Synthesis of new pyrido[4″,3″:4′,5′]thieno[2′,3′:4, 5]pyrimido-[2,1-b][1,3,4]thiadiazine derivatives

Article abstract of DOI:10.1080/10426500210671

Ethyl 2-methyl-11-oxo-9, 10-dihydro-1H, 11H-pyrido[4″,3″:4′,5′]thieno-[2′,3′:4, 5]pyrimido[2,1-b][1,3,4]thiadiazine-8(7H)-carboxylate 7 has been synthesised by the reaction of ethyl 3-amino-4-oxo-2-thioxo-1,3,4,5,6,8-hexahydropyrido[4′,3′:4,5] thieno[2,3-

Full text of DOI:10.1080/10426500210671

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Synthesis of New
Pyrido[4″,3″:4″,5″]thieno[2″,3″:4,5]pyrimido[2,1-b]
[1,3,4]thiadiazine Derivatives
Essam Kh. Ahmed a
a Chemistry Department, Faculty of Science , El-Minia University , Egypt
Published online: 27 Oct 2010.
To cite this article: Essam Kh. Ahmed (2002) Synthesis of New Pyrido[4″,3″:4″,5″]thieno[2″,3″:4,5]pyrimido[2,1-
b][1,3,4]thiadiazine Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:4, 989-1000, DOI:
10.1080/10426500210671
To link to this article: http://dx.doi.org/10.1080/10426500210671
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:989–1000
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
SYNTHESIS OF NEW
PYRIDO[400,300:40,50]THIENO[20,30:4,5]PYRIMIDO-
[2,1-B][1,3,4]THIADIAZINE DERIVATIVES
Essam Kh. Ahmed
Chemistry Department, Faculty of Science,
El-Minia University, Egypt
(Received July 24, 2001; accepted October 23, 2001)
Ethyl 2-methyl-11-oxo-9, 10-dihydro-1H, 11H-pyrido[400,300:40,50]thieno-
[20,30:4,5]pyrimido[2,1-b][1,3,4]thiadiazine-8(7 H)-carboxylate
7 has
been synthesised by the reaction of ethyl 3-amino-4-oxo-2-thioxo-
1,3,4,5,6,8-hexahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(2H)-
carboxylate 2 with allylbromide followed by treatment with bromine
and subsequent dehydrobromination of the brominated product 5 with
ethanolic sodium hydroxide. Its isomeric ethyl 2-methyl-11-oxo-9,10-
dihydro-3H,11H-pyrido [400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b]-
[1,3,4]thiadiazine-8(7H)-carboxylate 8 has been obtained by condensa-
tion of 2 with chloroacetone followed by cyclization of the intermediate
9 with p-toulenesulfonic acid. The thiadiazino derivatives 11, 13,
15 were prepared through the reaction of 2 with the appropriate
-halocarbonyl compounds followed by cyclization reactions of the
intermediates 10, 12, 14.
Keywords: Fused S; N-heterocycles; pyrido[40,30:4,5]thieno[2,3-d]-
pyrimidines; pyrido[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]-
thiadiazines
Pyridothienopyrimidines have been the subject of chemical and biologi-
cal studies on account of their interesting pharmacological properties
which include antiinflammatory,1 3 antipyretic,4,5 analgesic,6 and anti-
anaphylactic,7,8 activity. Also some are clinically efective antiallergic9
and a few possess significant hypocholesterolenic10 activity. In view of
the above activities and in continuation of our work in the synthesis of
13
such system,11
this article follows that line of research reporting on
a new series of linear fusion reactions of pyrido[40,30:4,5]thieno[2,3-d]-
pyrimidine derivatives, in which thiadiazine moiety was annelated,
Address correspondence to Essam Kh. Ahmed, Chemistry Department, Faculty of
Science, El-Minia University, El-Minia 61519, Egypt. E-mail: essamkhalaf24@yahoo.com
989

990
E. Kh. Ahmed
yielding pyrido[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]thiadia-
zines 7, 8, 11, 13, 15.
