Synthesis of New Fused Thienopyrimidines Derivatives as Anti-inflammatory Agents

Article abstract of DOI:10.1002/jhet.3056

5-Amino-2-(p-tolylamino)-4-phenylthieno[2,3-d]pyrimidine-6-carbonitrile 9, which was synthesized by an innovative method, was used as a versatile precursor for synthesizing pyrimido-thienopyrimidine, triazolopyrimidothienopyrimidine, and pyrimidothienotriazine compounds. Thus, reaction of aminothienopyrimidinecarbonitrile 9 with chloroacetylchloride in dioxane afforded the chloroacetylaminocarbonitrile derivative 10, which underwent nucleophilic substitution reactions with various primary and secondary amines gave the corresponding N-alkyl-(aryl)amino acetamides 11a,b. On the other hand, the reaction of aminocarbonitrile 9 with triethyl orthoformate followed by cyclization with hydrazine yielded an aminoiminopyrimidine derivative 13. The latter was used as versatile precursor for synthesis of new heterocyclic compounds. The structures of all the new compounds have been established on the basis of their analytical and spectral data (IR, ¹H NMR, ¹³C NMR, and MS). Some of the synthesized compounds were evaluated in vitro for their anti-inflammatory activity. All the tested compounds exhibited remarkable anti-inflammatory activity.

Full text of DOI:10.1002/jhet.3056

Month 2017
Synthesis of New Fused Thienopyrimidines Derivatives as
Anti-inflammatory Agents
a
a
b
a
a
Mahmoud S. Tolba, Mostafa Ahmed, *
Adel M. Kamal El-Dean, Reda Hassanien, and Mahmoud Farouk
a
Chemistry Department, New Valley Faculty of Science, Assiut University, Assiut 72511, Egypt
b
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
E-mail: drmostafa@scinv.au.edu.eg
*
Additional Supporting Information may be found in the online version of this article.
Received July 15, 2017
DOI 10.1002/jhet.3056
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
5
-Amino-2-(p-tolylamino)-4-phenylthieno[2,3-d]pyrimidine-6-carbonitrile 9, which was synthesized by
an innovative method, was used as a versatile precursor for synthesizing pyrimido-thienopyrimidine,
triazolopyrimidothienopyrimidine, and pyrimidothienotriazine compounds. Thus, reaction of
aminothienopyrimidinecarbonitrile
9
with chloroacetylchloride in dioxane afforded the
chloroacetylaminocarbonitrile derivative 10, which underwent nucleophilic substitution reactions with vari-
ous primary and secondary amines gave the corresponding N-alkyl-(aryl)amino acetamides 11a,b. On the
other hand, the reaction of aminocarbonitrile 9 with triethyl orthoformate followed by cyclization with
hydrazine yielded an aminoiminopyrimidine derivative 13. The latter was used as versatile precursor for
synthesis of new heterocyclic compounds. The structures of all the new compounds have been established
1
13
on the basis of their analytical and spectral data (IR, H NMR, C NMR, and MS). Some of the synthesized
compounds were evaluated in vitro for their anti-inflammatory activity. All the tested compounds exhibited
remarkable anti-inflammatory activity.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
[1]. Thienopyrimidines are interesting heterocyclic
compounds, and a lot of derivatives of these compounds
display therapeutic activity as antimicrobial [2–6],
antiviral [7–9], anti-inflammatory [10–12], antidiabetic
[13], antioxidant [14–16], antitumor [17–19], anticancer
In the past few years, thienopyrimidines and fused
thienopyrimidine derivatives have attracted great attention
owing to their inspiring array of pharmacological activities
©
2017 Wiley Periodicals, Inc.

M. S. Tolba, M. Ahmed, A. M. Kamal El-Dean, R. Hassanien, and M. Farouk
Vol 000
agents [20–24], and antimalarial [25,26]. Some
thienopyrimidine used as analgesic [27,28]. The
antibacterial activity of this class of compounds has been
underexplored.
mercaptopyrimidine compound (7). The structure of
compounds 3, 4, and 7 were established by their elemental
and spectral analyses. IR of compound 3 showed absorption
ꢀ
1
1
band at 3450 cm characteristic of 2NH groups. H NMR
spectrum of compound 3 showed two singlet signals at δ
10.20 and 11.69 characteristic of 2NH groups and the signals
characteristic of ethyl group in compound 2, disappeared. On
the other hand, IR spectrum of compound 7 revealed the
disappearance of absorption band characteristic of NH group
Moreover, thieno[2,3-d]pyrimidines have fascinated
importance
in
medicinal
chemistry,
exhibiting
pharmacological and therapeutic properties such as
antidepressant [29,30], antiplatelet [31], antihypertensive [32],
herbicidal [33], and plant growth regulatory properties [34]. In
continuation of our program for the synthesis of heterocyclic
compounds containing thienopyrimidine moiety [35–39], in
the present work, we report on the efficient synthesis of
thienopyrimidine derivatives. This study focused on the
synthesis and biochemical evaluation of the newly
synthesized heterocyclic compounds that were subjected
through anti-inflammatory evaluations.
1
in the starting material. While H NMR spectrum showed the
appearance of singlet signal at δ 11.36 characteristic of SH
group (Scheme 1).
When compound (7) allowed to react with
chloroacetonitrile in ethanol in the presence of sodium
acetate, alkylation of mercapto group was occurred
affording compound (8). Compound (8) undergoing
Thorpe–Ziegler cyclization reaction in refluxed ethanol in
the presence of sodium ethoxide giving 5-amino-4-phenyl-
2-p-tolylaminothieno[2,3-d]pyrimidine-6-carbonitrile (9).
The IR spectrum of compound 8 revealed two absorption
RESULTS AND DISCUSSION
ꢀ
1
5-Cyano-4-oxo-6-phenyl-2-thioxo-1,2,3,4-
bands for (2CN) groups at 2187 and 2226 cm , which
one of them disappeared upon Thorpe–Ziegler cyclization
to afford compound 9 and appearing of new bands
tetrahydropyrimidine (1) has been synthesized via
multicomponents reaction by one pot condensation
reaction according to the reported procedure [40], was
reacted with ethyl iodide and sodium acetate in refluxing
ethanol gave 2-ethylmercapto-4-oxo-6-phenyl-pyrimidine-
ꢀ
1 1
characteristic of (NH ) group at 3477 and 3387 cm . H
2
NMR spectrum of compound 8 showed signal at δ 4.63
1
corresponding to CH . On the other hand, the H NMR
2
5
-carbonitriles (2) according to the literature procedure
spectrum of compound 9 revealed the disappearance of
signal characteristic for methylene group in compound 8
and appearance of new signals characteristic of NH2
group. Mass spectrum gave a molecular ion peak at
375.03 as a base peak. C NMR spectrum of compound 9
revealed signal at δ 117.67 characteristic of CN and at δ
[
(
41]. The ethylmercaptopyrim-idinecarbonitriles derivative
2) was reacted with p-toluidine in ethanol under reflux to
give 2-(p-tolylamino)-6-oxo-4-phenyl-1,6-dihydropyrimidine
5-carbonitrile (3). Chlorination of the latter compound,
using phosphorusoxychloride, afforded 4-chloro-2-(p-
tolylamino)-6-phenyl-5-pyrimidine carbonitrile (4).
13
-
160.78 for (C–NH ) (Scheme 2).
