
90 (23), 77 (17), 39 (6).
3-Ethoxalylamino-2-Ethoxycarbonylmethylthio-4(3H)-Quinazolinone (8).
Yield: 2.46 g (65%); white solid; mp 127 ◦C–129 ◦C. IR (KBr): ν (cm−1) = 3220 (NHCO),
2980 (CH3), 2940 (CH2), 2900 (CH2), 1760, 1730, 1705 (C O), 1470 (CH2), 1310, 1270,
1180 (C O), 770 (C H arom.). 1H NMR (DMSO-d6, 300 MHz): δ = 1.21 (t, J = 7.2 Hz,
3H), 1.35 (t, J = 7.4 Hz, 3H), 4.16 (q, J = 7.2 Hz, 2H), 4.31 (s, 2H), 4.34 (q, J = 7.4
Hz, 2H), 7.39 (m, 2H), 7.95 (d, J = 7.0 Hz, 1H), 8.55 (d, J = 7.8 Hz, 1H), 11.92 (s, 1H).
Analysis for C16H17N3O6S (379.39): Calcd. C, 50.65; H, 4.52; N, 11.08; Found: C, 50.53;
H, 4.78; N, 11.21%. MS (70 eV) m/z = 380 (11), 379 (7), 308 (13), 307 (100), 206 (6), 186
(13), 163 (4), 162 (4), 146 (97), 145 (16), 144 (4), 120 (10), 119 (16), 118 (11), 91(23), 90
(23), 90 (29), 65 (4), 39 (4).
3-Benzoylamino-2-Ethoxycarbonylmethylthio-4(3H)-Quinazolinone (9).
Yield: 2.95 g (77%); white solid; mp 167 ◦C–169 ◦C. IR (KBr): ν (cm−1) = 3320 (NHCO),
3000 (CH arom.), 2950 (CH3), 2915 (CH2), 1740, 1680 (C O), 1480 (CH2), 1310, 1260,
1190 (C O), 1170, 770, 765 (C H arom.). 1H NMR (DMSO-d6, 300 MHz): δ = 1.22 (t,
J = 7.2 Hz, 3H), 4.17 (q, J = 7.2 Hz, 2H), 4.31 (s, 2H), 7.35 (m, 1H), 7.60 (m, 4H), 8.25
(m, 3H), 8.57 (d, J = 8.4 Hz, 1H), 11.17 (s, 1H). Analysis for C19H17N3O4S (383.43):
Calcd. C, 59.52; H, 4.47; N, 10.96; Found: C, 59.48; H, 4.43; N, 10.81%. MS (70 eV)
m/z = 384 (2), 383 (8), 265 (9), 264 (51), 263 (11), 105 (100), 90 (3), 77 (66), 76 (3), 44 (12),
39 (2).
2-Ethoxycarbonylmethylthio-3-Crotonoylamino-4(3H)-Quinazolinone
◦
◦
(10). Yield: 1.77 g (51%); white solid; mp 167 C–169 C. IR (KBr): ν (cm−1) = 3330
(NHCO), 3100 ( CH CH), 2950 (CH3), 2880 (CH2), 1740, 1700, 1680 (C O), 1660
(CO CH CH), 1620 ( CH CH), 1550 (NH, C N), 1480 (CH2), 1310, 1280, 1170
(C O), 770, 750 (C H arom.), 700 (C S). 1H NMR (DMSO-d6, 300 MHz): δ = 1.20 (t,
J = 7.2 Hz, 3H), 1.57 (d, J = 6.6 Hz, 3H), 4.17 (q, J = 7.2 Hz, 2H), 4.30 (s, 2H), 6.14 (d,
J = 15.3 Hz, 1H), 6.86 (m, 1H), 7.29 (m, 2H), 7.88 (d, J = 7.9 Hz, 1H), 8.39 (d, J = 8.4
Hz, 1H), 10.41 (s, 1H). Analysis for C16H17N3O4S (347.40): Calcd. C, 55.32; H, 4.93; N,
12.10; Found: C, 55.60; H, 5.17; N, 12.23%. MS (70 eV) m/z = 349 (2), 348 (4), 347 (23),
280 (7), 279 (52), 249 (11), 228 (90), 227 (15), 188 (11), 186 (3), 146 (17), 92 (8), 91 (5),
90 (8), 69 (100), 44 (40), 39 (18).
3-Cinnamoylamino-2-Ethoxycarbonylmethylthio-◦4(3H)-Quinazolinone
◦
(11). Yield: 2.30 g (56%); white precipitate; mp 155 C–157 C. IR (KBr): ν (cm−1) =
3280 (NHCO), 3080 ( CH ), 2980 (CH3), 1740, 1690 (C O), 1640 (CO CH CH),
1620 ( CH CH-Ar), 1540 (N H, C N), 1480 (CH2), 1475, 1310, 1280 (C O), 765,
745 (C H arom.). 1H NMR (DMSO-d6, 300 MHz): δ = 1.19 (t, J = 7.2 Hz, 3H), 4.15 (q,
J = 7.2 Hz, 2H), 4.31 (s, 2H), 6.89 (d, J = 15.7 Hz, 1H), 7.64 (m, 8H), 7.91 (d, J = 7.9 Hz,
1H), 8.40 (d, J = 8.5 Hz, 1H), 10.57 (s, 1H). Analysis for C21H19N3O4S (409.47): Calcd.
