Synthesis of 3-amino-3,4-dihydroquinazolin-4-one derivatives from anthranilic acid hydrazide and dicarboxylic acids

Article abstract of DOI:10.1134/S1070428007120160

Treatment of anthranilic acid hydrazide with 2 equiv of ethoxalyl chloride gave the corresponding diester which underwent cyclization in acetic anhydride to produce ethyl 3-(ethoxalylamino)-4-oxo-3,4-dihydroquinazoline-2-carboxylate. Acylation of anthrani

Full text of DOI:10.1134/S1070428007120160

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 12, pp. 1830–1835. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © L.A. Shemchuk, V.P. Chernykh, P.S. Arzumanov, I.L. Starchikova, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43,
No. 12, pp. 1827–1831.
Synthesis of 3-Amino-3,4-dihydroquinazolin-4-one Derivatives
from Anthranilic Acid Hydrazide and Dicarboxylic Acids
L. A. Shemchuk, V. P. Chernykh, P. S. Arzumanov, and I. L. Starchikova
National Pharmaceutical University, ul. Pushkinskaya 53, Khar’kov, 61002 Ukraine
Received August 21, 2006
Abstract—Treatment of anthranilic acid hydrazide with 2 equiv of ethoxalyl chloride gave the corresponding
diester which underwent cyclization in acetic anhydride to produce ethyl 3-(ethoxalylamino)-4-oxo-3,4-
dihydroquinazoline-2-carboxylate. Acylation of anthranilic acid hydrazide first with succinic anhydride and
then with ethoxalyl chloride led to the formation of 4-[2-(2-{[ethoxy(oxo)acetyl]amino}benzoyl)hydrazino]-4-
oxobutanoic acid whose cyclization in acetic acid afforded N-(2-ethoxycarbonyl-4-oxo-3,4-dihydroquinazolin-
3-yl)succinamic acid, while in acetic anhydride ethyl 3-(2,5-dioxopyrrolidin-1-yl)-4-oxo-3,4-dihydroquina-
zoline-2-carboxylate was obtained. The latter was brought into reactions with amines and hydrazine hydrate
and alkaline hydrolysis. Acylation of 2-[2-(2-aminobenzoyl)hydrazinocarbonyl]benzoic acid with ethoxalyl
chloride gave ethyl N-[2-(phthalimidocarbamoyl)phenyl]oxamate, and with succinic anhydride, 3-[4-oxo-3-
phthalimido-3,4-dihydroquinazolin-2-yl]propionic acid. 4-[2-(2-Aminobenzoyl)hydrazino]-4-oxobutanoic acid
reacted with phthalic anhydride in boiling acetic acid to give phthalazino[1,2-b]quinazoline-5,8-dione via
elimination of succinic acid residue.
DOI: 10.1134/S1070428007120160
Synthesis of quinazolinones on the basis of an-
thranilic acid and dicarboxylic acid hydrazides gives
rise to structures that are convenient for subsequent
chemical modification, in particular for the preparation
of tricyclic compounds [1–3]. This is important from
the viewpoint of design of biologically active sub-
stances and potential drugs since many medical agents
incorporate quinazolinone moiety as structural frag-
ment [4, 5].
Ethyl 4-oxo-3-(2,5-dioxopyrrolidin-1-yl)-3,4-dihy-
droquinazoline-2-carboxylate (VII) was synthesized
starting from 4-[2-(2-aminobenzoyl)hydrazino]-4-oxo-
butanoic acid (IV) which was prepared according to
the procedure described in [3]. The reaction of acid IV
with ethoxalyl chloride in glacial acetic acid in the
presence of triethylamine gave oxamate V, and heating
of the latter in acetic acid afforded quinazolin-4-one
derivative VI. By treatment of VI with acetic anhy-
dride we obtained the target succinimide VII. Com-
pound VII can also be obtained directly from ester V
(without isolation of intermediate acid VI) by the ac-
tion of acetic anhydride (Scheme 2).
The goal of the present work was to synthesize
3-amino-3,4-dihydroquinazolin-4-ones from diacyl
derivatives of anthranilic acid hydrazide (I) containing
various dicarboxylic acid moieties (Scheme 1). By
acylation of hydrazide I with 2 equiv of ethoxalyl
chloride we obtained diester II which readily under-
went cyclization to ethyl 3-[ethoxy(oxo)acetylamino]-
4-oxo-3,4-dihydroquinazoline-2-carboxylate (III)
(Scheme 1).
