May 2015
Synthesis and Evaluation of Antiplatelet Aggregation Activity of 2,4-Disubstituted
787
9-Chloro-5,6-dihydropyrimido[5,4-d]benzazepine and Related Compounds
(br t, 2H, J = 5.0 Hz, H6), 4.19 (br, 1H, deuterium oxide
exchangeable, NH), 6.69 (d, 1H, J = 2.0 Hz, H8), 6.87 (dd, 1H,
J = 9.0, 2.0 Hz, H10), 8.09 (d, 1H, J = 9.0 Hz, H11); FAB-msm/z
348 (MH+), 350 (MH+ + 2). Anal. Calcd for C18H19Cl2N3: C,
62.08; H, 5.50; N, 12.07. Found: C, 61.79; H, 5.36; N, 11.99.
4,9-Dichloro-2-phenyl-6,7-dihydro-5H-pyrimido[5,4-d][1]
10.0mmol) in dry 1,4-dioxane (3.0 mL) was refluxed for an
appropriate time, and the resulting solution was evaporated in
vacuo. Ice-water (50 mL) was poured into the residue, and the
aqueous mixture was extracted with ethyl acetate (20 mL × 3). The
organic layer was washed with water, sat. brine, dried over
anhydrous sodium sulfate, and evaporated. The residue (except for
benzazepine (10e).
The product was recrystallized from
11a) was recrystallized from the appropriate solvent to give 11.
9-Chloro-4-(morpholin-4-yl)-6,7-dihydro-5H-pyrimido[5,4-d]
benzene-methanol to give 10e (69%) as yellow prisms, mp
156–158 °C; IR (potassium bromide) cmÀ1: 3470 (NH); 1H NMR
(deuterochloroform): δ 3.17 (br t, 2H, J = 5.0 Hz, H5), 3.75 (br t,
2H, J = 5.0 Hz, H6), 4.38 (br, 1H, deuterium oxide exchangeable,
NH), 6.69 (d, 1H, J = 2.0 Hz, H8), 6.91 (dd, 1H, J = 9.0, 2.0 Hz,
H10), 7.36–7.73 (m, 3H, H3′, 4′, and 5′), 8.12–8.68 (m, 3H, H11,
2′, and 6′); FAB-msm/z 342 (MH+), 344 (MH+ + 2). Anal. Calcd
for C18H13Cl2N3: C, 63.17; H, 3.83; N, 12.28. Found: C, 63.08;
[1]benzazepine (11a).
The reaction mixture was refluxed for
2 h, and the yellow oily residue was chromatographed on silica
gel. The eluate of benzene-ethyl acetate (7:3 to 1:1) was
collected and evaporated to give viscous oily compound 11a
(87.0 mg, 82%); IR (chloroform) cmÀ1: 3440 (NH); 1H NMR
(deuterochloroform): δ 2.79 (br t, 2H, J = 5.0 Hz, H5), 3.25 (br t,
4H, J = 4.5 Hz, H3′ and 5′), 3.50–3.84 (m, 6H, H6, 2′, and 6′),
4.18 (br, 1H, deuterium oxide exchangeable, NH), 6.59 (d, 1H,
J = 2.0Hz, H8), 6.77 (dd, 1H, J = 9.0, 2.0 Hz, H10), 7.92 (d, 1H,
J = 9.0Hz, H11), 8.64 (s, 1H, H2); FAB-ms m/z 317 (MH+), 319
(MH+ + 2). The free base 11a was dissolved in ethanol (5.0 mL)-
conc. hydrochloric acid (1.0 mL) to make the hydrochloride salt
for elemental analysis. After removal of the acid in vacuo, the
residue was recrystallized from ethanol-ethyl acetate to give 11a
mono hydrochloride as yellow needles, mp 219–222 °C; Anal.
Calcd for C16H17ClN4O · HCl: C, 54.40; H, 5.14; N, 15.86.
H, 3.93; N, 12.12.
4,9-Dichloro-2-(4-methylphenyl)-6,7-dihydro-5H-pyrimido[5,4-d]
[1]benzazepine (10f).