C, 61.60; H, 4.68; N, 10.26; Found: C, 61.43; H, 4.26; N, 10.11%. MS (70 eV) m/z =

NOVEL 3-AMINO-2-(1H)-THIOXO-4(3H)-QUINAZOLINONE DERIVATIVES
85
410 (3), 323 (9), 322 (17), 321 (100), 236 (6), 235 (42), 202 (14), 178 (10), 163 (5), 162
(53), 160 (10), 145 (22), 144 (25), 134 (12), 131 (19), 130 (10), 103 (9), 102 (22), 91 (13),
76 (5), 57 (6), 44 (18), 39 (3).
2-Ethoxycarbonylmethylthio-3-(p-Nitrocinnamoyl)Amino-4(3H)-Quina-
zolinone (12). Yield: 3.22 g (71%); white solid; mp 209 ◦C–212 ◦C. IR (KBr): ν (cm−1) =
3280 (NHCO), 3080 ( CH ), 2980 (CH3), 2940 (CH2), 1740, 1690 (C O), 1635
(CO CH CH), 1625 ( CH CH-Ar), 1530 (N H, C N), 1480 (CH2), 1430, 1340
1
(NO2), 1310, 980 (CH CH trans), 770, 750 (C H arom.). H NMR (DMSO-d6, 300
MHz): δ = 1.20 (t, J = 7.2 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 4.31 (s, 2H), 7.12 (d, J =
15.7 Hz, 1H), 7.36 (m, 1H), 7.66 (m, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 7.9 Hz,
1H), 8.00 (d, J = 8.8 Hz, 1H), 8.27 (d, J = 8.8 Hz, 2H), 8.38 (d, J = 8.4 Hz, 2H), 10.65
(s,1H). Analysis for C21H18N4O6S (454.46): Calcd. C, 55.50; H, 3.99; N, 12.33; Found:
C, 55.73; H, 4.18; N, 12.61%. MS (70 eV) m/z = 456 (3), 455 (9), 454 (33), 435 (1), 336
(17), 335 (100), 334 (20), 279 (41), 278 (4), 177 (8), 176 (68), 160 (8), 147 (4), 146 (22),
133 (6), 131 (7), 130 (31), 120 (29), 119 (11), 118 (19), 102 (0), 90 (14), 76 (8), 44 (21).
3-Amino-2-Benzylcarbamoylmethylthio-4(3H)-Quinazolinone
(13). It
was prepared similarly as described.15
Synthesis of Compounds 14–16: General Procedure
An equimolar (0.01 mol) mixture of the ester 5 and the substituted benzylamine (p-
fluoro- 14, p-chloro- 15, o-chlorobenzylamine 16) in toluene (50 mL) was refluxed for 4 h
and subsequently cooled to ambient temperature. The solid obtained was filtrated, washed
with diethyl ether and recrystallized from ethanol.
3-Amino-2-(p-Fluorobenzylcarbamoylmethylthio)-4(3H)-Quinazolinone
(14). Yield: 1.50 g (42%); white solid; mp 172 ◦C–175 ◦C. IR (KBr): ν (cm−1) = 3440,
3400, 3300 (NH, NH2 + NHCO), 3080 (CH arom.), 2940 ( CH2 ), 1655 (NHCO), 1625
1
(NH), 1550 (NH, N C), 1160, 850, 760, 740 (C H arom.). H NMR (DMSO-d6, 500
MHz): δ = 4.16 (s, 2H), 4.29 (d, J = 5.0 Hz, 2H), 6.64 (m, 3H), 6.90 (d, J = 8.1 Hz, 1H),
7.85 (m, 2H), 7.74 (d, J = 6.2 Hz, 3H), 7.58 (d, J = 7.6 Hz, 1H), 8.85 (br, 1H). Analysis
for C17H15N4O2SF (358.39): Calcd. C, 56.97; H, 4.22; N, 15.63; Found: C, 57.19; H, 4.28;
N, 16.00%. MS (70 eV) m/z = 360 (4), 359 (12), 358 (59), 195 (2), 194 (13), 193 (12),
166 (22), 165 (29), 164 (10), 137 (19), 122 (11), 121 (9), 120 (100), 118 (53), 110 (4), 109
(47), 92 (22), 91 (6), 90 (2), 77 (4), 65 (11), 39 (3).
3-Amino-2-(p-Chlorobenzylcarbamoylmethylthio)-4(3H)-Quinazolinone
(15). Yield: 1.80 g (48%); white solid; mp 175 ◦C–176 ◦C. IR (KBr): ν (cm−1) =
3450, 3410, 3320 (NH2 + NHCO), 3080 (CH arom.), 2950 ( CH2 ), 1655 (NHCO),
1
1625 (NH), 1555 (NH, N C), 1458 ( CH2 ), 1165, 840, 750 (C H arom.). H NMR
(DMSO-d6, 500 MHz) δ = 4.19 (s, 2H), 4.33 (d, J = 5.9 Hz, 2H), 6.42 (m, 3H), 6.99 (d, J =
8.4 Hz, 1H), 7.28 (m, 5H), 7.58 (m, 1H), 8.88 (br, 1H). Analysis for C17H15N4O2SCl
(374.84): Calcd. C, 54.47; H, 4.03; N, 14.95; Found: C, 54.12; H, 4.18; N, 15.17%. MS (70
eV) m/z = 376 (24), 375 (13), 374 (63), 194 (19), 193 (18), 184 (7), 183 (11), 182 (24),
181 (28), 160 (5), 146 (21), 125 (32), 120 (100), 119 (7), 118 (59), 92 (21), 65 (10), 39 (2).
3-Amino-2-(o-Chlorobenzylcarbamoylmethylthio)-4(3H)-Quinazolinone
(16). Yield: 1.99 g (53%); white solid; mp 149 ◦C–150 ◦C. IR (KBr): ν (cm−1) = 3440,
3410, 3320 (NH2 + NHCO), 3100 (CH arom.), 2960 ( CH2 ), 1660 (NHCO), 1630
1
(NH), 1560 (NH, N C) 1170, 760, 740 (C H arom.). H NMR (DMSO-d6, 500 MHz):
δ = 4.20 (s, 2H), 4.38 (d, J = 5.8 Hz, 2H), 6.65 (m, 3H), 6.90 (d, J = 8.3 Hz, 1H), 7.26 (m,

86
W. NAWROCKA ET AL.
3H), 7.36 (m, 1H), 7.42 (m, 1H), 7.60 (m, 1H), 8.87 (br, 1H). Analysis for C17H15N4O2SCl
(374.84): Calcd. C, 54.47; H, 4.03; N, 14.95; Found: C, 54.18; H, 4.12; N, 15.30%. MS
(70 eV) m/z = 376 (22), 375 (12), 374 (58), 340 (6), 339 (27), 199 (6), 193 (7), 181 (15),
153 (12), 125 (29), 121 (8), 120 (100), 118 (53), 92 (20), 76 (10), 39 (2).
2-Benzylcarbamoylmethylthio-3-Cinnamoylamino-4(3H)-Quinazolinone
◦
◦
(17). Yield: 2.73 g (58%); white solid; mp 147 C–149 C. IR (KBr): ν (cm−1) = 3320
(NHCO), 3080 (CH ), 2880 (CH2), 1690 (C O), 1650 (C O, C C C O), 1620
(C C Ph), 1550 (N H, C N), 1490 (CH2), 1290 (CH CH trans), 770, 750 (C H
1
arom.), 700 (C S). H NMR (DMSO-d6, 300 MHz): δ = 4.19 (s, 2H), 4.32 (d, J = 5.9
Hz, 2H), 6.88 (d, J = 15.7 Hz, 1H), 7.26 (m, 6H), 7.31 (m, 3H), 7.45 (m, 4H), 7.89 (m,
1H), 8.44 (d, J = 7.8 Hz, 1H), 8.85 (br, 1H), 10.64 (s, 1H). Analysis for C26H22N4O3S
(470.54): Calcd. C, 66.37; H, 4.71; N, 11.91; Found: C, 66.29; H, 4.37; N, 12.15%. MS (70
eV) m/z = 470 (8), 453 (13), 452 (42 ), 377 (37), 322 (14 ), 290 (32), 250 (41), 247 (25),
204 (23), 132 (12), 131 (100), 103 (48), 102 (12), 92 (8.), 91 (6), 77 (22), 65 (8), 51 (4).
2-Benzylcarbamoylmethylthio-3-(p-Nitrocinnamoyl)Amino-4(3H)-Quina-
◦
◦
zolinone (18). Yield: 3.15 g (61%); white solid; mp 221 C–223 C. IR (KBr): ν
(cm−1) = 3320, 3300 (NHCO), 3080 (CH ), 2880 (CH2), 1690 (C O), 1660 (C O,
C C C O), 1620 (C C Ar), 1560 (N H, C N), 1530, 1340 (NO2), 1480 (CH2),
1290 (CH CH trans), 760, 740 (C H arom.). 1H NMR (DMSO-d6, 300 MHz): δ = 4.20
(s, 2H), 4.32 (d, J = 5.9 Hz, 2H), 7.11 (d, J = 15.7 Hz, 1H), 7.25 (m, 2H), 7.33 (m, 4H),
7.65 (m, 1H), 7.75 (d, J = 15.7 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.7 Hz,
2H), 8.26 (d, J = 8.7 Hz, 2H), 8.41 (d, J = 8.3 Hz, 1H), 8.84 (br, 1H), 10.71 (s, 1H).
Analysis for C26H21N5O5S (515.55): Calcd. C, 60.57; H, 4.11; N, 13.58; Found: C, 61.00;
H, 4.28; N, 13.47%. MS (70 eV) m/z = 515 (31), 422 (5), 335 (73), 295 (31), 221 (21),
176 (81), 147 (58), 146 (41), 130 (37), 91 (100), 76 (14), 65 (9).
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