2
Compound (4) was converted into the corresponding 4-
mercapto-2-(p-tolylamino)-6-phenyl-5-pyrimidine carbonitrile
5-Amino-2-(p-tolylamino)-4-phenylthieno[2,3-d]pyrimi-
dine-6-carbonitrile (9) was treated with chloroacetyl
chloride in dioxane followed by treatment with sodium
carbonate solution to afford the chloroacetamide
derivative (10). The IR spectrum of compound 10 showed
(7) by refluxing with thiourea to give thiurenium salt (5) that
refluxed in sodium hydroxide solution (10%) to give sodium
salt (6) which upon acidification with HCl afforded the
Scheme 1. Synthesis of 4-mercaptopyrimidine carbonitrile 7. Reagents and conditions: (a) Etl, AcONa, EtOH, Reflux 5 h; (b) p-toluidine, EtOH, Reflux
h; (c) POCl , Reflux 4h; (d)NH CSNH , EtOH, Reflux 5h; (e) NaOH (10%); (f) dil HCI
6
3
2
2
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DOI 10.1002/jhet

Month 2017
Synthesis of New Fused Thienopyrimidines Derivatives as
Anti-inflammatory Agents
Scheme 2. Synthesis of aminocarbonitrilethienopyrimidine 9. Reagents and conditions: (a) CICH
Reflux 0.5 h.
2
CN, AcONa, EtOH, Reflux 3h; (j) EtONa, EtOH,
disappearance of absorption bands characteristic of amino
group and appearance of absorption bands characteristic
Scheme 3. Synthesis and reactions of chloroacetyl derivative 10 and
Chloromethyl derivatives 12. Reagents and conditions: (a) ClCH COCI,
2
ꢀ
1
of 2NH at 3350 cm , and band characteristic of C=O
1 2
dioxan,Steam bath, Reflux 3h; (b) R R NH, EtOH, Reflux 2h; (c)
ꢀ
1
13
CICH COCI, Steam bath 70°C, Reflux 5h; (d) morpholin, dioxan,
2
amidic at 1678 cm
.
C NMR spectrum of compound
Reflux 3h.
1
0 revealed signal at δ 179.79 characteristic for CO. The
chloroacetyl derivative 10 underwent nucleophilic
substitution reactions with various primary and secondary
amines in refluxing ethanol for 2 h to afford the
corresponding N-alkyl-(aryl)aminoacetamides (11a,b).
While the reaction of 5-amino-2-(p-tolylamino)-4-
phenylthieno[2,3-d]pyrimidine-6-carbonitrile (9) with
excess chloroacetyl chloride on water bath under neat
condition for 5 h followed by treatment with sodium
carbonate
solution
gave
2-chloromethyl-3H-7-p-
0
0
tolylamino-4-oxo-9-phenylpyrimido[4 ,5 :4,5]thieno[2,3-d]
pyrimidine (12). IR spectrum of compound 12 revealed
appearance of absorption bands for 2NH and CO at 3278,
ꢀ
1
3
156, and 1668 cm, respectively and disappearance of
absorption band corresponding to cyano group in
compound 9. Mass spectrum of compound 12 gave a
peak at m/z = 432.65 corresponding to the molecular ion
amount of hydrazine hydrate in dioxane at room
temperature by stirring afforded the corresponding
aminoiminopyrimidine derivative (15). IR spectrum of
compound 15 showed absorption bands at ν 3487, 3390,
+
peak and the base peak [M ꢀ1, 65.23%].which in
ꢀ
1
agreement with the postulated structure. Chloromethyl
derivatives (12) underwent nucleophilic substitution
reactions with morpholine in refluxing dioxane to
3297 cm
for NH, NH2 accompanied with disap-
pearance of absorption band characteristic of cyano group
1
in the starting material. H NMR spectrum showed
afford
3H–p-tolylamino-2-morpholinomethyl-4-oxo-9-
singlet signal at δ 5.95 ppm for amino group in addition
to the singlet signal at δ 9.16 ppm for NH group. Mass
spectrum of 15 showed a molecular ion peak at 399.25 as
a base peak. The aminoiminopyrimidine compound (15)
was used as starting material to synthesize different
heterocyclic compounds. Thus, the boiling of
pyrimidinaminoimino compound (15) with triethyl
orthoformate and diethyl malonate afforded the
corresponding triazolopyrimidine derivatives (16) and
(17), respectively. Refluxing of aminoimino compound
(15) with benzaldehyde in ethanol in the presence of few
0
0
phenylpyrimido[4 ,5 :4,5]thieno[2,3-d] pyrimidine (13).
The formation of compound 13 was confirmed by
elemental and spectral data. Mass spectrum showed peak
1
at 484.02 as a molecular ion peak . H NMR of compound
1
3 showed multiplet signals at δ 3.3, 3.6, 3.7, 3.9 for four
methylene groups of morpholine ring singlet signal at δ
1
3
1
2.4 for (NH) group. C NMR spectrum of compound
(13) revealed signal at δ 53.76 characteristic of methylene
group and two signals at δ 52.76 and 67.98 for (4CH ) of
morpholine ring (Scheme 3).
2
The reaction of o-aminocyano derivative (9) with
triethyl orthoformate in acetic acid afforded
ethoxymethyleneamino derivative (14). The H NMR
spectrum of 14 revealed the appearance of a triplet signal
at δ 1.34 ppm for methyl group, quartet signal at
drops
of
piperidine
gave
the
corresponding
triazolopyrimidopyrimidine (18). Reaction of (15) with
acetylacetone gave the methyl triazolo compound (19)
rather than the triazepine compound (20). Methyltriazolo
derivative (19) was also obtained from the reaction of
compound (15) with ethyl acetoacetate. The structure of
compound 19 was established by mp, TLC, IR, and mass
spectra. Its IR spectrum showed absorption bands at
1
3
.66 ppm for methylene group, and a singlet signal at δ
8
.25 ppm for an azomethine proton. Reaction of
ethoxymethyleneamino derivative (14) with an equivalent
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. S. Tolba, M. Ahmed, A. M. Kamal El-Dean, R. Hassanien, and M. Farouk
Vol 000
Scheme 4. Synthesis and reactions of aminoimino compound 15. Reagents and condiotions: (a) CH(OEt)
3
,AcOH, Reflux 2h; (b) NH
2
NH
2
/dioxan, r.t.;
(
(
c) CH(OEt)
j) CH COCH
3
,AcOH, Reflux 3h; (d) CH
CO Et, Reflux 4h.
2
(CO
2
Et)
2
, Reflux 4h; (e) PhCHO, EtOH, piperidine, Reflux 3h; (f) CH
2
(CH
3
CO) , Reflux 2h;
2
3
2
2
ꢀ
1
1
13
3
465 cm characteristic of NH group. H NMR spectrum
ring. While the C NMR showed signal at δ 67.98 for
methylene group. Also, aminoimine compound (15) was
cyclized to the corresponding triazolopyrimido
thienopyrimidinethione (23) by heating with carbon
disulfide in the presence of pyridine on steam bath.
Compound (23) was easily alkylated using α-halogenated
carbonyl compounds in refluxing ethanol containing fused
sodium acetate to yield ethyl 7-phenyl-11-p-
of (19) showed a sharp signal at δ 2.36 for methyl group.
The mass spectrum showed a molecular ion peak at
23.22 as the base peak (Scheme 4).
The condensations proceed via cyclization of the imine
group with a retro aldol type elimination of acetone, in
the case of acetylacetone and elimination of ethyl acetate
in the case of ethyl acetoacetate as shown in [42]
4
0
0
0
0
(
Scheme 5).
tolylamino[1,3,5]triazolo[1″,2″:1 ,6 ] pyrimido[4 ,5 :4,5]
thieno[2,3-d]pyrimidine-2-ylsulfanyl]acetate (24). The IR
spectrum of compound 24 showed absorption band at
1712 cm for ester group. While the H NMR spectrum
showed triplet and quartet signals at δ 1.39–1.41 and
4.21–4.24, respectively for ethyl ester group in addition
Reaction of aminoimino compound (15) with phenacyl
bromide in hot ethanol containing
of triethyl amine afforded the corresponding
-phenyltriazinopyrimidothienopyrimidine derivative (21)
a few drops
ꢀ
1
1
3
rather than the 2-phenyltriazinopyrimidothienopyrimidine
derivative (22). The structure of compound 21 was
to singlet signal at
(Scheme 6).
δ
3.94 for –CH CO-group
2
1
13
established by TLC, H NMR, and C NMR spectra.
1
The H NMR spectrum of 21 showed a sharp signal at
Aminocyanothienopyrimidine (9) was reacted with a
δ 4.54 characteristic of methylene group of triazino
mixture of AcOH/HCl in sodium nitrite solution under
Scheme 5. Suggested mechanism for synthesis of compound 16.
Journal of Heterocyclic Chemistry
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Month 2017
Synthesis of New Fused Thienopyrimidines Derivatives as
Anti-inflammatory Agents
2 3 2
Scheme 6. Reactions of aminoimino compound 15. Reagents and conditions: (9)PhCOCH Br, EtOH, ET N, Reflux 2h; (b) CS , pyridine,Steam bath,
Reflux 4h; (c) CICH COOEt,EtOH,AcONa, Reflux 3h.
2
Scheme 7. Synthesis of and reactions of pyrimidothienotriazine derivative 25. Reagents and conditions: (a) AcOH, HCI, NaNO2, stirring 3h, r.t.;
b) p-toluidine, EtOH, Reflux 3h; (c) sulphaguanidine, EtOH, Reflux 4h.
(
cooling for
3
h
to afford the corresponding
four singlet signals at δ 2.95, 8.69, 9.42, and 10.17 for
pyrimidothienotriazine derivative (25). The IR spectrum
of compound 25 showed disappearance of absorption
(4NH) group and singlet signal at 6.29 for NH . On the
other hand, the C NMR spectrum of compound 27
2
13
bands of NH and CN groups. Nucleophilic substitution
showed signal at 159.89 for NH–C–NH (Scheme 7).
2
2
reaction of the chlorine atom with various primary
Anti-inflammatory evaluation.
The results of anti-
aromatic
amines
and
sulfa
drugs
in
the
inflammatory activity are summarized in (Table 1)
Figures 1 and 2. The activity was evaluated by using
carrageenan-induced paw edema assay, and indomethacin
was employed as standard for comparison of results [43].
The results revealed that it has been observed that several
newly prepared compounds (9, 10, 15, 17, 25, and 27)
pyrimidothienotriazine derivative (25) was performed by
reacting the chloro compound with different amines
under neat condition for short time followed by refluxing
in ethanol to afford compounds (26) and (27). The
structures of compounds 26 and 27 were established by
elemental and spectral data. The IR spectrum of 26
represented absorption band at ν 3341 cm
group. Also, the IR spectrum of compound 27 showed
absorption bands at ν 3469, 3297, 3256, 3157 cm for
showed
excellent
anti-inflammatory
properties
ꢀ
1
for NH
(61.42–82.85% inhibition of edema) as compared with
that by indomethacin (80.96% inhibition). In addition,
conversion of the amino thienopyrimidinecarbonitrile
derivative 9 to its triazinothieno-pyrimidine derivative 25,
increase the activity of compound compared with the
starting material, which is the most effective anti-
inflammatory agent, revealing higher activity (82.85%
inhibition) than that of indomethacin. However,
ꢀ
1
ꢀ
1
4
NH, NH groups and absorption band at ν 1393 cm
2
1
for SO NH group. The H NMR spectrum of compound
2
2
6 showed two singlet signals at δ 2.33 for 2CH group
3
and two singlet signals at δ 9.33 and 10.05 for 2NH. In
addition, the H NMR spectrum of compound 27 showed
1
Journal of Heterocyclic Chemistry
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M. S. Tolba, M. Ahmed, A. M. Kamal El-Dean, R. Hassanien, and M. Farouk
Vol 000
Table 1
Anti-inflammatory activity of tested compounds (9, 10, 15, 17, 25, and 27) using acute carrageenan-induced paw edema in rats (statistical analysis).
a,b,c
Paw edema inhibition (Swel ± SEM)
(%)
a
d
Compound
30 min
1(h)
2(h)
3(h)
4(h)
Potency
Edema induced by carrageenan (% edema inhibition relative to control)
9
1
1
1
2
2
0.73 ± 0.02
0.72 ± 0.02
0.72 ± 0.02
0.70 ± 0.00
0.70 ± 0.00
0.70 ± 0.00
0.67 ± 0.02
0.73 ± 0.02
0.72 ± 0.02
0.68 ± 0.02
0.68 ± 0.02
0.68 ± 0.02
0.64 ± 0.00
0.65 ± 0.03
0.58 ± 0.02
0.70 ± 0.00
0.68 ± 0.02
0.63 ± 0.02
0.58 ± 0.03
0.57 ± 0.03
0.53 ± 0.00
0.57 ± 0.04
0.55 ± 0.03
0.75 ± 0.00
0.62 ± 0.02
0.52 ± 0.03
0.52 ± 0.03
0.51 ± 0.03
0.51 ± 0.00
0.48 ± 0.02
0.45 ± 0.03
0.77 ± 0.02
0.57 ± 0.02
0.48 ± 0.02
0.47 ± 0.00
0.46 ± 0.03
0.42 ± 0.00
0.45 ± 0.03
0.43 ± 0.02
0.70 ± 0.05
61.42
74.29
75.71
77.14
82.85
78.57
80.96
–
0
5
7
5
7
Indomethacin
Control
Swel means difference in rat paw volume between right and left paw ± SE; % inhibition.
a
Dose 20 μmol/kg.
n = 6.
b
c
Statistically significant from the indomethacin at p < 0.05.
d
Potency was expressed as % edema inhibition of the tested compounds relative to % edema.
of compound 16 in position 2 by ethylacetate group
derivative 17 possessed higher activity (77.14%
inhibition) than the disubstituted derivative 15 (75.71%
inhibition). Finally, 27 exhibited more anti-inflammatory
activity (78.57% inhibition) comparable to that of
indomethacin (80.96% inhibition). Compound 9 exhibited
remarkable anti-inflammatory activity comparable to that
of indomethacin.
Figure 1. A plot of edema inhibition (mm) × time.
CONCLUSION
The objective of the present work was to synthesize,
characterize, and investigate the anti-inflammatory
and antimicrobial activities of some newly thieno[2,3-d]
pyrimidine derivatives. The starting compound 5-amino-4-
phenyl-2-p-tolylaminothieno[2,3-d]pyrimidine-6-carbonitrile
(9) that was used as a versatile precursor for synthesis to the
target compounds. Compounds 10, 15, 17, 25, and 27 were
the most anti-inflammatory activity comparable to
indomethacin.
Figure 2. A plot of paw edema inhibition (%) × time.
