Int. J. Pharm. Sci. Rev. Res., 15(1), 2012; nᵒ 04, 15-22
ISSN 0976 – 044X
Review Article
COMPARATIVE STUDY OF MICROWAVE AND CONVENTIONAL SYNTHESIS
AND PHARMACOLOGICAL ACTIVITY OF PYRIMIDINES: A REVIEW
1
2
3
1
Chandak Shilpa , Sharma Dipak , Sharma Vimukta , Dubey Arti
1
Department of Engineering Chemistry, VITS, Indore, MP, India.
2
Department of Chemical Sciences, Maharaja Ranjit Singh College of Professional Sciences, Indore, MP, India.
3
Principal, B.M. College of Pharmacy, Indore, MP, India.
Accepted on: 02-03-2012; Finalized on: 30-06-2012.
ABSTRACT
Pyrimidine derivatives play a vital role in many biological processes. Pyrimidine ring system is being present in nucleic acids, several
vitamins, coenzymes, uric acid and some marine microorganisms (e.g. Sponge). The nitrogen heterocycles in general and pyrimidines
in particular are found in several biologically active natural products and depict considerable therapeutic potential. Chalcone
derivatives have been prepared by condensation of various substituted aryl aldehydes and acetophenone in alkaline ethanol, while
pyrimidine-2-one derivatives have been prepared by the combination of chalcones and urea under conventional and ultrasonic
conditions. The compound substituted ethyl-1,2,3,6-tetrahydro-4-methyl-2-oxo/thioxo-6-phenyl-1-(4,6-diphenyl-1Himidazolyl-2yl)pyrimidine-5-carboxylates have been synthesized by condensing substituted Benzil and enthyl-1-formyl-1,2,3,6-tetrahydro-4methyl-6-phenyl-2-oxo/thioxo-pyrimidine-5-carboxylates in the presence of ammonium acetate were dissolved in glacial acetic. The
quinolinylpyrimidine derivatives were prepared by the condensation of quinolinyl chalcones with urea (or thiourea) under basic
conditions by using both conventional and microwave heating. A beneficial ultrasound effect was observed and high yields of the
products were obtained. Characterization and structural elucidation of the products have been done on the basis of chemical,
analytical and spectral analysis. The newly prepared pyrimidine derivatives were screened for antimicrobial activities.
Keywords: Pyrimidine derivatives,
chemotherapeutic agents.
Chalcone
derivatives,
INTRODUCTION
Heterocyclic rings have played an important role in
medicinal chemistry, serving as key templates central to
the development of numerous important therapeutic
agents1. Chalcone derivatives are important starting
materials for the synthesis of different classes of
heterocyclic compounds such as pyrazolines, thiophenes
and pyrimidines, etc. most of these compounds are highly
2
bioactive and are widely used in pharmaceutics .
Pyrimidine derivatives have found application in a wide
range of medicinal chemistry because of their diverse
3
3
biological activities, such as anti allergic , antitumor ,
antipyretic3 anti-inflammatory3, antiparasitic4, anti
5
5
5
5
fungal , antimalarial , antibacterial , antimycotic ,
6
1
7
7
anticancer , antimicrobial , anti HSV , anti-convulsion
7
and anti-viral also these compounds are considered to be
important for synthetic drugs (e.g. Barbituric acid
derivatives)8,
chemotherapeutic
agents
(e.g.
Sulfadiazine)8 and agricultural chemicals. During a
screening effort for antiviral agents, we found that multi
functionalized tetrahydropyrimidines derivatives bearing
bulky C-2 alkyl substituents depict cytostatic activity and
inhibit proliferation of murine leukemia, murine
mammary carcinoma, human T-lymphocyte and human
cervix carcinoma cells9, 3, 4-Dihydropyrimidin-2-(1H)-ones
(DHPMs) and their appropriately functionalized
derivatives have interesting pharmacological profiles10.
These are potent antihypertensive agents, mitotic kinesin
inhibitors, a1a-adrenergic receptor antagonists, or
Quinolinylpyrimidine,
Antimicrobial,
Biginelli
compounds,
hepatitis B virus replication inhibitors and depict a variety
of other biological effects. Although a large number of
DHPM derivatives have been prepared in a single-pot
Biginelli multi component reaction10 (MCR) and its
variants10, very useful and convincing structural variability
of these interesting heterocycles have been achieved
through chemical functionalization of all the six positions
around the DHPM core10. The 4-aryl-1, 2, 3, 4tetrahydropyrimidines has been given the name Biginelli
compounds. The main interest in Biginelli compounds,
however, is due to the strong antihypertensive activity
8
exhibited by certain derivatives .
Pyrimidines and fused pyrimidines, being an integral part
of DNA and RNA, play an essential role in several
biological
processes
and
have
considerable
pharmacological importance, particularly, the pyrimidine
ring can be found in nucleoside, antibiotics,
Cardiovascular as well as agrochemical and veterinarian
products. Pyrimidines present an interesting group of
compounds many of which possess wide-spread
pharmacological properties such as antidepressant,
anticon-vulsant activities. Heterocyclic compounds have
received considerable attention owing to their variety of
biological activities, especially as inhibitors of PDE5
extracted from human platelets, HIV-1 reverse
transcriptase, human EPK2. Also heterocyclic nitrogen
compounds are indispensable structural units for
medicinal chemists and used as antibiotics, anthelmintics.
anti-depressant and anti-inflammatory11.
International Journal of Pharmaceutical Sciences Review and Research
Available online at www.globalresearchonline.net
Page 15
Int. J. Pharm. Sci. Rev. Res., 15(1), 2012; nᵒ 04, 15-22
Table 1: Pharmacological activities of Pyrimidines
Ref.
no.
8
Pharmacological
Activity
Antimicrobial
activity
Structure
O
HN
CH
CH
3
O
3
O
NH
CH
3
ISSN 0976 – 044X
17
N
Antimicrobial
activity
N
NH
S
N
O
S N
CH3
O
18
HN
N
OR
Antiinflammatory
activity
N
NH
N
NC
2
F
12
Antifungal and
Antibacterial
activity
Ph
N
C 2 H 5 OOC
Antibacterial and
Antifungal
activity
O
N
H
O
N
H
HN
O
2
N
OH
19
Ph
N
H 3C
H 3C
Antibacterial
activity
NH
N
Cl
O
20
N
Antioxidant and
Antibacterial
activity
OH
O
N
N
Cl
O
N
Et
HS
CH3
11
N
Analgesic activity
COOEt
N
N
OCH
21
3
Antileishmanial
activity
N
SH
CN
N
N
H3CS
CH3
CH3
11
COOEt
N
N
NHph
Antiinflammatory
activity
N
N
22
Ph
C 6H 5
H
N
N
S
N
N
Ph
CH3
11
CH3
OH
N
CONHph
S
N
Antiparkinsonism
activity
CN
N
Ph
NH
Antibacterial and
Antibacterial
activity
CN
HN
N
H
N
H
14
O
C
CH3
PREPARATION METHODS
The chalcones were prepared by the Claisen Schmidt
condensation using both conventional as well as
ultrasonic assisted methods (Scheme I) 3.
Antimicrobial
activity
OH
CN
OCH
Cl
Et
3
OH
O
N
O
+
O
N
N
O
CH3
CH3
HN
Cl
Et
Scheme I
N
H
S
CN
15
Ph
Antibacterial and
antifungal
activity
N
NH
Ph
Ph
C 6H 5
O
N
NHSO
N
N
Ph
C6H 5
O
16
Antibacterial and
Antifungal
activity
Ph
CH3
S
C6 H5
O
23
N
13
Antibacterial and
Antifungal
activity
N
2
CH 3
Antimicrobial
activity
A series of quinolinylpyrimidine derivatives have been
prepared by using both conventional and microwave
induced heating. The compounds were prepared by the
condensation of quinolinyl chalcones with urea (or
thiourea) in basic media under prolonged refluxing
conditions or under microwave irradiations (Scheme II)3.
O
OH
N
O
NH
OH
NH2
O
+ H2N
N
O
Cl
O
N
Et
Et
O
Cl
Scheme II
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Available online at www.globalresearchonline.net
Page 16
Int. J. Pharm. Sci. Rev. Res., 15(1), 2012; nᵒ 04, 15-22
ISSN 0976 – 044X
Table 2: Comparison between microwave-assisted and conventional method of synthesis in terms of yield and time
Microwave Irradiation
Time (min)
Yield (%)
Structure
HN
NH
Conventional Heating
Time (hr.)
Yield (%)
Ref. No.
24
82
6.5
65
3
22
78
6
55
3
O
CH3
HN
NH
S
H3C
3
HN
21
80
6
54
24
76
6
58
3
28
78
5.5
60
3
25
75
5.5
61
3
22
73
5
65
3
29
75
5.5
55
3
8
79
12
64
3
8
78
12
64
3
8
69
12
62
8
72
12
65
3
8
78
12
65
3
8
75
12
63
NH
O
H3C
HN
NH
O
OCH 3
HN
NH
O
H3CO
HN
NH
O
OCH3
H3CO
HN
NH
O
(Me)2N
HN
NH
O
Ph
N
C2 H5COO
H3 C
N
H
Ph
N
H
N
O
Ph
NO 2N
C 2H 5COO
H 3C
N
H
Ph
N
H
N
O
Cl
Ph
N
C2H5COO
H3C
N
H
N
N
H
Ph
3
O
OCH 3
Ph
N
C 2H 5COO
H3C
N
H
N
N
H
Ph
O
Ph
N
C 2H 5COO
H 3C
N
H
N
N
H
Cl
Ph
S
Ph
N
C2 H5COO
H3 C
N
H
N
N
H
Ph
3
S
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Page 17
Int. J. Pharm. Sci. Rev. Res., 15(1), 2012; nᵒ 04, 15-22
ISSN 0976 – 044X
Microwave Irradiation
Time (min)
Yield (%)
Structure
Conventional Heating
Time (hr.)
Yield (%)
Ref. No.
Ph
NO 2
C2 H5 COO
N
H3C
N
H
OH
O
N
O
Et
OH
O
N
O
Ph
N
H
N
8
67
12
60
3
85
65
6
27
3
80
72
6
26
3
85
74
6
38
3
90
75
6
36
3
85
65
6
28
3
4.5
85
10
40
3
4.5
82
10
39
3
4.0
80
8
38
3
4.0
82
8
38
3
4.5
85
8
45
3
9
80
12
62
23
8.5
87
11
65
23
8.0
91
11
68
23
8.0
90
11.5
65
23
S
Cl
Cl
Me
OH
O
N
O
Me
OH
O
N
O
Cl
Ph
OH
O
N
O
OMe
Ph
O
N
NH
OH
N
Cl
O
Et
O
N
NH
OH
N
Cl
O
Me
O
N
NH
OH
N
O
Me
S
N
NH
OH
N
Cl
O
Ph
S
N
NH
OH
N
OMe
O
Ph
H 5 C6
H
N
N
Ph
S
N
Ph
C 6 H5
O
H3 CH4 C6
N
Ph
H
N
S
N
Ph
C6H4 CH3
O
H 3COH 4 C6
Ph
N
H
N
S
N
Ph
C 6H 4OCH 3
O
ClH4 C6
Ph
N
H
N
S
N
Ph
C6 H4 Cl
O
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Page 18
Int. J. Pharm. Sci. Rev. Res., 15(1), 2012; nᵒ 04, 15-22
Microwave Irradiation
Time (min)
Yield (%)
Structure
BrH 4C6
H
N
N
Ph
ISSN 0976 – 044X
Conventional Heating
Time (hr.)
Yield (%)
Ref. No.
S
N
Ph
8.5
85
12
67
23
9.0
82
12
60
23
8.0
87
12
70
23
9
86
11
67
23
8.5
92
11.5
72
23
9.0
80
12
60
23
NH
5
75
7
53
24
NH
4.5
78
6.5
54
24
NH
4
81
6.5
57
24
NH
4
87
6
65
24
NH
4.5
82
6.5
60
24
NH
5
73
7
52
24
4.5
85
6.5
63
24
4
79
6
56
24
C 6H 4Br
O
HOH 4 C6
N
Ph
H
N
S
N
Ph
C 6H 4 OH
O
O 2NH 4C6
N
Ph
H
N
S
N
Ph
C6 H4NO 2
O
Furyl
H
N
N
Ph
S
N
Ph
Furyl
O
Thionyl
H
N
N
Ph
S
N
Ph
Thionyl
O
Pyridnyl
N
Ph
H
N
S
N
Ph
Pyridnyl
O
CN
Ph
N
Ph
Ph
C6H5
CN
Ph
N
Ph
Ph
CH3C6H4
CN
Ph
N
Ph
Ph
CH3OC 6H 4
CN
Ph
N
Ph
ClC 6H 4 Ph
CN
Ph
N
Ph
BrCH4 Ph
CN
N
Ph
Ph
Ph
OHC 6H 4
CN
Ph
N
NH
Ph
No2 C6 H4
Ph
CN
Ph
N
NH
Ph
Furyl
Ph
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Int. J. Pharm. Sci. Rev. Res., 15(1), 2012; nᵒ 04, 15-22
ISSN 0976 – 044X
Microwave Irradiation
Time (min)
Yield (%)
Structure
Conventional Heating
Time (hr.)
Yield (%)
Ref.
No.
CN
Ph
N
NH
4
81
6
58
24
4.5
76
7
56
24
20
82
5.5
65
24
22
78
6
55
24
22
80
6
54
24
24
76
5.5
58
24
26
78
6
60
24
24
75
6
61
24
25
73
6.5
65
24
29
75
5.5
55
24
Ph
Ph
Thiodinyl
CN
Ph
N
NH
Ph
Ph
Pyridinyl
HN
NH
S
CH3
HN
NH
S
CH3
HN
NH
S
H3C
HN
NH
S
OCH 3
HN
NH
S
H3 CO
HN
H 3CO
NH
S
OCH 3
HN
NH
S
(Me)2N
HN
NH
S
Benzil (2.5m mole; 5.25g), ethyl-1-formyl-1, 2, 3, 6tetrahydro-4-methy-6-phenyl-2-thioxopyrimidine-5carboxylate and ammonium acetate were dissolved in
glacial acetic acid. The reaction mixture was subjected to
microwave irradiation to procedure substituted ethyl 1, 2,
3, 6-tetrahydro-4-methyl-2-oxo/thioxo-6-phenyl-1- (4, 5diphenyl-1-H-imidazol-2-yl)
pyrimidine-5-carboxylate
(scheme III)3.
The procedures for the Synthesis of 2-amino-3ethylcarboxylate-4, 5-diphenylpyrroles were followed as:
2-amino-2-phenylacetophenones and cyano-ethyl acetate
were dissolved in 10 ml of EtOH and the resulting solution
was adsorbed over 20g basic alumina or montmorillonite.
The beaker containing reaction mixture was then kept in
microwave oven in an alumina bath and irradiated for 6-7
minutes intermittently. Furthermore, synthesis of 2thioxo-3, 7-disubstituted-5, 6-diphenyl-pyrrolo [2, 3-d]
pyrimidin-4(1H)-ones was carried out using conventional
23
and microwave methods (Scheme IV) .
R1
R1
R2
R2
C2H5COOH
H3C
N
H
N
acetate / acidic alumina
CHO
N
N
C2H5COOH
Ammonium
+
O
O
Microwave irradiation
H3C
8 - min
N
H
O
N
H
O
Scheme III
Ph
+H5C6
CH
Ph
O
O
C
NH2
Basic alumina
C
CH2
Ph
OH
HN
Basic alumina NC
Ph
C6 H 5
H
N
N
CH2 COOEt
S
S
N
Ph
C 6H 5
H 5C 6
NH C
NH2 Ph
Basic alumina Ph
C 6H 5
O
COOEt
N
NH2
H5 C 6
Scheme IV
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Int. J. Pharm. Sci. Rev. Res., 15(1), 2012; nᵒ 04, 15-22
ISSN 0976 – 044X
To produce 3, 4-dihydrobenzo 2, 3-d pyrimidines in dry
media under microwave irradiations by the cyclization of
1, 3-cyclohexadiene derivatives with formamide under
24
acidic conditions (Scheme V) .
O
Ph
CN
C
+ H2C
CH
Ph
OH
Ph
Baisic Alumina
Ph
CN
NH2
O
C
CN
Ph
O
O
H3C
Srivastva S.K., Agarwal A., Murthy P.K., Chauhan P. M. S., Agarwal
S. K., Bhaduri A. P., Singh S. N., Fatima N. and Chatterjee R. K.,
Synthesis of several new series of heterocyclo-thiazolidin-arylidine
and thiadiazolyl-azetidines Biological active molecule, J. Med.
Chem. 42 (1999) 1667-1672.
5.
Katritzky A. R., Regiospecific Synthesis of 4-(2-Oxoalkyl) pyridines,
In Comprehensive Hetrocyclic Chemistry Rees, 25 (1984)
6.
Dlugosz A. and Dus D., Synthesis and biological studies of some
novel schife and hydra zones darivatives from 8-hydroxy quinoline
moiety, Farmaco, 51 (1996) 367.
7.
Afonso A. and Weinstein J., An efficient synthesis and DNA binding
interaction
study
of
some
novel
heterocyclic
fusedpyarzolequinolines: A potent antimicrobial agent, Gentles. M.
J. U.S. US, 5 (1995) 382- 572.
8.
8.Omar Abd El-Fattah, Eman Mostafa Hassan Abbas, Neama
Ahmed Mohamed and Sherien I. Abd-Elmoez1, Synthesis and
Evaluation of Some Tetrahydropyrimidine Derivatives as
Antimicrobial, Australian Journal of Basic and Applied Sciences,
4(1), (2010) 27-36.
9.
Singh K., Arora D. and Balzarini J., Regioselective addition reactions
at C-2 of 3,4-dihydropyrimidinones, Tetrahedron, 66 (41), (2010)
8175-8180.
NH2
CN
Ph
Ph
OH
Ph
4.
NH2
C
H5 C6
Ban M., Taquchi H., Katsushima T., Akoki S. and Wantanbe A.,
Synthesis of new calcineurin inhibitors via Pdcatalyzed crosscoupling reactions, Bioorg Med. Chem., 6, (1998) 1057-1067.
CN
Neutrarl Alumina
O
3.
Ph
Ph
Acidic Alumina
10. Kappe C.O., Iologically active dihydropyrimidones of the Biginellitype – A literature survey, Eur. J. Med. Chem., 35, (2000) 10431052.
CN
N
Ph
NH
Ph
C 6H 5
Ph
Scheme V
CONCLUSION
Pyrimidine and pyrimidine derivatives have proved for
many years to have significant therapeutic potential. They
come from a wide variety of natural sources and new
pyrimidine derivatives are being discovered or
synthesized on a regular basis. It is evident from the
research described that pyrimidine and pyrimidine
derivatives are a plentiful source of potential drugs
candidate in relation to its safety and efficacy. New
pyrimidine derivatives have been synthesized using
conventional and microwave heating methodology and
characterized. The advantages in the use of microwave
methodology are shorter reaction times, higher yields and
simplified work up procedures for the point of
purification of the prepared compound. The combination
of solvent free reaction condition and microwave
irradiation leads to significantly reduced reaction times,
enhanced conversions and sometime higher selectivity
with several advantages for the eco-friendly approach,
termed as “Green Chemistry”.
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