One-pot multicomponent synthesis of medicinally important purine quinazolinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.08.137

Herein, a protocol that involves microwave-assisted, multicomponent one-pot synthetic strategy for the construction of the medicinally important purine quinazolinone scaffold is reported. A series of compounds are prepared by cyclization and condensation

Full text of DOI:10.1016/j.tetlet.2012.08.137

Tetrahedron Letters 53 (2012) 6195–6198
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot multicomponent synthesis of medicinally important purine
quinazolinone derivatives
⇑
Sanghapal D. Sawant , Mahesuni Srinivas, G. Lakshma Reddy, V. Venkateswar Rao, Parvinder Pal Singh,
⇑
Ram A. Vishwakarma
Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi 180 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2012
Revised 29 August 2012
Accepted 30 August 2012
Available online 11 September 2012
Herein, a protocol that involves microwave-assisted, multicomponent one-pot synthetic strategy for the
construction of the medicinally important purine quinazolinone scaffold is reported. A series of com-
pounds are prepared by cyclization and condensation reactions using this approach. The compounds
are structural analogs of anticancer agents IC-87114 and CAL-101, which are highly isoform-selective
PI3K-d inhibitors and are presently under clinical investigation for chronic lymphocytic leukemia.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Purine quinazolinone
Multicomponent reaction
Microwave
PI3K-d inhibitors
Multicomponent reactions have been successfully adopted by
the chemists for the synthesis of a library of biologically active
molecules. These reactions have the potential to build complex
molecular scaffolds in a straightforward way compared to classical
organic synthesis. Since the last decade there has been an enor-
mous interest for the discovery of novel reactions of this type.1–3
The MCR strategy has several advantages and according to the cur-
rent synthetic requirements, environmentally benign multicompo-
nent reactions, particularly employing microwave approaches, are
highly desirable.4,5
The usefulness of the multicomponent reactions becomes
important when these strategies are employed and utilized for
the generation of privileged scaffolds for medicinal chemistry.
Our interest in microwave-assisted synthesis of medicinally
important scaffolds6 encouraged us to establish an efficient syn-
thesis of purine quinazolinone based derivatives. Recently we ini-
tiated a program on the synthesis of isoform-selective PI3K
inhibitors for targeting cancer utilizing the quinazolinone scaffold.
Quinazolinones are a class of heteroaromatic compounds that have
drawn more attention because of their biological and pharmaco-
logical attributes including anticancer, anti-HIV, antimicrobial
activity, etc.7 The structure of quinazolinone has been extensively
utilized as a valuable scaffold for drug discovery in medicinal
chemistry. Some synthetic quinazolinones, such as raltitrexed,
ispinesib, tempostatin, halofuginone etc. (Fig. 2) have been in the
market or are currently in clinical trials for various cancer treat-
ments. Many natural products containing quinazolinone core
structures viz. asperlicin C, benzomalvin A, circumdatin F, sclero-
tigenin, and many others (Fig. 3) have been reported as biologically
important molecules.8 The quinazolinone molecules are reported
as PI3K inhibitors as anticancer agents. The first isoform-selective
PI3K-d inhibitor reported was based on purine quinazolinone scaf-
fold, that is, IC87114 molecule patented by ICOS in 2001.9 This is
one of the most remarkable isoform-selective inhibitors described
in the first generation PI3K inhibitors list. This compound exhibited
nanomolar inhibition of PI3K-d and a 100- to 1000-fold selectivity
against the other class I PI3K’s.9 In subsequent years several mole-
cules based on quinazolinone scaffold entered into preclinical and
clinical investigation stages and one of the most promising PI3K-d
F
O
N
O
N
N
N
HN
HN
N
N
N
N
N
N
N
H2N
CAL 101
IC50= 2.5 nM
IC 87114
IC50= 130 nM
⇑
Corresponding authors.
E-mail addresses: sdsawant@iiim.res.in (S.D. Sawant), ram@iiim.res.in (R.A.
Figure 1. Structures of quinazolinone scaffold based anticancer molecules as
isoform-selective PI3K-d inhibitors.
Vishwakarma).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.137

