A novel synthetic routes to new 3-substituted-4-oxo-3,4,5,6,7,8- hexahydropyridol[4′,3′,4,5]-thieno[2,3-d]pyrimidine-7-carboxylic acid ethyl ester derivatives

Article abstract of DOI:10.1080/104265090507812

Orthoaminoester 1 was investigated by the reaction with ethylchloroformate, 5-phenyl-oxadiazol-2-thione and triethylorthoformate to afford the open structures, 2, 13 and 15. These compounds were subjected to ensuing cyclization in one step or more yielding 3-substituted-5,6-dihydro-8H-4-oxopyrido[4′, 3′,4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylic acid ethyl ester derivatives. Copyright Taylor & Francis Inc.

Full text of DOI:10.1080/104265090507812

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A Novel Synthetic Routes
to New 3-Substituted4-
oxo-3,4,5,6,7,8-
hexahydropyrido[, , ]
thieno[, ]pyrimidine-7-
carboxylic Acid Ethyl Ester
Derivatives
M. A. Ameen a , E. Kh. Ahmed a & F. F. Abdel-latif a
a Chemistry Department, Faculty of Science, El-
Minia University , El-Minia, Egypt
Published online: 01 Feb 2007.
To cite this article: M. A. Ameen , E. Kh. Ahmed & F. F. Abdel-latif (2005) A Novel
Synthetic Routes to New 3-Substituted4-oxo-3,4,5,6,7,8-hexahydropyrido[, , ]
thieno[, ]pyrimidine-7-carboxylic Acid Ethyl Ester Derivatives, Phosphorus, Sulfur, and
Silicon and the Related Elements, 180:1, 95-107, DOI: 10.1080/104265090507812
To link to this article: http://dx.doi.org/10.1080/104265090507812
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Phosphorus, Sulfur, and Silicon, 180:95–107, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090507812
A Novel Synthetic Routes to New 3-Substituted-
4-oxo-3,4,5,6,7,8-hexahydropyrido[4ꢀ,3ꢀ,4,5]-
thieno[2,3-d ]pyrimidine-7-carboxylic Acid
Ethyl Ester Derivatives
E. Kh. Ahmed
F. F. Abdel-latif
M. A. Ameen
Chemistry Department, Faculty of Science, El-Minia University,
El-Minia, Egypt
Orthoaminoester 1 was investigated by the reaction with ethylchloroformate, 5-
phenyl-oxadiazol-2-thione and triethylorthoformate to afford the open structures,
2, 13 and 15. These compounds were subjected to ensuing cyclization in one step
or more yielding 3-substituted-5,6-dihydro-8H-4-oxopyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-
d]pyrimidine-7(6H)-carboxylic acid ethyl ester derivatives.
Keywords
5-Phenyloxadiazol-2-thione; cyclization; ethylchloroformate; key-
intermediate; orthoaminoester; triethylorthoformate
Pyridothienopyrimidine and its derivatives show marked biologi-
cal activities such as anti-inflammatory, anti-pyretic, and analgesic
properties.1–6 These interesting activities make it desirable to our
work during the last few years in which we have been interested in
synthesis of substituted heterocycles containing a thienopyrimidine
moiety.7–13 2-Amino–3-carbethoxy thiophene derivatives have been
found to be important intermediates in the chemistry of pyrimidine.
Therefore they attracted much attention during recent years.14–19 The
present paper follows that line of research by reporting on a new se-
ries of reactions led to the formation of 3-substituted-4-oxo-3,4,5,6,7,8-
hexahydropyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid
ethyl ester derivatives starting from the bi-functional o-aminoester
compound.
Received January 26, 2004; accepted June 6, 2004.
Address correspondence to M. A. Ameen, Chemistry Department, Faculty of Science,
El-Minia University, El-Minia 61519, Egypt. E-mail: m ameen10@yahoo.com
95

