Synthesis and antiviral study of 4-(7,7-dimethyl-4-(piperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-yl) morpholine derivatives

Article abstract of DOI:10.1007/s00044-017-2077-5

Abstract: A series of 4-(7,7-dimethyl-4-(piperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine substituted sulfonamide and urea derivatives has been synthesized and characterized using spectral techniques. The antiviral activity of these compounds

Full text of DOI:10.1007/s00044-017-2077-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-2077-5
ORIGINAL RESEARCH
Synthesis and antiviral study of 4-(7,7-dimethyl-4-(piperazin-1-yl)-
,6,7,8-tetrahydroquinazolin-2-yl) morpholine derivatives
5
1 ●
2 ●
2 ●
Balaraman Selvakumar Naveen Gujjar Madhuri Subbiah
3
Kuppanagounder P. Elango
Received: 2 August 2017 / Accepted: 14 September 2017
©
Springer Science+Business Media, LLC 2017
Abstract A series of 4-(7,7-dimethyl-4-(piperazin-1-yl)-
,6,7,8-tetrahydroquinazolin-2-yl)morpholine substituted
●
●
●
5
Keywords Tetrahydroquinazoline Piperazine Morpholine
Avian paramyxo virus Antiviral
●
sulfonamide and urea derivatives has been synthesized and
characterized using spectral techniques. The antiviral
activity of these compounds against an avian paramyxo
virus (AMPV-1) was screened using MTT assay and found
that one of the sulfonamide derivatives (2d) show three-fold
higher antiviral activity than Ribavirin, a commercial anti-
viral drug substance.
Introduction
Heterocyclic chemistry is one of the important and largest
classical divisions of organic chemistry, which deals with
heterocyclic organic compounds (Katritzky et al. 1985;
Joule and Mills 2008; Hepworth et al. 1995). Traditionally,
majority of the biologically active substances possess het-
erocyclic rings; amongst pyrimidine template has an
important significance. The pyrimidine ring occurs as a part
structure of deoxyribonucleic acid (DNA), ribonucleic acid
Graphical abstract
(RNA), co-enzymes like folic acid, thiamine bromide, and
riboflavin (Looper et al. 2005; Kobayashi et al. 1991;
Skinner and Wunz 1951). Pyrimidine derivatives found
useful in the treatment of cancer, myocardial interaction,
and glaucoma (Noronha et al. 2008). Morpholine is another
important organic heterocyclic compound seen as a part
structure of several medicinal drugs along with pyrimidine
template (Cano et al. 2010, 2013). A review of literature
revealed that 2-(morpholin-4-yl)-5,6,7,8-tetrahydroquina-
zolin-4-amine derivatives were proved to show potent
hypoglycemic activity (Sekiya et al. 1980). Structure–
activity relationship study of 2-(morpholin-4-yl)-5,6,7,8-
tetrahydroquinazolin-4-amine derivatives revealed its
selective and potent inhibition of p97 ATPase (Chou et al.
2013) and GATA modulator (Dibyendu et al. 2010).
Piperazine is the most important heterocyclic compound
present in many of the notable drugs, which act as anti-
helmintic, anti-depressant, and anti-histamines (de Boer
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00044-017-2077-5) contains supplementary
material, which is available to authorized users.
*
Kuppanagounder P. Elango
drkpelango@rediffmail.com
1
2
Anthem Biosciences Pvt. Ltd., Bangalore 560 099, India
National Institute of Animal Biotechnology, Hyderabad 500 049,
India
3
Department of Chemistry, Gandhigram Rural Institute (Deemed
University), Gandhigram 624 302, India

Med Chem Res
et al. 2001). It is presumed that molecules containing all
these three heterocycles (pyrimidine, morpholine, and
piperazine) as a part of their structures would exhibit pro-
mising biological activity. Amprenavir, tipranavir, and
darunavir are commercially approved antiviral drugs which
has sulfonamide functional group in its entity and tri-
fluridine, mozenavir are few commercially available anti-
viral drugs which has urea functional group in its entity.
Owing to the known antiviral properties of sulfonamides
The main objective, therefore, of the present endeavor in
the synthesis, characterization and antiviral screening
against a NDV viz. an avian paramyxovirus (APMV-1) of
newer heterocyclic compounds viz. 4-(7,7-dimethyl-4-
(piperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-yl)
mor-
pholine (1), its sulfonamide (2) and urea (3) derivatives
(Fig. 1). To our delight one of the sulfonamide derivative
exhibited significant antiviral activity against African Green
Monkey Kidney cell line.
(
(
Supuran et al. 2004; Scozzafava et al. 2003) and urea
Suresh Kumar et al. 2014) with above mentioned hetero-
cyclic molecules (Izuru et al. 2012; Sudhakar Babu et al.
015), compounds being prepared with above all hetero-
2
Results and discussion
cyclic hubs would expect to show enhanced biological
activity.
In the recent evaluation towards antiviral research, study
on Newcastle disease virus (NDV) (APMV-1) has been
attractive area for virologists due to its oncolytic activity
and its use as a vaccine vector for both animals and humans
The overall protocol adopted for the synthesis of 1 is deli-
neated in Scheme 1. 3,3-Dimethyl cyclohexanone (4) on
treatment with dimethyl carbonate in the presence of
sodium hydride in THF yielded methyl-4,4-dimethyl-2-
oxocyclohexane-1-carboxylate (5), which underwent cycli-
zation with S-methylisothiourea hemisulfate in water to give
7,7-dimethyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4
(3H)-one(6) (Tetsuo et al. 1981; John et al. 2010). The
(
Dmitriy and Peter 2012; Ravindra et al. 2009). NDV is
economically important paramyxovirus that can infect more
than 250 bird species. The disease onset is rapid with
clinical signs appearing within 48 h. Currently used vac-
cines are not 100% protective and there is an unmet need to
combat the disease through other strategies that include
using antiviral drugs. As on date, there is no approved drug
against NDV. Ribavirin, a well-known broad spectrum
antiviral drug (Gilbert and Knight 1986) is approved for
treatment of respiratory syncytial virus, a human para-
myxovirus, which causes severe lower respiratory tract
infections in children. Ribavirin is expensive and there are
concerns about its efficacy. Furthermore, it is shown to have
potential toxic effects on exposed individuals when admi-
nistered via aerosol and the high cost (Hebert and
Guglielmo 1990; Fackler et al. 1990). All these factors
highlight the importance of developing novel antiviral
drugs.
intermediate
7,7-dimethyl-2-morpholino-5,6,7,8-tetra-
hydroquinazolin-4(3H)-one (7) was synthesized from 6 by
replacing the S-Me group with morpholine (Kengi et al.
2003). The conversion of 7 to 1 involves two nucleophilic
replacement reactions, first replacement of hydroxy group
by chloride group in the presence of POCl to give 8 and
3
then replacement of chloride group with piperazine (Sel-
vakumar et al. 2017) (Scheme 1).
As depicted in Scheme 2 several new sulfonamide
derivatives 2a–f were synthesized from 1 by treating with
corresponding substituted sulfonyl chlorides. Likewise, four
urea derivatives 3a–d were also synthesized from 1 by
treating with respective phenyl substituted isocyanate deri-
vatives. The structures of these compounds 2a–f and 3a–d
1
13
were confirmed by H and C nuclear magnetic resonance
Fig. 1 Structures of 4-(7,7-dimethyl-4-(piperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine (1), sulfonamide (2), urea (3) derivatives

Med Chem Res
Scheme 1 Synthesis of 4-(7,7-dimethyl-4-(piperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine (1)
Scheme 2 Synthesis of sulfonamide (2a–f) and urea derivatives (3a–d) of 1
(
NMR), infrared (IR), and liquid chromatography mass
cellular morphology of Vero cells, of Ribavirin was 31.25
µg/mL. The 50% cytotoxic concentration (CC50: dose that
inhibited the growth by 50% compared to untreated cells) of
Ribavirin was 400 µg/mL and 32% viral plaque reduction
was observed by Ribavirin at dose of 31.25 µg/mL.
Monolayers of Vero cells in 24-well plate were incubated
with five different concentrations of test compounds (0.1,
0.01, 0.001, 0.0001, and 0.00001 M) for 1 h. The cells were
washed with PBS thrice and then infected with a known
dose of NDV for 1 h. The cells were washed again with
PBS thrice and overlaid with methyl cellulose media. The
spectrometry (LCMS) spectra.
