Synthesis of Potential Selective COX-2 Enzyme Inhibitors Derived from Ethyl Ester of 2-Isothiocyanato-5-phenyl-3-thiophenecarboxylic Acid

Article abstract of DOI:10.1002/jhet.5570400519

Derivatives containing the thieno[2,3-d]pyrimidin-4-one system, potential selective COX-2 inhibitors, were prepared starting from ethyl ester of 2-isothiocyanato-5-phenyl-3-thiophenecarboxylic acid (2); their structural elucidation is also reported.

Full text of DOI:10.1002/jhet.5570400519

Sep-Oct 2003
869
Synthesis of Potential Selective COX-2 Enzyme Inhibitors Derived from
Ethyl Ester of 2-Isothiocyanato-5-phenyl-3-thiophenecarboxylic Acid
Andrea Santagati*, Agostino Marrazzo and Giuseppe Granata
Dipartimento di Scienze Farmaceutiche, Università di Catania, Viale A.Doria, 6, 95125 Catania, Italy
Received February 19, 2003
Derivatives containing the thieno[2,3-d]pyrimidin-4-one system, potential selective COX-2 inhibitors,
were prepared starting from ethyl ester of 2-isothiocyanato-5-phenyl-3-thiophenecarboxylic acid (2); their
structural elucidation is also reported.
J. Heterocyclic Chem., 40, 869 (2003).
Derivatives containing the thienopyrimidine systems
In this paper we report the synthesis and the structural
elucidation of a series of new derivatives containing the 6-
phenyl-thieno[2,3-d]pyrimidin-4-one heterocyclic system
as a stage of research of compounds with effective anal-
gesic and anti-inflammatory activities as selective COX-2
inhibitors.
The key compound was the ethyl ester of 2-isothio-
cyanato-5-phenyl-3-thiophenecarboxylic acid (2) pre-
pared, without the production of pollutants, in acetone at
room temperature from the reaction of amino ester 1 and
thiophosgene with subsequent dilution in water (Scheme
1). The reaction at room temperature with hydrazine or
with mesylhydrazine and treatment of the resulting
are reported to possess several important pharmacologi-
cal properties [1]; in particular some derivatives of the 6-
phenyl-1,3,4-thiadiazolo[3,2-a]thieno[2,3-d]pyrimidin-8-
one [2] showed interesting anti-inflammatory and anal-
gesic activities without ulcerogenic activity and with low
acute toxicity.
Recent developments in the research of non-steroidal
anti-inflammatory drugs (NSAIDs) as selective inhibitors
of COX-2 [3,4] have prompted us, on the basis of the
above heterocyclic system [2] and structures of leads [3,4],
to prepare new derivatives with the characteristic func-
tional groups of selective COX-2 inhibitor drugs.

870
A. Santagati, A. Marrazzo and G. Granata
Vol. 40
thiosemicarbazide derivative 3a and 3b with sodium
hydroxide in refluxing ethanol or refluxing water afforded
the amino-thioxo sodium salt 4a and 4b, whose acidifica-
tion with hydrochloric acid gave the amino-thioxo 5 and
methanesulfonamide-thioxo 7 derivatives, respectively.
The structure of the amino-thioxo derivatives 4a and 5
was confirmed by independent preparation of 2-ethoxy-
phenyl derivative 6. The compound obtained from the
condensation of amino-ester 1 with 2-chloro-5-(2-
ethoxyphenyl)-1,3,4-thiadiazole as reported by Russo et
al. [2] was identical to that prepared from amino-thioxo
derivative 5 and 2-ethoxybenzoic acid under appropriate
condition of reaction.
The addition of sodium salt of 2-iodobenzoic acid in the
presence of copper powder to an aqueous refluxing solu-
tion of methanesulfonamide 4b in sodium hydroxide gave
the disodium salt of the acid derivative 8. The structure of
methanesulfonamide derivatives 7 and 8 is in accordance
with analytical and spectral data.
From the sodium salt 4a of the amino-thioxo derivative,
several derivatives were obtained (Scheme 2).
Refluxing in ethanol with chloroacetone gave the
1
2-methyl thiadiazine derivative 9; in the ir and H nmr
spectra, the absence of a signal attributable to hydrogen
bonded to nitrogen and the presence of a signal at δ 3.79
attributable to the methylene protons of C-3 corroborated
the formation of the 1,2 unsaturated thiadiazine ring.
The synthetic routes to the methanesulfonamide 12 and
tricyclic methylthio derivatives 14 were completed
through the amino methyl-thio derivative 10 .
Dimesylation of the amino group and subsequent
1
hydrolysis gave the monomesyl 12, which in the ir and H
nmr spectra showed the characteristic signal attributable to
sulfonamidic hydrogen, in contrast with signals attribut-
able to the amino group for compound 10 and with no sig-
nals due to hydrogen bonded to nitrogen for the dimesyl
11, both of which are precursor compounds. The methyl
monomesyl derivative 12 was also obtained through the
methylation of the amino-thioxo monomesylated deriva-
tive 7, whose structure was thus confirmed.
Refluxing in pyridine with carbon disulfide yielded
through the thiadiazole-thioxo derivative 13 and subse-
quent methylation with dimethyl sulphate the methyl thia-
diazole derivative 14, which was identical to the product
obtained according to Russo et al. [2] from the condensa-
tion of amino ester 1 with 2-chloro-5-methylthio-1,3,4-
thiadiazole .
In preliminary tests as COX-2 activity inhibitors in
Human Whole Blood (HWB) ex vivo [5], derivatives 8 and
12 showed at 10 µM an inhibition of 35 % and 30 %,
respectively, in contrast with that of 100 % of
indomethacin.

Sep-Oct 2003
Synthesis of Potential Selective COX-2 Enzyme Inhibitors
871
EXPERIMENTAL
To a stirred solution of methanesulphonyl hydrazide [10] (0.8 g,
98% , 8.15 mmoles) in dichloromethane (25 ml) isothiocyanate 2
(2.10 g, 7.62 mmoles) in dichloromethane (50 ml) was added drop-
wise at room temperature. After the addition was complete, the
mixture was stirred at room temperature for 2 hours. The resulting
solid was collected, washed with dichloromethane, dried and crys-
tallized from ethanol/water to give 3b as a yellow amorphous
solid; yield 70%; mp 232-34° dec.; ir: 3295 and 3300 (NH), 1665
Melting points are uncorrected and were determined in open
capillary tubes on a SMP1 apparatus (Stuart Scientific,
Staffordshire). Ir spectra were recorded on a Perkin Elmer 1600
Series FT-IR in potassium bromide disks. Elemental analyses for
C, H, N, and S were obtained on an EA 1108 elemental analyzer
Fisons-Carlo Erba instrument.
-1
1
(C=O), 1315 and 1150 (SO -N) cm ; H nmr (dimethylsulfoxide-
1
13
2
H and C nmr spectra were recorded at 200 MHz on a Varian
d ): δ 1.33 (t, J=7.0 Hz, 3H, CH ), 3.13 (s, 3H , SO CH ), 4.36 (q ,
6
3
2
3
Gemini 200 spectrometer; chemical shifts (δ) are reported in ppm
from tetramethylsilane as internal standard; coupling constants
(J) are in Hertz (Hz). The mp ‘s of all crude compounds were
within –3 °C, if compared with the pure product; therefore, as
synthetic intermediates they could be used without further purifi-
cation. The purity of compounds was checked by thin layer chro-
matography on Merck silica gel 60 F-254 plates. All commercial
chemicals were purchased from Aldrich, Fluka, Merck and Carlo
Erba and were used without further purification.
J=7.0 Hz, 2H, CH ), 7.25-7.65 ( m, 6H, Ar-H and thiophene-H),
2
13
10.10, 10.91 and 12.40 ( s, 1H, NH); C nmr (dimethylsulfoxide-
d ): δ 14.23, 38.73, 60.85, 114.86, 119.37, 125.16, 127.59, 129.18,
6
132.04, 133.05, 148.64, 164.23, 177.30 .
Anal. Calcd. for C
H N O S : C, 45.11; H, 4.26; N, 10.52;
15 17 3 4 3
S, 24.06. Found: C, 44.85; H, 4.10; N, 10.20; S, 23.75.
3-Amino-2,3-dihydro-6-phenyl-2-thioxo-thieno[2,3-d]pyrim-
idin-4(1H)-one (5) from its Sodium Salt (4a).
Ethyl Ester of 2-Isothiocyanato-5-phenyl-3-thiophenecarboxylic
Acid (2).
A mixture of hydrazino-thioxo derivative 3a (3.2 g, 9.9
mmoles) in a solution of sodium hydroxide (0.42 g, 10.5 mmoles)
in ethanol (120 ml); was refluxed under stirring for 1 hour; the
resulting solid was collected while hot, washed with warm diox-
ane and dried to give 4a as pale yellow powder; yield 80%; mp
A solution of amino-ester 1 [6] (5.0 g, 21.6 mmoles) in acetone
(30 ml) was added slowly drop-wise at room temperature to a
stirred solution of thiophosgene (1.6 ml, 97 %, d=1.508, 20.35
mmoles) in acetone (15 ml). After 20 minutes of stirring at room
temperature water was added (200 ml): the solid separated was
collected, washed first with 5 % sodium hydroxide and then with
water, dried and crystallized from n-hexane to give the isothio-
cyanate 2 as yellow micro-needles; yield 50%; mp 94-95°. The
isothiocyanate 2 was identical to the sample obtained according
to previous paper [7,8]. The unreported spectra data are now
-1
1
311-14 ° dec.; ir: 3205 and 3120 (NH ), 1640 (C=O) cm ; H
2
nmr (dimethylsulfoxide-d ): δ 6.42 (s, 2H, NH ), 7.24-7.65 (m,
6
2
13
6H, Ar-H and thiophene-H); C nmr (dimethylsulfoxide-d ): δ
6
117.20, 117.30, 124.86, 127.05, 128.98, 131.98, 134.07, 154.23,
162.05, 169.72 .
Anal. Calcd. for C H N NaOS : C, 48.48; H, 2.69; N, 14.14;
12
8
3
2
S, 21.54. Found: C, 48.20; H, 2.50; N, 14.20; S, 21.60.
To a suspension of sodium salt 4a (1.0 g, 3.36 mmoles) in
water (50 ml) concentrated hydrochloric acid was added drop-
wise under stirring to obtain pH 3-4; the mixture was stirred at
room temperature for 1 hour; the resulting solid was collected,
treated with 5% sodium hydrogencarbonate, washed with water,
dried and crystallized from dimethylsulfoxide/water to give 5 as
a white powder; yield 50% ; mp 278-281° dec. The analytical and
spectral data of compound 5 are identical to those of a sample
-1
1
reported; ir: 2145 and 2100 (N=C=S), 1695 (C=O) cm ; H nmr
(dimethylsulfoxide-d ): δ 1.26 (t, J= 7.0 Hz , 3H, CH ), 4.23 (q,
6
3
J= 7.0 Hz , 2H, CH ), 7.22-7.68 (m, 6H, Ar-H and thiophene-H);
2
13
C nmr (dimethylsulfoxide-d ): δ 14.47, 59.10, 121.02, 122.20,
6
123.97, 125.28, 126.23, 128.95, 129.23, 133.69, 163.38, 164.28 .
Anal. Calcd. for C H NO S : C, 58.13; H, 3.80; N, 4.84; S,
14 11
2 2
22.14: Found: C, 58.50; H, 3.85, N, 4.80, S, 22.40
Ethyl Ester of 2-[(Hydrazinothioxomethyl)amino)]-5-phenyl-3-
thiophene- carboxylic Acid (3a).
obtained according to previous paper [9]; ir: 3285 and 3155 (NH
2
-1 1
or NH), 1655 (C=O) cm ; H nmr (dimethylsulfoxide-d ): δ 4.47
6
(br s, 2H, NH ), 7.19-7.72 (m, 6H, Ar-H and thiophene-H), 13.94
2
To a stirred solution of hydrazine hydrate (0.35 ml, 7.0
mmoles) in chloroform (15 ml) isothiocyanate 2 (1.7 g, 6.2
mmoles) in chloroform (15 ml) was added drop-wise at room
temperature. After the addition was complete, the mixture was
stirred at room temperature for 2 hours. The resulting solid was
collected, washed with chloroform, dried and crystallized from
ethanol to give 3a as yellow crystals; yield 55%; mp 224-26° dec.