96
E. Kh. Ahmed et al.
RESULTS AND DISCUSSION
Based upon the aforementioned, we decided to investigate our new tar-
get pyridothienopyrimidines. Esterification of 2-amino-3-carbethoxy-
4,5,6,7-tetrahydrothieno[2,3-c]pyrido-6-carboxylic acid ethyl ester
(1),20 led to the formation of compound 2. On ring closure of 2 using
hydrazine hydrate in presence of alcoholic KOH, gave 3. Neutraliza-
tion of 3 using HCl aqueous afforded 3-amino-pyridothienopyrimidine
4 in 71% yield (Scheme 1).
Benzoylation of 4 using benzoyl chloride in THF led to the
formation of 3-benzoylamino-1,2,3,4,5,6,7,8-octahydro-2,4-dioxopyrido-
[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid ethyl ester (5). The
same strategy to obtain compound 5 can be achieved by converting the
carbonyl group in 4 into C S group using P2S5 in pyridine to yield
our published compound 6.10 Subsequently benzoylation of 6 gave com-
pound 7, which on oxidation by H2O2 afforded the target compound 5
(Scheme 1).
The structural feature of our target compound 5 was elucidated
1
by H, 13C-NMR and IR spectra as well as elemental analysis. Ele-
mental analysis proved with satisfactory evidence that the molecu-
lar formula of 5 is C19H18N4O5S. The IR spectroscopy of 5 showed
absorption bands at 3250 and 1680 cm−1 related to the NH and car-
bonyl group. The 1H-NMR showed broad singlet at δH = 10.95 ppm
1
arise to the NH-amide proton. The 13C-NMR confirmed the H-NMR
spectroscopy by the appearing of four signals at δC = 146.65, 154.25,
157.12, and 164.86 ppm corresponding to the carbonyl groups present in
compound 5.
The amino group of compound 4 was chemically investigated by the
deamination or the reaction with some electrophiles such as acetic an-
hydride, chloroacetyl chloride, or benzaldehyde affording 8, 9, 10, and
11 respectively (Scheme 2).
Analytical data and spectroscopic properties were found to be in
a good agreement with these assigned structures (See Experimental
Section).
The amino group located in ortho position relative to an ester group
is considered a versatile site for preparation of thioxopyrimidonone 7
by the reaction of compound 1 with 5-phenyloxadiazol-2-thione (12)
to give compound 13, followed by ensuing cyclization in alcoholic
potassium hydroxide. The obtained product was identical in all aspects
with that described in Scheme 1. S-methylation of compound 7 with
iodomethane afforded the final product 3-benzoylamino-2-thiomethyl-
4-oxo-3,4,5,6,7,8 -hexahydropyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-
7-carboxylic acid ethyl ester (14) (Scheme 3).

Carboxylic Acid Ethyl Ester Derivatives
97
SCHEME 1
The structure of compound 14 was undoubtly proved by the help
of the 1H-NMR and IR spectra as well as elemental analysis. Ele-
mental analysis of 14 is in accordance to its molecular formula as
C20H20N4O4S2. The 1H-NMR spectrum of 14 showed triplet and quar-
tet corresponding to ester-protons. The methyl protons were resonated
as a singlet at δH = 2.55 ppm, whereas the NH proton appeared at

98
E. Kh. Ahmed et al.
SCHEME 2
SCHEME 3

Carboxylic Acid Ethyl Ester Derivatives
99
δH = 10.95 ppm (see the experimental). The IR spectroscopy of 14
showed the absorption of the NH and the carbonyl groups at 3250
and 1710–1680 cm−1, respectively. With these spectral and analytical
data, compound 14 was identified as 3-benzoylamino-2-thiomethyl-4-
oxo-3,4,5,6,7,8-hexahydropyrido[4ꢀ3ꢀ,4,5]thieno[2,3-d]pyrimidine-7-
carboxylic acid ethyl ester.
Analogously, compound 1 was proved to be a key intermediate for
other subsequent conversions. Thus, when it allowed to react with
triethylorthoformate, the reaction performed to produce compound
15, which was triturated with benzohydrazide to give 2-[(N-benzoyl-
hydrazinomethylene)-amino]-3-carbethoxy-4,5,6,7-tetrahydrothieno-
[2,3-c]pyrido-6-carboxylic acid ethyl ester (16). The pyrimidine ring
was built up when the open structure product was subjected to cy-
clization yielding 3-benzoylamino-4-oxo-3,4,5,6,7,8-hexahydropyrido-
[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid ethyl ester (17)
(Scheme 4).
SCHEME 4
1
Our target molecule 17 was proved using H-NMR and IR spectra
as well as elemental analysis. Elemental analysis of 17 is in accor-
dance on the proposed molecular formula C19H18N4O4S. The 1H-NMR
spectrum of 17 revealed the N CH-proton at δH = 8.50 ppm, whereas
the NH-proton appeared at δH = 11.00 ppm. The IR spectroscopy of 17
indicated the absorption of the NH and the carbonyl groups at 3250
and 1710–1680 cm−1, respectively. It is interesting to mention that the
products obtained were satisfactorily analyzed with the help of both the
elemental analysis and the spectroscopic data.