6196
S. D. Sawant et al. / Tetrahedron Letters 53 (2012) 6195–6198
O
O
N
NH
N
N
S
O
Cl
N
O
S
N
O
N
NH2
N
N
NH2
N
H
NH2
Nolatrexed/Thymitaq
Phase III, advanced cancers
Ispinesib
Phase II, Solid tumors
AZD4877
Potential clinical candidate
HOOC
OH
COOH
O
O
HN
Cl
Br
N
S
O
N
O
HN
N
N
NH
Raltitrexed
Halofuginone
FDA approved drug for colorectal cancer
Phase II, Bladder cancer
&
Approved drug for Scleroderma:
Veterinery medicine
Figure 2. Quinazolinone based compounds as drugs or clinical candidates.
O
N
H
O
N
O
H
N
N
N
N
N
O
HO
O
O
NH
N
HO
Febrifugine
Isofebrifugine
Asperlicin C
N
H
O
O
N
N
O
N
N
N
O
O
O
NH
N
N
NH
Circumdatin F
Benzomalvin A
Sclerotigenin
Figure 3. Quinazolinone based natural products as biologically important molecules.
isoform-selective inhibitors to date is CAL-101/GS1104 by Gilead
(initially developed by Calistoga) with IC50 of 2.5 nM (Fig. 1).10
In most of the cases, the quinazolinone structural scaffold is
built in multiple steps using conventional synthesis approach.9,11
To investigate the potential of the present strategy, we first exam-
ined the possibility of forming a cyclic intermediate containing
quinazolinone ring and thereafter subsequent conjugation reaction
of this intermediate with the adenine moiety in the same pot. In
the preliminary experiments, we were pleased to observe the for-
mation of quinazolinone scaffold as desired in a single step. The
reactions were carried out under microwave irradiation in one
pot giving purine quinazolinone compounds in good to excellent
yields (Table 3).
O
O
O
TEA, 0 oC
OH
O
OH
+ Cl
Cl
NH
NH2
Cl
1
3
2
Scheme 1. Synthesis of intermediate 3.
no benzoic acid 1 and 2-chloroacetyl chloride 2 were reacted in the
presence of triethylamine at 0 °C to give 2-(2-chloroacetamido)-6-
methylbenzoic acid as crystalline product 3. The next step gave
more than 95% conversion to form 5 with all the substrates used
for reactions to form the cyclized quinazolinone intermediate by
multicomponent strategy. Intermediate 3 was reacted with 2-
methyl aniline 4 using PCl3 as cyclizing agent under microwave
Subsequently, we initiated the optimization of reaction condi-
tions for all the steps using one-pot approach. The conversion in
the first step gives quantitative yields of 3 (Scheme 1), prepared
by a known method.12 The starting materials viz. 6-methyl-2-ami-