The antiviral activity of these compounds was screened
against African Green Monkey Kidney cell line, Vero cell
line. To test the antiviral activity these compounds were
initially screened by MTT (3-(4,5-dimethylthiazol-2-yl)-
2
,5-diphenyltetrazolium bromide) assay as described in lit-
erature (Gerlier and Thomasset 1986). The maximum non-
cytotoxic concentration (MNCC), at which no significant
changes were detected in cellular morphology of Vero cells
was used as the highest test dose for testing the antiviral
activity of the compounds by viral plaque reduction assay
using an avian paramyxo virus, which is a NDV (APMV-1).
A well-known antiviral drug, Ribavirin, was used for
comparing the antiviral potential of the test compounds. The
MNCC, at which no significant changes were detected in
cells were incubated at 37 °C with 5% CO for 5 days. The
2
cells were observed every day during the incubation period.
On the 5th day, the overlay media was removed and the
cells were fixed with cold methanol for 30 min. The cells
were then stained with 1% crystal violet and air dried. The

Med Chem Res
Table 1 Antiviral activity of 2a–f and 3a–d against Vero cell line
APMV-1
potential lead in antiviral drug development if the same or
similar analogs are modified and studied further.
Compound
numbers
Test concentration Percentage of
Plaque
reduction
percentage
(M) at which
antiviral activity
was observed
test virus
concentration
Experimental
All the chemicals used in the study are commercially
available high purity grade (Aldrich or Merck, India). The
solvents were of reagent grade and used as supplied com-
mercially. Thin layer chromatography (TLC) experiments
were performed on alumina-backed silica gel 40F254 plates
(Merck, Darmstadt, Germany). The plates were illuminated
2
2
2
2
2
2
3
3
3
3
a
b
c
0.001
79
21
0.1–0.00001
0.01
80
None
37
63
d
e
0.001
16
84
0.1–0.00001
0.1–0.00001
0.0001
90
None
None
37
f
115
63
under UV (254 nm) and KMnO . Melting points were
4
a
b
c
determined using a melting point apparatus (B-540 Buchi,
1
13
0.1–0.00001
0.001
233
76
None
24
Germany) without corrections. All H and C NMR spectra
were recorded on a Bruker 300 or 400 MHz NMR. Mole-
cular masses of unknown compounds were checked by
LCMS 6200 series Agilent Technology (Agilent, Benga-
luru, India). Chemical shifts are reported in ppm (δ) with
reference to internal standard tetramethylsilane. The signals
are designated as follows: singlet (s), doublet (d), triplet (t),
doublet of doublet (dd), doublet of triplet (dt), multiplet (m),
and broad singlet (bs). IR spectra were recorded using a
Bruker Alpha Fourier transform infrared spectrometer
(Bruker, Germany) using a diamond attenuated total
reflectance (ATR) single reflectance module (24 scans). All
reactions were carried out under a nitrogen/argon atmo-
sphere unless otherwise stated.
d
0.1–0.00001
0.0001
115
68
None
32
Ribavirin
number of plaques produced by viral infection was counted
in each well. The percentage of plaque reduction was
determined by calculating the reduction in the number of
plaques upon compound treatment compared to untreated
NDV infected cells which were defined as 100%. The
results obtained are collected in Table 1.
The structural modification caused by changing the
substituents in sulfonamide moiety (R) and urea moiety
(
R1) has a wide impact on anti-viral activity of the prepared
Compound 1 was prepared from commercially available
3,3-dimethyl cyclohexanone (4) over five steps using syn-
thetic procedure previously reported by our research group
(Skinner and Wunz 1951).
compounds. While test compounds 2b, 2e, 2f, 3b, and 3d
did not show any antiviral activity at the tested concentra-
tions, the test compounds 2a, 2c, 2d, 3a, and 3c showed
antiviral activity by inhibiting the plaque formation by 21,
3
7, 84, 37, 24% respectively at the minimum test dose when
General synthetic procedure for synthesis of 2a–f
compared to infected untreated controls. Interestingly,
compound 2d bearing trimethyl substituted phenyl ring
contained sulfonamide derivative and compound 3a bearing
simple phenyl ring contained urea derivative displayed
reasonably good activity compare to their other substituted
phenyl analogs. However, sulfonamide derivative 2d has
shown higher antiviral activity than urea derivatives 3a.
To a solution of 1 (0.01 mol) in THF (10 Vol), diisopropyl
ethylamine (0.03 mol) was added at about 10 °C and stirred
for 15 min. To this suspension, corresponding sulfonyl
chloride (a–f) (0.01 mol) was added and stirred for 3 h at
ambient temperature. Reaction completion was monitored
by TLC, the reaction was quenched with 10% sodium
bicarbonate solution and diluted with ethyl acetate. Organic
layer separated was washed with 10% of citric acid solution
and concentrated under reduced pressure. A few compounds
were purified by column chromatography using a mixture of
ethyl acetate-hexanes in silica gel to afford pure
compounds.
Conclusion
Herein, we have reported the novel synthesis of a series of
4
-(7,7-dimethyl-4-(piperazin-1-yl)-5,6,7,8-tetrahydroquina-
zolin-2-yl)morpholine substituted sulfonamide derivatives
2a–f) and urea derivatives (3a–d). We have tested the
4-(4-(4-((4-Fluorophenyl)sulfonyl)piperazin-1-yl)-7,7-
dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine (2a)
Compound 2a is an off-white solid. Yield: 75%, m.
(
antiviral activity of these compounds using MTT assay and
amongst, one of the sulfonamide derivatives (2d) was found
to be showed three-fold higher antiviral activity than that of
commercial antiviral drug Ribavirin, which may become
1
p:199–203 °C; H NMR (400 MHz, dimethyl sulphoxide
(DMSO)-d6, δ ppm): 0.93 (s, 6H, CH -tetrahydroquinazo-
3
line), 1.37(m, 2H, CH -tetrahydroquinazoline), 2.31 (s, 2H,
2

Med Chem Res
CH -tetrahydroquinazoline), 2.34 (m, 2H, CH -tetra-
(4-nitrophenyl-C), 150.5 (4-nitrophenyl-C), 159.3 (pyr-
imidine-C), 165.3 (pyrimidine-C); IR (ATR, υ cm ):1110
2
2
−1
hydroquinazoline), 3.00 (s, 4H, CH -piperazine), 3.35 (s,
2
4
7
H, CH -piperazine), 3.52–3.59 (m, 8H, CH -morpholine),
and 1170 (SO -symmetric-stretching), 1349 (SO -asym-
metric-stretching), 1417, 1529 (NSO bending), 1567
2-
2
2
2
2
.48–7.54 (m, 2H, CH-4-flurophenyl), 7.82–7.85 (m, 2H,
1
3
CH-4-flurophenyl); C NMR (75 MHz, DMSO-d , δ ppm):
2
(NSO bending), 2851, 2919; LCMS (ESI) m/z: 517.3 Da
6
2-
+
2.1 (tetrahydroquinazoline-C), 28.4 (tetrahydroquinazo-
[M + H] , Anal. calcd for C H N O S: C, 55.80; H, 6.24;
2
4 32 6 5
line-C), 29.3 (tetrahydroquinazoline-C), 35.7 (tetra-
hydroquinazoline-C), 44.4 (tetrahydroquinazoline-C), 46.0
N, 16.27; S, 6.21; found: C, 55.78; H, 6.27; N, 16.29; S,
6.20%.
(
6
piperazine-C), 46.4 (piperazine-C), 47.3(morpholine-C),
6.5 (morpholine-C), 106.5 (pyrimidine-C), 117.0–117.3
4-(4-(4-((2,4,6-Trimethylphenyl)sulfonyl)piperazin-1-yl)-
7,7-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine
(2d) Compound 2d is an off-white solid. Yield: 80%, m.
(
(
4-flurophenyl-C), 131.1–131.6 (4-flurophenyl-C), 159.3
pyrimidine-C), 163.9 (pyrimidine-C), 165.3–166.4 (4-
−
1
1
flurophenyl-C); IR (ATR, υcm ): 1108 and 1163 (SO2-
p:192–195 °C; H NMR (400 MHz, DMSO-d6, δ ppm):
symmetric-stretching), 1348 (SO -asymmetric-stretching),
0.97 (s, 6H, CH -tetrahydroquinazoline), 1.24 (s, 2H, CH -
2
3
2
1
542 (NSO bending), 1569 (NSO bending), 2832, 2920;
tetrahydroquinazoline),
hydroquinazoline), 2.29 (s, 4H, CH -piperazine), 2.36 (s,
1.42
(s,
2H,
CH -tetra-
2
-
2-
2
+
LCMS (ESI) m/z: 490.3 Da [M + H] ; Anal. calcd for
2
C H FN O S: C, 58.88; H, 6.59; N, 14.30; S, 6.55,
2H, CH -tetrahydroquinazoline), 2.57 (s, 9H, CH -aryl),
2
4
32
5
3
2
3
found: C, 58.86; H, 6.60; N, 14.31; S, 6.54%.
3.15 (s, 4H, CH -piperazine), 3.6 (s, 8H, CH -morpholine),
2 2
1
3
7
.1 (s, 2H, CH-Aryl); C NMR (75 MHz, DMSO-d , δ
6
4
-(4-(4-((4-Bromophenyl)sulfonyl)piperazin-1-yl)-7,7-
ppm): 20.9 (tetrahydroquinazoline-C), 22.9 (trimethylphe-
nyl-C), 23.2 (tetrahydroquinazoline-C), 35.4 (tetra-
hydroquinazoline-C), 39.1 (tetrahydroquinazoline-C), 44.3
(tetrahydroquinazoline-C), 44.9 (piperazine-C), 47.4 (mor-
pholine-C), 66.1 (morpholine-C), 130.2 (trimethylphenyl-
C), 132.4 (trimethylphenyl-C), 140.2 (trimethylphenyl-C);
dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine (2b)
Compound 2b is a white solid. Yield: 68%, m.p:
1
2
65–268 °C; H NMR (400 MHz, DMSO-d δ ppm): 0.98
6
,
(
s, 6H, CH -tetrahydroquinazoline), 1.39 (s, 2H, CH -tet-
3 2
rahydroquinazoline), 2.45 (m, 4H, CH -tetrahydroquinazo-
line), 3.07 (s, 4H, CH -piperazine), 3.67–3.69 (m, 8H, CH -
2
−1
IR (ATR, υ cm ): 1102 and1150 (SO -symmetric-
2
2
2
morpholine), 3.79 (s, 4H, CH -piperazine), 7.67–7.7 (d, 2H,
stretching), 1302 (SO -asymmetric-stretching), 1419, 1538
2
2
J = 8.1 Hz, CH-4-bromophenyl), 7.87–7.9 (d, 2H, J = 8.1
Hz, CH-4-bromophenyl); IR (ATR, υ cm ): 1107 and
(NSO -bending), 1564 (NSO bending), 2848, 2922;
LCMS (ESI) m/z: 514.3 Da [M + H] , Anal. calcd for
2
2-
−
1
+
1
166 (SO -symmetric-stretching), 1262 (SO -asymmetric-
C H N O S: C, 63.13; H, 7.65; N, 13.63; S, 6.24; found:
27 39 5 3
2
2
stretching), 1615 (NSO bending); LCMS (ESI) m/z: found:
C, 63.15; H, 7.68; N, 13.65; S, 6.21%.
2
-
+
5
50.3 Da [M + H] , Anal. calcd for C H BrN O S: C,
24 32 5 3
5
2.36; H, 5.86; N, 12.72; S, 5.82, found: C, 52.35; H, 5.89;
4-(4-(4-((naphthalen-1-yl)sulfonyl)piperazin-1-yl)-7,7-
dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine (2e)
Compound 2e is a pale-yellow solid. Yield: 63%, m.p:
N, 12.71; S, 5.81%.
1
4
-(4-(4-((4-Nitrophenyl)sulfonyl)piperazin-1-yl)-7,7-
187–191 °C; H NMR (400 MHz, DMSO-d δ ppm): 0.91
6
,
dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine (2c)
(s, 6H, CH -tetrahydroquinazoline), 1.35 (m, 2H, CH -tet-
3 2
Compound 2c is a yellow color solid. Yield: 82%, m.p:
rahydroquinazoline), 2.28 (s, 2H, CH -tetrahydroquinazo-
2
1
2
09–212 °C; H NMR (400 MHz, DMSO-d δ ppm): 0.93
line), 2.34 (s, 2H, CH -tetrahydroquinazoline), 3.19 (s, 4H,
6
,
2
(
s, 6H, CH -tetrahydroquinazoline), 1.24 (s, 2H, CH -tet-
CH -piperazine), 3.31 (s, 4H, CH -piperazine), 3.46 (s, 4H,
3
2
2
2
rahydroquinazoline), 1.36 (m, 2H, CH -tetrahydroquinazo-
CH -morpholine), 3.55 (s, 4H, CH -morpholine), 7.69–7.73
2 2
2
line), 2.3 (s, 4H, CH -piperazine), 2.34 (s, 2H, CH -
(m, 3H, CH-naphthyl), 8.11–8.18 (m, 2H, CH-naphthyl),
8.3–8.33 (d, 1H, J = 8.4 Hz, CH-naphthyl), 8.68–8.71 (d,
2
2
tetrahydroquinazoline), 3.1 (s, 4H, CH -piperazine),
2
1
3
3
.53–3.58 (s, 8H, CH -morpholine), 8.01–8.04 (d, 2H, J =
1H, J = 7.5 Hz, CH-naphthyl); C NMR (75 MHz, DMSO-
d6, δ ppm): 22.8 (tetrahydroquinazoline-C), 28.4 (tetra-
hydroquinazoline-C), 28.8 (tetrahydroquinazoline-C), 35.4
(tetrahydroquinazoline-C), 38.5 (tetrahydroquinazoline-C),
44.3 (piperazine-C), 45.6 (piperazine-C), 47.6 (morpholine-
C), 67.8 (morpholine-C), 106.5 (pyrimidine-C), 125.1
(pyrimidine-C), 127.5 (naphthyl-C), 128.7 (naphthyl-C),
129.1 (naphthyl-C), 129.6 (naphthyl-C), 130.8 (naphthyl-
C), 132.3 (naphthyl-C), 134.4 (naphthyl-C), 135.2 (naph-
thyl-C), 159.3 (pyrimidine-C), 165.3 (pyrimidine-C); IR
2
8
.4 Hz, CH-4-nitrophenyl), 8.44–8.47 (d, 2H, J = 8.1 Hz,
1
3
CH-4-nitrophenyl); C NMR (75 MHz, DMSO-d , δ ppm):
6
2
2.1 (tetrahydroquinazoline-C), 28.4 (tetrahydroquinazo-
line-C), 28.8(tetrahydroquinazoline-C), 38.5 (tetra-
hydroquinazoline-C), 44.3 (tetrahydroquinazoline-C), 46.0
(
6
piperazine-C), 46.4 (piperazine-C), 47.3 (morpholine-C),
6.4 (morpholine-C), 106.4 (pyrimidine-C), 125.2 (pyr-
imidine-C), 129.1 (4-nitrophenyl-C), 129.6 (4-nitrophenyl-
C), 132.0 (4-nitrophenyl-C), 132.1 (4-nitrophenyl-C), 141.1

Med Chem Res
ATR, υ cm− ): 1128 (SO -symmetric-stretching), 1257
1
CH -tetrahydroquinazoline), 2.46 (s, 2H, CH -tetra-
(
2
2
2
(
SO -asymmetric-stretching), 1418, 1539 (NSO bending),
hydroquinazoline), 2.49–2.53 (t, 2H, J = 6.6 Hz, CH -tetra-
2
2-
2
1
565 (NSO bending), 1728, 2845, 2920 (aryl CH-
hydroquinazoline), 3.42 (s, 4H, CH -piperazine), 3.63 (s, 4H,
2
-
2
+
stretching); LCMS (ESI) m/z: 522.3 Da [M + H] , Anal.
calcd for C H N O S: C, 64.47; H, 6.76; N, 13.42; S,
CH -piperazine), 3.72–3.75 (m, 8H, CH -morpholine), 6.39
2
2
1
3
(bs, 1H, NH-amide), 7–7.39 (m, 5H, aryl); C NMR (75
MHz, DMSO-d6, ppm): 22.3 (tetrahydroquina-
2
8 35 5 3
6
.15; found: C, 64.46; H, 6.79; N, 13.41; S, 6.16%.
δ
zoline-C), 28.5 (tetrahydroquinazoline-C), 29.3 (tetra-
hydroquinazoline-C), 35.9 (tetrahydroquinazoline-C), 44.1
(tetrahydroquinazoline-C), 44.4 (piperazine-C), 46.6 (mor-
pholine-C), 48.0 (piperazine-C), 66.5 (morpholine-C), 106.4
(pyrimidine-C), 118.6 (phenyl-C), 120.0 (phenyl-C), 122.2
(phenyl-C), 128.7 (phenyl-C), 129.2 (phenyl-C), 140.9
(phenyl-C), 155.5 (pyrimidine-C), 159.5 (pyrimidine-C),
165.1 (pyrimidine-C), 165.8 (C=O, urea); IR (ATR, υ
4
-(4-(4-((thiophen-2-yl)sulfonyl)piperazin-1-yl)-7,7-
dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine (2f)
Compound 2f is an off-white solid. Yield: 78%, m.p:
1
1
79–182 °C; H NMR (400 MHz, DMSO-d δ ppm): 0.95
6
,
(
s, 6H, CH -tetrahydroquinazoline), 1.39 (s, 2H, CH -tet-
3 2
rahydroquinazoline), 2.32 (s, 2H, CH -tetrahydroquinazo-
line), 2.37 (s, 2H, CH -tetrahydroquinazoline), 3.04 (s, 4H,
CH -piperazine), 3.39 (s, 4H, CH -piperazine), 3.55–3.59
2
2
−1
cm ): 1236, 1445 (H–N–C stretching), 1539 (N–C–N
2
2
(
s, 8H, CH -morpholine), 7.29–7.32 (t, 1H, J = 3.9 Hz, CH-
stretching), 1567 (NH-stretching), 1635 (C=O, stretching),
2
thiophene), 7.65–7.66 (d, 1H, J = 2.4 Hz, CH-thiophene),
3334 (NH- stretching); LCMS (ESI) m/z: 451.5 Da [M +
1
3
+
8
.07–8.09 (d, 1H, J = 4.2 Hz, CH-thiophene); C NMR
H] , Anal. calcd for C25H N O : C, 66.64; H, 7.61; N,
34 6 2
(
75 MHz, DMSO-d , δ ppm): 22.1(tetrahydroquinazoline-
18.65; found: C, 66.64; H, 7.65; N, 18.64 %.
6
C), 28.4 (tetrahydroquinazoline-C), 29.3 (tetrahydro-
quinazoline-C), 35.7 (tetrahydroquinazoline-C), 39.3
N-(2-chlorophenyl)-4-(7,7-dimethyl-2-morpholino-5,6,7,8-
tetrahydroquinazolin-4-yl) piperazine-1-carboxamide (3b)
(
4
tetrahydroquinazoline-C), 44.4 (tetrahydroquinazoline-C),
6.0 (piperazine-C), 46.3 (morpholine-C), 47.2 (piperazine-
C), 66.4 (morpholine-C), 106.5 (pyrimidine-C), 126.0
thiophene-C), 128.8 (thiophene-C), 129.0 (thiophene-C),
33.7 (pyrimidine-C), 134.5 (pyrimidine-C), 165.3 (pyr-
Compound 3b is an off-white solid. Yield: 76%, m.p:
1
2
12–216 °C. H NMR (400 MHz, CDCl δ ppm): 1.04 (s,
3
,
(
1
6
H, CH -tetrahydroquinazoline), 1.49–1.54 (t, 2H, J = 6.3
3
1
Hz, J = 6 Hz, CH -tetrahydroquinazoline), 2.47 (s, 2H,
−
1
2
2
imidine-C); IR (ATR, υ cm ): 1167 (SO -symmetric-
2
CH -tetrahydroquinazoline), 2.5–2.54 (t, 2H, J = 6 Hz, J
2
1
2
stretching), 1263, 1350 (SO -asymmetric-stretching), 1502,
2
=
6.3 Hz, CH -tetrahydroquinazoline), 3.42–3.46 (m, 4H,
2
1
537 (NSO bending), 1566 (NSO bending); LCMS (ESI)
2- 2-
CH -piperazine), 3.65–3.7 (m, 4H, CH -piperazine),
+
2
2
m/z: 478.2 Da [M + H] , Anal. calcd for C H N O S : C,
2
2 31 5 3 2
3
.72–3.76 (m, 8H, CH -morpholine), 6.95–7.01 (m, 1H,
2
5
5.32; H, 6.54; N, 14.66; S, 13.43; found: C, 55.30; H,
CH-2-chlorophenyl), 7.07 (s, NH), 7.24–7.3 (m, 1H, CH-2-
chlorophenyl), 7.34–7.37 (m, 1H, CH-2-chlorophenyl),
6
.56; N, 14.67; S, 13.45%.