100
E. Kh. Ahmed et al.
In conclusion and by the results available, we are assisted in the
synthesis new classes of pyridothienopyrimidines using efficient, facile,
and elegant methods of preparations rather than those suffering from
low yields due to the multiple steps described in their preparation.
EXPERIMENTAL
Melting points were determined on a Boetius melting point apparatus
and are uncorrected. Elemental analyses were performed on a Carol
1
Erba CHN-S Elemental Analyzer 1108. The 13C and H nmr spectra
were obtained using sa Bruker AC 300 (1H: 300.13 MHZ, 13C: 75.5
MHZ). The solvents were deuterated dimethyl sulfoxide and chloro-
form. The δ-values are given in ppm and the internal standard was
tetramethylsilane. The IR spectra were recorded on a Nicolet 250 FT-
IR spectrophotometer as potassium bromide pellets.
Synthesis of 2-Ethoxycarbonylamino-3-carbethoxy-
4,5,6,7-tetrahydrothieno[2,3-c]pyrido-6-carboxylic Acid
Ethyl Ester (2)
A mixture of 1 (2.98 g, 10 mmol) and ethylchloroformate (20 ml) was
refluxed for 2 h. The solvent was removed in vacuum. The resulting
solid product was recrystallized from ethanol as colorless needles.
Yield 93%, mp. 118–120◦C, (Found: C, 52.12: H, 6.02: N, 9.21, S, 8.44
Calc for C16H22N2O6S (370.42): C, 52.33: H, 6.08: N, 9.39, S, 8.64), IR
(KBr) ν = 3250 (NH), 1720 (ester C O), 1710 (ester C O), 1700 (ester
C O) cm−1, 1H NMR (DMSO): δH = 1.21 (t, 9H, COOCH2CH3), 2.85 (t,
2H, H-4), 3.65 (t, 2H, H-5), 4.11 (q, 6H, 3COOCH2CH3), 4.55 (s, 2H, H-
7), 10.25 (s, 1H, NH), 13C NMR (DMSO): δC = 13.80 (CH3), 14.02 (CH3),
14.38 (CH3), 25.72 (C-4), 41.03 (C-5), 42.10 (C-7), 60.38 (CH2), 60.85
(CH2), 62.08 (CH2), 114.68 (C-3), 121.67 (C-7a), 128.63 (C-3a), 148.62
(C O), 152.10 (C O), 154.51 (C O), 165.10 (C-2).
Synthesis of 3-Amino-1,2,3,4,5,6,7,8-octahydro-2,4-
dioxopyrido[3ꢀ,4ꢀ,4,5]thieno[2,3-d ]pyrimidine-7-
carboxylic Acid Ethyl Ester (4)
To a solution of 2 (3.7 g, 10 mmol) in ethanol (20 ml), potassium hy-
droxide (0.56 g, 10 mmol) dissolved in water (5 ml) and hydrazine hy-
drate (2 ml, were added. The reaction mixture was refluxed for 4 h.
The precipitate formed was filtered off, dried well to give the potassium
salt of 3. The salt 3 was dissolved in hot water and neutralized with