The versatile intermediate ethyl 3-amino-4-oxo-2-thioxo-1,3,4,5,6,8-
hexahydro-pyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(2H)-carboxylate
(2) was prepared by adding a benzene solution of diethyl 2-isothi-
ocyanato-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate 112
to hydrazine hydrate and subsequent prolonged heating of the reaction
mixture. Reaction of (2) with allyl bromide in the presence of sodium
hydroxide resulted in the formation of ethyl 2-(allylsulfanyl)-3-amino-
4-oxo-3,5,6,8-tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(4H)-
carboxylate (3). The structure of 3 has been confirmed on the basis
of 1H NMR studies which showed a doulet at 3.90 assignable to
two allylic protons ( CH2 CH CH2). It also gave two multiplets
at 5.80–6.20 (1H) and at 5.10–5.50 (2H), the former may be as-
signed to one vinylic protons CH CH2 and CH CH2. And a singlet
at 5.70 (2H) exchangeable with D2O which was assigned to the
amino function. Other analytical and spectroscopic data are given in
experimental section. Treatment of 3 with bromine in chloroform at
5 C led to the formation of ethyl 2-(bromomethyl)-11-oxo-2,3,9,10-
tetrahydro-1H,11H-pyrido[400,300:40,50]thieno[20,30:4,5] pyrimido[2, 1-b]-
[1,3,4]thiadiazine-8(7H)-carboxylate hydrobromide (4) which on
basification with 10% sodium carbonate solution librated its free
base (5).
Compound 5 on treatment with alcoholic sodium hydroxide under-
went dehydrohalogenation and gave rise to ethyl 2-methyl-11-oxo-
9,10-dihydro-1H,11H-pyrido[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b]-
[1,3,4]thiadiazine-8(7H)-carboxylate (7) instead of the expected
product (6) this may be due to greater stability of 7 as compared to 6, the
latter might have rearranged to the former. In fact 6 could have under-
gone rearrangement to (8) too but structure 7 has been assigned on the
basis of IR and 1H NMR studies. Compound 7 showed no IR absorption
1
1
band around 890 cm due to its exocyclic double bond. Its H NMR
exhibited a doublet (3H) because of allylic spilitting at 3.60 which
could be assigned to three methyl protons CH C CH3. It also showed
a quartet (1H) again because of allylic splitting at 4.90 assignable
to one vinylic protons CH C CH3. The single proton attached to
nitrogen appeared as a singlet (1H) exchangeable with D2O at 8.90. It
was thought desirable to prepare isomeric ethyl 2-methyl-11-oxo-9,10-
dihydro-3H,11H-pyrido[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]-
thiadiazine-8(7H)-carboxylate 8 by an alternative route by heating
in ethanol in the presence of p-toluenesulfonic acid the derivative
(9), previously obtained from 2 and chloroacetone. Structure of 8 is
1
supported by the results of IR and H NMR measurements. It gave

Synthesis of Thiadiazine Derivatives
991
1
an absorption band at 1680 cm
due to CO but the bands at
1
1
3420-3350 and 3120 cm due to the NH2 and at 1690 cm due to
carbonyl of ketone CH2 CO originally present in 9, disappeared. Its
1H NMR exhbited a singlet (3H) at 2.40 assignable to three methyl
protons. Besides it also gave singlet at 4.30 due to methylene protons
( S CH2 ). This eliminate the possibility of structure 7 and confirms
structure 8 (Scheme 1).
SCHEME 1

992
E. Kh. Ahmed
SCHEME 2
As illustrated in Scheme 2, the ethyl 2-phenyl(11a) and ethyl-2-
(4-bromophenyl) (11b)-11-oxo-9,10-dihydro-3H,11H-pyrido[400,300:40,50]-
thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]thiadiazine-8(7H)-carboxylate were
obtained by cyclizing in refluxing ethanol with a catalytic amount of
p-toluenesulfonic acid (p-TSA) the thio derivatives (10a,b) obtained
from amino-thioxo derivative 2 and 2-bromoacetophenone or 2,40-
dibromo-acetophenone in benzene in the presence of triethylamine,
respectively.
By reaction of the alkaline solution of the amino-thioxo
derivative 2 with ethyl bromoacetate, the ethyl 3-amino-2-[(2-ethoxy-
2-oxoethyl)sulfanyl]-4-oxo-3,5,6,8-tetra hydropyrido[40,30:4,5]thieno-
[2,3-d]pyrimidine-7(4H)-carboxylate (12) was formed. Heating of the
ester 12 in ethanol in the presence of sodium ethoxide and subsequent
acidification of the resulting mixture with hydrochloric acid or acetic
acid afforded the ethyl 2,11-dioxo-2,3,9,10-tetra hydro-1H,11H-pyrido-
[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]thiadiazine-8(7H )-
carboxylate (13), which is identical to the product obtained by

Synthesis of Thiadiazine Derivatives
993
treatment of 2 with chloroacetic acid. The structure of compound
13 was characterized by elemental analysis, IR, and 1H NMR. In
1
particular, the IR spectrum showed a band at 3180 cm attributable
1
to N H stretching and a broad band at 1680 cm due to overlapping
bands of the two carbonyl groups. Moreover, the 1H NMR spectrum ex-
hibited a broad signal at 11.70 confirming the presence of NH group,
and a signal at 4.30 attributable to the two methylene protons in
position 3.
Heating an alcoholic solution of 2 with chloroacetonitrile afforded
ethyl 3-amino-2-[cyanomethylsulfanyl]-4-oxo-3,5,6,8-tetrahydropyrido-
[40,30:4,5]thieno[2,3-d]pyrimidine-7(4H)-carboxylate (14). The str-
ucture of 14 was confirmed by analytical and spectral data. The IR
1
showed a sharp band at 2220 cm characteristic of the stretching
1
frequency of nitrile whereas the H NMR spectra showed a singlet at
4.40 ppm (2H, CH2CN) and broad singlet at 5.80 ppm (2H, NH2).
Compound 14 underwent cyclization when treated with concentrated
sulfuric acid at room temperature to yield ethyl 2-amino-11-oxo-
9,10-dihydro-3H,11H-pyrido[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b]-
[1,3,4]thiadiazine-8(7H )-carboxylate (15). The cyclization of 14 to
15 involved a nucleophilic addition at the cyano group followed by a
proton acquisition, resulting in ring closure and the formation of the
amino-substituted heterocycles.
EXPERIMENTAL
All m.p.s were recorded on a Gallenkamp apparatus and are uncor-
rected. Microanalyses were performed at the Microanalytical Labo-
1
ratory, Cairo University. 13C and H NMR spectra were recorded on
a Bruker AC 200 (1H: 200.13 MHz, 13C: 50.32 MHz), 5 mm dual
1H/13C-VT probe at 300 K; solvent: DMSO-d6 and CDCl3, respectively;
values are given in ppm, internal standard TMS ( = 0 ppm).
IR-spectra were recorded on a Shimadzu 470 Spectrophotometer in KBr
pellets.
Ethyl 3-amino-4-oxo-2-thioxo-1,3,4,5,6,8-
hexahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-
7(2H)-carboxylate (2)
A solution of diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine-3,6-dicarboxylate 1 (0.6 g, 0.0017 mol) in benzene (10 ml)
was added dropwise at room temperature to a stirred solution of
hydrazine hydrate (0.6 g, 0.018 mol) in benzene (5 ml). The suspension
was refluxed under stirring for 8 hours. After cooling, the solid

994
E. Kh. Ahmed
product was collected, by filtration washed with ethanol, dried, and
recrystallized from dioxane. Yield 0.52 g (91.2%) of compound 2 as
yellow crystals, m.p. 232–234 C (dec); (Found: C, 44.07; H, 4.30; N,
17.01; S, 19.50. C12H14N4O3S2 (326.40) requires C, 44.15; H, 4.32; N,
17.16; S, 19.64%); max/cm 1: 3400, 3320, 3180 (NH2, NH), 1700, 1680
(CO), 1200 (C S); H (DMSO-d6): 1.20 (t, J 7 Hz, 3H, COOCH2CH3), 2.90
(t, J 5.6 Hz, 2H, H-5), 3.60 (t, J 5.6 Hz, 2H, H-6), 4.20 (q, J 7 Hz, 2H,
COOCH2CH3), 4.50 (s, 2H, H-8), 6.30–6.50 (br, 2H, NH2);
(DMSO-
c
d6): 14.56 (q, COOCH2CH3), 25.26 (t, C-5), 40.74 (t, C-6), 46.75 (t, C-8),
60.95 (t, COOCH2CH3), 113.31 (s, C-4a), 128.28 (s, C-4b), 141.03 (s,
C-8a), 154.64 (s, C-4), 157.64 (s, C-9a), 161.63 (s, CO), 168.83 (s, C-2).