The product was recrystallized from
benzene-methanol to give 10f (68%) as yellow prisms, mp
194–196 °C; IR (potassium bromide) cmÀ1: 3425 (NH); 1H
NMR (deuterochloroform): δ 2.43 (s, 3H, Me), 3.16 (br t, 2H,
J = 5.0 Hz, H5), 3.48–3.97 (m, 3H, changed to 2H with addition
of deuterium oxide, H6 and NH), 6.70 (d, 1H, J = 2.0 Hz, H8),
6.91 (dd, 1H, J = 9.0, 2.0 Hz, H10), 7.29 (d, 2H, J = 9.0 Hz, H3′
and 5′), 8.21 (d, 1H, J = 9.0 Hz, H11), 8.39 (d, 2H, J = 9.0 Hz,
H2′ and 6′); FAB-ms m/z 356 (MH+), 358 (MH+ + 2). Anal.
Calcd for C19H15Cl2N3: C, 64.06; H, 4.24; N, 11.80. Found: C,
64.27; H, 4.37; N, 11.79.
Found: C, 54.20; H, 4.92; N, 15.83.
9-Chloro-2-methyl-4-(morpholin-4-yl)-6,7-dihydro-5H-pyrimido
[5,4-d][1]benzazepine (11b). The reaction mixture was refluxed
for 6 h, and the product was recrystallized from ethanol to give
11b (62%) as pale yellow needles, mp 195–197 °C; IR (potassium
bromide) cmÀ1: 3260 (NH); 1H NMR (deuterochloroform): δ 2.61
(s, 3H, Me), 2.84 (br t, 2H, J = 5.0 Hz, H5), 3.31 (br t, 4H,
J = 4.5Hz, H3′ and 5′), 3.54–3.91 (m, 6H, H6, 2′, and 6′), 4.43
(br, 1H, deuterium oxide exchangeable, NH), 6.68 (d, 1H,
J = 2.0Hz, H8), 6.87 (dd, 1H, J = 9.0, 2.0 Hz, H10), 7.97 (d, 1H,
J = 9.0Hz, H11); FAB-ms m/z 331 (MH+), 333 (MH+ + 2). Anal.
Calcd for C17H19ClN4O: C, 61.72; H, 5.79; N, 16.94. Found: C,
4,9-Dichloro-2-(4-chlorophenyl)-6,7-dihydro-5H-pyrimido
[5,4-d][1]benzazepine (10 g).
The product was recrystallized
from benzene-methanol to give 10g (53%) as pale yellow prisms,
1
mp 199–201 °C; IR (potassium bromide) cmÀ1: 3420 (NH); H
NMR (deuterochloroform): δ 3.16 (br t, 2H, J = 5.0 Hz, H5), 3.80
(br t, 2H, J = 5.0 Hz, H6), 4.30 (br, 1H, deuterium oxide
exchangeable, NH), 6.74–7.15 (m, 2H, H8 and 10), 7.44 (d, 2H,
J = 9.0 Hz, H3′ and 5′), 8.15 (d, 1H, J = 9.0 Hz, H11), 8.42 (d, 2H,
J = 9.0 Hz, H2′ and 6′); FAB-ms m/z 376 (MH+), 378 (MH+ + 2).
Anal. Calcd for C18H12Cl3N3: C, 57.40; H, 3.21; N, 11.16.
61.52; H, 5.68; N, 16.85.
9-Chloro-2-ethyl-4-(morpholin-4-yl)-6,7-dihydro-5H-pyrimido
Found: C, 57.43; H, 3.37; N, 11.31.
4,9-Dichloro-2-(4-methoxyphenyl)-6,7-dihydro-5H-pyrimido
[5,4-d][1]benzazepine (11c). The reaction mixture was refluxed
for 8.5 h, and the product was recrystallized from ethanol to give
11c (67%) as pale yellow prisms, mp 182–184 °C; IR (potassium
bromide) cmÀ1: 3350, 3280 (NH); 1H NMR (deuterochloroform):
δ 1.28 (t, 3H, J = 7.5 Hz, Me), 2.60–3.02 (m, 4H, H5, CH2CH3),
3.25 (br t, 4H, J = 4.5 Hz, H3′ and 5′), 3.43–3.91 (m, 6H, H6, 2′,
and 6′), 4.08 (br, 1H, deuterium oxide exchangeable, NH), 6.60
(d, 1H, J = 2.0 Hz, H8), 6.80 (dd, 1H, J = 9.0, 2.0 Hz, H10), 7.95
(d, 1H, J = 9.0 Hz, H11); FAB-msm/z 345 (MH+), 347 (MH+ + 2).