Carboxylic Acid Ethyl Ester Derivatives
101
HCl 2N. The resulting product was filtered off, dried, and crystallized
from ethanol as colorless needles. Yield 71%, mp. 185–187◦C, (Found:
C, 46.31: H, 4.51: N, 17.94, S, 10.23 Calc for C12H14N4O4S (310.3): C,
46.44: H, 4.55: N, 18.05, S, 10.31), IR (KBr) ν = 3350–3250 (NH2, NH),
1
1710 (ester C O), 1690 (C O) cm−1, H NMR (DMSO): δH = 1.21 (t,
3H, COOCH2CH3), 2.85 (t, 2H, H-5), 3.65 (t, 2H, H-6), 4.11 (q, 2H,
COOCH2CH3), 4.55 (s, 2H, H-8), 5.85 (s, 2H, NH2), 8.35 (s, 1H, NH),
13C NMR (DMSO): δC = 14.28 (CH3), 24.78 (C-5), 40.51 (C-6), 42.21
(C-8), 60.79 (CH2), 110.94 (C-4a), 115.59 (C-4b), 121.65 (C-8a), 129.14
(C-9a), 149.16 (C O), 154.50 (C O), 156.17 (C O).
Synthesis of 3-Benzoylamino-1,2,3,4,5,6,7,8-octahydro-
2,4-dioxopyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d] pyrimidine-
7-carboxylic Acid Ethyl Ester (5)
Method A
Compound 7 (2.15 g, 5 mmol) was dissolved in 5% NaOH solution
(10 ml) at room temperature. Then 30% H2O2 (10 ml) was added drop-
wise and the mixture neutralized with acetic acid. Stirring continued
for 30 min. The precipitate isolated by suction filtration, washed with
water, dried, and recrystallized from ethanol as pale yellow crystals, in
90% yield.
Method B
Synthesis of 5 and 7 (General procedures). To a suspension of 4 or
6 (10 mmol) in THF (20 ml), Triethylamine (0.95 g, 10 mmol) was added
and then benzoyl chloride (1.4 g, 10 mmol) in THF (5 ml) added dropwise
with stirring in ice path over a period of 20 min. The mixture stirred at
room temperature for 3 h. The solvent was distilled off at atmospheric
pressure and the residue treated with ethanol. The solid product so
formed was collected by filtration, dried, and crystallized from suitable
solvent.
Synthesis of 3-Benzoylamino-1,2,3,4,5,6,7,8-octahydro-
2,4-dioxopyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-7-
carboxylic Acid Ethyl Ester (5)
Yield 76%, mp 193–195◦C, (Found: C, 55.01: H, 4.26, N, 13.46, S, 7.61
Calc for C19H18N4O5S (414.42):C, 55.06: H, 4.38: N, 13.52, S, 7.72), IR
(KBr) ν = 3250 (NH), 3000 (arom. CH), 1710 (ester C O), 1680 (C O)
cm−1, 1H NMR (DMSO): δH = 1.21 (t, 3H, COOCH2CH3), 2.85 (t, 2H, H-
5), 3.65 (t, 2H, H-6), 4.11 (q, 2H, COOCH2CH3), 4.55 (s, 2H, H-8), 7.11–
8.00 (m, 5H, Ar-H), 10.95 (s, 1H, NH). 13C NMR (DMSO): δC = 14.23

102
E. Kh. Ahmed et al.
(CH3), 24.87 (C-5), 40.21 (C-6), 41.20 (C-8), 60.79 (CH2), 110.94 (C-
4a), 114.63 (C-4b), 121.45 (C-8a), 127.11, 128.11, 129.87, 130.98 (Ar-
C) 131.69 (C-9a). 146.65 (C O), 154.25 (C O), 157.12 (C O), 164.86s
(C O).
Synthesis of 3-Benzoylamino-1,2,3,4,5,6,7,8-octahydro-
4-oxo-2-thioxopyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-7-
carboxylic Acid Ethyl Ester (7)
Yield 72%, mp. 160–162◦C, (Found: C, 52.91: H, 4.09: N, 12.93. S, 14.64
Calc for C19H18N4O4S2 (430.48): C, 53.01: H, 4.21: N, 13.0, S, 14.87) IR
(KBr) ν = 3250 (NH), 3000 (arom. CH), 1700 (ester C O), 1680 (C O)
1
cm−1. H NMR (DMSO): δH = 1.21 (t, 3H, COOCH2CH3), 2.85 (t, 2H,
H-5), 3.65 (t, 2H, H-6), 4.11 (q, 2H, COOCH2CH3), 4.55 (s, 2H, H-8),
7.11–8.00 (m, 5H, Ar-H), 10.50 (s, 2H, NH), 12.15 (s, 1H, NH).
Synthesis of 3-Amino-4-oxo-2-thioxo-1,3,4,5,6,8-
hexahydropyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-
7(2H)-carboxylate (6)
To a solution of 4 (0.62 g, 2 mmol) in pyridine (10 ml), P2S5 (0.45 g,
2 mmol) was added. The reaction mixture was refluxed for 6 h. The
mixture was filtered off. The filtrate was concentrated and then, the
residue extracted with diethyl ether. The obtained solid product was
recrystallized from methanol to give pale yellow crystals in 83% yield.
(Lit [10]).
Synthesis of 1,2,3,4,5,6,7,8-Octahydro-2,4-
dioxopyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-7-
carboxylic Acid Ethyl Ester (8)
To a suspension of 4 (0.31 g, 1 mmol) in acetic acid (2 ml) and water
(10 ml), a solution of NaNO2 (0.28 g, 4 mmol) in water (1 ml) was added.
After stirring for 15 min at room temperature, 40% sodium hydroxide
solution was added (3 ml). The reaction mixture was warmed to clear
solution. After cooling 50% H2SO4 added dropwise till pH 2. The precipi-
tated product was filtered off, washed with water, dried, and crystallized
from ethanol as pale yellow crystals.
Yield 92%, mp. 271–272◦C, (Found: C, 48.73: H, 4.32: N, 14.08. S,
10.64 Calc for C12H13N3O4S (295.3): C, 48.81: H, 4.44: N, 14.23, S,
10.84), IR (KBr) ν = 3250 (NH), 1710 (ester C O), 1680 (C O) cm−1
,
1H NMR (DMSO): δ = 1.21 (t, 3H, COOCH2CH3), 2.85 (t, 2H, H-5), 3.65
(t, 2H, H-6), 4.11 (q, 2H, COOCH2CH3), 4.55 (s, 2H, H-8), 10.99 (s, 1H,

Carboxylic Acid Ethyl Ester Derivatives
103
NH), .99 s, H, H). 13C NMR (DMSO): δ = 14.40 (CH3), 24.64 (C-5), 40.96
(C-6), 42.21 (C-8), 60.91 (CH2), 112.11 (C-4a), 121.63 (C-4b), 136.94 (C-
8a), 150.32 (C-9a), 151.72 (C O), 154.13 (C O), 159.39 (C O).
Synthesis of 3-Acetylamino-2,4-dioxo-1,2,3,4,5,6,7,8-
octahydropyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-7-
carboxylic Acid Ethyl Ester (9)
A mixture of 4 (0.62 g, 2 mmol) and acetic anhydride (5 ml) was stirred
at room temperature for 1 h. The reaction mixture was poured into
water. The precipitate formed was filtered off, dried, and crystallized
from ethanol as colorless needles.
Yield 92%, mp. 182–183◦C (Found: C, 47.63: H, 4.47: N, 15.81, S,
9.14, Calc for C14H16N4O5S (352.35): C, 47.72: H, 4.58: N, 15.90, S,
9.08), IR (KBr) ν = 3250 (NH), 1710 (ester C O), 1680 (C O) cm−1. 1H
NMR (DMSO): δ = 1.21 (t, 3H, COOCH2CH3), 2.03 (s, 3H, CH3), 2.85
(t, 2H, H-5), 3.65 (t, 2H, H-6), 4.11 (1, 2H, COOCH2CH3), 4.55 (s, 2H,
H-8), 10.37 (s, 1H, NH), .70 s, H, H), 13C NMR (DMSO): δ = 14.28 (CH3,
ester), 20.10 (CH3), 24.74 (C-5), 40.20 (C-6), 42.22 (C-8), 60.83 (CH2),
111.44 (C-4a), 122.61 (C-4b), 124.51 (C-8a), 148.59 (C-9a), 150.07 (C O),
156.55 (C O), 167.87 (C O), 171.63 (C O).
Synthesis of 3-(2-Chloro-acetylamino)-2,4-dioxo-
1,2,3,4,5,6,7,8-octahydropyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]-
pyrimidine-7-carboxylic Acid Ethyl Ester (10)
Compound 4 (0.62 g, 2 mmol) was dissolved in dry chloroform (5 ml). To
this solution chloroacetyl chloride (0.6 g, 5.35 mmol) in dry chloroform
(2 ml) was added dropwise with stirring at room temperature over a
period of 1.5 h. The solvent was distilled on vacuum and the residue
treated with ethanol. The solid product so formed was collected by fil-
tration, dried and crystallized from ethanol as colorless powder.
Yield 83%, mp. 185–187◦C, (Found: C, 43.34: H, 3.83: N, 14.36. S,
8.24, Calc for C14H15ClN4O5S (386.79): C, 43.47: H, 3.91: N, 14.48, S,
8.27), IR (KBr) ν = 3250 (NH), 3000 (aliph. CH), 1700 (ester C O),
1
1680 (C O) cm−1, H NMR (DMSO): δH = 1.21 (t, 3H, COOCH2CH3),
2.85 (t, 2H, H-5), 3.65 (t, 2H, H-6), 4.11 (q, 2H, COOCH2CH3), 4.30 (s,
2H, CH2) 4.55 (s, 2H, H-8), 10.83 (s, 1H, NH), 2.43 (s, 1H, NH), 13C
NMR (DMSO): δC = 14.41 (CH3), 24.81 (C-5), 40.20 (C-6), 40.51 (CH2),
42.31 (C-8), 60.98 (CH2, ester), 111.42 (C-4a), 122.94 (C-4b), 129.65 (C-
8a), 148.41 (C-9a), 150.16 (C O), 154.60 (C O), 156.16 (C O), 165.01
(C O).

104
E. Kh. Ahmed et al.
Synthesis of 3-Benzylidineamino-2,4-dioxo-
1,2,3,4,5,6,7,8-octahydropyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]-
pyrimidine-7-carboxylic Acid Ethyl Ester (11)
To a mixture of 4 (0.62 g, 2 mmol) and benzaldehyde (0.22 g,
2 mmol) in ethanol (10 ml), a catalytic amount of piperidine was
added. The reaction mixture was refluxed for 2 h. After concen-
tration and cooling at room temperature, the precipitated product
was filtered off, dried, and recrystallized from methanol as colorless
powder.
Yield 87%, mp. 280–282◦C, (Found: C, 57.20: H, 4.51: N, 14.00, S, 8.13,
Calc for C19H18N4O4S (398.42): C, 57.28: H, 4.55: N, 14.06, S, 8.03), IR
(KBr) ν = 3250 (NH), 3000 (arom. CH), 1710 (ester C O), 1680 (C O),
1
1635 (C N) cm−1. H NMR (DMSO): δH = 1.21 (t, 3H, COOCH2CH3),
2.85 (t, 2H, H-5), 3.65 (t, 2H, H-6), 4.11 (q, 2H, COOCH2CH3), 4.55 (s,
2H, H-8), 7.11–8.00 (m, 5H, Ar-H), 8.65 (s, 1H, CH), 12.35 (s, 1H, NH).
13C NMR (DMSO): δC = 14.37 (CH3), 24.78 (C-5), 40.13 (C-6), 42.22 (C-
8), 60.80 (CH2), 111.64 (C-4a), 115.48 (C-4b), 122.22 (C-8a), 147.29 (C-
9a), 127.11, 128.11, 129.87, 130.91 (Ar-C) 149.01 (C O), 154.51 (C O),
155.27 (C O), 170.75 (CH N).
Synthesis of 2-(3-Benzoylamino-thioureido)-3-
carbethoxy-4,5,6,7-tetrahydrothieno[2,3-c]pyrido-6-
carboxylic Acid Ethyl Ester (13)
A mixture of compound 1 (0.6 g, 2 mmol) and 5-phenyloxadiazol-
2-thione (12) (0.36 g, 2 mmol) in m-cresol (10 ml) was heated at
150◦C for 5 h. The solvent was distilled off at atmospheric pressure
and the residue treated with n-hexane. Then the solid product so
formed was filtered off, dried, and crystallized from methanol as yellow
crystals.
Yield 71%, mp. 181–183◦C, (Found: C, 52.82: H, 5.00: N, 11.62, S,
13.24 Calc for C21H24N4O5S2 (476.55): C, 52.93: H, 5.08: N, 11.76, S,
13.43), IR (KBr) ν = 3250 (3NH), 3000 (arom. CH), 1700 (ester 2 O),
1680 (C O) cm−1, 1H NMR (DMSO): δH = 1.21 (t, 6H, 2COOCH2CH3),
2.85 (t, 2H, H-4), 3.65 (t, 2H, H-5), 4.11 (q, 4H, 2COOCH2CH3), 4.55
(s, 2H, H-7), 7.11–8.00 (m, 5H, Ar-H), 10.55 (s, 1H, NH), 11.00 (s, 1H,
NH), 12.45 (s, 1H, NH). 13C NMR (DMSO): δC = 13.82 (CH3), 14.27
(CH3), 25.63 (C-4), 40.55 (C-5), 41.45 (C-7), 60.38 (CH2), 60.73 (CH2),
111.44 (C-3), 122.36 (C-7a), 127.11, 128.11, 129.87, 130.98 (Ar-C).148.72
(C-3a), 154.46 (C-2). 165.37 (C O), 166.58 (C O), 176.80 (C O), 178.86
(C S).

Carboxylic Acid Ethyl Ester Derivatives
105
3-Benzoylamino-1,2,3,4,5,6,7,8-octahydro-4-oxo-2-
thioxopyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-7- carboxylic
Acid Ethyl Ester (7)
Method A
A mixture of 13 (0.48 g, 1 mmol) and solution of KOH (0.11 g, 2 mmol),
in ethanol (10 ml) was refluxed for 2 h. After removing the solvent, the
residue diluted with water and acidified with HCl 2N. The product was
collected by filtration, washed with water, dried, and recrystallized from
DMF/water as pale yellow crystals in 75% yield.
Synthesis of 3-Benzoylamino-2-thiomethyl-4-oxo-
3,4,5,6,7,8-hexahydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d]-
pyrimidine-7-carboxylic Acid Ethyl Ester (14)
To a suspension of 7 (1.29 g, 3 mmol) in sodium hydroxide 1N (12 ml),
methyl iodide (0.72 g, 5 mmol) was added. The reaction mixture was
stirred at room temperature for 2 h. The solid precipitate was collected
by filtration, washed with water, dried, and crystallized from methanol
as pale yellow crystals.
Yield 81%, mp. 152◦C, (Found: C, 54.15: H, 4.56: N, 12.46, S, 14.34
Calc for C20H20N4O4S2 (444.53): C, 54.04: H, 4.53: N, 12.60, S. 14.40), IR
(KBr) ν = 3250 (NH), 3000 (arom. CH), 1710 (ester C O), 1680 (C O)
1
cm−1, H NMR (DMSO): δH = 1.21 (t, 3H, COOCH2CH3), 2.55 (s, 3H,
SCH3), 2.85 (t, 2H, H-5), 3.65 (t, 2H, H-6), 4.11 (q, 2H, COOCH2CH3),
4.55 (s, 2H, H-8), 7.11–8.00 (m, 5H, Ar-H), 10.95 (s, 1H, NH).
Synthesis of 2-Ethoxymethyleneamino 3-carbethoxy-
4,5,6,7-tetrahydrothieno[2,3-c]pyrido-6-carboxylic
Acid Ethyl Ester (15)
A mixture of 1 (2.98 g, 10 mmol), triethylorthoformate (20 ml) and few
drops of acetic anhydride was refluxed for 7 h. The solvent was removed
under reduced pressure. The resulting solid product was crystallized
from benzene/petroleum ether as colorless needles.
Yield 69%, mp. 110◦C, (Found: C, 53.87: H, 6.11: N, 7.75, S, 9.14, Calc
for C16H22N2O5S (354.42): C, 53.92: H, 6.18: N, 7.86, S, 9.02), IR (KBr)
1
ν = 1710 (ester C O), 1690 (ester C O), 1625 (C N) cm−1, H NMR
(DMSO): δH = 1.21 (t, 6H, 2COOCH2CH3), 1.35 (t, 3H, OCH2CH3), 2.85
(t, 2H, H-4), 3.65 (t, 2H, H-5), 4.11 (q, 4H, 2COOCH2CH3), 4.35 (q,
2H, OCH2CH3), 4.55 (s, 2H, H-7), 8.55 (s, 1H, CH). 13C NMR (DMSO):
δC = 13.80 (CH3), 14.02 (CH3), 14.38 (CH3), 25.72 (C-4), 41.03 (C-5),

106
E. Kh. Ahmed et al.
42.10 (C-7), 60.38 (CH2), 60.85 (CH2), 62.08 (CH2), 111.45 (C-3), 122.35
(C-7a), 128.32 (C-3a), 144.62 (C O), 154.10 (C O), 158.54 (CH N),
163.78 (C-2).
Synthesis of 2-[(N-Benzoyl-hydrazinomethylene)-amino]-3-
carbethoxy-4,5,6,7-tetrahydrothieno[2,3-c]-
pyrido-6-carboxylic Acid Ethyl Ester (16)
To a solution of 15 (1.1 g, 3 mmol) in ethanol (10 ml), benzohydrazide
(0.408 g, 3 mmol) was added. The reaction mixture was stirred at room
temp. for 1 h. The precipitate formed was filtered off, dried, and recrys-
tallized from ethanol as colorless needles.
Yield 74%, mp. 192–194◦C, (Found: C, 56.70: H, 5.36: N, 12.50, S, 7.11,
Calc for C21H24N4O5S (444.49) C, 56.74: H, 5.44: N, 12.60, S. 7.20), IR
(KBr) ν = 3250 (2NH), 3000 (arom. CH), 1710 (C O), 1690 (ester C O),
1
1625 (C N) cm1. H NMR (DMSO): δH = 1.21 (t, 3H, COOCH2CH3),
1.35 (t, 3H, COOCH2CH3), 2.85 (t, 2H, H-4), 3.65 (t, 2H, H-5), 4.11 (q,
2H, COOCH2CH3), 4.35 (q, 2H, COOCH2CH3), 4.55 (s, 2H, H-7), 7.11–
8.00 (m, 5H, Ar-H), 8.55 (s, 1H, CH), 10.55 (s, 1H, NH), 11.45 (s, 1H, NH).
13C NMR (DMSO): δC = 13.80 (CH3), 14.02 (CH3), 25.72 (C-4), 41.03 (C-
5), 42.10 (C-7), 60.38 (CH2), 60.85 (CH2), 108.13 (C-3), 120.72 (C-7a),
127.11, 128.11, 129.87, 130.98 (Ar-C), 132.74 (C-3a), 142.52 (CH N),
149.37 (C O), 154.57 (C O), 161.90 (C O), 164.66 (C-2).
Synthesis of 3-Benzoylamino-4-oxo-3,4,5,6,7,8-
hexahydropyrido[4ꢀ,3ꢀ,4,5]thieno[2,3-d]pyrimidine-7-
carboxylic Acid Ethyl Ester (17)
A mixture of 16 (0.89 g, 2 mmol) and solution of potassium hydroxide
(0.17 g, 3 mmol) dissolved in ethanol (10 ml) was refluxed for 2 h. The re-
action mixture was acidified with HCl 2N. The product was collected by
filtration, washed with water, dried, and crystallized from DMF/water
as yellow crystals.
Yield 65%, mp. 96–98◦C, (Found: C, 57.17: H, 4.43: N, 14.02, S, 8.14
Calc for C19H18N4O4S (398.42) C, 57.28: H, 4.55: N, 14.06, S, 8.03), IR
(KBr) ν = 3250 (NH), 3000 (arom. CH), 1710 (ester C O), 1680 (C O),
1
1625 (C N) cm−1. H NMR (DMSO): δH = 1.21 (t, 3H, COOCH2CH3),
2.85 (t, 2H, H-5), 3.65 (t, 2H, H-6), 4.11 (q, 2H, COOCH2CH3), 4.55 (s,
2H, H-8), 7.11–8.00 (m, 5H, Ar-H), 8.50 (s, 1H, CH), 11.85 (s, 1H, NH),
13C NMR (DMSO): δC = 13.80 (CH3), 25.72 (C-5), 41.03 (C-6), 42.10
(C-8), 60.38 (CH2), 115.19 (C-4a), 126.68 (C-4b), 130.82 (C-8a), 127.11,
128.11, 129.87, 130.98 (Ar-C) 149.18 (C-2), 154.62 (C-9a).155.10 (C O),
161.00 (C O), 166.25 (C O).

Carboxylic Acid Ethyl Ester Derivatives
107
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