Ethyl 2-(allylsulfanyl)-3-amino-4-oxo-3,5,6,8-
tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(4H)
carboxylate (3)
To a solution of 2 (0.32 g, 0.001 mol) in 5% sodium hydroxide solution
(1 ml), allyl bromide (0.13 g, 0.001 mol) dissolved in ethanol (2 ml) was
added dropwise with stirring at room temperature. There was immedi-
ate separation of 3. After keeping the mixture over night it was diluted
with water, the precipitate was collected under suction, washed with
water, dried, and crystallized from ethanol. Yield 0.3 g (83.3%) of com-
pound 3 as colorless crystals, m.p. 158–159 C; (Found: C, 48.96; H, 4.79;
N, 15.10; S 17.30. C15H18N4O3S2 (366.47) requires C, 49.16; H, 4.94; N,
15.28; S, 17.49%); max/cm 1: 3380 (NH2), 1700, 1670 (CO), 1660 (C N);
(DMSO-d6): 1.3 (t, J 7 Hz, 3H, COOCH2CH3), 2.90 (t, J 5.6 Hz, 2H,
H
H-5), 3.70 (t, J 5.6 Hz, 2H, H-6), 3.90 (d, J 7 Hz, 2H, CH2 CH CH2),
4.10 (q, J 7 Hz, 2H, COOCH2CH3), 4.60 (s, 2H, H-8), 5.10–5.50 (m, 2H,
CH2 CH CH2), 5.70 (s, 2H, NH2), 5.80–6.20 (m, 1H, CH CH2).
Ethyl 2-(bromomethyl)-11-oxo-2,3,9,10-tetrahydro-1H,
11H-pyrido[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b]-
[1,3,4]thiadiazine-8(7H)-carboxylate-hydrobromide (4)
A solution of bromine (0.32 g, 0.002 mol) in chloroform (6 ml) was
added dropwise to a solution of 3 (0.73 g, 0.002 mol) in 5 ml chloro-
form with constant stirring at 5 C. The reaction mixture was kept at
room temperature for 4 h until the color of bromine had completly dis-
appeared. On evaporating the solvent, the solid thus obtained was col-
lected and crystallized from dioxane. Yield 0.74 g (71.15%) of compound
4 as yellow crystals, m.p. 260–262 C; (Found: C, 34.11; H, 3.30; N, 10.48;
S, 12.10. C15H18N4O3S2 Br2 (526.26) requires C, 34.23; H, 3.44; N, 10.64;
S, 12.18%).

Synthesis of Thiadiazine Derivatives
995
Ethyl 2-(bromomethyl)-11-oxo-2,3,9,10-
tetrahydro-pyrido[400,300:40,50]thieno[20,30:4,5]pyrimido
[2,1-b][1,3,4]-thiadiazine-8(7H)-carboxylate (5)
Compound 4 (0.52 g, 0.001 mol) was treated with 10% sodium carbon-
ate solution, then the precipitate was filtered, washed with water, and
crystallized from ethanol. Yield. 0.4 g (90.9%) of compound 5 as color-
less crystals, m.p. 192–193 C; (Found: C, 40.32; H, 3.67; N, 12.65; S,
14.22. C15H17N4O3S2Br (445.34) requires C, 40.45; H, 3.84; N, 12.58; S,
14.39%); max/cm 1: 3180 (NH), 1710, 1680 (CO),
(DMSO-d6): 1.20
H
(t, 3H, COOCH2CH3), 2.90 (t, 2H, H-10), 3.40 (t, 2H H-9), 3.60 (d, 2H,
CH2Br), 4.10 (q, 2H, COOCH2CH3), 4.32 (d, 2H, S CH2), 4.60 (s, 2H,
H-7), 6.20–6.40 (m, 1H, CH CH2Br).