EXPERIMENTAL
comparing the activity of 2-chloro-N-(6-cyano-4-phenyl-2-
All melting points are uncorrected and measured on a
Fisher-Johns apparatus. Elemental analyses were
determined on an Elemental Analyzer system GmbH-
VarioEL V2.3 micro-analyzer in the central lab of Assiut
University. Their results were found to be in good
agreement (±0.2%) with the calculated values. FT-IR
(
p-tolylamino) thieno[2,3-d]pyrimidin-5-yl)acetamide 10,
it was observed that substitution with an electron-
withdrawing group, chloro acetamideamino, in the side
chain 10 74.29% inhibition seems more favorable for
constructing an anti-inflammatory active agent than the
case of substitution amino group, as exhibited
spectra were recorded on
a Pye-Unicam Sp-100
in
9
(61.42%
inhibition).
While,
the
spectrophotometer using KBr wafer technique and values
ꢀ
1
1
13
aminoiminothienopyrimidine derivative 15 showed a
significant increase in the anti-inflammatory (75.71%
inhibition). However, replacement of the hydrogen atom
represented in cm
.
H NMR and C NMR were
carried out on Varian Gemini 300 MHz. The electron
impact mass spectra were recorded on JEOL JMS-600
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of New Fused Thienopyrimidines Derivatives as
Anti-inflammatory Agents
spectrometer. Compounds 1 and 2 were prepared according
to literature procedure [40,41] with mp 298–300°C and
under reflux for 3 h and then cooled. The solid product
was filtered off, washed with water, dried, and
recrystallized from ethanol-water (1:1) to afford 8 as a pale
green crystals in 55% yield; mp: 177–179°C; ir: NH 3387,
CH aromatic 3047, CH aliphatic 2959, 2CN 2187,
2
38–240°C, respectively.
2
-(p-Tolylamino)-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-
carbonitrile (3). Compound 2 (30 g, 99 mmol) fused with
20 g) p-toluidine for 3 h. Then ethanol (50 mL) was added
ꢀ
1 1
(
2216 cm ; H NMR: δ (DMSO-d ) 2.31 (s, 3H, CH ),
6 3
and the reflux was continued for 3 h. After cooling, the
crystals is filtrated, washed with ethanol, and dried in air,
recrystallized from dioxane-ethanol (1:1) to give 3 as pale
green crystals in 73% yield; mp: 294–296°C; ir: NH
4.63 (s, 2H, CH ), 7.11–7.66 (m, 9H, ArH), and 11.87
2
+
(s, 1H, NH); ms: m\z 374.13 (M ꢀ1). Anal. Calcd for
C H N S (357.44): C, 67.25%; H, 4.23%; N, 19.55%; S,
20 15 5
8.97%. Found: C, 67.28%; H, 4.25%; N, 19.53%; S, 8.94%.
ꢀ
1 1
3
450, CH aromatic 3093, CN 2195, CO 1646 cm ; H
5-Amino-4-phenyl-2-p-tolylamino-thieno[2,3-d]pyrimidine-
6-carbonitrile (9). A solution of compound 8 (10 mmol)
NMR: (CDCl ) δ 2.32 (s, 3H, CH ), 7.08–7.40 (m, 9H,
3
3
ArH), 10.20 (s, 1H, NH), and 11.69 ppm (s, 1H, NH);
in absolute ethanol (20 mL) and few drops of sodium
ethoxide prepared by 0.5 g of finely divided sodium
metal in absolute ethanol (20 mL) solution was refluxed
for 30 min. The precipitated that formed after cooling
was filtered off, dried, and recrystallized from ethanol-
water (1:2) into 9 yellow crystals in 65% yield; mp:
+
ms: m\z 301.25 (M ꢀ1) as molecular ion peak. Anal.
Calcd for C H N O (302.34): C, 71.51%; H, 4.67%; N,
18 14 4
1
8.53%. Found: C, 71.47%; H, 4.71%; N, 18.45%.
4
-Chloro-2-(p-tolylamino)-6-phenyl-5-pyrimidine
carbonitrile (4). Compound 3 (20 g, 66 mmol) in POCl3
40 mL) was refluxed for 4 h. After cooling, the reaction
(
208–210°C; ir: NH 3477, 3387, CH aromatic 3047, CH
2
ꢀ
1 1
mixture was poured into water/ice mixture (600 g), then
neutralized using sodium carbonate solution. The reaction
mixture was stirred for 30 min; the formed precipitate
was collected by filtration, washed several times with
water, dried in air, and recrystallized from ethanol-water
aliphatic 2959, CN 2187 cm ; H NMR: (DMSO-d ) δ
6
2.31 (s, 3H, CH ), 6.47 (s, 2H, NH ), 7.11–7.66 (m, 9H,
3
2
13
ArH), and 11.87 (s, 1H, NH); C NMR: 21.13 (C21:
CH3 p-toluidine), 83.56 (C6: C–CN), 110.98 (C4a),
120.56 (C10, C14), 125.97 (C11, C13), 131.87 (C17,
C19), 139.67 (C16, C20), 117.67 (C22: CN), 121.96
(C12), 128.98 (C18), 142.55 (C9), 148.98 (C4),
(1:2) to afford white crystals of 4 in 95% yield; mp:
1
68–170°C; ir: NH 3450, CH aromatic 3069, CH
ꢀ
1 1
aliphatic 2970, CN 2214 cm ; H NMR (DMSO-d ) δ:
154.77 (C2), 160.78 (C5: C–NH ), 178.98 (C7a: N–C–S);
6
2
+
2
.31 (s, 3H, CH ), 6.95–7.67 (m, 9H, 2ArH), and 9.73
ms:m\z 375.03 (M ) and base peak. Anal. Calcd for
3
+
(s, 1H, NH); ms: m\z 320.15 (M ) and base peak. Anal.
C H N S (357.44): C, 67.25%; H, 4.23%; N, 19.55%; S,
20 15 5
Calcd for C H ClN (320.78): C, 67.42%; H, 4.06%;
8.97%. Found: C, 67.29%; H, 4.26%; N, 19.51%; S, 8.93%.
18
13
4
Cl, 11.05%; N, 17.47%. Found: C, 67.37%; H, 4.04%;
Cl, 11.09%; N, 17.42%.
2
-Chloro-N-(6-cyano-4-phenyl-2-(p-tolylamino)thieno[2,3-d]
pyrimidin-5-yl)acetamide (10).
A mixture compound 9
4
-Mercapto-2-(p-tolylamino)-6-phenyl-5-pyrimidine
(1.6 g, 4.2 mmol), and chloroacetyl chloride (0.8 mL,
7 mmol) in dioxane (25 mL) was heated on steam bath for
3 h. After cooling, the mixture was poured onto water and
neutralized with diluted sodium carbonate solution. The
solid thus formed was filtered, washed with water, dried,
and recrystallized from ethanol-water (2:1) to afford 10 as
a pale green crystals in 56% yield; mp: 176–178°C; ir:
2NH 3350, CH aromatic 3058, CH aliphatic 2922, 2851,
carbonitrile (7). A mixture of 4 (3.20 g, 10 mmol) and
thiourea (20 mmol) in ethanol (100 mL) was heated
under reflux for 5 h and then allowed to cool. The yellow
precipitate formed was filtered off and washed with
ethanol. The thiouronium salt was dissolved in NaOH
(
10%, 50 mL) and then acidified with dilute HCl to just
neutral. The crude product was collected by filtration,
washed several times with water, dried in air, and
recrystallized from ethanol-dioxane (1:2) to give 7 as a
yellow crystals in 80% yield; mp: 317–319°C; ir: NH
177, CH aromatic 3051, CH aliphatic 2974, CN
212 cm ; H NMR (DMSO-d ) δ: 2.31 (s, 3H, CH ),
ꢀ
1 1
CN 2214, CO amidic 1678 cm ; H NMR (DMSO-d )
6
δ 2.31 (s, 3H, CH ), 4.27 (s, 2H, CH Cl), 6.94–7.62 (m,
3
2
9H, 2ArH), 11.01 (s, 1H, NHCO), and 11.78 (s, 1H,
13
3
2
6
NH); C NMR: 21.13 (C21: CH3 p-toluidine), 42.77
ꢀ
1 1
(C24: CH CO), 97.15 (C6: C–CN), 114.78 (C4a), 116.55
6
3
2
.95–7.66 (m, 9H, 2ArH), 9.57 (s, 1H, NH), and 11.36
(C10, C14), 125.89 (C11, C13), 126.89 (C17, C19),
142.99 (C16, C20), 119.45 (C26: CN), 128.87 (C18),
132.11 (C12), 138.46 (C15), 137.54 (C5), 143.34 (C9),
152.69 (C4), 153.39 (C2), 137.99 (C23: CO),
+
(
s, 1H, SH); ms: m\z 317.04 (M ꢀ1). Anal. Calcd for
C H N S (318.40): C, 67.90%; H, 4.43%; N, 17.60%;
18 14 4
S, 10.07%. Found: C, 67.86%; H, 4.48%; N, 17.64%; S,
0.03%.
+
1
179.69 (C7a: N–C–S); ms: m\z 433.12 (M ) and base
peak. Anal. Calcd for C H ClN OS (433.93): C,
5
-Cyano-6-phenyl-2-p-tolylamino-pyrimidine-4-sulfanyl
22 16
5
acetonitrile (8).
1
A mixture of compound 7 (4 g,
2 mmol), chloroacetonitrile (2 mmol), and sodium
acetate (0.75 g, 8.5 mmol) in ethanol (20 mL) was heated
60.88%; H, 3.74%; Cl, 8.19%; N, 16.14%; S, 7.41%.
Found: C, 60.93%; H, 3.70%; Cl, 8.16%; N, 16.19%;
S, 7.44%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. S. Tolba, M. Ahmed, A. M. Kamal El-Dean, R. Hassanien, and M. Farouk
Vol 000
N-(2-cyano-5-p-tolylamino-4-yl-thieno[2,3-d]pyrimidin-5-yl)-
-alkyl(aryl)-aminoacetamide (11a,b). A mixture of (0.5 g,
Found: C, 60.94%; H, 3.68%; Cl, 8.21%; N, 16.09%;
S, 7.43%.
2
1
.15 mmol) of chloroacetamide derivative 10 and the
3
H-p-Tolylamino-2-morpholinomethyl-4-oxo-9-phenylpyrimido
0
0
corresponding amine (2 mmol) was dissolved in 20 mL
ethanol and refluxed for 2 h. The solid precipitate that
was formed, filtered off, dried, and recrystallized from the
proper solvent.
[4 ,5 :4,5]thieno[2,3-d]pyrimidine (13).
A mixture of
compound 12 (4.13 g, 9.5 mmol) and morpholin
20 mmol) was heated for 5 min, and then ethanol
(
(20 mL) was added. The mixture was refluxed for 3 h.
The solid product that is formed on hot was filtrated off,
dried, and recrystallized from dioxane-ethanol (1:1) to
afford 13 as a white crystals in 71.50% yield; mp:
06–308°C; ir: 2NH 3276, 3178, CH aromatic 3053, CH
aliphatic 2968, 2917, CO 1663 cm
N-(2-cyano-5-p-tolylamino-4-yl-thieno[2,3-d]pyrimidin-5-yl)-
2
-phenylaminoacetamide (11a). The solid thus formed was
filtered, washed with water, dried, and recrystallized from
ethanol-water (2:1) to give 11a as a yellow needles in
7
3
ꢀ
1
1
7% yield; mp: 225–227°C; ir: 3NH 3436, 3261, CH
;
H NMR
aromatic 3053, CH aliphatic 2920, CN 2223, CO amidic
(DMSO-d ) δ: 2.31 (s, 3H, CH ), 3.3, 3.6, 3.7, 3.9 (m,
6
3
ꢀ
1 1
1
3
665 cm . H NMR (DMSO-d ) δ: 2.31 (s, 3H, CH ),
6 3
8H, 4CH
), 4.6 (s, 2H, CH
), 7.5 (m, 5H, ArH), 7.85 (d,
2
2
13
.97 (s, 2H, CH NH), 5.92 (s, 1H, NHPh), 7.10–7.63
2
4H, ArH), 10.2 (s, 1H, NH), and 12.4 (s, 1H, NH);
NMR: 21.13 (C23: CH3 p-toluidine), 52.76 (C26, C30),
3.76 (C24: CH –N), 67.98 (C27, C29), 113.77 (C9a),
C
(
m, 14H, 3ArH), 11.33 (s, 1H, NHCO), and 11.69 (s, 1H,
+
NH); ms: m\z 488.05 [M ꢀ2]. Anal. Calcd for
5
2
C H N OS (490.59): C, 68.55%; H, 4.52%; N, 17.14%;
28
22
6
114.86 (C4a), 116.87 (C12, C16), 125.78 (C13, C15),
130.65 (C19, C21), 142.65 (C18, C22), 128.65 (C20),
S, 6.55%. Found: C, 68.58%; H, 4.56%; N, 17.18%;
S, 6.51%.
1
32.43 (C14), 140.35 (C17), 142.87 (C4), 143.87 (C11),
N-(2-cyano-5-p-tolylamino-4-yl-thieno[2,3-d]pyrimidin-5-yl)-
150.45 (C9), 155.99 (C7), 173.87 (C2), 181.09 (C5a:
2
-diethylaminoacetamide (11b). The solid thus formed was
N-C-S). Anal. Calcd for C H N O S (484.58): C,
2
6 24 6 2
filtered, washed with water, dried, and recrystallized from
ethanol-water (1:2) as a pale brown crystals of 11b in
6
6
4.45%; H, 5.00%; N, 17.32%; S, 6.61%. Found: C,
4.41%; H, 5.04%; N, 17.36%; S, 6.57%.
6
7% yield; mp: 118–120°C; ir: 2NH 3321, CN 2217,
1
-Ethoxymethyleneamino-5-p-tolylamino-7-phenylthieno[2,
ꢀ
1
1
CO amidic 1685 cm
; H NMR (DMSO-d ) δ 1.05
6
3-d]pyrimidine-2-carbonitrile (14). mixture of
A
(
(
6
1
t, J = 7.5 Hz, 6H, 2CH ), 2.32 (s, 3H, CH ), 2.79
3 3
aminocarbonitrile compound 9 (3 g, 8 mmol) and triethyl
orthoformate (6 mL, 40 mmol) in acetic acid (10 mL) was
refluxed for 2 h. The resultant solid product 14 was
filtered off, washed with water, dried, and crystallized
from dioxane-water (1:1) to give 14 as a yellow crystals
in 83% yield; mp: 148–150°C; ir: NH 3302, CH aromatic
q, J = 6.4 Hz, 4H, 2CH ), 3.4 (s, 2H, COCH N),
2 2
.96–7.63 (m, 9H, 2ArH), 9.65 (s, 1H, NHCO), and
1
3
1.04 (s, 1H, NH); C NMR: 12.34 (C27, C29), 21.13
(
C21: CH p-toluidine), 47.78 (C26, C28), 57.66 (C24:
3
CH CO), 96.52 (C6: C–CN), 114.12 (C4a), 115.99
2
(
C10, C14), 125.55 (C11, C13), 126.23 (C17, C19),
42.88 (C16, C20), 118.86 (C30: CN), 129.12 (C18),
32.22 (C12), 138.12 (C15), 140.21 (C5), 143.21 (C9),
3
051, CH aliphatic 2959, 2918, 2869, CN 2207, C=N
ꢀ
1 1
1
1
1
1644 cm ; H NMR (DMSO-d ) δ: 1.34 (t, J = 8.2 Hz,
6
3
H, CH ), 3.66 (q, J = 7.2 Hz, 2H, CH ), 6.95–7.75 (m,
3 2
50.98 (C4), 153.27 (C2), 161.88 (C23: CO), 175.66
9H, 2ArH), 8.25 (s, 1H, N=CH), and 11.86 (s, 1H, NH);
+
13
(C7a: N–C–S); ms: m\z 470.12 (M ). Anal. Calcd for
C NMR: 14.70 (C28: CH ester), 21.13 (C21: CH p-
3
3
C H N OS (470.60): C, 66.33%; H, 5.55%; N,
26
26
6
toluidine), 63.58 (C27: CH
2
ester), 100.98 (C6), 114.78
1
1
7.86%; S, 6.82%. Found: C, 66.29%; H, 5.51%; N,
7.89%; S, 6.85%.
