JOURNAL OF CHEMICAL RESEARCH 2016 19
filter cake was washed with water, and recrystallised from methanol
to afford corresponding 5-substituted amino-8H-phthalazino[1,2-b]
quinazolin-8-one as light-green powder.
with the structures of 6a–f, for example, IR shows a carbonyl
peak at 1667 cm−1 corresponding to a stretching vibration in 6a.
The 1H NMR spectrum for compound 6a exhibits a sharp singlet
at 3.05 ppm, corresponding to the methyl proton at position 5 of
phthalazino[1,2-b]quinazolinone. In the mass spectrum of 6a,
the peak appeared at m/z 277 ([M + H]+, 100%), which is in
accordance with its molecular formula. IR, H NMR, MS and
elemental analyses of the target compounds confirmed their
structural integrity.
Method
B
(liquid amines): 5-chloro-8H-phthalazino[1,2-b]
quinazolin-8-one (5.0 mmol) was directly dissolved liquid substituted
amine (20 mL), and the mixture was heated to 60 °C and stirred for 7
hours. After cooling to r.t., the mixture was then filtered and washed
with water to give crude product which was recrystallised from
methanol to give the target compound as light-green powder.
1
5-(Methylamino)-8H-phthalazino[1,2-b]quinazolin-8-one
(6a):
Method A; yield 81.5%; m.p. 327–329 °C; IR (νmax, cm–1) KBr: 3374,
2936, 1667 (C=O), 1619, 1570, 1548, 1487, 1466, 1417, 1384, 1345,
1314, 1304, 1275, 1234, 1166, 1136, 1105, 1021, 960, 917, 869, 770, 743,
Experimental
Unless specified otherwise, all starting materials and reagents were
obtained from commercial suppliers without further purification. All
melting points were taken on a Beijing Taike X-4 microscopy melting
point apparatus and were uncorrected. 1H NMR spectra were recorded
on a Bruker Biospin 600 MHz or Bruker Biospin 300 MHz instrument
using TMS as the internal standard. All chemical shifts were reported
in ppm. IR spectra were recorded as KBr pellets on a PerkinElmer
Spectrum one FTIR spectrometer. Mass spectra were recorded on a
Waters Quattro micro API mass spectrometer (ESI, direct injection).
Elemental analysis was carried out on a Carlo Erba 1108 analyser and
are found within the range of theoretical value.
Synthesis of 2-aminobenzohydrazide (2): A mixture of methyl
2-aminobenzoate (30.3 g, 0.20 mol) and 80% N2H4·H2O (50 mL) in
EtOH (100 mL) was refluxed for 13 h. After completion of the reaction
as indicated by TLC, the resulting solid which formed on cooling
was collected by filtration and crystallised from ethanol to give
2-aminobenzohydrazide: Colourless crystalline solid; yield 25.1 g,
82.8%; m.p. 121–123 °C; IR (νmax, cm–1) KBr: 3443, 3324, 3026, 1619,
1578, 1506, 1449, 1338, 1317, 1293, 1262, 1172, 1150, 1105, 1031, 957,
940, 855, 821, 794, 755, 743, 664; MS (ESI) m/z: 152 [M + H]+; Anal.
calcd for C7H9N3O: C, 55.62; H, 6.00; N, 27.80; found: C, 55.86; H,
6.17; N, 28.01%.
Synthesis of 5H-phthalazino[1,2-b]quinazoline-5,8(6H)-dione (4):
To a solution of 2-aminobenzohydrazide (14.2 g, 94.0 mmol) in N,N-
dimethylacetamide (100 mL), phthalic anhydride (15.3 g, 103 mmol)
was added at r.t., the resulting mixture was heated to reflux for 12 h.
Upon cooling to r.t., the solid which formed was collected by filtration,
washed with EtOH and dried to afford 5H-phthalazino[1,2-b]
quinazoline-5,8(6H)-dione: Yellow powder; yield 16.4 g, 62.3%; m.p.
283–285 °C; IR (νmax, cm–1) KBr: 3194, 3085, 1687, 1669, 1605, 1590,
1556, 1485, 1463, 1438, 1372, 1332, 1264, 1256, 1235, 1168, 1312, 1101,
767; 1H NMR (300 MHz, DMSO-d6) δ 12.95 (br. s, 1H), 8.83 (d, J = 7.6
Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.20 (br. s, 1H), 8.00 (m, 2H), 7.90
(m, 2H), 7.60 (m, 1H); MS (ESI) m/z: 264 [M + H]+; Anal. calcd for
C15H9N3O2: C, 68.44; H, 3.45; N, 15.96; found: C, 68.58; H, 3.47; N,
16.07%.
1
696, 680; H NMR (600 MHz, DMSO-d6) δ 8.92 (m, 1H, ArH), 8.27
(m, 1H, ArH), 8.24 (m, 1H), 7.98 (m, 2H), 7.87 (m, 1H), 7.83 (d, J = 7.8
Hz, 1H), 7.68 (m, 1H), 3.05 (s, 3H, CH3); MS (ESI) m/z: 277 [M + H]+;
Anal. calcd for C16H12N4O: C, 69.55; H, 4.38; N, 20.28; found: C, 69.69;
H, 4.29; N, 20.39%.
5-{[2-(Dimethylamino)ethyl]amino}-8H-phthalazino[1,2-b]
quinazolin-8-one (6b): Method B; yield 76.8%; m.p. 221–224 °C; IR
(νmax, cm–1) KBr: 3379, 3062, 2932, 2815, 2764, 1683 (C=O), 1619,
1610, 1543, 1466, 1348, 1313, 1275, 1176, 1138, 1062, 1039, 765,
693,683; 1H NMR (600 MHz, DMSO-d6) δ 8.87 (m, 1H), 8.24 (m, 2H),
7.94 (m, 1H), 7.97 (m, 2H), 7.83 (m, 1H), 7.78 (m, 1H), 7.50 (m, 2H),
3.59 (t, J = 5.4 Hz, 2H), 2.63 (t, J = 5.4 Hz, 2H), 2.24 (s, 6H); MS (ESI)
m/z: 334 [M + H]+; Anal. calcd for C19H19N5O: C, 68.45; H, 5.74; N,
21.01; found: C, 68.66; H, 5.69; N, 21.09%.
Ethyl
2-[(8-oxo-8H-phthalazino[1,2-b]quinazolin-5-yl)amino]
acetate (6c): Method A; yield 61.5%; m.p. 213–215 °C; IR (νmax, cm–1)
KBr: 3354, 2994, 2960, 2933, 1752 (C=O), 1667 (C=O), 1622, 1609,
1567, 1464, 1339, 1316, 1276, 1190, 1163, 1151, 1091, 1047, 1020, 767,
1
695, 681; H NMR (600 MHz, DMSO-d6) δ 8.90 (m, 1H), 8.29 (m,
1H), 8.24 (m, 1H), 8.12 (m, 1H), 7.99 (m, 2H), 7.84 (m, 1H), 7.80 (d,
J = 7.8 Hz, 1H), 7.51 (m, 1H), 4.24 (d, J = 6.0 Hz, 2H, NHCH2), 4.15
(q, J = 7.2Hz, 2H, CH2), 1.23 (t, J = 7.2 Hz, 3H, CH3); MS (ESI) m/z:
349 [M + H]+; Anal. calcd for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08;
found: C, 65.89; H, 4.79; N, 15.96%.
5-Morpholino-8H-phthalazino[1,2-b]quinazolin-8-one (6d): Method
B; yield 81.4%; m.p. 224–226 °C; IR (νmax, cm–1) KBr: 3060, 2990, 2841,
1710 (C=O), 1609, 1568, 1538, 1467, 1455, 1404, 1345, 1272, 1187, 1123,
1
1033, 908, 783, 767, 693; H NMR (600 MHz, DMSO-d6) δ 8.89 (m,
1H), 8.28 (dd, J = 1.2 Hz, J = 7.8 Hz, 1H), 8.08 (m, 1H), 7.97 (m, 2H),
7.89 (m, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.55 (m, 1H), 3.88 (m, 4H), 3.36
(m, 4H); 13C NMR (150 MHz, DMSO-d6) δ 157.52, 153.96, 146.04,
143.64, 134.51, 133.01, 132.78, 130.01, 127.24, 126.89, 126.47, 126.11,
125.62, 122.19, 120.05, 65.92 (2C), 51.17 (2C); MS (ESI) m/z: 333 [M +
H]+; Anal. calcd for C19H16N4O2: C, 68.66; H, 4.85; N, 16.86; found: C,
68.43; H, 4.99; N, 16.65%.
Synthesis of 5-chloro-8H-phthalazino[1,2-b]quinazolin-8-one (5): A
mixture of 5H-phthalazino[1,2-b]quinazoline-5,8(6H)-dione (10.0 g,
38.0 mmol), POCl3 (20 mL) was heated at reflux for 5 h. After cooling
to r.t., the reaction mixture was slowly added to ice/water with vigorous
stirring. The mixture was then filtered, washed with cold water and
dried to yield 5-chloro-8H-phthalazino[1,2-b]quinazolin-8-one which
was used in the next step without further purification: Yellow solid;
yield 6.7 g, 62.6%; IR (νmax, cm–1) KBr: 3074, 2924, 1711, 1667, 1607,
1596, 1574, 1555, 1484, 1458, 1384, 1342, 1274., 1225, 1171, 1158,
1148, 1104, 1026, 994, 968, 909, 871, 854, 779; MS (ESI) m/z: 283 [M
+ H]+; Anal. calcd for C15H8ClN3O: C, 63.96; H, 2.86; N, 14.92; found:
C, 64.01; H, 2.95; N, 15.03%.
5- [(Furan-2-ylmethyl) amino] - 8H-phthalazino [1, 2-b]
quinazolin-8-one (6e): Method B; yield 64.9%; m.p. 283–285 °C;
IR (νmax, cm–1) KBr: 3342, 2931, 1663 (C=O), 1621, 1609, 1567, 1539,
1487, 1467, 1417, 1384, 1340, 1317, 1305, 1275, 1252, 1233, 1216, 1179,
1165, 1146, 1136, 1079, 1046, 1006, 959, 925, 906, 883, 820, 769, 753,
696; 1H NMR (300 MHz, DMSO-d6) δ 8.89 (m, 1H), 8.29 (m, 2H), 8.11
(m, 1H), 7.94 (m, 2H), 7.82 (m, 2H), 7.53 (m, 2H), 6.69 (d, J = 6.0 Hz,
1H), 6.40 (d, J = 6.0 Hz, 2H), 4.68 (d, J = 5.4 Hz, 2H, CH2); MS (ESI)
m/z: 343 [M + H]+; Anal. calcd for C20H14N4O2: C, 70.17; H, 4.12; N,
16.37; found: C, 70.33; H, 4.22; N, 16.55%.
5- [(1,4-Dioxaspiro [4.5] decan- 8-ylmethyl) amino] - 8H-
phthalazino[1,2-b]quinazolin-8-one (6f): Method A; yield 67.23% m.p.
230–232 °C; IR (νmax, cm–1) KBr: 3364, 2927, 2883, 1672 (C=O), 1616,
1570, 1543, 1487, 1467, 1446, 1384, 1343, 1313, 1275, 1238, 1177, 1138,
1101, 1077, 1032, 947, 938, 896; 1H NMR (600 MHz, DMSO-d6) δ 8.89
(d, 1H, J = 7.2 Hz), 8.32 (d, J = 7.2 Hz), 8.23 (d, 1H, J = 8.4 Hz), 7.94 (m,
2H), 7.83 (m, 1H), 7.78 (d, 1H, J = 8.4 Hz), 7.50 (m, 2H), 3.84 (m, 4H),
3.40 (m, 2H), 1.90 (m, 1H), 1.83 (m, 2H), 1.70 (m, 2H), 1.44 (m, 2H),
1.30 (m, 2H); MS (ESI) m/z: 417 [M + H]+; Anal. calcd for C24H24N4O3:
C, 69.21; H, 5.81; N, 13.45; found: C, 69.35; H, 5.88; N, 13.54%.
Synthesis of N-1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amides (6a–
f); general procedure
Method A (solid amines): To the suspension of Et3N (15.0 mmol) in
DMF (20 mL), substituted amine hydrochloride (6.0 mmol) was added
at r.t.. The mixture was stirred for 30 min before the slow addition
of 5-chloro-8H-phthalazino[1,2-b]quinazolin-8-one (5.0 mmol).
The mixture was warmed to 80 °C and stirred for 12 h. The reaction
mixture was poured into stirring water (300 mL), then filtered. The