Ethyl 2-methyl-11-oxo-9,10-dihydro-1H,11H-pyrido-
[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]-
thiadiazine-8(7H)-carboxylate (7)
To a solution of 5 (0.66 g, 0.0015 mol) in 25% ethanol (20 ml) 2% ethano-
lic sodium hydroxide (30 ml) was added at 45 C. After 20 min crushed
ice (100 g) was added. The separated product was collected by filtra-
tion, dried, and recrystallized from ethanol. Yield 0.33 g (61.1%) of com-
pound 7 as colorless crystals, m.p. 187–188 C; (Found: C, 49.50; H, 4.28;
N, 15.45; S, 17.70. C15H16N4O3S2 (364.43) requires C, 49.43; H, 4.42; N,
15.37; S, 17.59%); max/ cm 1: 3180 (NH), 2950 (CH aliph.), 1720, 1680
(CO), 1660 (C N); H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.90 (t, 2H,
H-10), 3.40 (t, 2H, H-9), 3.60 (d, 3H, CH3), 4.10 (q, 2H, COOCH2CH3),
4.60 (s, 2H, H-7), 4.90 (q, 1H, CH C CH3), 8.90 (s, 1H, NH).
Ethyl 3-amino-2[(2-oxopropyl)sulfanyl]-4-oxo-3,5,6,8-
tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(4H)-
carboxylate (9)
Chloroacetone (0.11 g, 0.0011 mol) was added to a hot suspention of 2
(0.32 g, 0.001 mol) in 5% sodium hydroxide solution (1 ml, 0.04 g, 0.001
mol) and ethanol (10 ml). The mixture was gently warmed under stir-
ring for 2 hours, then poured into water (20 ml) and the resulting solid
was collected by filtration, dried, and recrystallized from ethanol/water.
Yield 0.22 g (59.4%) of compound 9 as colorless crystals, m.p. 150–152 C;
(Found: C, 47.25; H, 4.62; N, 14.51; S, 16.63. C15H18N4O4S2 (382.44)
requires C, 47.10; H, 4.74; N, 14.65; S, 16.76%); max/cm 1: 3420-3350
(NH2), 2900 (CH aliph.), 1720, 1690, 1680 (CO);
(DMSO-d6): 1.20 (t,
H
J 7 Hz, 3H, COOCH2CH3), 2.60 (s, 3H, COCH3), 2.80 (t, J 5.6 Hz, 2H,

996
E. Kh. Ahmed
H-5), 3.40 (t, J 5.6 Hz, 2H, H-6), 3.57 (s, 2H, CH2 CO ), 4.10 (q, J 7 Hz,
2H, COOCH2CH3), 4.60 (s, 2H, H-8), 5.80 (s, 2H, NH2).
Ethyl 2-methyl-11-oxo-9,10-dihydro-3H,11H-pyrido-
[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]-
thiadiazine-8(7H)-carboxylate (8)
A mixture of 9 (0.38 g, 0.001 mol) and p-TSA (20 mg) in ethanol
(20 ml) was refluxed for 3 h. The solution was then cooled to room tem-
perature. The resulting precipitate was collected by filtration, dried,
and recrystallized from ethanol. Yield 0.2 g (55.5%) of compound 8 as
yellow needless, m.p. 222–224 C; (Found: C, 49.35; H, 4.30; N, 15.22;
S, 17.45. C15H16N4O3S2 (364.43) requires C, 49.43; H, 4.42; N, 15.37;
S, 17.59%); max/cm 1: 2990 (CH aliph.), 1700, 1670 (CO), 1640 (C N);
(DMSO-d6): 1.20 (t, J 7 Hz, 3H, COOCH2CH3), 2.40 (s, 3H, CH3),
H
2.70 (t, J 5.6 Hz, 2H, H-10), 3.40 (t, J 5.6 Hz, 2H, H-9), 4.10 (q, J 7 Hz,
2H, COOCH2CH3), 4.30 (s, 2H, S CH2), 4.60 (s, 2H, H-7).
Ethyl 3-amino-2-{[2-phenyl-2-oxoethyl]sulfanyl}-4-oxo-
3,5,6,8-tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-
7(4H)-carboxylate (10a)
2-bromoacetophenone (0.32 g, 0.0016 mol) was added to a stirred so-
lution of 2 (0.5 g, 0.0015 mol) and triethylamine (8 drops) in ben-
zene (15 ml), and the mixture was stirred at room temperature for
30 min, then diluted with water (50 ml). The resulting solid product
was collected by filtration, washed with water, dried, and recrystal-
lized from dioxan/water. Yield 0.55 g (80.9%) of compound 10a as col-
orless crystals, m.p. 180–182 C; (Found: C, 54.14; H, 4.65; N, 12.76;
S, 14.60. C20H20N4O4S2 (444.54) requires C, 54.03% H, 4.53; N, 12.60;
S, 14.42%); max/cm 1: 3400-3320 (NH2), 3120 (Ar CH), 1720, 1690
(CO); H (DMSO-d6): 1.20 (t, J 7 Hz, 3H, COOCH2CH3), 2.80 (t, J 5.6 Hz,
2H, H-5), 3.60 (t, J 5.6 Hz, 2H, H-6), 4.10 (q, J 7 Hz, 2H, COOCH2CH3),
4.50 (s, 2H, S CH2), 4.60 (s, 2H, H-8), 5.80 (s, 2H, NH2), 7.50–7.90 (m,
5H, Ar H).
Ethyl 3-amino-2-{[2-(4-bromophenyl)-2-oxoethyl]-
sulfanyl}-4-oxo-3,5,6,8-tetrahydropyrido[40,30:4,5]-
thieno[2,3-d]pyrimidine-7(4H)-carboxylate (10b)
2,40-dibromoacetophenone (0.31 g, 0.0011 mol) was added to a stirred
solution of 2 (0.32 g, 0.001 mol ) and triethylamine (5 drops) in benzene
(10 ml), and the mixture was stirred at room temperature for 40 min,

Synthesis of Thiadiazine Derivatives
997
then diluted with water (50 ml). The resulting solid product was col-
lected by filtration, washed with water, dried, and recrystallized from
dioxane/water. Yield 0.46 g (90.2%) of compound 10b as yellow crys-
tals, m.p. 220–222 C; (Found: C, 45.70; H, 3.77; N, 10.85; S, 12.34.
C20H19N4O4S2Br (523.43) requires C, 45.89; H, 3.65; N, 10.70; S,
12.25%); max/cm 1: 3450-3350 (NH2), 3050 (Ar CH), 1720, 1690, 1680
(CO); H (DMSO-d6): 1.30 (t, J 7 Hz, 3H, COOCH2CH3), 2.90 (t, J 5.6 Hz,
2H, H-5), 3.60 (t, J 5.6 Hz, 2H, H-6), 4.10 (q, J 7 Hz, 2H, COOCH2CH3),
4.50 (s, 2H, S CH2), 4.60 (s, 2H, H-8), 5.70 (s, 2H, NH2), 7.60 (d, J 7.7 Hz,
2H, Ar H), 8.08 (d, J 7.7 Hz, 2H, Ar H).
Ethyl 2-phenyl-11-oxo-9,10-dihydro-3H,11H-pyrido-
[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]-
thiadiazine-8(7H)-carboxylate (11a)
The solution of compound 10a (0.44 g, 0.001 mol) in ethanol (10 ml),
p-toluenesulfonic acid (20 mg) was refluxed for 2 h. After cooling, the
solid product was collected by filtration, washed with warm ethanol,
dried, and recrystallized from dioxane. Yield 0.3 g (71.4 %) of compound
11a as yellow crystals, m.p. 256–257 C; (Found: C, 56.18; H, 4.32; N,
13.05; S, 14.90. C20H18N4O3S2 (426.52) requires C, 56.32; H, 4.25; N,
13.13; S, 15.03%); max/cm 1: 3050 (Ar CH), 1710, 1680 (CO), 1640
(C N);
(DMSO-d6): 1.20 (t, J 7 Hz, 3H, COOCH2CH3), 2.90 (t, J
H
5.6 Hz, 2H, H-10), 3.70 (t, J 5.6 Hz, 2H, H-9), 4.20 (q, J 7 Hz, 2H,
COOCH2CH3), 4.30 (s, 2H, S CH2), 4.60 (s, 2H, H-7), 7.70–8.10 (m,
5H, Ar–H).
Ethyl 2-(4-bromophenyl)-11-oxo-9,10-dihydro-3H,11H-
pyrido[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]-
thiadiazine-8(7H)-carboxylate (11b)
The solution of compound 10b (0.52 g, 0.001 mol) in ethanol (10 ml),
p-toluenesulfonic acid (20 mg) was refluxed for 2 h. After cooling, the
solid product was collected by filtration, washed with warm ethanol,
dried, and recrystallized from dioxane. Yield 0.35 g (70%) of com-
pound 11b as yellow crystals, m.p. 255–257 C; (Found: C, 47.44; H, 3.28;
N, 10.94; S, 12.51. C20H17N4O3S2Br (505.41) requires C, 47.52; H, 3.38;
N, 11.08; S, 12.68%); max/cm 1: 3080 (Ar CH), 1730, 1710 (CO);
H
(DMSO-d6): 1.20 (t, J 7 Hz, 3H, COOCH2CH3), 2.80 (t, J 5.6 Hz, 2H,
H-10), 3.70 (t, J 5.6 Hz, 2H, H-9), 4.10 (q, J 7 Hz, 2H, COOCH2CH3),
4.30 (s, 2H, CH2), 4.60 (s, 2H, H-7), 7.70 (d, J 8 Hz, 2H, Ar H), 7.90 (d,
J 8 Hz, 2H, Ar H).

998
E. Kh. Ahmed
Ethyl 3-amino-2-[(2-ethoxy-2-oxoethyl)sulfanyl]-4-oxo-
3,5,6,8-tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidin-
7(4H)-carboxylate (12)
Ethyl bromoacetate (0.19 g, 0.0012 mol) was added to a hot suspen-
sion of 2 (0.32 g, 0.001 mol) in ethanolic potassium hydroxide solution
(0.15 g KOH in 20 ml ethanol). The mixture was refluxed for 2 h and then
filtered while hot. The white solid product separated at room tempera-
ture from the ethanolic filtrate was collected by filtration, washed with
ethanol, dried, and recrystallized from ethanol. Yield 0.31 g (75.6%) of
compound 12 as colorless crystals, m.p. 158–159 C; (Found: C, 46.46;
H, 4.64; N, 13.45; S, 15.41. C16H20N4O5S2 (412.50) requires C, 46.58;
H, 4.88; N, 13.58; S, 15.54%); max/cm 1: 3350-3280 (NH2), 1730, 1710,
1680 (CO);
(DMSO-d6 ): 1.10 (t, J 7 Hz, 3H, COOCH2CH3), 1.30
H
(t, J 7 Hz, 3H, COOCH2CH3), 2.80 (t, J 5.6 Hz, 2H, H-5), 3.60 (t, J 5.6
Hz, 2H, H-6), 4.10 (q, J 7 Hz, 2H, COOCH2CH3), 4.20 (q, J 7 Hz, 2H,
COOCH2CH3), 4.50 (s, 2H, S CH2), 4.60 (s, 2H, H-8), 5.80 (s, 2H, NH2).
Ethyl 2,11-dioxo-2,3,9,10-tetrahydro-1H,11H-pyrido-
[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]-
thiadiazine-8(7H)-carboxylate (13)
Method A: To a hot solution of sodium (0.026 g, 0.0011 mol) in ethanol
(10 ml), the thioacetate derivative 12 (0.41 g, 0.001 mol) was added
over 5 min. The solution after refluxing for 30 min, was stirred at
room temperature for 1 h and then concentrated under reduced pres-
sure, acidified with glacial acetic acid (0.2 ml) or 10% hydrochloric acid
(1.1 ml) and then stirred for 30 min. The resulting solid product was col-
lected by filtration, washed with water, dried, and recrystallized from
dioxane/water. Yield 0.2 g (55.5%) of compound 13 as colorless crys-
tals, m.p. 310–312 C; (Found: C, 45.78; H, 3.78; N, 15.15; S, 17.38.