Anal. Calcd for C18H21ClN4O: C, 62.69; H, 6.14; N, 16.25.
[5,4-d][1]benzazepine (10 h).
The product was recrystallized
from acetone-methanol to give 10 h (69%) as yellow needles, mp
167–168 °C; IR (potassium bromide) cmÀ1: 3370 (NH); 1H NMR
(deuterochloroform): δ 3.13 (br t, 2H, J = 5.0 Hz, H5), 3.71 (br t,
2H, J = 5.0 Hz, H6), 3.87 (s, 3H, OMe), 4.20 (br, 1H, deuterium
oxide exchangeable, NH), 6.61–7.12 (m, 4H, H8, 10, 3′, and
5′), 8.18 (d, 1H, J = 9.0 Hz, H11), 8.44 (d, 2H, J = 9.0 Hz, H2′
and 6′); FAB-ms m/z 372 (MH+), 374 (MH+ + 2). Anal. Calcd
for C19H15Cl2N3O: C, 61.30; H, 4.06; N, 11.29. Found: C,
Found: C, 62.82; H, 6.12; N, 16.34.
61.25; H, 4.16; N, 11.32.
4,9-Dichloro-2-trifluoromethyl-6,7-dihydro-5H-pyrimido[5,4-d]
9-Chloro-2-cyclohexyl-4-(morpholin-4-yl)-6,7-dihydro-5H-
pyrimido[5,4-d][1]benzazepine (11d). The reaction mixture
was refluxed for 51h, and the product was recrystallized from
water–methanol to give 11d (42%) as pale yellow needles, mp
159–161 °C; IR (potassium bromide) cmÀ1: 3350, 3260 (NH); 1H
NMR (deuterochloroform): δ 1.17–2.30 (m, 10H, cyclohexyl-H),
2.55–3.04 (m, 3H, H5 and 1′), 3.30 (br t, 4H, J = 4.5 Hz, H3′
and 5′), 3.59–4.00 (m, 6H, H6, 2′, and 6′), 4.11 (br, 1H,
deuterium oxide exchangeable, NH), 6.68 (d, 1H, J = 2.0 Hz,
H8), 6.82 (dd, 1H, J = 9.0, 2.0 Hz, H10), 8.05 (d, 1H,
J = 9.0 Hz, H11); FAB-ms m/z 399 (MH+), 401 (MH+ + 2).
Anal. Calcd for C22H27ClN4O: C, 66.24; H, 6.82; N, 14.04.
Found: C, 65.91; H, 6.75; N, 13.98.
[1]benzazepine (10i).
methanol to give 10i (44%) as yellow prisms, mp 156–157 °C; IR
(potassium bromide) cmÀ1 3350 (NH); 1H NMR
(deuterochloroform): δ 3.24 (br t, 2H, J = 5.0 Hz, H5), 3.77 (br t,
2H, J = 5.0 Hz, H6), 4.04 (br, 1H, deuterium oxide exchangeable,
NH), 6.70 (d, 1H, J = 2.0 Hz, H8), 6.88 (dd, 1H, J = 9.0, 2.0 Hz,
H10), 8.17 (d, 1H, J = 9.0 Hz, H11); FAB-msm/z 334 (MH+), 336
(MH+ + 2). Anal. Calcd for C13H8Cl2F3N3: C, 46.73, H, 2.41; N,
12.58. Found: C, 46.96; H, 2.65; N, 12.61.
General procedure for the synthesis of 9-chloro-4-
(morpholin-4-yl)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine
(11a–i). A mixture of 10a–i (1.00 mmol) and morpholine (871 mg,
The product was recrystallized from
:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet