H.M. Aly et al. / European Journal of Medicinal Chemistry 46 (2011) 4566e4572
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(%):247[Mþ2] (1.44), 84 (100). Anal. Calcd. For C13H15N3O2: C, 63.66;
-antipyrine 2 (2.3 g, 10 mmol) and thiophene-2-carbaldehyde
(1.12 g, 10 mmol) in ethanol (50 mL) cooled at 5e10 ꢁC was added
aqueous sodium hydroxide (70%, 5 mL) drop wise with constant
stirring. The reaction mixture was further stirred for 2 h and left
over night. The reaction mixture was neutralized with concentrated
hydrochloric acid, and then the solid separated was collected and
crystallized from benzene to give brown crystals 10: Yield, 75%;
m.p. 240e242 ꢁC; IR, cmꢀ1: 3218 (NH), 3079 (CH-arom.), 2993 (CH-
H, 6.16; N, 17.13. Found: C, 63.36; H, 6.06; N, 17.03.
5.1.2. Ethyl 4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-ylamino)-2,4-dioxobutanoate (3)
To a stirred solution of 2 (2.3 g, 10 mmol) and diethyl oxalate
(5.4 g, 40 mmol) was added drop wise a solution of sodium eth-
oxide (1.36 g, 20 mmol). The reaction mixture was refluxed for 5 h,
cooled and then acidified with acetic acid (3%). The solid separated
was collected and crystallized from dioxane to give yellow crystals
3: Yield, 76%; m.p. 100e102 ꢁC; IR, cmꢀ1: 3259 (NH), 3050 (CH-
aliph.), 1711, 1665 (2C]O). 1H NMR (DMSO-d6)
d: 2.1 (s, 3H, CH3),
3.3 (s, 3H, NeCH3), 6.8 (s, 2H, CH]CH), 7.1e7.8 (m, 8H, AreHþ NH),
9.0 (s, H, NH). 13C NMR (DMSO-d6): 12.4 (CH3, aliphatic), 39.6
(NeCH3), 103.5, 113.0, 119.1, 127.6, 128.6, 129.8, 130.9, 132.5, 136.2,
137.6 (10C, aromatic carbons), 160.8, 164.9(2C]O). MS, m/z (%): 339
[M þ 2] (2.04),121 (100%). Anal. Calcd. For C18H17N3O2S: C, 63.70; H,
5.05; N, 12.38; S, 9.45. Found: C, 63.40; H, 4.85; N, 12.08; S, 9.35.
arom.), 2968 (CH-aliph.), 1750 (C]O,
a
- ketoester), 1700 (
b-dike-
tone), 1669(C]O, antipyrine). 1H NMR (DMSO-d6)
d
: 1.6 (t, 3H, CH3
ester), 2.7(s, 3H, CH3), 3.1 (s, 3H, NeCH3), 3.4(s, 2H, eCOCH2CO-),
4.1 (q, 2H, CH2 ester), 7.2e7.5 (m, 5H, AreH), 9.1 (s, H, NH). MS, m/z
(%): 345[M þ 2](7.11), 132(100). Anal. Calcd. For C17H19N3O5: C,
59.12; H, 5.75; N, 12.17. Found: C, 59.42; H, 6.06; N, 12.37.
5.1.6. Ethyl N-3-cyano-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazol-4-ylamino)thiophen-2-ylformimidate (11). A mixture of
compound 6 (1.6 g, 5 mmol) and triethyl orthoformate (20 mL) was
heated under reflux for 2 h. The solid product was collected and
crystallized from benzene to give orange crystals 11: Yield, 83%; m.p.
240e242 ꢁC; IR, cmꢀ1: 3228 (NH), 3097 (CH-arom.), 2935(CH-aliph.),
5.1.3. General procedure for the reaction of 4-acetyl antipyrine with
sulfur and activated nitrile derivatives
A mixture of acetylantipyrine 2 (2.3 g,10 mmol), activated nitrile
such as malononitrile and/or ethyl cyanoacetate (10 mmol), sulfur
(10 mmol), ethanol (50 mL) and piperidine were refluxed for 3h.
The solid which separated was filtered, washed with ethanol, dried
and crystallized from ethanol to give 6 and 7.
2218 (C^N), 1661 (C]O), 1593 (CH]N). 1H NMR (DMSO-d6)
d: 1.1(t,
3H, CH3 ethyl), 2.2(s, 3H, CH3), 3.4 (s, 3H, N-CH3), 4.1(q, 2H, CH2
ethyl), 4.4(s,1H, NH), 7.4e8.4(m, 6H, AreHþ N]CH). Anal. Calcd. For
C19H19N5O2S: C, 59.82; H, 5.02; N, 18.36; S, 8.41. Found: C, 59.92; H,
5.32; N, 18.56; S, 8.71.
5.1.3.1. Spectral data of 2-amino-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-yl amino) thiophene-3-carbonitrile (6). Yield,
85%; m.p. 115e117 ꢁC; IR, cmꢀ1: 3390, 3226 (br, NH2/NH), 3188 (CH-
arom.), 2922 (CH-aliph.), 2206 (C^N), 1662 (C]O). 1H NMR (DMSO-
5.1.7. 4-(3-Amino-4-imino-3,4-dihydrothieno[2,3-d]pyrimidin-5-
ylamino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one(12). A
mixture of 11 (1.9 g, 5 mmol) and hydrazine hydrate (0.25 g,
5 mmol) in ethanol (60 mL) was heated under reflux for 3 h. The
solid product was filtered on hot, dried, and crystallized from
ethanol to give yellow crystals 12: Yield, 80%; m.p. 220e222 ꢁC; IR,
cmꢀ1: 3310, 3215 (NH2/NH), 3007 (CH-arom.), 2919 (CH-aliph.),
d6) d: 1.9 (s, 3H, CH3), 3.1 (s, 3H, NeCH3), 4.3 (s, 2H, NH2), 5.5 (s, H, CH
thiophene), 7.5e7.9 (m, 5H, AreH), 8.3 (s, 1H, NH). MS, m/z (%): 325
[Mþ](10.17), 63(100%). Anal. Calcd. For C16H15N5OS: C, 59.06; H,
4.65; N, 21.52; S, 9.85. Found: C, 59.46; H, 4.95; N, 21.72; S, 9.95.
5.1.3.2. Spectral data of ethyl 2-amino-4-(1,5-dimethyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazol-4-yl amino)thiophene-3-carboxylate
(7). Yield, 70%; m.p. 240e242 ꢁC; IR, cmꢀ1: 3309(NH2), 3247
(NH), 3065 (CH-arom.), 2996 (CH-aliph.), 1705, 1685 (2C]O). 1H
1664 (C]O). 1H NMR (DMSO-d6)
d: 2.0(s, 3H, CH3), 3.1 (s, 3H,
NeCH3), 6.0 (s, 2H, NH2), 7.5e7.9 (m, 8H, Ar-HþC]NH). 13C NMR
(DMSO-d6): 12.3 (CH3, aliphatic), 39.5 (NeCH3), 102.6, 113.5, 115.9,
119.3, 127.0, 128.9, 131.2, 136.8, 145.3, 163.1, 164.2 (11C, aromatic
carbons), 160.7 (pyrazoleeC¼O). MS, m/z (%):367 [M þ 2] (100%).
Anal. Calcd. For C17H17N7OS: C, 55.57; H, 4.66; N, 26.68; S, 8.73.
Found: C, 55.87; H, 4.96; N, 26.88; S, 8.93.
NMR (DMSO-d6) d: 1.2 (t, 3H, CH2CH3), 1.6 (s, 3H, CH3), 3.3 (s, 3H,
NeCH3), 4.1 (q, 2H, CH2CH3), 5.9 (s, H, CH thiophene), 7.4e7.6 (m,
5H, AreH), 8.3 (s, 1H, NH), 9.6 (s, H, NH2). MS, m/z (%):372(Mþ)
(100%). Anal. Calcd. For C18H20N4O3S: C, 58.05; H, 5.41; N, 15.04; S,
8.61. Found: C, 58.45; H, 5.61; N, 15.24; S, 8.91.
5.1.8. 2-Chloro-N-(3-cyano-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-ylamino)thiophen-2-yl)acetamide
(13). To
5.1.4. Ethyl-2-amino-6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazol-4-ylamino)-4-(furan-2-yl)-4H-pyran-3-carboxylate (9).
To a mixture of 4-acetylantipyrine 2 (2.3 g, 10 mmol) and in ethanol
(50 mL) containing a few drops of piperidine of ethyl 2-cyano-3-
(furan-2-yl)acrylate were added. The reaction mixture was refluxed
for 2 h; and then left to cool at room temperature. The solid
separated was collected and crystallized from dioxane to give
brown crystals 9: Yield, 87%; m.p.100e102 ꢁC; IR, cmꢀ1: 3325, 3250
(NH2, NH), 3009 (CH-arom.), 2905(CH-aliph.), 1780, 1668 (2C]O).
stirred suspension of 6 (1.6 g, 0.005 mol), and chloroacetyl chloride
(0.5 g, 5 mmol) in dimethylformamide (20 mL) at room tempera-
ture, for 30 min was added. The reaction mixture was cooled,
diluted with water and the solid obtained was collected and
recrystallized from dioxane to give orange crystals 13: Yield, 60%;
m.p. 120e122 ꢁC; IR, cmꢀ1: 3248 (2NH), 3091 (CH-arom.), 2960
(CH-aliph.), 2168 (C^N), 1724, 1669 (2C]O). 1H NMR (DMSO-d6)
d:
4.2 (s, H, CH2), 5.8 (s, H, CH thiophene), 7.0e7.9 (m, 6H, AreHþ NH),
9.4(s, 1H, NH). 13C NMR (DMSO-d6): 12.4 (CH3, aliphatic), 39.3
(NeCH3), 43.5 (CH2, aliphatic), 116.09 (C^N), 64.6, 93.2, 113.0,
116.0, 119.0, 128.6, 129.4, 130.8, 136.5, 145 (10C, aromatic carbons),
160.8, 164.9 (2C]O). MS, m/z (%): 401 [M þ 2] (22.07), 311 (100%).
Anal. Calcd. For C18H16ClN5O2S: C, 53.80; H, 4.01; N, 17.43; S, 7.98.
Found: C, 53.90; H, 4.21; N, 17.73; S, 8.28.
1H NMR (DMSO-d6)
d: 1.3(t, 3H, CH3 ethyl), 2.4(s, 3H, CH3), 3.2 (s,
3H, NeCH3), 4.2(q, 2H, CH2 ethyl), 4.6(s, 1H, NH), 6.3e7.5(m, 12H,
AreHþ NH2). 13C NMR (DMSO-d6): 12.5 (CH3, aliphatic), 13.9 (CH3,
ester), 38.9 (NeCH3), 60.9 (CH2, ester), 30.3, 75.5, 75.9, 105.2, 106.0,
109.4, 112.1, 119.4, 129.1, 131.2, 136.5, 140.0, 15104, 152.2 (14C,
aromatic carbons), 160.2, 166.5(2C]O),167.0(pyraneeCeNH2). MS,
m/z (%): 339[M þ 1] (1.94), 50 (100%). Anal. Calcd. For C23H24N4O5:
C, 63.29; H, 5.54; N, 12.84. Found: C, 63.49; H, 5.74; N, 12.94.
5.1.9. 4-(4-Aminothieno[2,3-d]pyrimidin-5-ylamino)-1,5-dimethyl-
2-phenyl-1,2-dihydropyrazol-3-one (15). A solution of compound 6
(1.6 g, 5 mmol), in formamide (20 mL) was refluxed for 5 h; the
reaction mixture was cooled, and then poured onto ice cooled
water. The formed solid was recrystallized from dioxane to yellow
5.1.5. N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl)-3-(thiophen-2-yl)acrylamide (10). To
a mixture of 4-acetyl