C14H14N4O4S2 (366.43) requires C, 45.89; H, 3.85; N, 15.29; S, 17.50%);
max/cm 1: 3180 (NH), 1700, 1680 (CO);
(DMSO-d6): 1.20 (t, J 7 Hz,
H
3H, COOCH2CH3), 2.80 (t, J 5.6 Hz, 2H, H-10), 3.70 (t, J 5.6 Hz, 2H,
H-9), 4.10 (q, J 7 Hz, 2H, COOCH2CH3), 4.30 (s, 2H, H-3), 4.60 (s, 2H,
H-7), 11.70 (s, 1H, NH).
Method B: A mixture of 2 (0.64 g, 0.002 mol), chloroacetic acid
(0.22 g, 0.0022 mol) and anhydrous sodium acetate (0.2 g, 0.0024 mol)
in absolute ethanol (15 ml) was refluxed on a steam-bath for 6 h, then
cooled and poured into cold water. The resulting solid was collected
by filtration, dried, and crystallized from dioxane/water. Yield 0.48 g
(66.6%) of compound 13 as colorless crystals, m.p. 311–313 C. The com-
pound is identical to that obtained according to method A.

Synthesis of Thiadiazine Derivatives
999
Ethyl 3-amino-2-[cyanomethylthio]-4-oxo-3,5,6,8-
tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-
7(4H)-carboxylate (14)
Compound 2 (0.64 g, 0.002 mol) dissolved in 10 ml of absolute ethanol
was mixed with chloroacetonitrile (0.3 g, 0.004 mol) and refluxed for
4 h. The solvent was evaporated and the residue dissolved in water.
Neutralization with sodium carbonate gave a precipitate which was
filtered, washed with cold water, and crystallized from ethanol/water.
Yield 0.43 g (60.5%) of compound 14 as pale yellow crystals, m.p. 198–
199 C; (Found: C, 45.89; H, 4.25; N, 19.30; S, 17.65. C14H15N5O3S2
1
(365.44) requires C, 46.01; H, 4.13; N, 19.16; S, 17.54%); max/cm
3340 (NH2), 2220 (CN), 1700,1680 (CO), 1640 (C N);
:
(DMSO-d6):
H
1.20 (t, J 7 Hz, 3H, COOCH2CH3), 2.90 (t, J 5.6 Hz, 2H, H-5), 3.60
(t, J 5.6 Hz, 2H, H-6), 4.10 (q, J 7 Hz, 2H, COOCH2CH3), 4.40 (s, 2H,
S CH2CN), 4.60 (s, 2H, H-8), 5.80 (s, 2H, NH2).
Ethyl 2-amino-11-oxo-9,10-dihydro-3H,11H-pyrido-
[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3,4]-
thiadiazine-8(7H)-carboxylate (15)
Compound 14 (0.36 g, 0.001 mol) was dissolved in 5 ml of concen-
trated sulfuric acid and left for 3 h at room temperature. After dilu-
tion with water and neutralization with 20% ammonium hydroxide,
the solid product was collected, dried, and recrystallized from ethanol.
Yield 0.25 g (69.4%) of compound 15 as brown crystals, m.p. 257–258 C;
(Found: C, 46.12; H, 4.35; N, 19.33; S, 17.62. C14H15N5O3S2 (365.44)
requires C, 46.01; H, 4.13; N, 19.16; S, 17.54); max/cm 1: 3400-3340
(NH2), 1720, 1680 (CO), 1640 (C N); H (DMSO-d6): 1.20 (t, J 7 Hz, 3H,
COOCH2CH3), 2.80 (t, J 5.6 Hz, 2H, H-10), 3.60 (t, J 5.6 Hz, 2H, H-9),
3.90 (s, 2H, S CH2), 4.10 (q, J 7 Hz, 2H, COOCH2CH3), 4.60 (s, 2H,
H-7), 7.20 (s, 2H, NH2).
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