Molecule VII possesses ester group and succin-
imide ring which are capable of readily reacting with
nitrogen- and oxygen-centered nucleophiles. Thus
imide VII reacted with primary amines to produce the
corresponding amides VIIIa–VIIIc with conservation
Scheme 1.
O
O
O
N
NHCOCOOEt
COOEt
Δ
2EtOCOCOCl
NHNH2
NHNHCOCOOEt
N
NH2
NHCOCOOEt
I
II
III
1830

SYNTHESIS OF 3-AMINO-3,4-DIHYDROQUINAZOLIN-4-ONE DERIVATIVES
1831
Scheme 2.
O
O
O
H
N
NHCOCH2CH2COOEt
EtOCOCOCl
N
OH
N
I
+
H
H
O
O
O
O
NH2
NHCOCOOEt
IV
V
O
NHCOCH2CH2COOEt
AcOH, Δ
N
N
COOEt
VI
Ac2O
O
O
N
N
Ac2O
O
N
COOEt
VII
of the ester group (Scheme 3). The product structure
indicates higher reactivity of the imide ring toward
nucleophiles, as compared to the ester group.
rather than the ester group may be rationalized in terms
of steric factors.
In the reaction of imide VII with hydrazine hydrate
we isolated ~30% of hydrazide IX (Scheme 3). Pre-
sumably, the process involves initial opening of the
imide ring (as in the reaction with amines), followed
by elimination of succinic acid residue. 3-Acylamino-
3,4-dihydroquinazolin-4-ones are known to readily
lose the acyl group; such transformations were de-
scribed in [7, 8]. Due to high nucleophilicity of hydra-
zine, the reaction is accompanied by hydrazinolysis of
the ester group. Treatment of imide VII with excess
alkali led to the formation of acid X [9] as a result of
decarboxylation of intermediate 4-oxoquinazoline-2-
carboxylic acid (Scheme 3).
We performed AM1 calculations of electron density
on the carbonyl carbon atoms in molecule VII with
MMX optimization of the geometric parameters [6].
The charge on the ester carbonyl carbon atom was
estimated at +0.428, and those on the imide carbonyl
carbon atoms, at +0.394 and +0.378. These values
suggest higher reactivity of the ester group rather than
imide ring. The difference between the charges on the
imide carbonyl carbon atom is likely to result from
rupture of conjugation therein. An analogous relation
was obtained by MINDO/3, MNDO, and PM3 calcula-
tions. The fact that the reaction involves the imide ring
Scheme 3.
O
NHCOCH2CH2CONHR
RNH2 (1 equiv)
N
O
N
N
O
COOEt
OH–
NHCOCH2CH2COOH
VIIIa–VIIIc
N
VII
NH2
H2NNH2 (1 equiv)
N
X
N
CONHNH2
IX
VIII, R = Pr (a), PhCH2 (b), furfuryl (c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

SHEMCHUK et al.
1832
O
O
O
N
N
NHNHCOCH2CH2COOH
N
O
NHCOCH2CH2COOH
CH2CH2COOH
A
B
O
N
COCH2CH2COOH
O
H
N
O
N
O
N
N
N
C
D
The structure of ester V implies that its cyclo-
dehydration could produce both quinazolinone and
imide ring. We previously [3] failed to determine the
ring closure sequence for analogous structures despite
numerous attempts. Preferential formation of quinazo-
linone structure rather than imide ring on heating of
ester V in boiling acetic acid is likely to be favored by
the presence of a bulky substituent (ethoxalylamino
group) in the ortho position of the benzene ring, which
hinders closure of succinimide ring. We presumed in
[10] that the quinazoline and imide rings are formed
simultaneously and proposed structure B for the cyclo-
dehydration product of bis-acid A. The 1H NMR spec-
trum of the product did not contradict the proposed
structure. However, it remained unclear why com-
pound B was readily converted into pyrazinoquinazo-
line D even upon crystallization from ethanol whereas
it did not change upon crystallization from anhydrous
dioxane.
mediate formation of structure C explains well the
transformation of the cyclodehydration product upon
crystallization. An indirect evidence in favor of the
formation of structure C was obtained by studying
cyclodehydration of other diacyl derivatives of anthra-
nilic acid hydrazide, namely those containing oxalic,
succinic, and phthalic acid residues. The presence of
a phthalic acid moiety turned out to be the main factor
determining the cyclization direction; the position of
the o-carboxybenzoyl substituent is also important. If
the latter is attached to the hydrazine fragment, phthal-
imide ring closure occurs preferentially. In fact, the
acylation of acid XI [3] with ethoxalyl chloride in the
cold gave phthalimide XII (Scheme 4). In the reaction
of XI with succinic anhydride at elevated temperature
we isolated compound XIII. Phthalic acid is known to
readily (as compared to other dicarboxylic acids) un-
dergo imide ring closure; in addition, enhanced nucleo-
philicity of the hydrazide group in XI also favors
imide ring closure (α effect) [11].