The analytical and spectral data of 3a were identical to those of a
sample obtained according to previous paper [9]; ir: 3345, 3245
13
(br s, 1H, NH); C nmr (dimethylsulfoxide-d ): δ 117.46,
6
117.97, 125.47, 128.44, 129.27, 132.17, 136.41, 148.00, 152.54,
167.15 .
Anal. Calcd. for C H N OS : C, 52.35; H, 3.27; N, 15.27; S,
12
9
3
2
23.27. Found: C, 52.20; H, 3.15; N, 15.30; S, 23.40.
2-(2-Ethoxyphenyl)-6-phenyl-8H-[1,3,4]thiadiazolo[3,2-
a]thieno[2,3-d]pyrimidin-8-one (6).
A mixture of amino-thioxo derivative 5 (0.38 g, 1.38 mmoles),
phosphorus pentoxide (0.3 g), methanesulfonic acid (0.6 ml) and
2-ethoxybenzoic acid (2.0 g, 98%, 11.8 mmoles) was heated at
100° for 2 hours. After cooling to room temperature, the reaction
mixture was treated with ice/water and 5% sodium hydroxide
was added to obtain pH 9-10. The resulting solid was collected,
washed with water, dried and crystallized from dioxane/water to
give 6 as a pale yellow powder; yield: 40%; mp 258-61°. The
analytical and spectral data of 2-ethoxyphenyl derivative 6 were
identical to those of a sample obtained according to Russo et al.
-1
1
and 3185 (NH or NH ), 1685 (C=O) cm ; H nmr (dimethylsul-
2
foxide-d ): δ 1.33 (t, J=7.2 Hz, 3H, CH ), 4.32 (q, J=7.2 Hz, 2H,
6
3
CH ), 6.5 (br s, 3H, NH and NH ), 7.27-7.63 (m, 6H, Ar-H and
2
2
13
thiophene-H), 9.92 (s, 1H, NH); C mnr (dimethylsulfoxide-d ):
6
δ 14.28, 60.48, 113.42, 119.25, 124.99, 127.29, 129.15, 131.10,
133.39, 150.11, 164.16, 176.71 .
Anal .Calcd. for C
H N O S : C, 52.33; H, 4.67; N, 13.08;
14 15 3 2 2
S, 19.93. Found: C, 52.50; H, 4.75; N, 12.95; S, 19.60.
Ethyl Ester of 2-({[2-(Methylsulfonyl)hydrazino]carbonoth-
ioyl}amino)-5-phenylthiophene-3-carboxylic Acid (3b).
-1
1
[2] (see Scheme 1); ir: 1705 (C=O) cm ; H nmr (trifluoroacetic

872
A. Santagati, A. Marrazzo and G. Granata
Vol. 40
acid-d): δ 1.73 (t, J= 7.0 Hz, 3H, CH ), 4.40 (q, J= 7.0, 2H, CH ),
7.68-7.09 (m, 10H, Ar-H and thiophene-H) .
3-Amino-2-(methylthio)-6-phenylthieno[2,3-d]pyrimidin-4(3H)-
one (10).
3
2
Anal. Calcd. for C
S, 15.80. Found: C, 62.50; H, 3.55; N, 10.40; S, 15.95.
H N O S : C,62.22; H, 3.70; N, 10.37;
21 15 3 2 2
A mixture of sodium salt 4 (0.68 g, 2.3 mmoles), and methyl
iodide (0.45 ml, 99 %, d=2.27) in water (40 ml) was stirred at
room temperature for 1.5 hours. The resulting solid was col-
lected, washed with water, dried and crystallized from diox-
ane/water to give 10 as pale yellow microcrystals; yield 60 % ;
N-(4-Oxo-6-phenyl-2-thioxo-1,4-dihydrothieno[2,3-d]pyrim-
idin-3(2H)-yl)methanesulfonamide (7).