1
3
8
.21–8.25 (m, 1H, CH-2-chlorophenyl); C NMR (75
MHz, DMSO-d , δ ppm): 21.8 (tetrahydroquinazoline-C),
6
General synthetic procedure for synthesis of 3a–d
2
8.0
quinazoline-C), 35.4 (tetrahydroquinazoline-C), 43.7
tetrahydroquinazoline-C), 44.0 (piperazine-C), 46.1 (mor-
pholine-C), 47.5 (piperazine-C), 66.0 (morpholine-C),
05.9 (pyrimidine-C), 125.5 (2-chlorophenyl-C), 126.7 (2-
(tetrahydroquinazoline-C),
28.9
(tetrahydro-
To a solution of compound 1 (0.01 mol) in THF (10
volumes), Triethyl amine (0.03 mol) was added. After stir-
ring the mixture for 15 min, corresponding isocyante (0.01
mol) was added and gradually heated to about 65 °C for 5 h.
Reaction completion was monitored by TLC and reaction
was quenched with water and product was extracted with
ethyl acetate. The organic layer was washed with brine
solution and concentrated under reduced pressure. Crude
obtained was purified by column chromatography using a
mixture of ethyl acetate-hexanes to afford pure urea deri-
vatives 3a–d.
(
1
chlorophenyl-C), 127.2 (2-chlorophenyl-C), 129.2 (pyr-
imidine-C), 155.0 (pyrimidine-C), 159.0 (pyrimidine-C),
−
1
1
64.6 (C=O, urea); IR (ATR, υ cm ): 1252, 1392 (H–N–C
stretching), 1516 (N–C–N stretching), 1564 (NH-stretch-
ing), 1630 (C=O, stretching), 2847, 3343 (NH- stretching);
+
LCMS (ESI) m/z: 485.8 Da [M + H] , Anal. calcd for
C H ClN O : C, 61.91; H, 6.86; N, 17.33; found: C,
2
5
33
6 2
61.90; H, 6.90; N, 17.35.
4
4
3
-(7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-
-yl)-N-phenylpiperazine-1-carboxamide (3a) Compound
a is an off-white solid. Yield: 86%, m.p: 205–208 °C;
N-(3,4-dichlorophenyl)-4-(7,7-dimethyl-2-morpholino-5,6,
7,8-tetrahydroquinazolin-4-yl)piperazine-1-carboxamide
1
H NMR (400 MHz, DMSO-d6, δ ppm): 1.03 (s, 6H,
(3c) Compound 3c is an off-white solid. Yield: 73%, m.p:
1
CH -tetrahydroquinazoline), 1.48–1.53 (t, 2H, J = 6.3 Hz,
182–185 °C; H NMR (400 MHz, CDCl , δ ppm): 1.03 (s,
3
3

Med Chem Res
Acknowledgements We are thankful to the Management, Anthem
Biosciences, Bangalore, India, for their invaluable support and allo-
cation of resources for this work. We would like to thank the Ana-
lytical Chemistry team of Anthem Biosciences for having carried out
all the analytical work.
6
H, CH -tetrahydroquinazoline), 1.48–1.53 (t, 2H, J = 6.0
3 1
Hz, J = 6.3 Hz, CH -tetrahydroquinazoline), 2.46–2.52
2
2
(
m, 4H, CH -tetrahydroquinazoline), 3.41 (s, 4H, CH -
2
2
piperazine), 3.62 (s, 4H, CH -piperazine), 3.72–3.75 (m,
2
8
H, CH -morpholine), 6.53 (s, NH), 7.22–7.25 (d, 2H, J =
2
8
.7 Hz, CH-3,4-dichlorophenyl), 7.33–7.36 (d, 2H, J = 8.7
Compliance with ethical standards
1
3
Hz, CH-3,4-dichlorophenyl), 7.64 (s, 1H); C NMR (75
MHz, DMSO-d , δ ppm): 22.3 (tetrahydroquinazoline-C),
Conflict of interest The authors declare that they have no competing
interests.
6
2
8.4 (tetrahydroquinazoline-C), 29.3 (tetrahydroquinazo-
line-C), 35.9 (tetrahydroquinazoline-C), 44.0 (tetra-
hydroquinazoline-C), 44.4 (piperazine-C), 46.5
morpholine-C), 47.9 (piperazine-C), 66.5 (morpholine-C),
(
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