Our present results led us presume that the cycliza-
tion of bis-carboxylic acid A yields structure C as
a result of preferential quinazoline ring closure. Inter-
The reaction takes a different path when the phthal-
ic acid residue is attached to the amino group. The
Scheme 4.
O
O
N
EtOCOCOCl
N
H
O
NHCOCOEt
O
O
H
XII
N
N
I
+
H
O
O
O
O
NH2
O
OH
O
XI
N
N
O
O
O
O
N
CH2CH2COOH
XIII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

SYNTHESIS OF 3-AMINO-3,4-DIHYDROQUINAZOLIN-4-ONE DERIVATIVES
1833
Scheme 5.
O
O
O
N
H
N
(1)
; (2)
, AcOH
O
O
O
O
O
N
O
O
O
I
IV
XIV
H 4.68; N 12.70. C15H15N3O6. Calculated, %: C 54.06;
H 4.54; N 12.61.
acylation of acid IV with phthalic anhydride, followed
by heating in boiling acetic acid, gave phthalazino-
quinazoline XIV [3, 10] (Scheme 5). Compound XIV
can also be obtained by successive acylation of hydra-
zide I with succinic and phthalic anhydrides in acetic
acid. Here, the predominant process is closure of quin-
azoline ring, and subsequent cyclization with forma-
tion of phthalazine ring is accompanied by elimination
of succinic acid. This reaction scheme not only ex-
plains the formation of XIV but also provides an in-
direct proof for intermediacy of structure C.
4-[2-(2-{[Ethoxy(oxo)acetyl]amino}benzoyl)-
hydrazino]-4-oxobutanoic acid (V). Triethylamine,
1.4 ml (0.01 mol), was added to a cold solution of
2.5 g (0.01 mol) of acid IV in 5 ml of acetic acid, and
1.1 ml (0.01 mol) of ethoxalyl chloride was added
dropwise. The mixture was left overnight and diluted
with water, and the colorless precipitate was filtered
off, dried, and recrystallized from ethanol. Yield 2.1 g
1
(60%), mp 178–180°C. H NMR spectrum, δ, ppm:
1.32 t (3H, CH3), 2.45–2.51 s (4H, CH2CH2), 4.3 q
(2H, OCH2), 7.28 t (1H, 5-H), 7.63 t (1H, 4-H), 7.89 d
(1H, 3-H), 8.52 d (1H, 6-H), 10.1 s (1H, NHCO),
10.68 s (1H, NHCO), 12.15–12.38 d (2H, NHCO, OH).
Found, %: C 51.41; H 4.98; N 12.05. C15H17N3O7. Cal-
culated, %: C 51.28; H 4.88; N 11.96.
EXPERIMENTAL
1
The H NMR spectra were measured in DMSO-d6
on a Varian M 200 spectrometer (200 MHz) relative to
tetramethylsilane as internal reference.
Ethyl [2-(2-{[ethoxy(oxo)acetyl]amino}benzoyl)-
hydrazino]oxoacetate (II). Triethylamine, 3.04 ml
(0.02 mol), was added on cooling to a solution of
1.51 g (0.01 mol) of anthranilic acid hydrazide (I) in
7 ml of acetic acid, and 2.46 ml (0.02 mol) of ethoxalyl
chloride was added dropwise. The mixture was left
overnight and diluted with water, and the precipitate
was filtered off, dried, and recrystallized from ethanol.
Yield 2.2 g (63%), mp 156–158°C. 1H NMR spectrum,
δ, ppm: 1.36 m (6H, CH2CH3), 4.31 m (4H, OCH2),
7.26 t (1H, 5-H), 7.60 t (1H, 4-H), 7.90 d (1H, 3-H),
8.57 d (1H, 6-H), 10.86 s (1H, NHCOCO), 10.99 s
(1H, CONHNH), 12.41 s (1H, NHCO). Found, %:
C 51.40; H 4.92; N 12.02. C15H13N3O7. Calculated, %:
C 51.28; H 4.88; N 11.96.