S. D. Sawant et al. / Tetrahedron Letters 53 (2012) 6195–6198
6197
O
N
O
H2N
O
O
4
N
N
Adenine 6, 1 eq.
PCl3, 4 eq., µW
350 W, 50 oC
Cl
OH
N
+
NH2
N
N
K2CO3, µW
Cl
NH
N
N
N
100 W, 100 oC
N
N
N
3
O
5: >95%
N
N
NH2
7a': 20%
7a: 80%
Scheme 2. One-pot multicomponent synthesis of IC87114 using microwave irradiation.
5
5
6'
4'
3'
12
11
O
6'
4'
3'
12
11
O
Table 3
Synthesis of purine quinazolinone derivatives at optimized conditions
6
3
5
6
3
1'
5
4
N
7
2'
7'
1'
4
N
7
2'
7'
2
R1
O
8
2
1''
10
8
N
1''
9
10
R
N
1
N 2''
9
NH211''
1
N
10''
N 9''
N2''
3''
10''
9''
3''
8''
R2
N
N
N8''
5''
6''
4''
N
N
4''
N
5''
R3
7''
N
N
7''
6''
H2N11''
7a
N
N
7a'
H2N
7
Figure 4. Regioisomers 7a and 7a0.
Purine quinazolinone derivatives
Table 1
Optimization of reaction conditions for synthesis of 5
Entry
a
R
R1
R2
R3
Yielda
7
Entry
Substrate
MW
Reaction
Product yieldsa (%): 5
(Watt)
time (min)
1
3
100
250
350
450
3
3
3
3
45
78
>95
–CH3
–H
–H
80
Decomposed product
b
c
–F
–F
–H
–H
–H
–H
75
73
a
Isolated yields.
Table 2
Optimization of the reaction conditions for the synthesis of 7 using intermediate
compound 5
Entry
Substrate
MW
(Watt)
Temperature
(°C)
Reaction
time (min)
Product
yieldsa (%)
NH
7a0
d
–CH3
–H
72
7a
CF3
a
5
50
100
150
50
100
150
50
3
5
7
3
5
7
3
5
7
3
5
7
3
5
7
3
5
7
3
5
7
3
5
7
3
5
7
35
38
40
50
52
52
56
58
59
62
64
64
70
80
74
67
69
65
10
15
10
5
8
8
7
10
9
e
f
–H
–H
–H
–H
–H
–H
76
75
10
12
12
13
13
14
13
17
20
17
15
15
14
2
2
2
—
—
—
—
—
—
CF3
CF3
b
5
g
h
i
–F
–F
–F
–F
–H
–H
–H
–H
–H
–H
–H
–H
76
71
79
71
100
150
50
OCF3
c
5
100
150
F
3
2
—
—
NO2
j
—
(continued on next page)
a
Isolated yields.

6198
S. D. Sawant et al. / Tetrahedron Letters 53 (2012) 6195–6198
In conclusion, we have developed an environmentally friendly
Table 3 (continued)
and efficient microwave-assisted one-pot multicomponent meth-
od for the synthesis of biologically important purine quinazolinone
derivatives in good yields. The biological potential of these com-
pounds is being studied and will be published in due course.
Entry
R
R1
R2
R3
Yielda
76
7
S
k
–CH3
–H
–H
COOMe
Acknowledgments
l
–CH3
–CH3
–H
–H
73
76
Authors M.S., G.L.R., and V.V.R. thank CSIR for the award of se-
nior research fellowship. Authors thank for the support from
Instrumentation Division of IIIM-J.
m
CF3
Supplementary data
Supplementary data (1H/13C NMR, DEPT at 135°, mass for some
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.137.
n
–CH3
–H
77
NH2
F
References and notes
o
p
–CH3
–CH3
–H
–H
–H
80
71
Cl
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a
Isolated yields.
irradiation for 3 min at 350 W to give the intermediate 5, that is, 2-
(chloromethyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one. This
intermediate without purification was used for coupling reaction
with adenine 6,13 in the presence of K2CO3 (100 W microwave
power, 5 min, 100 °C) to give the desired purine quinazolinone
derivative 7a and 7a0 as regioisomers in the ratio of 80:20
(Scheme 2).
The structures of these two regioisomers have been confirmed
by comparison of 1H NMR data with that of the reported com-
pounds.9d In H NMR of 7a, the methylene group at 100 position
1
(Fig. 4) shows double doublet at d 4.79 and 5.11 with J = 17.2 and
17.2 Hz. However, the same methylene group at 100 position in case
of 7a0 shows quartet at d 5.23 with J = 17.6 and 17.2 Hz (1H NMR of
both regioisomers is given in Supplementary data). While optimi-
zation of the reaction, it was observed that change in reaction con-
ditions like change in microwave power or temperature and time
gave different results, which are summarized in Tables 1 and 2.
The percentage conversion in the formation of intermediate 5 at
100, 250, and 350 W, was 45, 78, and >95 while at 450 W the prod-
uct decomposed (Table 1). However, the conversion of 5 to 7 re-
quired several experiments for optimization of the reaction
conditions. The best condition for the conversion of 5 to 7a/a0
was found to be irradiation with 100 W microwave power for
5 min at 100 °C. Therefore, all the reactions were performed under
the optimized conditions (Table 2, entry b at 100 W for 5 min MW
irradiation), and the examples are given in Table 3.
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