A solution of mesylthiosemicarbazide derivative 3b (1.0 g,
2.5 mmoles) and sodium hydroxide (0.22 g, 5.5 mmoles) in water
(30 ml) was refluxed under stirring for 3 hours; the solution, con-
taining the disodium salt 4b, was filtered, quenched and acidified
with concentrated hydrochloric acid to pH 3-4: the resulting solid
was collected, washed with water, dried and crystallized from
acetonitrile/water to give the monomesyl amino derivative 7 as
grey amorphous powder; yield 45%; mp 280-84° dec.; ir: 3215
-1
1
mp 217-20°; ir: 3290 and 3175 (NH ), 1680 (C=O) cm ; H nmr
2
(dimethylsulfoxide-d ): δ 2.42 (s, 3H, SCH ), 5.81 (s, 2H, NH ),
6
3
2
13
7.30-7.76 (m, 6H, Ar-H and thiophene-H); C nmr (dimethylsul-
foxide-d ): δ 14.39, 117.15, 120.93, 125.54, 128.35, 129.20,
6
132.79, 138.06, 157.06, 161.83, 162.34 .
Anal. Calcd. for C H N OS : C, 53.97; H, 3.80; N, 14.53; S,
13 11
3
2
22.14. Found: C, 53.70; H, 3.65; N, 14.20; S, 21.95.
-1
1
N-(Methylsulfonyl)-N-[2-(methylthio)-4-oxo-6-phenylth-
ieno[2,3-d]pyrimidin-3(4H)-yl]methanesulfonamide (11).
(NH), 1675 (C=O), 1350 and 1165 (SO -N) cm ; H nmr
2
(dimethylsulfoxide-d ): δ 3.28 (s, 3H, CH ), 7.30-7.71 (m, 6H,
6
3
Ar-H and thiophene-H), 10.43 (s, 1H, NH), 14.00 (br s, 1H, NH);
To a stirred solution of methyl derivative 10 (0.25 g, 0.865
mmoles) and triethylamine (1 ml) in dichloromethane (30 ml) a
solution of methanesulfonyl chloride (0.22 ml, 2.85 mmoles,
99.5 %, d=1.480) in dichloromethane (10 ml) was added slowly
drop-wise; the mixture was stirred at room temperature for 3
hours; the organic phase was washed with water, dried on sodium
sulphate and concentrated under vacuum to give a solid that was
collected, washed with diethyl ether, dried to give derivative 11
as an orange powder, resulted pure on thin layer chromatography;
yield 68 % ; mp> 185° dec.; ir: 1715 (C=O), 1370 and 1165
13
C nmr (dimethylsulfoxide-d ): δ 44.48, 117.98, 118.42, 125.47,
6
128.53, 129.26, 132.00, 136.93, 149.54, 155.23, 174.98 .
Anal. Calcd. for C H N O S : C, 44.19; H, 3.11; N, 11.89;
13 11
3 3 3
S, 27.19. Found: C, 44.51; H, 3.13; N, 11.52; S, 26.80.
2-({3-[(Methylsulfonyl)amino]-4-oxo-6-phenyl-3,4-dihydroth-
ieno[2,3-d]pyrimidin-2-yl}thio)benzoic Acid (8).
A mixture of methylsulfonylhydrazino derivative 3b (2.0 g,
5.0 mmoles) and sodium hydroxide (0.4 g, 10 mmoles) in water
(100 ml) was refluxed under stirring for 2 hours; the mixture was
filtered while hot and to the resulting solution 2-iodobenzoic acid
(1.27 g, 98%, 5.0 mmoles), dissolved in a small amount of 5%
sodium hydroxide, and 65 mg of powdery copper were added.
The mixture was then refluxed under stirring for 7 hours. After
cooling to room temperature, the mixture was filtered and the
resulting solution was quenched and acidified with concentrated
hydrochloric acid to pH 3-4. The resulting solid was collected,
washed with water, dried and purified by chromatography on sil-
ica gel column (eluent: ethyl acetate/methanol 1/3) to give 8 as a
whitish powder; yield 50%; mp 239-41° dec.; ir: 3302 (NH),
-1
1
(SO -N) cm ; H nmr (dimethylsulfoxide-d ): δ 2.60 (s, 3H,
2
6
SCH ), 3.79 (s, 6H, 2xSO CH ), 7.43-7.83 (m, 6H, Ar-H and
3
2
3
13
thiophene-H); C nmr (dimethylsulfoxide-d ): δ 14.36, 45.94,
6
117.14, 120.92, 125.53, 128.33, 129.19, 132.77, 138.03, 157.04,
161.80, 162.33 .
Anal. Calcd. for C
H N O S : C, 40.44; H, 3.37; N, 9.43; S,
15 15 3 5 4
28.76. Found: C, 40.10; H, 3.15; N, 9.60; S, 28.50.
N-[2-(Methylthio)-4-oxo-6-phenylthieno[2,3-d]pyrimidin-
3(4H)-yl]methanesulfonamide (12).
A mixture of dimesyl derivative 11 (0.1 g, 0.22 mmoles) in a
solution of potassium hydroxide (1 M) in water (10 ml) and
tetrahydrofuran (90 ml) was stirred for 1 hour; the resulting solu-
tion was acidified with concentrated hydrochloric acid to pH 4-5,
and then extracted with ethyl acetate; the extracts were concen-
trated under vacuum to give a residue that was collected and dis-
solved in 10% sodium hydroxide; the resulting solution was fil-
tered and acidified with concentrated hydrochloric acid to pH 4-
5, and the solid that separated was collected, washed with water
and dried to give the monosulfonyl derivative 12 as an amor-
phous powder, resulted pure on thin layer chromatography ; yield
42 %; mp 248-51° dec.; ir: 3190 (NH), 1700 (C=O), 1345 and
-1
1
1700 (C=O), 1345 and 1155 (SO -N) cm ; H nmr (dimethylsul-
2
foxide-d ): δ 3.38 (s, 3H, CH ), 7.32-7.95 (m, 10H, Ar-H and
6
3
13
thiophene-H), 11.45 (br s, 1H, NH), 13.15 (br s, 1H, COOH);
C
nmr (dimethylsulfoxide-d ): δ 43.44, 118.22, 125.21, 125.34,
6
125.76, 126.43, 127.21, 128.10, 128.31, 129.18, 129.79, 131.99,
132.26, 132.83, 134.45, 135.69, 168.41, 170.32 .
Anal. Calcd. for C
H N O S : C, 50.73; H, 3.17; N, 8.88;
20 15 3 5 3
S,20.29. Found: C, 50.40; H, 3.22; N, 8.70; S, 19.90.
2-Methyl-7-phenyl-3H,9H-thieno[2’,3’:4,5]pyrimido[2,1-b]-
[1,3,4]thiadiazin-9-one (9).
A mixture of sodium salt 4a (0.39 g, 1.33 mmoles), chloroace-
tone (0.15 ml, 95%, d=1.162) in ethanol (20 ml) was refluxed for
2.5 hours. After cooling to room temperature, the resulting solid
was collected, washed firstly with ethanol and then with water,
dried and crystallized from ethanol/dioxane to give 9 as yellow
-1 1
1160 (SO -N) cm ; H nmr (dimethylsulfoxide-d ): δ 2.48 (s,
2
6
3H, SCH ), 3.34 (s, 3H, SO CH ), 7.40-7.80 (m, 6H, Ar-H and
3
2
3
thiophene-H), 11.27 (s, 3H, NH, deuterium oxide exchangeable);
13
C nmr (dimethylsulfoxide-d ): δ 14.99, 45.96, 117,69, 121.04,
6
125.84, 129.22, 129.32, 132.20, 140.50, 155.36, 161.48, 161.90.
-
microcrystals; yield 60%; mp 252-254° dec.; ir: 1680 (C=O) cm
Anal. Calcd. for C
H N O S : C,45.77; H,3.54; N,11.44;
14 13 3 3 3
1
1
; H nmr (dimethylsulfoxide-d ): δ 2.36 (s, 3H, CH ), 3.79 (s,
2H, CH ), 7.32-7.83 (m, 6H, Ar-H and thiophene-H); C nmr
S,26.15. Found: C, 45.80; H, 3.85; N, 11.10; S, 25.75.
6
3
13
2
From Monomesyl Derivative 7.
(dimethylsulfoxide-d ): δ 23.44, 24.80, 118.02, 123.32, 125.64,
6
128.59, 129.25, 132.60, 139.14, 151.23, 153.98, 159.65, 160.31 .
To a solution of thioxo-monomesyl derivative 7 (0.13 g, 0.37
mmoles), dissolved in a solution of potassium hydroxide (42 mg,
0.73 mmoles) in water (20 ml), methyl iodide (0.3 ml, 99 %,
Anal. Calcd. for C H N OS : C, 57.50; H, 3.51; N, 13.41; S,
15 11
3
2
20.44. Found: C, 57.20; H, 3.50; N, 13.15; S, 20.35.

Sep-Oct 2003
Synthesis of Potential Selective COX-2 Enzyme Inhibitors
873
d=2.27 ) was added and the mixture was stirred at room tempera-
ture for 1.5 hour; the mixture was filtered and the filtrate was
acidified with concentrated hydrochloric acid to pH 4-5, and the
solid that separated was collected, washed with water and dried
to give 12 as an amorphous powder, resulted pure at thin layer
chromatography; yield 50 %. This compound was identical to
that obtained from hydrolysis of dimesyl derivative 11.
nmr (trifluoroacetic acid-d): δ 2.83 (s, 3H, SCH ), 7.40-7.67 (m,
6H, Ar-H and thiophene-H).
3
Anal. Calcd. for C H N OS : C,50.75; H, 2.72; N, 12.68;
14
9
3
3
29.00. Found: C, 50.50; H, 2.75; N, 12.50; S, 28.80.
REFERENCES AND NOTES
2-(Methylthio)-6-phenyl-8H-[1,3,4]thiadiazolo[3,2-a]thieno[2,3-
d]pyrimidin-8-one (14).
[1] J. B. Press, The Chemistry of Heterocyclic Compounds, Vol.
44, Thiophene and its Derivatives, S. Gronowitz, ed. John Wiley and
Sons, New York, 1985, pp. 353-436; 1991, pp. 397-478.
[2] F. Russo, A. Santagati, M. Santagati, A. Caruso, S.
Trombadore and M. Amico-Roxas, Eur. J. Med. Chem., 21, 119 (1986).
[3] D. L. DeWitt, Mol. Pharmacol., 55, 625 (1999).
[4] G. Dannhardt and W. Kiefer, Eur. J. Med. Chem., 36, 109
(2001).
[5] P. Patrignani, M. R. Panara, A. Greco, O. Fusco, C. Natoli, S.
Jacobelli, F. Cipollone, A. Ganci, C. Crèminon, J. Maclouf and C.
Patrono, J. Pharmacol. Exp. Ther., 271, 1705 (1994).
[6] K. Gewald, E. Schinke and H. Bottcher, Chem. Ber., 99, 94
(1966).
A mixture of amino thiomethyl derivative 10 (0.2 g, 0.7
mmoles) and carbon disulfide (0.7 ml, 99.9 %, d=1.266) in pyri-
dine (2 ml), was refluxed under stirring for 12 hours. The reaction
mixture was cooled to room temperature, and the yellow solid
that separated was collected by filtration under vacuum, washed
with diethylether and dried to give the crude 6-phenyl-2-thioxo-
1,2-dihydro-8H-[1,3,4]thiadiazolo[3,2-a]thieno[2,3-d]pyrimidin-
8-one (13) as a yellow powder (0.2 g) . A mixture of the crude
derivative 13 (0.20 g) suspended in water (30 ml) with sodium
hydroxide (25 mg) and dimethyl sulphate (0.5 ml, 99% d=1.33)
was stirred at room temperature for 4 hours. The resulting solid
was collected, washed with water, dried and crystallized from
dimethylformamide to give 14 as yellow microcrystals; yield: 47
%; mp 260-63°; the analytical and spectral data of thiomethyl
derivative 14 were identical to those of a sample obtained accord-
[7] F. Kienzle, A. Kaiser and R. E. Minder, Helv. Chim. Acta, 66,
148 (1983).
[8] R. Böhm, R. Müller and R. Pech, Pharmazie, 45, 827 (1990).
[9] A. Santagati, M. Modica, M. Santagati, A. Caruso and V.
Cutuli, Pharmazie, 49, 64 (1994).
-1
1
ing to Russso et al [2], (see Scheme 2 ); ir: 1690 (C=O) cm ; H
[10] A. G. Newcombe, Can. J. Chem., 33, 1250 (1955).