N-(2-Ethoxycarbonyl-4-oxo-3,4-dihydroquin-
azolin-3-yl)succinamic acid (VI). A mixture of 3.51 g
(0.01 mol) of compound V and acetic acid was heated
for 40 min under reflux and was then left overnight.
The mixture was diluted with water, and the precipitate
was filtered off, dried, and recrystallized from ethanol.
Yield 1.9 g (56%), mp 175–177°C. 1H NMR spectrum,
δ, ppm: 1.35 t (3H, CH3), 2.84 t (2H, COCH2), 3.2 t
(2H, CH2COOH), 4.3 q (2H, OCH2), 7.39 t (1H, 6-H),
7.67 t (1H, 7-H), 8.0 d (1H, 8-H), 8.6 d (1H, 5-H),
12.2 s (1H, NH), 12.4 br.s (1H, OH). Found, %:
C 54.19; H 4.67; N 12.71. C15H15N3O6. Calculated, %:
C 54.06; H 4.54; N 12.61.
Ethyl 3-(2,5-dioxopyrrolidin-1-yl)-4-oxo-3,4-di-
hydroquinazoline-2-carboxylate (VII). a. A mixture
of 0.33 g (0.001 mol) of compound VI and excess
acetic anhydride was heated for 40 min at 70–80°C
and was then left overnight. The mixture was diluted
with water, and the precipitate was filtered off. Yield
0.21 g (68%), mp 159°C.
Ethyl 3-{[ethoxy(oxo)acetyl]amino}-4-oxo-3,4-di-
hydroquinazoline-2-carboxylate (III). A solution of
1.0 g (0.05 mol) of diester II in a minimal volume of
acetic anhydride was heated for 1 h at 70–80°C. Yield
1
0.48 g (51%), mp 58–60°C. H NMR spectrum, δ,
ppm: 1.3 m (6H, CH2CH3), 4.4 m (4H, OCH2), 7.73 t
(1H, 6-H), 7.84 d (1H, 8-H), 8.00 t (1H, 7-H), 8.23 d
(1H, 5-H), 12.45 s (1H, NHCO). Found, %: C 54.20;
b. A mixture of 0.35 g (0.001 mol) of compound V
and 0.09 ml (0.001 mol) of acetic anhydride was
heated for 20 min at 70–80°C and was then left over-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

SHEMCHUK et al.
1834
night. The mixture was diluted with water, and the pre-
cipitate was filtered off. Yield 0.23 g (73%), mp 157–
159°C. H NMR spectrum, δ, ppm: 1.35 t (3H, CH3),
3.1 s (4H, CH2CH2), 4.4 q (2H, OCH2), 7.75 t (1H,
6-H), 7.95 d (1H, 8-H), 8.05 t (1H, 7-H), 8.21 d (1H,
5-H). Found, %: C 57.26; H 4.22; N 13.41. C15H13N3O5.
Calculated, %: C 57.14; H 4.16; N 13.33.
the precipitate was filtered off. Yield 1.6 g (60%),
mp 225°C (from ethanol) [9].
1
Ethyl N-[2-(phthalimidocarbamoyl)phenyl]-
oxamate (XII). A solution of 2.9 g (0.01 mol) of
compound XI in 5 ml of acetic acid was cooled, 1.4 ml
(0.01 mol) of triethylamine was added, and 1.1 ml
(0.01 mol) of ethoxalyl chloride was added dropwise
on cooling. The mixture was left overnight and diluted
with water, and the precipitate was filtered off, dried,
and recrystallized from ethanol. Yield 2.4 g (64%),
Ethyl 4-oxo-3-[4-oxo-4-(propylamino)butanoyl-
amino]-3,4-dihydroquinazoline-2-carboxylate
(VIIIa). Propylamine, 0.83 ml (0.01 mol), was added
to a solution of 3.15 g (0.01 mol) of compound VII in
a minimal amount of dioxane, and the mixture was
refluxed for 1 h and left overnight. The precipitate was
filtered off and dried. Yield 2.6 g (71%), mp 108–
1
mp 138–140°C [5, 10]. H NMR spectrum, δ, ppm:
1.26 t (3H, CH3), 4.25 q (2H, OCH2), 7.3–7.87 m (8H,
H
arom), 11.72 s (1H, NHCO), 12.18 s (1H, CONH).
Found, %: C 59.97; H 4.06; N 11.17. C19H15N3O6. Cal-
culated, %: C 59.84; H 3.96; N 11.02.
1
110°C. H NMR spectrum, δ, ppm: 0.9 t (3H, CH2-
CH2CH3), 1.2–1.5 m (5H, OCH2CH3, CH2CH2CH3),
2.51 q (2H, NHCH2), 4.3 q (2H, COCH2), 7.6–7.9 m
(4H, Harom), 8.15 t (1H, CONHCH2), 11.3 s (1H,
NHCO). Found, %: C 57.87; H 5.99; N 15.06.
C18H28N4O5. Calculated, %: C 57.75; H 5.92; N 14.96.
3-(4-Oxo-3-phthalimido-3,4-dihydroquinazolin-
2-yl)propionic acid (XIII). Succinic anhydride, 1.0 g
(0.01 mol), was added to a solution of 2.9 g (0.01 mol)
of compound XI in acetic acid, the mixture was heated
for 30 min under reflux and diluted with water, and the
precipitate was filtered off and recrystallized from
ethanol. Yield 2.5 g (70%). 1H NMR spectrum, δ, ppm:
2.74 t (2H, CH2CO), 3.02 t (2H, CH2), 7.6–8.15 m
(8H, Harom), 12.15 s (1H, OH). Found, %: C 62.98;
H 3.70; N 11.69. C19H13N3O5. Calculated, %: C 62.81;
H 3.61; N 11.57.
Ethyl 3-[4-(benzylamino)-4-oxobutanoylamino]-
4-oxo-3,4-dihydroquinazoline-2-carboxylate (VIIIb)
was synthesized in a similar way. Yield 3.1 g (75%),
1
mp 130–132°C. H NMR spectrum, δ, ppm: 1.3 t (3H,
CH3), 2.35 t (2H, COCH2), 2.65 t (2H, CH2CO), 4.2 d
(2H, NHCH2), 4.35–4.4 q (2H, OCH2), 7.25 m (5H,
Harom), 7.6–8.3 m (4H, Harom), 8.4 t (1H, CONH), 11.25 s
6H-Phthalazino[1,2-b]quinazoline-5,8-dione
(XIV). a. Phthalic anhydride, 1.48 g (0.01 mol), was
added to a solution of 2.5 g (0.01 mol) of acid IV in
acetic acid, the mixture was heated for 20 min at 60–
70°C and diluted with water, and the precipitate was
filtered off and recrystallized from ethanol. Yield 2.2 g
(83%), mp 263–265°C. Found, %: C 68.56; H 3.59;
N 16.09. C15H9N3O2. Calculated, %: C 68.44; H 3.45;
N 15.96.
(1H, NHCO). Found, %: C 62.69; H 5.37; N 13.38.
C22H22N4O5. Calculated, %: C 62.55; H 5.25; N 13.26.
Ethyl 3-[4-(furan-2-ylmethylamino)-4-oxobutan-
oylamino]-4-oxo-3,4-dihydroquinazoline-2-carbox-
ylate (VIIIc) was synthesized in a similar way. Yield
1
3.35 g (82%), mp 143–145°C. H NMR spectrum, δ,
ppm: 1.35 t (3H, CH3), 2.2–2.8 m (4H, CH2CH2), 4.3 d
(2H, NHCH2), 4.4 q (2H, OCH2), 6.1 d (1H, 3′-H),
6.3 t (1H, 4′-H), 7.5. d (1H, 5′-H), 7.6–8.3 m (4H,
Harom), 8.4 t (1H, NHCH2), 11.4 s (1H, NHCO). Found,
%: C 58.39; H 4.97; N 13.68. C20H20N4O6. Calculated,
%: C 58.25; H 4.89; N 13.59.
b. Succinic anhydride, 1.0 g (0.01 mol), was added
to a solution of 1.51 g (0.01 mol) of hydrazide I in
acetic acid, the mixture was cooled, 1.48 g (0.01 mol)
of phthalic anhydride was added, and the mixture was
heated for 30 min under reflux and diluted with water.
Yield 1.9 g (75%), mp 260–262°C.
3-Amino-4-oxo-3,4-dihydroquinazoline-2-carbo-
hydrazide (IX). Hydrazine hydrate, 0.49 ml (0.01 mol),
was added to a solution of 3.15 g (0.01 mol) of com-
pound VII in ethanol, the mixture was left overnight,
and the precipitate was filtered off and dried. Yield
0.66 g (30%), mp 196–198°C [12].
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