(C7a), 116.55 (C16, C20), 125.89 (C17, C19), 130.87
(C9, C13), 145.76 (C10, C12), 119.45 (C22), 128.87
(C18), 132.10 (C12), 143.65 (C9), 153.98 (C4), 155.18
2
-Chloromethyl-3H-7-p-tolylamino-4-oxo-9-phenylpyrimido
0
0
+
[4 ,5 :4,5]thieno[2,3-d]pyrimidine (12).
Compound 9 (2 g,
(C25), 167.71 (C5), 179.87 (C3a); ms: m/z 413.24 (M ,
5.3 mmol) and chloroacetyl chloride (5 mL) was heated on
77.98%). Anal. Calcd for C H N OS (413.50): C,
2
3 19 5
steam bath for 5 h. Then poured into cold water (100 mL),
neutralized with sodium carbonate solution (10%) to just
alkaline. The solid product was filtrated off, dried, and
recrystallized from dioxane-water (1:1) to give 12 as green
fine in 77.70% yield; mp: 330–332°C; IR: 2NH
66.81%; H, 4.64%; N, 16.94%; S, 7.75%. Found: C,
66.77%; H, 4.68%; N, 16.91%; S, 7.79%.
0 0
-Amino-4-imino-7-p-tolylamino-9-phenylpyrimido[4 ,5 :4,5]
3
thieno[2,3-d]pyrimidine (15). A solution of 14 (4 g, 1 mmol)
in warm dioxane was stirred at room temperature, and
0.8 mL, 1.6 mmol of hydrazine hydrate was added to the
solution. Stirring of the mixture continued for 2 h. The solid
precipitate that was formed filtered off, dried, and
recrystallized from ethanol-dioxane (2:1) as a white crystals
3
278,3156, CH aromatic 3031, CH aliphatic 2934, 2867,
ꢀ
1
1
CO 1668 cm ; H NMR (DMSO-d ) δ: 3.6, 3.7, 3.9
6
(
s, 8H, 4CH ), 4.4 (s, 2H, CH ), 7.5 (m, 3H, ArH), 7.9 (d,
2
2
+
2
6
6
H, ArH), and 13.0 (s, 1H, NH); ms: m\z 432.65 (M ꢀ1,
5.23%). Anal. Calcd for C H ClN OS (433.92): C,
of 15 in 62% yield; mp: 228–230°C; ir: 2NH, NH 3487,
22
16
5
2
ꢀ
1
1
0.90%; H, 3.72%; Cl, 8.17%; N, 16.14%; S, 7.39%.
3390, 3297, 2960, CH aliphatic 2854 cm ; H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of New Fused Thienopyrimidines Derivatives as
Anti-inflammatory Agents
(
2
1
DMSO-d ) δ: 2.31 (s, 3H, CH ), 4.15 (s, 1H, NH), 5.95 (s,
give 18 as pale yellow crystals in 75% yield; mp:
271–273°C; ir: 2NH 3399, CH aromatic 3057, CH
6
3
H, NH ), 6.94–7.70 (m, 9H, 2ArH), 9.16 (s, 1H, NH), and
2
13
ꢀ1
1
1.77 (s, 1H, NH); C NMR: 21.13 (C23: CH3 p-
aliphatic 2918, C=N 1597 cm ; H NMR (DMSO-d ) δ:
6
toluidine), 112.76 (C9a), 116.85 (C18, C22), 125.84 (C19,
C21), 130.98 (C12, C14), 143.87 (C11, C15), 126.76 (C4a),
2.31 (3H, s, CH ), 7.20–7.70 (14H, m, 3ArH), 8.48 (1H,
s, CH pyrimidine), 9.11 (1H, s, NH), and 11.17 (1H, s,
3
1
1
1
28.78 (C13), 143.35 (C17), 132.10 (C20), 140.69 (C10),
NH). Anal. Calcd for C H N S (487.59): C, 68.97%;
H, 4.34%; N, 20.11%; S, 6.58%. Found: C, 68.93%; H,
4.39%; N, 20.15%; S, 6.54%.
28 21 7
43.87 (C2), 148.77 (C9b), 151.79 (C5, C9),156.55 (C7),
+
79.35 (C5a); ms: m/z 399.25 (M , 94.98%). Anal. Calcd
0 0
2-Methyl-7-diphenyl-9-p-tolylamino[1,2,4]triazolo[1″,5″:1 ,6 ]
for C H N S: (399.48): C, 63.14%; H, 4.24%; N,
21 17 7
0
0
2
2
4.54%; S, 8.08%. Found: C, 63.20%; H, 4.20%; N,
4.53%; S, 8.04%.
pyrimido[4 ,5 :4,5]thieno[2,3-d] pyrimidine (19). Method A.
A
mixture of compound 15 (0.7 g, 1.75 mmol) and
acetylacetone (3 mL, 30 mmol) was heated under reflux
for 2 h. The product formed after cooling was filtered off
and recrystallized from ethanol as yellow crystals of 19
in 71% yield; mp: 254–256°C.
0
0
9
-Phenyl-7-p-tolylamino-[1,2,4]triazolo[1″,5″:1 ,6 ]pyrimido
0
0
[4 ,5 :4,5]thieno[2,3-d]pyrimidine (16).
Compound 15
(0.7 g, 1.75 mmol) and triethyl orthoformate (5 mL) were
heated under reflux for 3 h. The solid product obtained on
hot was filtered off, dried, and recrystallized from ethanol to
give 16 as a white crystals in 74% yield; mp: 278–280°C;
ir: NH 3181, CH aromatic 3054, CH aliphatic 2966,
Method B.
A mixture of compound 15 (0.7 g,
1.75 mmol) and ethyl acetoacetate (4 mL, 30 mmol) in
ethanol (20 mL) in the presence of a few drops of
piperidine was heated under reflux for 3 h. The resultant
solid product was filtered, washed with water, dried, and
crystallized from ethanol to afford 19 as yellow crystals
in 78% yield; mp: 254–256°C; ir: 2NH 3465, 3350, CH
ꢀ
1 1
2
6
9
956 cm ; H NMR (DMSO-d ) δ: 2.31 (s, 3H, CH ),
.96–7.69 (m, 9H, 2ArH), 9.32 (s, 1H, CH pyrimidine),
.85 (s, 1H, CH triazole), and 11.82 (s, 1H, NH); ms:
6 3
+
m/z 409.12 (M , 53.51%). Anal. Calcd for C H N S
22 15 7
ꢀ
1
1
(409.48): C, 64.53%; H, 3.69%; N, 23.94%; S, 7.83%.
aliphatic 2921, 2850, C=N 1629 cm
(DMSO-d ) δ: 2.31 (s, 3H, CH ), 2.36 (s, 3H, CH
6.94–7.69 (m, 9H, 2ArH), 9.18 (s, 1H, CH pyrimidine),
11.40 (s, 1H, NH). Anal. Calcd for C23 S (423.50):
;
H NMR
Found: C, 64.50%; H, 3.72%; N, 23.90%; S, 7.87%.
