Synthesis and properties of 1,2-dihydro-4(3H)-quinazolinones

Article abstract of DOI:10.1007/s11172-017-1852-2

We modified the preparative-scale method for the synthesis of 2-aryl 1,2-dihydro-4(3H)-quinazolinone derivatives obtained in high yields by the reaction of new and commercially available aromatic aldehydes with anthranilic acid amides. A series of quinazolinone derivatives possessing anticancer and antiparasitic activities, as well as capable of preventing the progress of neurodegenerative diseases were characterized. There are grounds for clinical trials of these substances in order to select compounds being promising for clinical application.

Full text of DOI:10.1007/s11172-017-1852-2

Russian Chemical Bulletin, International Edition, Vol. 66, No. 6, pp. 1044—1058, June, 2017
1044
Synthesis and properties of 1,2-dihydro-4(3H)-quinazolinones
D. S. Khachatryan,a S. K. Belus,a V. A. Misyurin,b M. A. Baryshnikova,b A. V. Kolotaev,a and K. R. Matevosyanc
aInstitute of Chemical Reagents and High Purity Chemical Substances (IREA),
3 Bogorodskii val, 107076 Moscow, Russian Federation.
E-mail: derenik-s@yandex.ru
bN. N. Blokhin Russian Cancer Research Center, Ministry of Health of the Russian Federation,
24 Kashirskoe sh., 115478 Moscow, Russian Federation
cD. Mendeleev University of Chemical Technology of Russia,
9 Miusskaya pl., 125047 Moscow, Russian Federation
We modified the preparative-scale method for the synthesis of 2-aryl 1,2-dihydro-4(3H)-
quinazolinone derivatives obtained in high yields by the reaction of new and commercially
available aromatic aldehydes with anthranilic acid amides. A series of quinazolinone derivatives
possessing anticancer and antiparasitic activities, as well as capable of preventing the progress
of neurodegenerative diseases were characterized. There are grounds for clinical trials of these
substances in order to select compounds being promising for clinical application.
Key words: anthranilamides, aromatic aldehydes, quinazolinones, stereochemistry, cyclo-
condensation, inhibition of signaling pathways, blocking of DNA repair, anticancer drugs,
neurodegenerative diseases.
One of the most promising strategies for the therapy
of cancer, autoimmune, and some neurodegenerative
diseases is the application of targeted drugs. The basis for
targeted therapy is the presence of a target in the cell signal-
ing pathway which can be affected using a substance pos-
sessing a high affinity to this target. If certain signaling
pathway is active predominantly in a tumor cell or a cell
responsible for autoimmunity, the interruption of this
pathway can result in the death of such cell populations.
Normal cells will remain unaffected.
To expand the range of already known targeted drugs,
numerous new compounds are being synthesized and
studied worldwide annually. Among them are quin-
azolinone and its derivatives. Quinazolinone derivatives
are known to possess some significant pharmacological
effects. Different researchers consider them as antibiotics,1
cardiostimulators,2 vasodilators,3 and analgetics.4 In ad-
dition, these derivatives extensively suppress the prolif-
eration of tumor cells.5 In Refs 6 and 7, the reduction of
4-quinazolinones with sodium borohydride afforded the
1,2-dihydro derivatives which possess a higher bioactivity
than their precursors.
The present work is dedicated to the study of both
starting anthranilic acid amides and final 1,2-dihydro-
4(3H)-quinazolinone derivatives and summarizes the re-
sults of our studies performed in recent years.
Results and Discussion
Synthesis of anthranilic acid derivatives
One of the most common methods for the synthesis of
anthranilic acid amides 7 based on the reaction of isatoic
anhydride 6 with aliphatic and aromatic amines8—10 (see
Scheme 1) was found to be unsuitable for our purposes
due to side processes, which does not provide satisfactory
yields of target compounds.11 Therefore, we chose an
alternative one-pot phosphaso method including the
preparation step of phosphorylenimine amides 8 (Scheme 2).
When various amines are involved in the above-men-
tioned reaction, aliphatic and aromatic amines were found
to smoothly react with anthranilic acid affording derivatives
of anthranilic acid amide in high yields. For example,
propyl-, phenyl-, and 4-substituted phenylamides, as well
as furfuryl-, benzyl, and aminoalkylamides 7a—h were
obtained by this method in yields of 70—80%. The excep-
tion was 2,6-disubstituted phenylamines and tertiary
alkylamines, the use of which resulted in oligomerization
of anthranilic acid instead of amidation due to steric hin-
drances (the starting amines were regenerated).
For this reason, the development of convenient prepara-
tion methods and the synthesis of a wide range of new 1,2-di-
hydro-4(3H)-quinazolinones seem to be a topical problem.
Among known available routes for the synthesis of
structures to be sought (Scheme 1), the route B appears
to be the most attractive, since, in our opinion, it allows one
to obtain more various 4-quinazolinones by varying sub-
stituents in the used anthranilic acid amides and aldehydes.
The structures of synthesized compounds were deter-
mined from the comparison of their physicochemical
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1044—1058, June, 2017.
1066-5285/17/6606-1044 © 2017 Springer Science+Business Media, Inc.

Synthesis of 1,2-dihydro-4(3H)-quinazolinones
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1045
Scheme 1
R = Alk, Ar; R´ = Alk, Ar, Het
Scheme 2
constants with known samples and some of these structures
1
were additionally confirmed by the analysis of H NMR
spectra and data from elemental analysis (Table 1).
Thus, the chosen route allowed us to synthesize eight
derivatives of anthranilic acid amides and to determine the
range of applicability of this method.
Synthesis of anisaldehyde derivatives
Chloromethylation used to introduce functional groups
into the aromatic ring is known to proceed most smooth-
ly in the case of aromatic substrates activated with electron-
donating substituents. It is also known that the presence
of methoxy substituents in the benzene ring favors an
increase in the bioactivity. Therefore, we chose anisalde-
hyde as the research object and synthesized new aromatic
aldehydes by its chloromethylation followed by substitution
of different nucleophiles for the chlorine atom.
These studies allowed us to develop a method for the
preparative-scale preparation of 4-methoxy-3-chlorometh-
ylbenzaldehyde by the reaction of which with different
NH, OH, and SH acids about one hundred of new aro-
matic aldehydes have been synthesized (for details, see
Refs 12 and 13).
R´ = Pr (a), Ph (b), 4-MeOC6H4 (c), 4-FC6H4 (d), 4-MeC6H4 (e),
(f), Bn (g), CH2CH2NEt2 (h)
this process, we tested different commonly known meth-
ods by the example of reaction between the substituted
anisaldehyde 9 and anthranilic acid benzylamide 7g, which
results in the intermediate formation of Schiff bases 10
(Scheme 3). However, all these attempts resulted in either
compound 10 or a mixture of compounds 10 and 11m most
likely due to the fact that, under selected conditions, in-
termediates 10 are poorly soluble and, until completion
of the process, precipitate either individually or as a mix-
ture with the final quinazolinone 11m.
By selection of different solvents, we found conditions
(long-term reflux of reagents in a mixture of xylene and
acetic acid) under which quinazolinone 11m was the only
reaction product.
The method found can be applied with success for
the preparation of numerous quinazolinone derivatives
11a—y, 12a—l, and 13a,b by condensation of the synthe-
sized anthranilic acid amides with aldehydes (including
commercially available ones) except for some aldehydes
(indolyl, furyl, pyridyl, and pyrazolyl carbaldehydes).
Synthesis of 1,2-dihydro-4(3H)-quinazolinones
The literature data on the synthesis of quina-
zolinones6,7,14 by the above-chosen route (see the pream-
ble) include the reaction of anthranilic acid amides 7 with
aliphatic or heteroaromatic aldehydes or their acetals in
ethanol under the action of hydrochloric acid. Our attempts
to use the synthesized aromatic aldehydes under these
conditions does not lead to positive solutions (the starting
reagents were isolated). Therefore, to find conditions for

1046 Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
Khachatryan et al.
1
Table 1. Yields, melting points, data from elemental analysis, and H NMR spectra for anthranilic acid amides 7а—h (the solvent was
DMSO-d for 7a,c—g and CDCl for 7b,h)
6
3
1
Com- Yield M.p./C
pound (%)
Found
Molecular
formula
H NMR,  (J/Hz)
(%)
H
Calculated
C
7a
67
102
58.61
58.23
5.16
5.43
C
10H14N2O
1.00 (t, 3 H, CH3); 1.65, 3.40 (both m, 2 H each, 2 CH2);
5.20 (br.s, 2 H, NH2); 6.20 (br.s, 1 H, NHCO);
6.60—6.80, 7.15—7.35 (both m, 2 H each, CHAr
)
7b
7c
7d
82
78
83
128—129
147—148
97—98
60.31
60.45
62.01
62.11
65.32
65.05
5.63
5.54
6.26
6.12
6.44
6.06
C13H12N2O
C14H14N2O2
C13H11FN2O
5.20 (br.s, 2 H, NH2); 6.70 (m, 2 H, CHAr); 7.20—7.70
(m, 7 H, CHAr); 7.90 (br.s, 1 H, NHCO)
3.75 (c, 3 H, OCH3); 6.30 (br.s, 2 H, NH2); 6.70—7.60
(m, 8 H, CHAr); 8.80 (br.s, 1 H, NHCO)
6.15 (br.s, 2 H, NH2); 6.34, 6.61 (both m, 1 H each, 2 CHAr);
7.12 (d, 2 H, CHAr, J = 8.2); 7.20 (m, 1 H, CHAr);
7.58 (d, 2 H, CHAr, J = 8.2); 7.60 (m, 1 H, CHAr);
9.76 (br.s, 1 H, NHCO)
7e
7f
77
86
141
66.85
66.65
6.58
6.71
C14H14N2O
C12H12N2O2
2.26 (с, 3 H, CH3); 6.30 (br.s, 2 H, NH2); 6.58 (dd,
1 H, CHAr, J = 8.2, J = 1.2); 6.71 (d, 1 H, CHAr, J = 8.2);
7.12 (d, 2 H, CHAr, J = 8.4); 7.20 (dd, 1 H, CHAr
,
J = 8.2, J = 7.9); 7.58 (d, 2 H, CHAr, J = 8.4);
7.60 (m, 1 H, CHAr); 9.85 (br.s, 1 H, NHCO)
84—85
68.25
68.04
7.54
7.22
4.39 (d, 2 H, CH2, J = 1.9); 6.33, 6.43 (both d, 1 H each,
2 CHFur, J = 3.9); 6.46 (br.s, 2 H, NH2); 6.50 (t, 1 H,
CHAr, J = 9.2); 6.63 (d, 1 H, CHAr, J = 6.7); 7.11
(t, 1 H, CHAr, J = 9.3); 7.41 (d, 1 H, CHAr, J = 6.7);
7.51 (br.s, 1 H, CHFur); 8.72 (br.s, 1 H, NH)
7g
7h
81
65
90—91
Oil
74.66
74.25
6.01
6.24
C14H14N2O
С13H21N3O
4.37 (d, 2 H, CH2, J = 2.2); 5.76 (br.s, 2 H, NH2); 6.55
(d, 1 H, CHAr, J = 7.9); 7.20—7.40 (m, 7 H, CHAr);
7.65 (d, 1 H, CHAr, J = 7.6); 8.91 (br.s, 1 H, NH)
1.00 (t, 6 H, (CH3CH2)2N); 2.40—2.70 (m, 6 H, (CH3CH2)2N +
+ NHCH2CH2); 3.50 (m, 2 H, NHCH2CH2); 5.60
(br.s, 2 H, NH2); 6.60 (m, 2 H, CHAr); 6.90 (br.s, 1 H,
66.23
66.35
8.88
9.00
NHCH2); 7.20, 7.30 (both m, 1 H each, 2 CHAr
)
Scheme 3
In the case of using indolyl, furyl, pyridyl, and pyrazolyl
our attempts to alkylate 2-aryl quinazolinone 12l with
methyl iodide and to acylate with acetyl chloride and
benzoyl chloride were failed, while the reaction with phe-
nyl isocyanate afforded the corresponding carbamide
derivative 16 (Scheme 5).
When carboxyl-containing aromatic aldehydes (2-aldo-
benzoic acids 17a,b) were used in the synthesis of quinazol-
inones, the reactions were completed by the formation of
intramolecular acylation products 18a,b (Scheme 6).
carbaldehydes, the reaction is completed by the formation
of compounds 14 (Scheme 4; sh own by the example of
indole-2-carboxaldehyde) due to thermal elimination of
the aromatic residue from the 2 position of the quina-
zolinone ring (cf. Ref. 15).
The works6,7 showed that quinazolinones 5 having alkyl
substituents in the 2 position readily undergo alkylation
with alkyl halides to form 1-alkyl derivatives. However,

Synthesis of 1,2-dihydro-4(3H)-quinazolinones
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1047
11
R1
R2
11
R1
R2
11
R1
R2
11
R1
R2
a
b
Ph
Ph
h 4-MeOC6H4
2-FC6H4O
n
o
Bn
Bn
t
i
j
4-FC6H4
u
2-FC6H4
2-FC6H4
2-FC6H4O
c 4-MeOC6H4
4-MeC6H4 2,4,6-Cl3C6H2O
p
Bn
Bn
4-O2NC6H4O
v
2,4,6-Cl3C6H2O
d
4-FC6H4
k
l
4-MeC6H4
4-MeC6H4
q
r
3-MeOC6H4O
2-FC6H4O
w
x
2-FC6H4
2,4,6-Br3C6H2O
4-O2NC6H4O
2-MeOC6H4O
e 4-MeOC6H4
Pr
Pr
f
4-MeOC6H4
m
Bn
2-FC6H4O
s
y
g 4-MeOC6H4
12
a
R1
R2
12
d
R1
Ph
R2
12
g
R1
R2
12
j
R1
R2
4-FC6H4
4-FC6H4
4-MeOC6H4
Et2N(CH2)2
4-ClC6H4
b
c
Bn
Ph
e
Ph
3-FC6H4
h
i
Bn
Pr
Ph
k
l
Et2N(CH2)2
3-FC6H4
2,4-(MeO)2C6H3 f 4-MeOC6H4
(a), 2-FC6H4 (b)
4-FC6H4
Pr
2,4-(MeO)2C6H3
13: R1
=
2-Aminobenzhydrazide (19) also enters into the anal-
ogous reaction with aromatic aldehydes followed by cycli-
zation of the bis-arylmethylidene intermediate 21 into the
2-aryl 3-arylmethylideneamine quinazolinone derivative
22 (Scheme 7).
The structures of all synthesized compounds were
1
established by IR and H and 13C NMR spectroscopy
(Tables 2 and 3) and the structures of some compounds
were additionally determined by 2D NMR spectroscopy
and chromatography-mass spectrometry on a chiral col-

1048 Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
Khachatryan et al.
Scheme 4
The structures of quinazolinones 11g and 22d were
confirmed by the cumulative 1H and 13C NMR, DEPTq,
HSQC, NOESY, COSY, and HMBC spectra. The NOESY
correlations for the protons of quinazolinone 11g are
shown in Fig. 1. The H(5) ( 7.63) and H(7) ( 7.23) pro-
tons typical of this quinazolinone system are downfield
shifted with regard to the H(6) and H(8) protons ( 6.67)
whose signal merges into one multiplet and the H(2)
proton neighbor to the NH group (d,  7.40, J  2 Hz) is
the most upfield shifted (d,  6.10, J  2 Hz).
As could be expected, quinazolinone 22d (see Fig. 1)
is in the anti-conformation, which is confirmed by the fact
1
that the H NMR spectrum contains one signal for the
H(22) proton as a singlet at  8.77.
The introduction of the hydrazone fragment into the
quinazolinone system has no significant effect on the
chemical shifts of the H(5)—H(8) protons, which allowed
their identification also in other obtained quinazolinones
22a—c,e,f.
Scheme 5
Bioactivit y study of quinazolinones
The activity of resulting substances was studied by
high-throughput screening (HTS) performed on an auto-
mated systems for testing different effects. HTS allows one
to rapidly detect and confirm in independent experiments
the main effects exerted by the test substance on bio-
chemical processes in living cells.19
umn. The last method also confirmed that the synthesized
quinazolinones 11g and 22d (2R- and 2S-isomers) ex-
hibit stereoisomerism6—18 and exist as racemic mixtures.
Scheme 6
R = H (7b, 17a, 18a), OMe (7c, 17b, 18b)
Scheme 7
R = 4-Cl (a), 4-OMe (b), 4-Br (c), 2,3-(MeO)2 (d), 4-Me (e), 3,4-methylenedioxy (f)

Synthesis of 1,2-dihydro-4(3H)-quinazolinones
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1049
1
Table 2. Yields, melting points, data from elemental analysis, and IR and H NMR spectra for compounds 11a—y, 12a—l, 13a,b, 16,
and 18a,b
1
Com- Yield
pound- (%)
M.p.
/С
Found
Calculated
Molecular
formula
IR spectrum,
ν/cm–1
H NMR (DMSO-d ), (J/Hz)
6
(%)
C
H
N
11a
86 159—160 72.64 6.42
72.71 6.34
9.69
9.78
C
26H27N3O3 3297.6 (N—H), 2.11—2.26 (br.t, 4 H, CH2Omorph); 3.33 (br.s,
1004.6—1158.0 1 H + H2O); 3.50 (br.t, 4 H, CH2Nmorph
,
(C—O—C,
morph.),
J = 4.4); 3.70 (br.s, 3 H, OMe); 6.22 (d, 1 H,
2-Het, J = 2.0); 6.66—6.78 (m, 2 H, 6-Het,
1633.1 (C=O), 8-Het); 6.89 (d, 1 H, CHAr, J = 8.5);
1611.2 (CAr=С) 7.12—7.37 (m, 1 H, 7-Het + 8 H, CHAr);
7.50 (d, 1 H, NH, J = 1.9); 7.70
(d, 1 H, 5-Het, J = 7.7)
1.95, 2.09 (both br.s, 3 Н each, 2 Me); 3.76
(br.s, 3 H, OMe); 5.05 (br.s, 2 Н, NCH2);
11b
11c
93 159—160 68.53 5.38 11.81 C27H25N4O2Cl
68.57 5.33 11.85
3285.9
(N—H),
1638.0 (C=O), 6.15 (br.s, 1 H, 2-Het); 6.66—6.78 (m, 2 H,
1610.9 (CAr=С), 6-Het, 8-Het); 6.89 (d, 1 H, CHAr, J = 8.5);
2838.2
(CArOCH3)
7.12—7.37 (m, 8 H, 7-Het + 7 CHAr); 7.46
(d, 1 H, NH, J = 1.9); 7.70 (br.d,
1 H, 5-Het, J = 7.3)
94 194.5— 71.32 5.63
195.5 71.36 5.61
5.22
5.20
C32H30N2O6 3292.8 (N—H), 1.13 (t, 3 H, OCH2CH3, J = 7.1); 3.68
2837.7
(CArOCH3),
(s, 3 H, OCH3); 3.76 (s, 3 H); 4.20 (q, 2 H,
OCH2CH3, J = 7.1); 4.98—5.12 (m, 2 H,
1630.4 (C=O), OCH2); 6.13 (s, 1 H, 2-Het); 6.65—6.81 (m, 2 H,
1606.1 (CAr=С) 6-Het + 8-Het + 2 H, CHAr); 6.94 (d, 1 H,
12-CHAr, J = 8.8); 6.99—7.13 (m, 4 H, CHAr);
7.20—7.30 (m, 2 H, 7-Het + CHAr);
7.38 (br.s, 1 H, NH); 7.43—7.53 (m, 1 H, CHAr);
7.56 (br.s, 1 H, 15-CHAr); 7.66 (dd, 1 H,
6-Het, J = 7.7, J = 1.5); 7.69 (d, 1 H,
о-CH(ArCO2Et), J = 8.3)
11d
11e
95 281—282 70.37 5.11
70.44 5.12
8.23 C30H26FN3O4
8.21
3292.8
(N—H),
2840.6
1.99 (s, 3 H, CH3CO); 3.71 (s, 3 H, OMe);
6.12 (br.s, 1 H, 2-Het); 6.66—6.77 (m, 2 H,
6-Het, 8-Het); 6.81—6.89, 7.08—7.16
(CArOCH2),
(both m, 2 H each, CHAr); 7.21—7.31 (m, 1 H,
1616.9 (C=O), 7-Het + 2 H, CHAr); 7.40—7.50 (m, 1 H,
1601.9 (CAr=С) NH + 2 H, CHAr); 7.70 (d, 1 H, 5-Het,
J = 7.5); 9.91 (s, 1 H, CONH)
92 194—195 72.00 5.33
71.93 5.39
8.97
8.99
C28H25N3O4
3288.6
(N—H),
1626.8
3.71, 3.76 (both s, 3 H each, OMe); 4.93 (s,
2 H, OCH2); 6.08 (d, 1 H, 2-Het, J = 2.0);
6.18 (dt, 1 H, 5-CHPy, J = 10.0, J = 1.3);
6.39 (dd, 1 H, 3-CHPy, J = 9.8, J = 1.4);
(С—NPy),
1654.6 (C=O), 6.65—6.73 (m, 2 H, 6-Het, 8-Het);
2836.4
(CArOCH3)
6.76—6.83 (m, 2 H, m-CHArOMe); 6.92 (d,
1 H, 12-CHAr, J = 8.5); 6.97 (d, 1 H,
4-CHPy, J = 2.1); 7.02—7.09 (m, 2 H,
o-CHArOMe); 7.17—7.29 (m, 2 H, 11-CHAr
+ 7-Het); 7.36 (d, 1 H, NH, J = 1.9);
7.38—7.46 (m, 2 H, 6-CHPy + 15-CHAr);
7.63 (dd, 1 H, 5-Het, J = 7.8, J = 1.3)
+
11f
93 198—198.5 65.43 5.37 13.66
65.49 5.30 13.64
C28H27N5O5 3259.7 (N—H), 2.34, 2.38 (both s, 3 H each, Me); 3.72, 3.78
2837.3
(CArOCH3),
(both s, 3 H each, OMe); 5.17 (s, 2 H, CH2N);
6.04 (d, 1 H, 2-Het, J = 2.4); 6.57 (d, 1 H,
1631.5 (C=O), 15-CHAr, J = 2.1); 6.59—6.67 (m, 2 H, 6-Het,
1609.9 (C=N), 8-Het); 6.79—6.86 (m, 2 H, m-CHArOMe);
1561.4 (CAr=С) 6.96 (d, 1 H, 12-CHAr, J = 8.5); 7.00—7.08
(m, 2 H, o-CHArOMe); 7.16—7.24 (m, 2 H,
11-CHAr, 7-Het); 7.39 (d, 1 H, NH, J = 2.4);
7.56 (dd, 1 H, 5-Het, J = 7.9, J = 1.3)
(to be continued)

1050
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
Khachatryan et al.
Table 2 (continued)
1
Com- Yield
pound- (%)
M.p.
/С
Found
Calculated
Molecular
formula
IR spectrum,
ν/cm–1
H NMR (DMSO-d ), (J/Hz)
6
(%)
C
H
N
11g
93 229—229.5 64.34 4.77 14.45 C26H23N5O5 3294.7 (N—H), 3.71, 3.76 (both s, 3 H each, OMe); 5.28 (s,
64.32 4.77 14.43
2839.1
2 H, CH2N); 6.10 (d, 1 H, 2-Het, J = 1.9);
(CArOCH3),
6.62—6.72 (m, 2 H, 6-Het, 8-Het);
1627.0 (C=O), 6.78—6.86 (m, 2 H, m-CHArOMe); 6.95 (d, 1 H,
1608.6 (C=N), 12-CHAr, J = 8.5); 6.99 (d, 1 H, 15-CHAr, J = 1.9);
1509.0 (CAr=С) 7.04—7.12 (m, 2 H, o-CHArOMe); 7.19—7.27
(m, 2 H, 11-CHAr, 7-Het); 7.39 (d, 1 H, CHAr
,
NH, J = 1.8); 7.63 (d, 1 H, 5-Het, J = 7.6);
8.21 (s, 1 H, 3-CHPyr); 8.73 (s, 1 H, 5-CHPyr
3.70, 3.76 (both s, 3 H each, OMe); 5.04 (s,
2 H, OCH2); 6.15 (d, 1 H, 2-Het, J = 2.1);
6.65—6.74 (m, 2 H, 6-Het, 8-Het);
)
11h
92 177—178 71.93 5.12
71.89 5.20
5.73 C29H25FN2O4
5.78
—
6.78—6.85 (m, 2 H, m-CHArOMe); 6.89—7.00
(m, 2 H, CHAr); 7.03—7.15 (m, 4 H, CHAr);
7.16—7.32 (m, 1 H, 7-Het + 2 H, CHAr);
7.45 (br.s, 2 H, 15-CHAr, NH); 7.68 (dd,
1 H, 5-Het, J = 7.6, J = 1.0)
2.05—2.36 (br.s, 2 H, CH2); 3.33 (br.s,
4 H, CH2 (morph.)); 3.43—3.65 (m, 4 H,
CH2 (morph.)); 3.73 (s, 3 H, OMe); 6.22
11i•
•HCl
88 183—185 64.62 5.71
64.53 5.62
8.84 C26H27ClFN3O3
8.68
1608.5;
1506.4
(CAr=С),
1639.3 (C=O), (br.s, 1 H, 2-Het); 6.67—6.80 (m, 2 H,
3316.9 (N—H), 6-Het, 8-Het); 6.86—6.98 (br.s, 1 H,
2849.6 (CArOCH3), CHAr); 7.07—7.17 (m, 2 H, CHAr); 7.18—7.42
1008.4—1153.2 (m, 4 H, 7-Het + NH + 2 CHAr); 7.47 (br.s,
(C—O—C,
morph.)
3297.0
(N—H),
2836.9
(CArOCH3),
1 H, 15-CHAr); 7.64 (br.s, 1 H, 5-Het,
J = 7.6); 10.39 (br.s, 1 H, NH+)
11j
92 154—154.5 62.85 4.22
62.89 4.19
5.07 C29H23Cl3N2O3
5.06
2.26 (s, 3 H, Me); 3.69 (s, 3 H, OMe); 4.95
(s, 2 H, OCH2); 6.18 (d, 1 H, 2-Het,
J = 2.6); 6.66—6.77 (m, 2 H, 6-Het, 8-Het);
6.95 (d, 1 H, 12-CHAr, J = 8.6); 7.13 (br.s,
2940.1 (CH3), 5 H, CHAr); 7.22—7.29 (m, 1 H, 7-Het);
1632.8 (C=O), 7.32 (dd, 1 H, CHAr, J = 8.5, J = 2.3);
1551.1 (CAr=С) 7.55 (d, 1 H, NH, J = 2.3); 7.58 (d, 1 H,
11-CHAr, J = 2.6); 7.65 (s, 1 H, CHAr);
7.69 (dd, 1 H, 5-Het, J = 7.8, J = 1.4)
11k
94 168—169 66.57 4.95 14.94 C26H23N5O4
66.51 4.94 14.92
3295.9
(N—H),
2841.4
2.24 (s, 3 H, Me); 3.76 (s, 3 H, OMe);
5.27 (s, 2 H, CH2N); 6.14 (d, 1 H, 2-Het,
J = 2.3); 6.62—6.73 (m, 2 H, 6-Het, 8-Het);
6.95 (d, 1 H, 12-CHAr, J = 8.6); 6.98 (d,
(CArOCH3),
2925.5 (CH3), 1 H, 15-CHAr, J = 2.2); 7.03—7.12 (m,
1633.0 (C=O), 4 H, o-CHArOMe + m-CHArOMe); 7.19—7.29
1610.6 (C=N), (m, 2 H, 11-CHAr, 7-Het); 7.44 (d, 1 H, NH,
1504.8
J = 2.3); 7.64 (dd, 1 H, 5-Het, J = 7.7, J = 1.3);
8.21 (d, 1 H, 3-CHPyr, J = 0.4);
(CAr=С)
8.71 (s, 1 H, 5-CHPyr
)
11l
93 195—196 71.99 5.42
71.92 5.39
8.94 C28H25N3O2S
8.99
3323.7
(N—H),
2.23 (s, 3 H, Me); 3.76 (s, 3 H, OMe);
4.26 (s, 2 H, CH2S); 6.11 (d, 1 H, 2-Het,
2949.0 (CH3), J = 2.3); 6.64—6.72 (m, 2 H, 6-Het, 8-Het);
2835.2
(CArOCH3),
6.89 (d, 1 H, 12-CHAr, J = 8.3); 6.98—7.06
(m, 4 H, CHAr); 7.07—7.13 (m, 1 H, 5-CHPy);
1631.9 (C=O), 7.16—7.28 (m, 1 H, 7-Het + 2 H, CHAr);
1609.2 (C=N), 7.43—7.48 (m, 2 H, NH + 15-CHAr); 7.57—7.64
1578.8
(CAr=С)
(m, 1 H, 4-CHPy); 7.65—7.70 (m, 1 H, 5-Het);
8.37—8.41 (m, 1 H, 6-CHPy
)
(to be continued)

Synthesis of 1,2-dihydro-4(3H)-quinazolinones
Table 2 (continued)
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1051
1
Com- Yield
pound- (%)
M.p.
/С
Found
Calculated
Molecular
formula
IR spectrum,
ν/cm–1
H NMR (DMSO-d ), (J/Hz)
6
(%)
C
H
N
11m
11n
11o
11p
11q
11r
92 142—142.5 74.40 5.44
74.34 5.38
5.97 C29H25FN2O3
5.98
3300.0
(N—H),
2839.3
3.74 (d, 1 H, NCH2(a), J = 15.3); 3.79 (s, 3 H,
OMe); 5.05 (s, 2 H, OCH2); 5.26 (d, 1 H,
NCH2(b), J = 15.3); 5.68 (d, 1 H, 2-Het,
J = 2.3); 6.62 (d, 1 H, 8-Het, J = 8.0); 6.67
(CArOCH3),
1632.8 (C=O), (dt, 1 H, 6-Het, J = 7.6, J = 1.1); 6.89—6.98
1610.5 (С=N), (m, 1 H, CHAr); 7.02 (d, 1 H, 12-CHAr
,
1499.4
(CAr=С)
J = 8.6); 7.05—7.35 (m, 1 H, 7-Het + 10 H,
CHAr); 7.38 (d, 1 H, NH, J = 2.2);
7.68 (dd, 1 H, 5-Het, J = 7.8, J = 1.4)
3.74 (d, 1 H, NCH2(a), J = 15.3); 3.81 (s, 3 H,
OCH3); 5.21 (d, 1 H, NCH2(b), J = 15.3); 5.28
(s, 2 H, CH2NPyr); 5.61 (d, 1 H, 2-Het,
J = 2.4); 6.54 (d, 1 H, 8-Het, J = 8.1); 6.64
94 189—190 66.44 4.99 15.05 C26H23N5O4
66.51 4.94 14.92
3292.4
(N—H),
2840.6
(CArOCH3),
999.8 (N—O), (br.t, 1 H, 6-Het, J = 7.8); 6.88 (d, 1 H, CHAr
,
1635.4 (C=O), J = 2.0); 7.01 (d, 1 H, 12-CHAr, J = 8.5);
1611.5 (С=N), 7.15—7.36 (m, 7 H, 7-Het + NH + 5 CHAr);
1524.8
(CAr=С)
3272.1
(N—H),
2843.8
7.62 (dd, 1 H, 5-Het, J = 7.7, J = 1.4); 8.19
(s, 1 H, 3-CHPyr); 8.77 (s, 1 H, 5-CHPyr
)
93 244—245 67.57 5.50 14.06 C28H27N5O4
67.59 5.47 14.08
2.37 (s, 6 H, 2 Me); 3.71 (d, 1 H, NCH2(a)
J = 15.3); 3.81 (s, 3 H, OMe); 5.09—5.26
(m, 3 H, NCH2(b) + CH2NPyr); 5.57 (d,
1 H, 2-Het, J = 2.4); 6.49 (d, 1 H,
,
(CArOCH3),
1621.6 (C=O), 15-CHAr, J = 2.1); 6.54 (d, 1 H, 8-Het,
1611.9 (С=N), J = 8.1); 6.59 (dt, 1 H, 6-Het, J = 7.5,
1562.5
(CAr=С),
2930.5 (CH3)
3311.5
(N—H),
2841.3
(CArOCH3),
J = 1.1); 7.01 (d, 1 H, 12-CHAr, J = 8.6);
7.11—7.36 (m, 8 H, 7-Het + NH + 6 CHAr);
7.55 (dd, 1 H, 5-Het, J = 7.7, J = 1.4)
3.72—3.84 (m, 4 H, CH3 + NCH2(a)); 5.15
(s, 2 H, OCH2); 5.25 (d, 1 H, NCH2(b),
93 170—171 70.24 5.15
70.29 5.09
8.57
8.48
C29H25N3O5
J = 15.4); 5.68 (d, 1 H, 2-Het, J = 2.3);
6.60 (d, 1 H, 8-Het, J = 8.0); 6.66 (br.t,
1624.9 (C=O), 1 H, 6-Het, J = 7.5); 7.03 (d, 1 H, 12-CHAr
,
1592.4
(CAr=С),
994.0 (N—O)
J = 8.6); 7.10—7.16 (m, 2 H, m-CH(ArNO2));
7.16—7.38 (m, 9 H, 7-Het + NH + 7 CHAr);
7.65 (dd, 1 H, 5-Het, J = 7.7, J = 1.2);
8.15—8.23 (m, 2 H, o-CH(ArNO2))
3.73 (s, 3 H, OMe); 3.75—3.82 (m, 3 H,
OMe + 1 H, NCH2(a)); 4.96 (s, 2 H, OCH2);
5.26 (d, 1 H, NCH2(b), J = 15.4); 5.67 (d,
1 H, 2-Het, J = 2.0); 6.47—6.56 (m, 3 H,
95 144—145 74.96 5.93
74.98 5.87
5.82
5.83
C
30H28N2O4
3296.3
(N—H),
2835.7
(CArOCH3),
1624.9 (C=O), CHAr); 6.63 (d, 1 H, 8-Het, J = 8.1); 6.68
1614.5; 1582.5 (br.t, 1 H, 6-Het, J = 7.5); 7.00 (d, 1 H,
(CAr=С),
2928.6 (CH2)
12-CHAr, J = 8.6); 7.13—7.36 (m, 9 H,
7-Het + 8 CHAr); 7.39 (d, 1 H, NH,
J = 1.9); 7.69 (br.d, 1 H, 5-Het, J = 7.6)
3.75—3.87 (m, 3 H, OCH3 + 1 H, CH2(a)N);
94 118—119 70.76 4.69
70.73 5.06
6.07 C27H23FN2O4
6.11
3066.8
(C—H, furan), 5.06 (s, 2 H, OCH2); 5.15 (d, 1 H, CH2(b)N,
1611.3
J = 15.1); 5.71 (d, 1 H, 2-Het, J = 2.3); 6.26
(C—C, furan), (d, 1 H, 3-CHFur); 6.35—6.38 (m, 1 H, 4-CHFur);
1634.7 (C=O), 6.61 (d, 1 H, 8-Het, J = 8.1); 6.63—6.70 (m,
3305.5 (N—H) 1 H, 6-Het); 6.89—6.99 (m, 1 H, CHAr); 7.02
(d, 1 H, 12-CHAr, J = 8.6); 7.05—7.13 (m, 1 H,
CHAr); 7.13—7.22 (m, 3 H, 7-Het + 2 CHAr);
7.22—7.32 (m, 2 H, NH + CHAr); 7.39 (d,
1 H, 15-CHAr, J = 2.4); 7.54—7.57 (m, 1 H,
CHAr); 7.66 (dd, 1 H, 5-Het, J = 7.8, J = 1.4)
(to be continued)

1052
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
Khachatryan et al.
Table 2 (continued)
1
Com- Yield
pound- (%)
M.p.
/С
Found
Calculated
Molecular
formula
IR spectrum,
ν/cm–1
H NMR (DMSO-d ), (J/Hz)
6
(%)
C
H
N
11s
90 125—126 62.73 4.63 15.20 C24H21N5O5 3276.1 (N—H), 3.79 (s, 3 H, OMe); 3.83 (d, 1 H, NCH2(a)
,
62.74 4.61 15.24 3123.8 (C—H, J = 15.6); 5.15 (d, 1 H, NCH2(b), J = 15.6);
furan),
2840.2
(CArOCH3),
1612.3 (C—C,
furan),
5.30 (d, 2 H, CH2NPyr, J = 2.0); 5.65 (d,
1 H, 2-Het, J = 2.1); 6.26 (d, 1 H, 3-CHFur
,
J = 3.1); 6.34—6.39 (m, 1 H, 4-CHFur);
6.57 (d, 1 H, 8-Het, J = 8.0); 6.63 (br.t,
1 H, 6-Het, J = 7.4); 6.89 (d, 1 H, 5-CHFur
,
1626.1 (C=O), J = 2.0); 7.01 (d, 1 H, 12-CHAr, J = 8.6);
1581.2 (C=N), 7.18 (dt, 1 H, 7-CHAr, J = 7.7, J = 1.6);
1503.2 (CAr=С) 7.22—7.28 (m, 2 H, 11-CHAr, 15-CHAr);
7.55 (d, 1 H, NH, J = 1.0); 7.60 (dd, 1 H,
5-Het, J = 7.7, J = 1.2); 8.19 (s, 1 H,
3-CHPyr); 8.77 (s, 1 H, 5-CHPyr
)
11t
91 163—164 67.29 5.10
8.45
8.41
C28H25N3O6 3074.1 (C—H, 2.54 (s, 3 H, CH3); 3.79 (s, 3 H, OCH3); 3.83
67.33 5.04
furan),
1610.8 (C—C,
furan),
(d, 1 H, NCH2(a), J = 15.6); 5.12 (s, 2 H,
CH2O); 5.14 (d, 1 H, NCH2(b), J = 15.6);
5.65 (d, 1 H, 2-Het, J = 2.1); 6.27 (d, 1 H,
3-CHFur, J = 3.1); 6.37 (d, 1 H, 4-CHFur, J = 3.1);
2937.3 (CH2),
3303.2 (N—H), 6.58 (d, 1 H, 8-Het, J = 8.0); 6.65 (t, 1 H, 6-Het,
2838.4
(CArOCH3),
3010.5 (CH3)
J = 7.4); 6.97 (d, 1 H, J = 2.0); 7.01—7.38 (m,
6 H, 7-Het + 5 CHAr); 7.56 (d, 1 H, NH, J = 1.0);
7.62 (dd, 1 H, 5-Het, J = 7.7, J = 1.2); 8.19
(d, 1 H, m-CH(ArNO2), J = 8.0)
11u
11v
11w
94 129—130 71.15 4.76
71.18 4.69
5.87 C28H22F2N2O3
5.93
3297.7
(N—H),
2840.2
2.08 (s, 3 H, Me); 3.76 (s, 3 H, OMe); 5.02
(s, 2 H, CH2O); 6.19 (br.s, 1 H, 2-Het);
6.71—6.81 (m, 2 H, 6-Het, 8-Het); 6.89—7.06
(m, 3 H, CHAr); 7.07—7.30 (m, 6 H, 7-Het +
5 CHAr); 7.31—7.37 (m, 2 H, CHAr); 7.41
(br.s, 1 H, 15-CHAr); 7.51 (d, 1 H, NH,
J = 2.2); 7.67 (dd, 1 H, 5-Het, J = 7.7, J = 1.4)
3.69 (s, 3 Н, ОСН3); 4.93 (br.s, 2 Н, ОСН2);
6.20 (br.s, 1 H, 2-Het); 6.71—6.82 (m, 2 H,
(CArOCH3),
1590.7
(C=O)
92 160—161.5 60.37 3.55
60.29 3.61
4.92 C28H20FCl3N2O3
5.02
1635.3
(C=O),
1609.1
(CAr=С),
3294.9
(N—H)
6-Het, 8-Het); 6.93 (d, 1 H, 12-CHAr
,
J = 8.6); 7.04—7.39 (m, 6 Н, 7-Het +5 СНAr);
7.46 (br.s, 1 H, 15-CHAr); 7.60 (d, 1 Н, NH,
J = 2.2); 7.67 (s, 2 Н, m-СНArCl); 7.70 (dd,
1 Н, 5-Het, J = 7.8, J = 1.6)
93 166—167 48.63 2.95
48.66 2.92
4.04 C28H20Br3FN2O3
4.05
1372.7
(C—F),
1635.3
(C=O),
1609.4
(CAr=С),
3291.9
(N—H)
3.71 (s, 3 H, OMe); 4.83—4.96 (m, 2 H,
OCH2); 6.20 (br.s, 1 H, 2-Het); 6.30—6.70
(m, 2 H, 6-Het, 8-Het); 6.93 (d, 1 H,
12-CHAr, J = 8.8); 7.04—7.38 (m, 6 H,
7-Het + 5 CHAr); 7.45 (br.s, 1 H, CHAr);
7.66 (d, 1 H, NH, J = 2.0); 7.71 (dd, 1 H,
5-Het, J = 7.7, J = 1.0); 7.65
(s, 2 H, m-CHArBr)
11x
88 175—176 67.13 5.61
67.10 5.63
9.36
9.39
C25H25N3O5 1619.5 (CAr=С), 0.80 (t, 3 H, γ-Me (Pr), J = 7.3); 1.40—1.62
1639.4 (C=O), (m, 2 H, β-Me); 2.60—2.74 (m, 1 H, α-CH2(a));
2838.2
(CArOCH3),
3.70—3.80 (m, 1 H, α-CH2(b)); 3.81 (s, 3 Н,
ОСН3); 5.18 (s, 2 Н, ОСН2); 5.79 (d, 1 Н, 2-Het,
2965.3 (CH2), J = 2.0); 6.55—6.70 (m, 2 Н, 6-Het, 8-Het); 7.05
3292.6 (N—H) (d, 1 H, 12-CHAr, J = 8.6); 7.11—7.19 (m, 2 H,
o-CH(ArNO2) + 1 H, 11-CHAr); 7.25—7.33
(m, 2 Н, 15-CHAr, 7-Het); 7.39 (d, 1 H, NH,
J = 2.2); 7.61 (dd, 1 H, 5-Het, J = 7.9, J = 1.3);
8.21 (m, 2 H, m-CH(ArNO2))
(to be continued)

Synthesis of 1,2-dihydro-4(3H)-quinazolinones
Table 2 (continued)
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1053
1
6
Com- Yield
pound- (%)
M.p.
/С
Found
Calculated
Molecular
formula
IR spectrum,
ν/cm–1
H NMR (DMSO-d ), (J/Hz)
(%)
C
H
N
11y
86 111.5—112 72.23 6.49
72.20 6.52
6.54
6.48
C26H28N2O4
2834.6
0.80 (t, 3 Н, γ-Me (Pr), J = 7.8); 1.48 (m, 2 Н,
(CArOCH3),
β-CH2); 2.68, 3.70 (both m, 1 Н each, α-CH2);
2935.2; 2959.9 3.72, 3.79 (both s, 3 H each, OCH3); 4.97 (s,
(CH2), 3297.9 2 H, OCH2); 5.79 (d, 1 Н, 2-Het, J = 2.1);
(N—H),
1621.9
(CAr=С),
6.47—6.55 (m, 3 Н, СНAr); 6.59—6.68 (m,
2 H, 6-Het, 8-Het); 7.01 (d, 1 H, 12-CHAr
,
J = 8.5); 7.11—7.22 (m, 2 Н, 7-Het + СНAr);
1665.2 (C=O) 7.26 (br.s, 2 H, СНAr); 7.43 (d, 1 Н, NH,
J = 2.1); 7.63 (d, 1 Н, 5-Het, J = 7.5)
5.97 (d, 2 H, OCH2O, J = 2.7); 6.19 (d, 1 H,
2-Het, J = 2.1); 6.69—6.78 (m, 2 H, 6-Het,
12a
12b
12c
93 272.5—273 69.63 4.15
69.61 4.17
7.71 C21H15FN2O3
7.73
933.3
(С—O—C,
benzodioxole), 8-Het); 6.80 (br.s, 2 H, CHAr); 6.93 (br.s,
1611.3;
1 H, CHAr); 7.10—7.20 (m, 2 H, CHAr);
1502.0 (CAr=С), 7.21—7.33 (m, 1 H, 7-Het + 2 H, CHAr);
1639.3 (C=O), 7.49 (d, 1 H, NH, J = 2.1); 7.71 (dd, 1 H,
3297.9 (N—H) 5-Het, J = 7.8, J = 1.3)
95 176—176.5 73.68 5.09
73.73 5.06
7.84
7.82
C22H18N2O3
929.3
(С—O—C,
3.83, 5.27 (both d, 1 H each, NCH2Ph, J = 15.3);
5.67 (d, 1 H, 2-Het, J = 2.4); 5.98 (s, 2 H,
benzodioxole), OCH2O); 6.61—6.72 (m, 4 H, CHAr); 6.75
1610.6; 1501.1
(CAr=С),
3319.7 (N—H), 5-Het, J = 7.7, J = 1.4)
1628.1 (C=O)
(dd, 1 H, CHAr, J = 8.1, J = 1.6); 6.82—6.88
(m, 1 H, NH + 6 H, CHAr); 7.69 (dd, 1 H,
91 169—170.5 73.41 5.52
73.32 5.59
7.75
7.77
C22H20N2O3
3360.8
(N—H),
2840.4
3.69 (s, 3 H, p-ArOCH3); 3.74 (s, 3 H,
o-ArOCH3); 6.32 (d, 1 H, CHAr, J = 2.5);
6.43 (dd, 1 H, CHAr, J = 8.5, J = 2.3);
6.52 (d, 1 H, 2-Het, J = 2.5); 6.70 (t, 1 H,
(CArOCH3),
1654.4 (C=O), 8-Het, J = 7.5); 6.77 (d, 1 H, 6-Het,
1611.5
(CAr=С)
J = 8.1); 7.11 (d, 1 H, CHAr, J = 2.2);
7.12—7.25 (m, 1 H, 7-Het + 4 H, CHAr);
7.26—7.36 (m, 2 H, NH + CHAr);
7.73 (d, 1 H, 5-Het, J = 7.8)
6.31 (d, 1 H, 2-Het, J = 2.4); 6.68—6.80 (m,
2 H, 6-Het, 8-Het); 7.08—7.19 (m, 2 H,
CHAr); 7.20—7.28 (m, 1 H, 7-Het + 2 H,
CHAr); 7.29—7.37 (m, 3 H, CHAr);
7.38—7.45 (m, 2 H, CHAr); 7.61 (d, 1 H,
NH, J = 2.3); 7.72 (dd, 1 H, 5-Het,
J = 1.3, J = 7.8)
12d
93 229.5—230.5 75.39 4.77
75.46 4.75
8.75
8.80
C
20H15FN2O
3293.1
(N—H),
1629.0
(C=O),
1605.4
(CAr=С)
12e
12f
89 191—191.5 75.44 4.78
75.46 4.75
8.79 C20H15FN2O
8.80
3297.6
(N—H),
1636.0
(C=O),
1609.8
(CAr=С)
2831.4
(CArOCH3),
6.34 (d, 1 H, 2-Het, J = 2.6); 6.73 (t, 1 H,
6-Het, J = 7.9); 6.78 (d, 1 H, 8-Het,
J = 8.1); 7.04—7.14 (m, 1 H, CHAr);
7.15—7.40 (m, 1 H, 7-Het + 8 H, CHAr);
7.69 (d, 1 H, NH, J = 2.8); 7.73 (dd, 1 H,
5-Het, J = 7.8, J = 1.1)
92 225.5—226 77.53 5.33
77.58 5.35
9.64
9.69
C28H23N3O2
3.65 (s, 3 H, OMe); 3.82 (s, 3 H, NMe);
6.38 (d, 1 H, 2-Het, J = 1.8); 7.68—7.77
3305.5 (N—H), (m, 2 H, 6-Het, 8-Het); 7.78—7.84 (m, 2 H,
1633.0 (C=O), m-CHArOMe); 7.13—7.22 (m, 3 H, CHAr);
1603.5
(CAr=С)
7.23—7.31 (dt, 1 H, 7-Het, J = 7.6, J = 1.7);
7.41—7.48 (m, 1 H, CHAr); 7.51 (br.s, 1 H,
NH + 2 H, CHAr); 7.56 (d, 1 H, CHAr, J = 8.1);
7.76 (dd, 1 H, 5-Het, J = 7.8, J = 1.3);
8.04 (d, 1 H, CHAr, J = 7.7);
8.11 (br.s, 1 H, CHAr
)
(to be continued)

1054
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
Khachatryan et al.
Table 2 (continued)
1
Com- Yield
pound- (%)
M.p.
/С
Found
Calculated
Molecular
formula
IR spectrum,
ν/cm–1
H NMR (DMSO-d ), (J/Hz)
6
(%)
C
H
N
12g
94 243—244 70.65 4.93
70.58 4.85
7.40
7.48
C22H18N2O4
2898.7
(CArOCH3),
3291.6
(N—H),
1632.6
(C=O),
1605.4
(CAr=С)
3400.0
(N—H),
1631.9
(C=O),
1618.5
(CAr=С)
3298.3
(N—H),
1605.2;
1589.8
3.72 (s, 3 H, OMe); 5.96 (dd, 2 H, OCH2O,
J = 4.2, J = 0.8); 6.11 (d, 1 H, 2-Het,
J = 2.3); 6.67—6.77 (m, 2 H, 6-Het, 8-Het);
6.79 (br.s, 2 H, CHAr); 6.84—6.93 (m, 3 H,
CHAr); 7.10—7.18 (m, 2 H, o-CHArOMe);
7.27 (dt, 1 H, 7-Het, J = 7.7, J = 1.5);
7.44 (d, 1 H, NH, J = 2.2); 7.70 (dd, 1 H,
5-Het, J = 7.8, J = 1.4)
3.82 (d, 1 H, NCH2(a), J = 15.4); 5.32 (d, 1 H,
NCH2(b), J = 15.4); 5.74 (d, 1 H, 2-Het,
J = 2.6); 6.59—6.73 (m, 2 H, 6-Het, 8-Het);
7.17—7.41 (m, 12 H, 7-Het + NH + 10 CHAr);
7.69 (dd, 1 H, 5-Het, J = 7.8, J = 1.5)
12h
12i
88 162—163 80.21 5.76
80.23 5.77
8.89
8.91
C21H18N2O
90 154—155 71.86 6.01
71.81 6.03
9.85 C17H17FN2O
9.85
0.83 (t, 3 H, γ-Me (Pr), J = 7.2); 1.36—1.65
(m, 2 H, β-CH2); 2.65—2.77, 3.75—3.88
(both m, 1 H each, α-CH2); 5.86 (d, 1 H, 2-Het,
J = 2.3); 6.59—6.69 (m, 2 H, 6-Het, 8-Het);
7.13—7.23 (m, 1 H, 7-Het + 2 H, m-CHArF);
7.30—7.40 (m, 1 H, NH + 2 H, o-CHArF);
7.64 (d, 1 H, 5-Het, J = 7.7)
(CAr=С),
1626.5
(C=O),
2970.6 (CH2)
—
12j
87 116.5—117 67.16 6.72 11.75 C20H24ClN3O
67.12 6.76 11.74
0.90 (t, 6 H, CH2CH3, J = 7.1); 2.33—2.48
(m, 5 H, β-CH2(b), CH2CH3); 2.53—2.67
(m, 1 H, β-CH2(a)); 2.76—2.90 (m, 1 H,
α-CH2(b)); 3.75—3.87 (m, 1 H, α-CH2(a)); 5.97
(d, 1 H, 2-Het, J = 2.3); 6.57—6.68 (m, 2 H,
6-Het, 8-Het); 7.19 (dd, 1 H, 7-Het, J = 7.8,
J = 1.5); 7.31 (d, 1 H, NH, J = 2.1); 7.35 (d, 2 H,
o-CHAr, J = 8.5); 7.43 (d, 2 H, m-CHAr
,
J = 8.5); 7.59—7.67 (m, 1 H, 5-Het)
12k
12l
85 106.5—107 70.43 7.01 12.35 C20H24FN3O
70.36 7.08 12.31
—
—
0.91 (t, 6 H, CH2CH3, J = 7.1); 2.33—2.48
(m, 5 H, β-CH2(b), CH2CH3); 2.54—2.67
(m, 1 H, β-CH2(a)); 2.80—2.92 (m, 1 H,
α-CH2(b)); 3.79—3.91 (m, 1 H, α-CH2(a));
5.98 (d, 1 H, 2-Het, J = 2.3); 5.98—6.65
(m, 2 H, 6-Het, 8-Het); 7.09—7.25 (m, 4 H,
7-Het, CHAr); 7.31—7.46 (m, 2 H, CHAr
,
NH); 7.59—7.68 (m, 1 H, 5-Het)
88 161—162 69.86 6.81
69.92 6.79
8.62
8.58
C19H22N2O3
0.83 (t, 3 H, γ-Me (Pr), J = 7.2); 1.36—1.65
(m, 2 H, β-CH2); 2.65—2.77 (m, 1 H, α-CH2);
3.69 (s, 3 H, p-ArOCH3); 3.74 (s, 3 H,
o-ArOCH3); 3.75—3.88 (m, 1 H, α-CH2); 5.81
(d, 1 H, 2-Het, J = 2.1); 6.30 (d, 1 H, CHAr
,
J = 2.5); 6.41 (dd, 1 H, CHAr, J = 8.4, J = 2.3);
6.59—6.69 (m, 2 H, 6-Het, 8-Het); 7.11 (d, 1 H,
CHAr, J = 2.4); 7.14—7.19 (m, 1 H, 7-Het); 7.32
(d, 1 H, NH, J = 2.2); 7.58 (d, 1 H, 5-Het, J = 7.8)
1.27 (t, 3 H, OCH2CH3, J = 7.3); 3.89—4.00
(m, 2 H, OCH2CH3 + 1 H, NCH2(a));
13a
92 112—113 68.76 5.21
68.78 5.15
5.76 C28H25ClN2O4
5.73
3306.0
(N—H),
2927.6 (CH3), 5.07—5.17 (m, 2 H, OCH2 + 1 H, NCH2(b));
2980.2 (CH2), 5.71 (d, 1 H, 2-Het, J = 2.0); 6.28 (d, 1 H,
3061.1 (C—H, 3-CHFur, J = 3.2); 6.35—6.40 (m, 1 H,
furan),
4-CHFur); 6.60—6.71 (m, 2 H, 6-Het,
(to be continued)

Synthesis of 1,2-dihydro-4(3H)-quinazolinones
Table 2 (continued)
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1055
1
Com- Yield
pound- (%)
M.p.
/С
Found
Calculated
Molecular
formula
IR spectrum,
ν/cm–1
H NMR (DMSO-d ), (J/Hz)
6
(%)
C
H
N
13a
1610.9 (C—C,
furan),
8-Het); 6.78 (dd, 1 H, CHAr, J = 8.3,
J = 1.9); 6.94—7.01 (m, 2 H, CHAr);
1632.8 (C=O) 7.21 (dt, 1 H, 7-Het, J = 7.6, J = 1.6);
7.28 (d, 1 H, NH, J = 2.0); 7.33—7.41
(m, 2 H, CHAr); 7.45—7.52 (m, 1 H, CHAr);
7.53—7.58 (m, 2 H, CHAr); 7.67 (dd,
1 H, 5-Het, J = 7.8, J = 1.3)
1.24 (t, 3 H, ОCH2CH3, J = 7.3); 4.20 (q,
2 H, ОCH2CH3, J = 7.3); 5.07 (s, 2 H,
13b
16
89 198—198.5 69.33 4.79
69.25 4.81
5.54 C29H24ClFN2O3
5.57
3301.1
(N—H),
1637.4 (C=O), OCH2); 6.20 (br.s, 1 H, CHAr);
1609.9 (С=N), 6.65—7.60 (m, 1 H, NH + 14 H, CHAr);
1501.3 (CAr=С) 7.70 (d, 1 H, 5-Het, J = 8.1)
87 178—179 70.03 6.17
70.09 6.11
9.41
9.43
C26H27N3O4 1633.7 (CAr=С), 0.85 (t, 3 H, γ-Me (Pr), J = 7.3); 1.47—1.72
1683.5 (C=O), (m, 2 H, β-CH2); 2.80—2.94 (m, 1 H,
2837.6
(CArOCH3),
α-CH2(a)); 3.78, 3.84 (both s, 3 H each, OMe);
3.87—4.01 (m, 1 H, α-CH2(b)); 6.33 (dd,
2965.8 (CH2), 1 H, 2-Het, J = 7.8, J = 1.1); 6.87 (t, 1 H,
3230.8 (N—H) 6-Het, J = 8.0); 6.96 (dd, 1 H, 8-Het,
J = 8.0, J = 1.3); 7.05 (t, 1 H, CHAr
,
J = 7.3); 7.20—7.36 (m, 5 H, CHAr);
7.41—7.52 (m, 3 H, CHAr); 7.88 (dd, 1 H,
5-Het, J = 7.7, J = 1.4); 8.88 (s, 1 H, NH)
6.10 (d, 1 H, CHAr, J = 7.7); 7.02 (s, 1 H, 2-Het);
7.35—7.45 (m, 3 H, CHAr); 7.45—7.53 (m, 2 H,
CHAr); 7.57 (t, 2 H, CHAr, J = 7.5); 7.73—7.82
(m, 1 H, CHAr); 7.89 (d, 1 H, CHAr, J = 7.5);
8.04 (dd, 1 H, 5-Het, J = 1.2, J = 7.8);
8.12 (d, 1 H, J = 8.1)
18a
18b
83 198—199 77.23 4.37
77.29 4.32
8.50
8.58
C21H14N2O2
1719.4
(C=O),
1654.4
(CAr=С),
1364.3
(С—N)
2834.9
(CArOCH3),
1709.9,
75 224—225 69.18 4.86
69.22 4.84
6.77
6.73
C24H20N2O5
3.78, 3.82, 3.90 (all s, 3 H each, OMe); 5.85
(d, 1 H, CHAr, J = 8.3); 6.73 (br.s, 1 H, m-CHAr);
6.80 (s, 1 H, 2-Het); 6.89 (br.s, 1 H, m-CHAr´);
1665.2 (C=O), 7.10 (d, 1 H, CHAr, J = 8.5); 7.13 (br.s, 1 H,
1602.9 (CAr=С), o-CHAr); 7.38 (t, 1 H, 6-Het, J = 7.6);
1349.6 (С—N) 7.68 (br.s, 1 H, o-CHAr´); 7.74 (t, 1 H, 7-Het,
J = 7.8); 8.01 (d, 1 H, 8-Het, J = 7.8);
8.08 (d, 1 H, 5-Het, J = 8.0)
The SAR analysis allows one to determine chemical
proliferative activity of tumor cells. In addition, compound
11k stimulates the expression of the Rab9 gene encoding
the protein responsible for the vesicular transport from
endosomes to the Goldgi apparatus.21 The activity of this
protein increases the rate of propagation of low-molecular-
weight substances, including drugs, within a cell, which
can increase the sensitivity of tumor cells to therapy.
Finally, compound 11k stimulates the function of the SWI/
SNF complex, which retards division processes and pre-
vents the action of oncoproteins.
Quinazolinone 11k increases the expression level of
the NPC1 gene which is fixed in the membranes of endo-
somes and exosomes and mediates the intracellular trans-
port of cholesterol and lipoproteins. Defects in this gene
favor the development of neurogenerative diseases, such
as the Niemann—Pick disease and, possibly, the Alzheimer
groups responsible for different biological effects in vivo.20
The above-mentioned methods allow one to determine
both potentially useful properties of new molecules and
possible negative consequences of their use in the disease
treatment. The results of the bioactivity studies of quin-
azolinone derivatives by the above-mentioned methods
are specified in the Pubchem database (https://pubchem.
ncbi.nlm.nih.gov/).
In our case, compounds 11 and 18 are racemates.
According to the data from the studies performed,
compound 11k (Pubchem CID 2888389) possesses the
highest bioactivity. Compound 11k inhibits the aldehyde
dehydrogenase ALDH1A1, which can decrease the rate of
malignancy growth of tumor cells, as well as can block the
KCNK3 potassium channel causing a decrease in the

1056
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
Khachatryan et al.
1
Table 3. Yields, melting points, data from elemental analysis, and IR and H NMR spectra for aryl quinazolinones 22a—f
1
Com- Yield
pound- (%)
M.p.
/С
Found
Molecular
formula
IR spectrum,
ν/cm–1
H NMR (DMSO-d ), (J/Hz)
6
(%)
N
Calculated
C
H
22a
22b
22c
88
84
90
192—192.5
224—225
206—207
63.60 3.89 10.57
63.65 3.82 10.60
C
21H15Cl2N3O
3321.9
(N—H),
1632.1
(C=O),
1610.7
(C=N),
6.51 (d, 1 H, 2-Het, J = 3.1); 6.75 (t, 1 H,
6-Het, J = 7.5); 6.81 (d, 1 H, 8-Het,
J = 8.1); 7.26—7.34 (m, 1 H, CHAr);
7.35—7.45 (m, 4 H, CHAr); 7.47—7.54
(m, 2 H, CHAr); 7.68—7.75 (m, 3 H, CHAr);
7.92 (d, 1 H, NH, J = 3.0);
1503.9 (CAr=С) 8.90 (s, 1 H, N=CH)
71.33 5.53 10.79 C23H21N3O3
71.30 5.46 10.85
1504.0
(CAr=С),
3.68, 3.79 (both s, 3 H each, OMe); 6.37 (d, 1 H,
2-Het, J = 2.6); 6.73 (t, 1 H, 6-Het); 6.78 (d,
1605.5 (С=N), 1 H, 8-Het, J = 8.1); 6.84—6.91 (m, 2 H);
1625.4 (C=O), 6.96—7.03 (m, 2 H, CHAr); 7.24—7.33 (m,
2838.6
(CArOCH3),
3331.8 (N—H) 1 H, NH, J = 2.7); 8.75 (s, 1 H, N=CH)
1508.1
(CAr=С),
3 H, CHAr); 7.61—7.68 (m, 2 H, CHAr); 7.70
(dd, 1 H, CHAr, J = 7.8, J = 1.3); 7.74 (d,
52.03 3.05 8.74 C21H15Br2N3O
51.99 3.12 8.66
6.50 (d, 1 H, 2-Het, J = 2.5); 6.75 (t, 1 H,
6-Het, J = 7.0); 6.81 (d, 1 H, 8-Het,
1587.7 (C=O), J = 8.5); 7.27—7.37 (m, 3 H, CHAr);
1611.0 (С=N), 7.51—7.57 (m, 2 H, CHAr); 7.66 (s, 4 H,
3318.3 (N—H) CHAr); 7.72 (d, 1 H, CHAr, J = 8.5); 7.93
(d, 1 H, NH, J = 2.3); 8.88 (s, 1 H, N=CH)
22d
22e
22f
77
85
83
170—171
192—193
229—230
67.03 5.71 9.43 C25H25N3O5 3349.4 (N—H), 3.61, 3.79, 3.81, 3.90 (all s, 3 Н each, ОСН3);
67.10 5.63 9.39
2831.9
(CArOCH3),
6.63 (d, 1 H, 2-Het, J = 2.6); 6.69—7.39
(m, 10 H, CHAr); 7.77 (d, 1 H, NH, J = 2.5);
1610.0 (С=N), 8.77 (s, 1 Н, N=CH)
1632.4 (C=O)
77.76 5.93 11.75 C23H21N3O 3318.6 (N—H), 2.20, 2.32 (both s, 3 Н each, СН3); 6.49 (d, 1 H,
77.72 5.95 11.82
1608.4 (С=N), 2-Het, J = 2.5); 6.72 (t, 1 H, 6-Het, J = 7.0);
1629.4 (C=O), 6.78 (d, 1 H, 8-Het, J = 8.5); 7.13—7.32 (m,
2919.4 (CH3), 7 H, CHAr); 7.61—7.71 (m, 4 H, CHAr); 7.82
1505.0 (CAr=С) (d, 1 H, NH, J = 2.3); 8.88 (s, 1 H, N=CH)
66.42 4.16 10.07 C23H17N3O5
66.50 4.12 10.12
914.1—930.7
(С—O—C,
5.96 (d, 2 H, OCH2O, J = 1.4); 6.08 (d, 2 H,
OCH2O, J = 2.3); 6.33 (d, 1 H, 2-Het,
benzodioxole), J = 2.6); 6.69—6.88 (m, 4 H, CHAr); 6.94
1500.9 (C=O), (d, 1 H, CHAr, J = 1.1); 6.98 (d, 1 H, CHAr
1350.4 (С—N), J = 8.0); 7.17 (dd, 1 H, CHAr, J = 8.0,
1609.6 (CAr=С), J = 1.3); 7.25 (s, 1 H, CHAr); 7.30 (t, 1 H,
1655.4 (С=N), 7-Het, J = 7.7); 7.70 (d, 1 H, 5-Het, J = 6.9);
3296.6 (N—H) 7.75 (d, 1 H, NH, J = 2.5);
,
8.78 (s, 1 H, N=CH)
disease.22 This disease is difficult to treat due to the inac-
cessibility of neurons protected by the blood-brain bar-
rier. Low-molecular-weight compounds have a chance to
overcome the barrier, arrest the consequences of insuffi-
cient NPC1 protein activity, and to cease the cell death.
Quinazolinone 11k also forms different versions of the
mRNA splicing of the SMN2 gene. The SMN2 gene en-
codes the protein significant for the stability of motor
neurons. Abnormalities in the splicing of SMN2 mRNA
results in the nonfunctional protein synthesis.23 As a result,
the muscular atrophy progresses, which terminates by
a fatal event for the patient. The correction of splicing
processes can restore the normal functions of motor neu-
rons. However, quinazolinone 11k can have neurotoxic-
ity due to inhibition of neuropeptide Y2.
Compound 11k can facilitate the course of bloody
flux,24 since it inactivates Shiga toxins, which are produced
by the Shigella dysenteriae pathogen.
Compound 11r (CID 3712338) inhibits the NF-B
protein and thereon dependent signaling pathway.
Moreover, it can blocks the CACNA1G calcium channel
and increase the mitochondrial membrane permeability
by activating ClpP and thereby facilitating initiation of the
internal apoptosis pathway. The substance with such char-
acteristics can have potent anticancer effect. At the same
time, quinazolinone 11r is the GRP7 neuropeptide recep-

Synthesis of 1,2-dihydro-4(3H)-quinazolinones
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
1057
Fig. 1. NOESY correlation for quinazolinones 11g and 22d.
chloroform—methanol (8 : 2) as the eluent; the chromatograms
were developed under an UV lamp and in iodine vapors. H NMR
spectra were recorded on a Bruker AVANCE III NanoBay
Fourier-transform NMR spectrometer equipped with a super-
conducting magnet at a working frequency of 300 MHz in the
mode of deuterium stabilization (thermal stabilization at 25 C)
tor agonist and can have unpredictable effect on the nerv-
ous system of a patient.
1
The 6aS-enantiomer of derivative 18a (CID 919001)
blocks the TDP1 and ELG1 protein, which increases the
genome instability in a tumor cell and can result in its
death due to fatal abnormality in the gene transcription.
In addition, tetracycle 18a can decrease the intensity of
tumor cell proliferation by suppression of the ATG4B
protease function.
using Me Si as the internal standard. Elemental analysis was
4
performed on a Eurovector EuroEA 3000 CHNS analyzer.
Melting points were measured on a standard melting point ap-
paratus (PTP No. 26649) with certified thermometers. The ratio
of enantiomers was determined by HPLC on an YMC CHIRAL
NEA (R) chiral column (250×4.6 mm, 5 m) using an UV detec-
tor at a wavelength of 220 nm.
The racemic mixture of the tetracyclic compound 18a
(CID 3674352) is toxic for cardiomyocytes.
Compound 18a decomposes the TDP-43 protein. It is
known that this protein forms aggregations in the neuron cyto-
plasm. This is one of the reasons for the development of
amyotrophic lateral sclerosis, incurable neurodegenerative
disease.25 The elimination of its aggregations can retard neuro-
degenerative processess and improve the status of the patient.
Thus, quinazolinones 11k,r and 18a exhibit anticancer
activity by the mechanism of inhibition of DNA repair
systems and proliferative activity. Compounds 11k and 18a
can be useful in the therapy of neurodegenerative dis-
eases. Compound 11k was found to have a potential for
the treatment of dysentery. However, to confirm the
therapeutic activity and safety for healthy tissues, the
above-described compounds must be subjected to com-
prehensive clinical trials.
Thus, the studies performed allowed us to synthesize
a series of 1,2-dihydro-4(3H)-quinazolinone derivatives and
the regularities found favored their tailor-made synthesis.
The heterocorrelation 2D NMR experiments allowed
determining the structures of quinazolinones obtained.
According to the data from the bioactivity studies, the
quinazolinone derivatives can have effective action on
many molecular targets within cells. Based on the quina-
zolinone derivatives, one can design new anticancer and
antiparasitic drugs, as well as can use them in the therapy
of neurodegenerative diseases.
Solvents and reagents (ACROS) were used as received. New
aldehydes in required amounts were synthesized according to the
13
earlier described procedures.
Synthesis of anthranilic acid amides 7a—h (general procedure).
To a solution of amine (0.05 mol) in pyridine (20 mL) cooled to
0—5 C, a solution of phosphorus trichloride (0.01 mol) was
added dropwise with stirring. After keeping for 0.5 h under these
conditions, anthranilic acid (0.2 mol) was added and the mixture
was heated on a water bath for 3—4 h with stirring. The reaction
mixture was cooled to room temperature and, after standing,
decanted from the precipitate of polyphosphorous acid. The
solvent was removed in vacuo, the residue was treated with a
mixture of ethyl acetate and diluted with hydrochloric acid
(1 : 10). The organic layer was separated, washed with a solution
of sodium bicarbonate, dried with sodium sulfate, and concen-
trated in vacuo. The precipitate was recrystallized from ethanol, the
crystals formed were separated, and dried in air. The yields and phys-
icochemical characteristics of amides 7a—h are given in Table 1.
Synthesis of quinazolinones (general procedure). To a solution
of amino amide (0.005 mol) in a xylene—acetic acid (1 : 1) mix-
ture (10 mL), 0.005 mol of the corresponding aldehyde (0.01 mol
for the synthesis of compound 22) was added and the mixture
was refluxed for 3—5 h (TLC control by aldehyde). After keeping
under these conditions, the solvent was removed in vacuo, 2%
hydrochloric acid was added to the residue, and the precipitate
that formed was filtered off. The filter precipitate was washed with
5% soda solution and water and, if necessary, recrystallized from
aqueous ethanol. The yields and physicochemical characteristics
of 2-aryl quinazolinones 11a—y, 12a—l, 13a,b, 16, 18a,b, and
22a—f are given in Tables 2 and 3.
Experimental
2-{4-Methoxy-3-[(4-nitro-1H-pyrazol-1-yl)methyl]phenyl}-
3-(4-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (11g).
The course of reactions and the purity of quinazolinones
obtained were controlled by TLC on Silufol UV-254 plates using
HPLC conditions: A) H O, 0.01% TFA; B) MeCN, 0.01% TFA,
2

1058
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
Khachatryan et al.
–1
45%; the flow rate was 1 mL min , t (1) = 19.55 min (56%);
and Development in High-Priority Development Trends
of the Scientific and Technological Complex of Russia for
2014—2020", unique identifier RFMEFI57614X0044).
R
13
t (2) = 21.41 min (43%). C NMR (DMSO-d ), : 51.09
R
6
(C(22)); 55.16 (C(20) (OMe)); 55.68 (C(14) (OMe)); 72.73
(C(2)); 110.72 (C(14)); 113.73 (C(20), C(18)); 114.54 (C(8));
115.16 (C(4a)); 117.32 (C(6)); 123.48 (C(12)); 127.11 (C(11));
127.77 (C(5)); 128.15 (C(15)); 128.25 (C(17), C(21)); 130.68 (C(5)
(Pyr)); 132.83 (C(10)); 133.41 (C(16)); 133.48 (C(7)); 134.92
(C(4) (Pyr)); 135.80 (C(3) (Pyr)); 146.62 (C(8a)); 156.48 (C(13));
157.29 (C(19)); 162.18 (C=O).
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The authors are grateful to M. A. Yurovskaya for in-
valuable help and support in the discussion and preparation
of this work, as well as to the researchers of the Analytical
Test Center of the Federal State Unitary Enterprise "IREA"
for their help in the structural determination of synthesized
compounds.
This work was financially supported in part by the
Ministry of Education and Science of the Russian
Federation (Grant Agreement No. 14.576.21.0044 dated
on August 5, 2014, the Federal Target Program "Research
Received March 1, 2016;
in revised form February 16, 2017