6
3
),
3
0
0
Ethyl-9-phenyl-7-p-tolylamino-[1,2,4]triazolo[1″,5″:1 ,6 ]
0
0
pyrimido[4 ,5 :4,5]thieno[2,3-d]
pyrimidine-2yl
acetate
H N
17 7
(
17). A mixture of 15 (0.7 g, 1.75 mmol) and diethyl
C, 65.23%; H, 4.05%; N, 23.15%; S, 7.57%. Found: C,
malonate (5 mL) was heated under reflux for 4 h. After
cooling, the solid product was filtered, washed with
water, dried, and crystallized from ethanol: brown
crystals; mp 146–148°C; yield 64%; IR: NH 3287, CH
65.27%; H, 4.02%; N, 23.11%; S, 7.61%.
0 0
,8-Diphenyl-10-p-tolylamino-2H-[1,2,5]triazino[1″,6″:1 ,6 ]
3
0
0
pyrimido[4 ,5 :4,5]thieno[2,3-d] pyrimidine (21). A mixture
of compound 15 (0.6 g, 1.5 mmol) and phenacyl
bromide (0.4 g, 2.0 mmol) in ethanol (20 mL) in the
presence of a few drops of triethyl amine (0.3 mL) was
heated under reflux for 2 h. The solid product thus
obtained after cooling was filtrated off, dried, and
recrystallized from ethanol to give 21 as yellow crystals
in 63% yield; mp: 264–266°C; ir: NH 3345, CH
ꢀ
1
1
aliphatic 2934, 2982, CO ester 1753 cm
;
H NMR
(
DMSO-d ) δ: 1.37 (t, J = 8 Hz, 3H, CH ester), 2.31
6
3
(
s, 3H, CH3), 4.18 (s, 2H, CH CO), 4.25
2
(
9
q, J = 6.7 Hz, 2H, CH ), 6.94–7.70 (m, 9H, 2ArH),
2
13
.19 (s, 1H, CH pyrimidine), 11.17 (s, 1H, NH);
C
NMR: 14.70 (C30: CH3 ester), 21.13 (C25: CH3 p-
ꢀ
1 1
toluidine), 36.33 (C26: CH CO), 61.18 (C29: CH2
aliphatic 2917, C=N 1647 cm ; H NMR (DMSO-d )
2
6
ester), 113.98 (C6b), 115.78 (C14, C18), 126.43 (C15,
C17), 131.43 (C21, C23), 143.87 (C20, C24), 129.34
δ: 2.30 (s, 3H, CH ), 4.54 (s, 2H, CH triazine), 7.27–
3
2
7.67 (m, 14H, 3ArH), 9.77 (s, 1H, CH pyrimidine),
13
(C22), 132.21 (C11a), 132.66 (C16), 138.78 (C6a),
11.51 (s, 1H, NH); C NMR δ: 21.76 (C33: CH3 p-
toluidine), 67.98 (C2), 113.34 (C7b), 116.56 (C22, C26),
125.64 (C23, C25), 143.22 (C28, C32), 130.66 (C29,
C31), 129.26 (C16, C19), 129.46 (C15, C19), 126.87
(C17), 129.07 (C12a), 128.89 (C30), 132.87 (C24),
140.76 (C27), 141.22 (C12b), 143.34 (C21), 144.87
(C7a), 146.89 (C6), 151.35 (C8), 155.45 (C10), 157.88
1
41.02 (C19), 141.55 (C11b), 143.22 (C13), 147.21
(
(
C5), 152.66 (C7), 157.45 (C9), 165.12 (C2), 168.54
C27: CO), 181.99 (C10a); ms: m/z 495.12 (M ,
+
9
6
6
9.90%). Anal. Calcd for C H N O S (495.57): C,
5.23%; H, 4.05%; N, 23.15%; S, 7.57%. Found: C,
26 21 7 2
5.19%; H, 4.09%; N, 23.19%; S, 7.53%.
+
0
2
,7-Diphenyl-9-p-tolylamino-2,3dihydro[1,2,4]triazolo[1″,5″:1 ,
(C3), 181.09 (C11a: N–C–S); ms: m/z 501.23 (M +2,
0
0
0
6
]pyrimido[4 ,5 :4,5]thieno[2,3-d] pyrimidine (18). Compound
78.89%). Anal. Calcd for C H N S (499.71): C,
29 21 7
1
5 (0.6 g, 1.5 mmol) and excess benzaldehyede (4 mL)
69.72%; H, 4.24%; N, 19.63%; S, 6.42%. Found: C,
and piperidine were fused for 15 min, and then absolute
ethanol (10 mL) was added then reflux was continued for
additional 2 h. The solid product that was formed on hot
filtered off and recrystallized from dioxane-water (1:2) to
69.68%; H, 4.27%; N, 19.56%; S, 6.38%.
0
0
7-Phenyl-11-p-tolylamino[1,3,5]triazolo[1″,2″:1 ,6 ]pyrimido
[4 ,5 :4,5]thieno[2,3-d]pyrimidine-2-(3H)-thion
0
0
(23).
A
mixture of compound 15 (0.7 g, 1.75 mmol) and carbon
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. S. Tolba, M. Ahmed, A. M. Kamal El-Dean, R. Hassanien, and M. Farouk
Vol 000
disulfide (1.5 mL) in pyridine (3 mL) was heated under
reflux on a water bath for 4 h. The resultant solid product
was filtered, washed with water, dried, and crystallized
from ethanol to give 23 as orange crystals in 63% yield;
mp: 274–276°C; ir: 2NH 3395, 3287, CH aliphatic 2917,
116.09 (C12, C16), 125.87 (C13, C15), 127.87 (C19,
C21), 141.87 (C19, C21), 130.44 (C20), 131.66 (C9a),
132.76 (C14), 143.98 (C4a), 144.33 (C11), 148.36 (C17),
150.90 (C7), 155.76 (C4), 164.76 (C9b), 168.88 (C5a:
+
N–C–S); ms: m/z 405.12 (M +1, 42.43%) and the base
ꢀ
1 1
2
849, C=N 1655 cm ; H NMR (DMSO-d ) δ: 2.30 (s,
peak. Anal. Calcd for C H ClN S (404.88): C, 59.33%;
6
20 13
6
3
H, CH ), 6.94–7.69 (m, 9H, 2ArH), 8.35 (s, 1H, CH
H, 3.24%; Cl, 8.76%; N, 20.76%; S, 7.92%. Found: C,
3
pyrimidine), 11.60 (s, 1H, NH), and 12.77 (s, 1H, NH);
C NMR δ: 21.13 (C25: CH3 p-toluidine), 113.87 (C6b),
59.29%; H, 3.21%; Cl, 8.79%; N, 20.79%; S, 7.85%.
13
0
0
4,7-Di p-tolylamino-9-phenylpyrimido[5 ,4 :4,5]thieno[3,2-
d]triazine (26).
116.87 (C14, C18), 125.76 (C15, C17), 130.76 (C21,
A mixture of compound 25 (0.25 g,
C23), 143.66 (C20, C24), 128.98 (C22), 128.44 (C11a),
6.17 mmol) and p-toluidine (2 mmol) was gently fused
for 5 min, and then ethanol (10 mL) was added. The
mixture was refluxed for 3 h. The solid precipitate that
formed during reflux was filtered, dried, and
recrystallized from ethanol to give 26 as buff fine in 92%
yield; mp: 244–246°C; ir: 2NH 3461, 3339, CH aromatic
1
1
1
32.11 (C16), 140.09 (C19), 143.23 (C13), 149.55 (C6a),
46.56 (C11b), 149.55 (C5), 152.28 (C7), 155.32 (C9),
77.87 (C2), 181.02 (C10a: N–C–S); ms: m/z 440.76
+
(
M ꢀ1, 65.87%). Anal. Calcd for C H N S (441.54):
22 15 7 2
C, 59.85%; H, 3.42%; N, 22.21%; S, 14.52%. Found: C,
9.88%; H, 3.46%; N, 22.17%; S, 14.56%.
ꢀ
1
1
5
3050, CH aliphatic 2918, 2865, C=N 1592 cm ; H
NMR (CDCl ) δ: 2.33 (s, 6H, 2CH ), 6.95–7.75 (m, 13H,
0
0
Ethyl 7-phenyl-11-p-tolylamino[1,3,5]triazolo[1″,2″:1 ,6 ]
3
3
0
0
pyrimido[4 ,5 :4,5]thieno[2,3-d] pyrimidine-2-yl sulfanyl]
acetate (24).
3ArH), 9.33 (s, 1H, NH), and 10.05 (s, 1H, NH). Anal.
A mixture of compound 23 (0.6 g,
.35 mmol) and ethyl chloroacetate (2 mmol) in ethanol
15 mL) in the presence of fused sodium acetate (0.85 g,
.01 mmol) was heated under reflux for 3 h. After
Calcd for C H N S (475.58): C, 68.19%; H, 4.45%; N,
27 21 7
1
(
0
2
0.62%; S, 6.74%. Found: C, 68.16%; H, 4.42%; N,
20.59%; S, 6.71%.
0
0
N-[7-p-tolylamino-9-phenylpyrimido[5 ,4 :4,5]thieno[3,2-d]
cooling, the solid product was filtered, washed with
water, dried, and recrystallized from ethanol-water (1:1)
to afford 24 as yellow crystals in 57% yield; mp:
triazine]-sulfaguanidine (27). A mixture of compound 25
(0.25 g, 6.17 mmol) and sulphaguanidine (2 mmol) was
gently fused for 5 min, and then ethanol (10 mL) was
added. The mixture was refluxed for 3 h. The resultant
solid product was filtered, washed with water, dried, and
recrystallized from ethanol to afford 27 as white crystals
1
1
89–190°C; ir: 2NH 3324, CH aliphatic 2922, 2851, CO
ꢀ
1 1
712, C=N 1646 cm ; H NMR (CDCl ) δ: 1.39–1.41
3
(
(
t, J = 7.5 Hz, 3H, CH ester), 2.31 (s, 3H, CH ), 3.94
3 3
s, 2H, CH CO), 4.21–4.24 (q, J = 6.34 Hz, 2H, CH2
in 75% yield; mp: 266–268°C; ir: NH , 4NH 3469, 3297,
2
2
ester), 6.94–7.53 (m, 9H, 2Ar–H), 8.99 (s, 1H, CH
pyrimidine), 10.66 (s, 1H, NH); C NMR δ: 14.70 (C31:
3256, 3157, CH aromatic 3050, CH aliphatic 2998, C=N
1586, SO NH 1393 cm ; H NMR (DMSO-d ) δ: 2.32
1
3
ꢀ1
1
2 6
CH3 ester), 21.13 (C25: CH p-toluidine), 36.86 (C27:
(s, 3H, CH ), 2.95 (s, 1H, NH), 6.29 (s, 2H, NH ),
3 2
3
CH CO), 61.18 (C30: CH ester), 114.41 (C6b), 115.96
7.01–7.93 (m, 13H, ArH), 8.69 (s, 1H, NH), 9.42 (s, 1H,
2
2
13
(C14, C18), 126.02 (C15, C17), 131.66 (C21, C23),
NH), 10.17 (s, 1H, NH); C NMR: 21.13 (C34: CH p-
3
1
43.54 (C20, C24), 128.75 (C22), 131.93 (C11a), 132.33
toluidine), 115.98 (C12, C16), 124.02 (C25, C29), 126.22
(C13, C15), 128.55 (C19, C21), 129.66 (C26, C28),
142.33 (C18, C22), 119.78 (C9a), 129.35(C4b), 131.33
(C20), 134.33 (C27), 136.55 (C14), 144.42 (C11), 147.21
(C17), 149.44 (C7), 152.32 (C5), 154.66 (C1), 155.44
(C24), 159.89 (C4a), 174.66 (C8a: N-C-S); ms: m/z
(
(
(
C16), 140.00 (C19), 142.16 (C6a), 144.88 (C11b), 144.99
C5), 151.87 (C7), 156.02 (C9), 160.21 (C2), 168.73
C28: C = O ester), 181.57 (C10a: N–C–S); ms: m/z
+
5
25.66 (M ꢀ2, 98.89%). Anal. Calcd for C H N O S
2
6 21 7 2 2
(527.60): C, 59.19%; H 4.01%; N, 18.58%; S, 12.15%.
+
Found: C, 59.15%; H, 4.05%; N, 18.54%; S, 12.11%.
582.32 (M , 65.64%). Anal. Calcd for C H N O S
27
22 10
2
2
0
0
(582.67): C, 55.66%; H, 3.81%; N, 23.04%; S, 11.01%.
Found: 55.69%; H, 3.78%; N, 23.07%; S, 11.04%.
4
-Chloro-7-p-tolylamino-9-phenylpyrimido[5 ,4 :4,5]thieno
[
3,2-d]triazine (25). Compound 9 (1.3 g, 3.4 mmol) in a
mixture of acetic acid (10 mL) and concentrated
hydrochloric acid (7 mL), a sodium nitrite solution
Anti-inflammatory Evaluation.
Anti-inflammatory
activity was measured using carrageenan-induced rat paw
edema assay [43]. Edema was induced by subplantar
injection. Adult albino rats, weighing 150–200 g, were
used. The animals were allowed food and water ad
libitum, except during the experiment. They were housed
in a room at 23 ± 2°C with a 12 h light/dark cycle. The
animals were randomly allocated into groups of six
animals each at the beginning of the experiment and were
fasted for 24 h before the experiment with free access to
(10%), (4 mL, 6 mmol) was added with stirring during
5
min. The stirring was continued at 5°C for 3 h. The
formed precipitate was collected and crystallized from
ethanol-water (2:1) to afford 25 as white plates in 62.5%
yield; mp: 186–188°C; ir: NH 3181, CH aromatic 3051,
ꢀ
1
1
CH aliphatic 2848 cm
; H NMR (CDCl ) δ: 2.36
3
(
(
s, 3H, CH p-toluidine), 6.90–7.54 (m, 9H, 2ArH), 10.22
3
13
s, 1H, NH); C NMR: 21.87(C23: CH p-toluidine),
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of New Fused Thienopyrimidines Derivatives as
Anti-inflammatory Agents
water. All of the compounds and the reference drug were
suspended in a 0.5% carboxymethyl cellulose solution.
The standard drug indomethacin was administered orally
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at a dose of 20 μmol/kg . The tested compounds were
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet