Polycyclic N-heterocyclic compounds 76: Synthesis and antiplatelet evaluation of 2,4-disubstituted 5,6-Dihydro[1]benzofuro[3′,2′:2,3] oxepino[4,5-d]pyrimidines

Article abstract of DOI:10.1002/jhet.1539

Reaction of several Vilsmeier reagents with 5-amino-2,3-dihydro[1] benzofuro[3,2-b]oxepin-4-carbonitrile gave tetracyclic 2-substituted 4-chloro-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d] pyrimidines. The structure of one of these, the 4-chloro-2-phenyl derivative, was confirmed by X-ray crystallography. Treatment of the 4-chloro derivatives with simple amines as nucleophile afforded 2-substituted 4-amino derivatives. A pentacyclic compound was also obtained by dehydrative ring closure. These products were evaluated for antiplatelet activity, and some showed potency comparable with that of aspirin.

Full text of DOI:10.1002/jhet.1539

May 2014
Polycyclic N-Heterocyclic Compounds 76:
Synthesis and Antiplatelet Evaluation of 2,4-Disubstituted
5,6-Dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]pyrimidines
661
a
b
b
b
c
d
*
Kensuke Okuda, Jun-ichi Takano, Takashi Hirota, Kenji Sasaki, Yuta Nishina, and Hiroyuki Ishida
aLaboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
bLaboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama
700-8530, Japan
cResearch Core for Interdisciplinary Sciences, Okayama University, Kita-ku, Okayama 700-8530, Japan
dDepartment of Chemistry, Faculty of Science, Okayama University, Kita-ku, Okayama 700-8530, Japan
*
E-mail: okuda@gifu-pu.ac.jp
Received July 31, 2011
DOI 10.1002/jhet.1539
Published online 2 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
O
R2
CN
O
O
N
N
NH2
R1
Reaction of several Vilsmeier reagents with 5-amino-2,3-dihydro[1]benzofuro[3,2-b]oxepin-4-carbonitrile
gave tetracyclic 2-substituted 4-chloro-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]pyrimidines. The
structure of one of these, the 4-chloro-2-phenyl derivative, was confirmed by X-ray crystallography. Treatment
of the 4-chloro derivatives with simple amines as nucleophile afforded 2-substituted 4-amino derivatives. A
pentacyclic compound was also obtained by dehydrative ring closure. These products were evaluated for
antiplatelet activity, and some showed potency comparable with that of aspirin.
J. Heterocyclic Chem., 51, 661 (2014).
INTRODUCTION
accessible by a dehydrative ring closure. Evaluation of
these compounds as antiplatelet agents revealed that certain
new derivatives have potency comparable with that of
aspirin as antiplatelet aggregation agents.
As part of our research to develop new medicinally active
compounds, we have been investigating the syntheses and
biological evaluation of heterocycles containing new ring
systems, which are accessible by rearrangement reactions.
During the course of this work, we have reported that
reaction of 3-(3-cyanopropoxy)[1]benzofuran-2-carbonitriles
(1) with potassium tert-butoxide gave both 5-amino-1,2-
dihydro[1]benzofuro[3,2-d]furo[2,3-b]pyridines (2, the
Smiles rearrangement product) and 5-amino-2,3-dihydro
[1]benzofuro[3,2-b]oxepin-4-carbonitriles (3, the Thorpe–
Ziegler reaction product), both of which were comprised
of new ring systems (Scheme 1) [1]. We have already
observed that polycyclic ring-fused pyrimidines with
substituents at the 2- and/or 4-position showed antiplatelet
aggregation activities [2–12]. As current antiplatelet drugs
are known to have certain detrimental side effects and
low efficacy, there continues to be much research directed
to the development of new drugs in this class [13–19]. We
thus have investigated additional compounds on the basis
of the antiplatelet activity shown by our fused pyrimidine
lead compounds. Here, we describe the preparation of
tetracyclic 2-substituted 4-chloro-5,6-dihydro[1]benzofuro
[3′,2′:2,3]oxepino[4,5-d]pyrimidines (4), readily accessible
from 3, and the further elaboration of 4 to 2,4-disubstituted
5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]pyrimidines
(5–9). Pentacyclic 1,2,4,5-tetrahydro[1]benzofuro[2′,3′:6,7]
oxepino[4,5-e]imidazo[1,2-c]pyrimidine (10) was also
RESULTS AND DISCUSSION
Chemistry.
In the first step of the synthesis, the
functionality present in compound 3 was exploited for the
construction of a pyrimidine ring leading to the new
heterocyclic ring system 5,6-dihydro[1]benzofuro[3′,2′:2,3]
oxepino[4,5-d]pyrimidines 4. Thus, reaction of 3 with Vilsmeier
reagents gave 4a–e in 80–90% yield (Scheme 2). Structures of
4a–e were determined on the basis of the disappearance of the
enamine and nitrile groups and the appearance of chlorine
atoms in their IR and MS spectra. In addition, the NMR spectra
and elemental analyses supported these structures. Moreover,
X-ray crystallographic analysis of the 4-chloro-2-phenyl
derivative (4d) confirmed the structure of compounds (4) as a
new ring system (Fig. 1) [20]. Crystallographic data and
experimental details are listed in Table 1.
The reactive 4-chlorine atom of compound 4 can be
readily displaced by nitrogen, oxygen, and sulfur nucleo-
philes. Simple amines were used as nucleophiles in this report
to prepare 4-substituted derivatives as potential pharmaceuti-
cally active compounds. Thus, compounds 4a–e were treated
with ammonia, methylamine, dimethylamine, ethylamine,
and 2-aminoethanol to give 5a–e (28–61%), 6a–e (76–94%),
© 2013 HeteroCorporation

662
K. Okuda, J. Takano, T. Hirota, K. Sasaki, Y. Nishina, and H. Ishida
Vol 51
Scheme 1. Substrate (1) with base and products (2 and 3).
O
O
O
tert-BuOK
CN
+
N
CN
CN
THF
O
O
O
NH2
NH2
1
2
3
Table 1
Crystal data and experimental details for 4d.
Scheme 2. Preparation of 4.
Empirical formula
Formula weight
Crystal system
Space group
a (Å)
C20H13ClN2O2
348.79
Monoclinic
P21/c
10.1183(6)
9.6213(3)
17.1413(7)
90
106.659(2)
90
1598.69(13)
4
b (Å)
c (Å)
a (ꢀ)
b (ꢀ)
g (ꢀ)
V (Å3)
Z
Dcalc (g cmÀ3
)
1.449
0.255
720
m (mmÀ1
F(000)
)
Crystal size (mm)
Temperature (K)
Radiation (Å)
θmax (ꢀ)
0.10 Â 0.30 Â 0.40
230
Mo Ka 0.71075
30.0
Dataset
À14 ≤ h ≤ 14
À13 ≤ k ≤ 13
À24 ≤ l ≤ 24
30 436
4649
3719
Total reflections
Independent reflections
Observed reflections [I > 2s(I)]
Rint
0.027
Number of reflections
Number of parameters
R[F2 > 2s(F2)]
4649
236
0.0462
0.1341
wR(F2)
S
1.06
Weighting scheme w
w = 1/[s2(F2o) + (0.0673P)2 + 0.3785P]
Δrmin (e Å 3)
P = (F2o + 2F2c)/3
À0.38
Δrmax (e Å 3)
0.39
Figure 1. ORTEP representation of 4d.
X-ray diffraction data were collected at 230 K by o scans on a Rigaku
RAPID II IP diffractometer. The structure was solved and refined by
SHLEXS97 and SHLEXL97 [21], respectively. H atoms were placed in
geometrically idealized positions (C–H = 0.94 or 0.98 Å) and allowed to
ride on their parent atoms, with Uiso(H) = 1.2Ueq(C). One methylene
group of the seven-membered ring was found to be disordered over two
positions in a difference Fourier map. The two site-occupancy factors
were refined to 0.423(4) and 0.577(4).
7a–e (71–97%), 8a–e (60–81%), and 9a–e (69–96%), res-
pectively (Scheme 3). Finally, the pentacyclic ring product
10, an analogue of 4, was prepared from 9a in 57% yield
through a ring closure reaction by the action of phosphoryl
chloride (Scheme 4). All derivatives 4–10 satisfy Lipinski’s
rule of five, and thus, they are expected to have drug-like prop-
erties [22].
Biology. With these derivatives in hand, the antiplatelet
aggregation activities were examined with the use of an
in vitro screening test. The inhibitory activities of compounds
4–10 at 2.5 mM with the use of DMF (final concentration
4.3%) as a cosolvent against platelet aggregation induced by
collagen (final concentration 14.3 mg/mL) was assayed to
demonstrate the possible therapeutic potential of these
compounds.
The inhibitory assay was executed by a turbidimetric
method developed by Born and Cross [23] with the use
of an aggregometer. The results are shown in Table 2.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis and Antiplatelet Evaluation of 2,4-Disubstituted
663
5,6-Dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]pyrimidines
Scheme 3. Preparation of 5–9.
O
O
O
NH2
NMe2
NHMe
O
O
O
N
N
N
N
N
N
R
R
R
5a R=H (51%)
7a R=H (97%)
6a R=H (76%)
5b R=Me (34%)
5c R=Et (61%)
5d R=Ph (28%)
7b R=Me (71%)
7c R=Et (84%)
7d R=Ph (73%)
6b R=Me (85%)
6c R=Et (94%)
6d R=Ph (82%)
5e R=p-Tolyl (44%)
7e R=p-Tolyl (76%)
6e R=p-Tolyl (81%)
N nucleophiles
4a-e
O
O
H
N
NHEt
OH
O
O
N
N
N
N
R
R
8a R=H (60%)
9a R=H (95%)
8b R=Me (79%)
8c R=Et (66%)
9b R=Me (80%)
9c R=Et (69%)
9d R=Ph (96%)
9e R=p-Tolyl (86%)
8d R=Ph (81%)
8e R=p-Tolyl (72%)
and group 2 (H and ethyl), their inhibitory mechanism
may be different. More detailed examination is needed to
clarify this point. On the basis of these results, we are
currently exploring development of additional derivatives
with antiplatelet aggregation activity.
Scheme 4. Preparation of 10.
EXPERIMENTAL
All melting points were determined on a Yanagimoto micro-
melting point apparatus and are uncorrected. Elemental analyses
were performed on a Yanagimoto MT-5 CHN Corder elemental
analyzer. The electron impact (EI)–mass, fast atom bombardment
(FAB)–mass (m-nitrobenzyl alcohol was used as the matrix), and
electron spray ionization (ESI)–mass spectra were obtained on a
VG70-SE mass spectrometer or a Micromass AutoSpec-OA-
Tof. The IR spectra were recorded on a Japan Spectroscopic
diffraction grating A-102 or FT/IR-200 spectrophotometer, and
frequencies are expressed in cmÀ1. The 1H NMR spectra were
recorded on a Varian VXR-200 instrument or a Hitachi R-1500
instrument with tetramethylsilane as an internal standard. Chemical
shifts are given in ppm (d) and J values in Hz, and the signals are
designated as follows: s, singlet; d, doublet; dd, double doublet; t,
triplet; q, quartet; br, broad; m, multiplet. Column chromatography
was performed on silica gel (IR-60-63-210-W, Daiso). TLC was
carried out on Kieselgel 60F254 (Merck) or silica gel 70FM
(Wako).
4-Chloro-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]
pyrimidine (4a). Enaminonitrile 3 [1] (1.50 g, 6.63 mmol) was
added to a solution of N,N-dimethylformamide (1.45 g, 19.8 mmol)
in phosphoryl chloride (10 mL) at pre-stirred 0 ꢀC for 1 h, and the
mixture was stirred at 80 ꢀC for an additional 1.5 h. After
evaporation of excess phosphoryl chloride in vacuo, ice water
(100 mL) was added to the residue, and the resulting solution was
neutralized with sodium bicarbonate. The yellow precipitation that
formed was filtered off and recrystallized from ethanol to give 4a
(1.50 g, 83%) as colorless needles, mp 219–221 ꢀC; 1H NMR
(deuterochloroform): d 3.43 (t, 2H, J = 4.1 Hz, H5), 4.55 (t, 2H,
J =4.1Hz, H6), 7.30–7.74 (m, 4H, H8, 9, 10, and 11), 8.90 (s, 1H,
Next, a detailed comparison of the inhibitory activity in
terms of IC50 of the compounds, which showed significant
difference (P < 0.01) at a final concentration of 25 mM with
that of aspirin (26.1 Æ 1.0%), was determined. Comparison
of the rate of inhibition of test compounds with that of
aspirin revealed that the substituted tetracyclic compounds
4, 7, and 8 showed bioactivity superior to aspirin. Among
them, 4d is the most potent. In the 2-phenyl series (4d–9d),
replacement of the 4-chlorine atom with an amino group
was invariably detrimental to activity. In contrast, substi-
tution with a 4-dimethylamino or 4-ethylamino moiety
enhanced activity with the combination of 2-H and 2-ethyl
moiety and 7a, 7c, 8a, and 8c having similar potency.
Taken together, these results point to a possible differen-
tiation of mechanism of action that can divide the series of
compounds into two groups. Considering the 4-position,
only compounds 4a–e have a hydrophobic substituent
(Cl). The other compounds tested (series 5–9) have hydro-
gen donor and/or acceptor substituents. In the first series,
the potent 4d reveals that a phenyl group is favored in
the 2-position. In contrast, the active members of the
second group (7a, 7c, 8a, and 8c) show that H and ethyl
are favorable for activity. As the allowable substituents in
the 2-position differ greatly between group 1 (phenyl)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

664
K. Okuda, J. Takano, T. Hirota, K. Sasaki, Y. Nishina, and H. Ishida
Vol 51
Table 2
Effects of 4–10 on rabbit platelet aggregation in vitro induced by collagen.
Compound
% inhibitiona
IC50 (mM)b
Compound
% inhibitiona
IC50 (mM)b
4a
4b
4c
4d
4e
6a
6b
6c
6d
6e
8a
8b
8c
8d
8e
10
19.6 Æ 2.8
18.1 Æ 0.3
20.1 Æ 1.2
45.6 Æ 3.8*
5.7 Æ 3.7
–
–
–
5a
5b
5c
5d
5e
7a
7b
7c
7d
7e
9a
9b
9c
9d
9e
Aspirin
14.3 Æ 6.8
14.4 Æ 6.1
19.5 Æ 1.1
25.7 Æ 1.1
0.95 Æ 0.05
46.5 Æ 2.0*
12.4 Æ 1.2
52.6 Æ 1.0*
15.9 Æ 4.1
10.6 Æ 7.5
22.9 Æ 0.5
24.4 Æ 5.5
19.2 Æ 8.7
8.0 Æ 1.3
–
–
–
–
2.3 (1.8–2.8)
–
–
–
–
–
–
–
25.7 Æ 1.7
3.0 Æ 2.2
2.9 (2.3–4.5)
–
15.1 Æ 2.9
3.8 Æ 2.8
2.4 (1.3–4.1)
–
–
–
–
–
–
–
4.8 Æ 3.8
46.6 Æ 1.0*
8.7 Æ 4.2
2.6 (1.8–7.1)
–
45.2 Æ 4.5*
16.4 Æ 1.3
11.6 Æ 2.0
8.7 Æ 1.3
2.9 (2.1–3.6)
–
–
–
9.5 Æ 1.1
26.1 Æ 1.0
6.5 (5.3–8.8)
aData represent % inhibition of the vehicle control group (mean Æ SE of at least three experiments) at a final concentration of 2.5 mM.
bExperiments were repeated at least three times each at final concentrations of 2.5, 5.0, and 7.5 mM (in the case of aspirin, final concentrations were 2.5,
5.0, and 10.0 mM). Figures in parentheses represent 95% confidence limits of IC50
*Significant difference from aspirin at P < 0.01.
.
H2); FAB–ms: m/z 273 (MH+). Anal. Calcd for C14H9ClN2O2: C,
61.66; H, 3.33; N, 10.27. Found C, 61.81; H, 3.54; N, 10.22.
4-Chloro-2-methyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
evaporated in vacuo. The residue was recrystallized from
acetonitrile to give 4d (370mg, 80%) as colorless needles, mp
218–221 ꢀC; 1H NMR (deuterochloroform): d 3.42 (t, 2H,
J = 4.2Hz, H5), 4.57 (t, 2H, J = 4.2 Hz, H6), 7.30 (t, 1H,
J = 7.8Hz, H9), 7.44–7.56 (m, 4H, H10 and H3′, 4′, 5′), 7.61 (br
d, 1H, J = 8.2 Hz, H11), 7.69 (br d, 1H, J = 7.8 Hz, H8), 8.00–8.23
(m, 2H, H2′ and 6′); FAB–ms: m/z 349 (MH+). Anal. Calcd for
C20H13ClN2O2: C, 68.87; H, 3.76; N, 8.03. Found: C, 68. 83; H,
3.93; N, 8.04.
Crystals for X-ray analysis were grown from an acetonitrile–
water (ca. 9:1) solution by slow evaporation. This analytical
sample was dried and subjected to X-ray crystallographic analysis
described in Table 1.
[4,5-d]pyrimidine (4b).
Using the same procedure described
earlier for the preparation of 4a, reaction of 3 (500 mg, 2.21 mmol)
with the Vilsmeier reagent [prepared from a stirred mixture of N,
N-dimethylacetamide (578 mg, 6.63mmol) and phosphoryl
chloride (10mL) at 0 ꢀC for 1 h] at 80 ꢀC for 1.5 h gave 4b
(570mg, 90%), recrystallized from acetonitrile as colorless
prisms, mp 225–227 ꢀC; 1H NMR (deuterochloroform): d 2.81
(s, 3H, CH3), 3.41 (t, 2H, J = 4.0 Hz, H5), 4.54 (t, 2H, J = 4.0 Hz,
H6), 7.23–7.70 (m, 4H, H8, 9, 10, and 11); FAB–ms: m/z 287
(MH+). Anal. Calcd for C15H11ClN2O2: C, 62.84; H, 3.87; N,
9.77. Found: C, 62.92; H, 3.97, N, 9.90.
4-Chloro-2-ethyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5-d]pyrimidine (4c). Using the same procedure, reaction of 3
(300 mg, 1.33 mmol) with the Vilsmeier reagent [prepared from a
stirred mixture of N,N-dimethylpropionamide (402 mg, 3.97 mmol)
and phosphoryl chloride (10 mL) at 0 ꢀC for 1h] at 80ꢀC for 1.5h
gave 4c (330 mg, 83%), recrystallized from acetonitrile as colorless
needles, mp 111–113 ꢀC; 1H NMR (deuterochloroform): d 1.43
(t, 3H, J =7.6Hz, CH3), 3.05 (q, 2H, J=7.6Hz, CH2CH3), 3.41
(t, 2H, J= 4.2 Hz, H5), 4.54 (t, 2H, J= 4.2Hz, H6), 7.23–7.72
(m, 4H, H8, 9, 10, and 11); FAB–ms: m/z301 (MH+). Anal. Calcd
for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31. Found: C, 63.58,
H, 4.43; N, 9.17.
4-Chloro-2-(4-methylphenyl)-5,6-dihydro[1]benzofuro
[3′,2′:2,3]oxepino[4,5-d]pyrimidine (4e). To a solution of N,N,4-
trimethylbenzamide (2.16 g, 13.2 mmol) in phosphoryl chloride
(10 mL) pre-stirred at 0 ꢀC for 1 h was added 3 (1.00 g, 4.42mmol),
and the mixture was stirred at 80 ꢀC for an additional 1.5 h. After
evaporation of excess phosphoryl chloride in vacuo, ice water
(100 mL) was added to the residue, and the resulting solution was
neutralized with sodium bicarbonate. The aqueous mixture was
extracted with ethyl acetate (50 mL Â 5); the combined organic
layer was washed with sat. brine, dried over anhydrous magnesium
sulfate, and evaporated in vacuo. The residue was recrystallized
from ethyl acetate to give 4e (1.44 g, 90%) as colorless needles, mp
1
225–229 ꢀC; H NMR (deuterochloroform): d 2.44 (s, 3H, CH3),
4-Chloro-2-phenyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5-d]pyrimidine (4d). To a solution of N,N-dimethylbenzamide
(594 mg, 3.98 mmol) in phosphoryl chloride (10 mL) pre-stirred at
0 ꢀC for 1 h was added 3 (300 mg, 1.33 mmol), and the mixture was
then stirred at 80 ꢀC for an additional 1.5 h. After evaporation of
excess phosphoryl chloride in vacuo, ice water (100 mL) was
added to the residue, and the resulting solution was neutralized
with sodium bicarbonate. The aqueous mixture was extracted with
ethyl acetate (50 mL Â 5); the combined organic layer was washed
with sat. brine, dried over anhydrous magnesium sulfate, and
3.45 (t, 2H, J=4.2Hz, H5), 4.57 (t, 2H, J=4.2Hz, H6), 7.22–7.71
(m, 6H, H8, 9, 10, 11 and H3′, 5′), 8.45 (br d, 2H, J=8.3Hz, H2′
and 6′); FAB–ms: m/z363 (MH+). Anal. Calcd for C21H15ClN2O2:
C, 69.52; H, 4.17; N, 7.72. Found: C, 69.63; H, 4.28; N, 7.63.
General procedure for the preparation of 2-substituted
4-amino-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]
pyrimidines (5a–e). Liquid ammonia (50mL) was added to a
solution of 4a–e (200 mg) in dry 1,4-dioxane (5.0mL), and the
mixture was heated in a metal cylinder at 110ꢀC for 2 days under
40kg/cm2. After removal of ammonia and solvent, ice water
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Synthesis and Antiplatelet Evaluation of 2,4-Disubstituted
665
5,6-Dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]pyrimidines
(50 mL) was added to the residue. In the case of 5a, the mixture was
extracted with ethyl acetate (50 mLÂ 3). The combined organic
layer was washed with 1 N aq. sodium hydroxide, sat. brine, dried
over anhydrous sodium sulfate, and evaporated in vacuo. The
residue was recrystallized from benzene. In the case of 5b–e, the
resulting precipitate was filtered off after addition of ice water,
then purified with column chromatography followed by
recrystallization from a suitable solvent, as described in the
succeeding texts.
EI–ms: m/z 343 (M+). Anal. Calcd for C21H17N3O2: C, 73.45; H,
4.99; N, 12.24. Found: C, 73.34; H, 5.09; N, 11.96.
General procedure for the preparation of 2-substituted
4-methylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5-d]pyrimidines (6a–e).
Forty percent methanolic
methylamine (10 mL) was added to a solution of 4a–e (4a:
100 mg, 4b–e: 200 mg) in tetrahydrofuran (THF, 2.0 mL), and
the reaction was then stirred at room temperature until
disappearance of starting material was shown by TLC analysis.
After evaporation of the reaction mixture, ice water (50 mL) was
added to the residue. The precipitated solid was collected on a
filter and recrystallized from a suitable solvent, as described in the
succeeding texts.
4-Amino-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]
pyrimidine (5a).
Recrystallization from benzene gave 5a (51%)
as colorless needles, mp 135–138 ꢀC; IR (potassium bromide): 3400,
3180 (NH) cmÀ1; H NMR (DMSO-d6): d 3.04 (t, 2H, J=4.0Hz,
1
H5), 4.47 (t, 2H, J= 4.0 Hz, H6), 6.84 (br s, 2H, deuterium oxide
exchangeable, NH2), 7.26–7.70 (m, 4H, H8, 9, 10, and 11), 8.33
(s, 1H, H2); FAB–ms: m/z254 (MH+). Anal. Calcd for
C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.12; H,
4.63; N, 16.88.
4-Methylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5-d]pyrimidine (6a).
Starting material was consumed after
stirring for 2.5 h. After workup as described earlier, the precipitate
was recrystallized from acetonitrile to give 6a (76%) as colorless
plates, mp 274–275 ꢀC; IR (potassium bromide): 3310 (NH)
cmÀ1; 1H NMR (DMSO-d6): d 2.88 (d, 3H, J = 4.0 Hz, changed to
singlet with the addition of deuterium oxide, CH3), 3.02 (t, 2H,
J = 4.0 Hz, H5), 4.46 (t, 2H, J = 4.0Hz, H6), 7.18 (br d, 1H,
J = 4.0 Hz, deuterium oxide exchangeable, NH), 7.30, 7.75 (each
br dd, each 1H, J = 8.0, 7.0 Hz, H 9 and 10), 7.58–7.66 (m, 2H,
H8 and 11), 8.43 (s, 1H, H2); FAB–ms: m/z 268 (MH+). Anal.
Calcd for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72. Found: C,
4-Amino-2-methyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5-d]pyrimidine (5b).
The eluate of benzene–ethyl acetate
(1:2) was evaporated in vacuo, and the residue was recrystallized
from ethanol to give 5b (34%) as colorless prisms, mp >300 ꢀC;
IR (potassium bromide): 3340, 3150 (NH) cmÀ1 1H NMR
;
(deuterochloroform): d 2.37 (s, 3H, CH3), 2.99 (t, 2H, J = 4.0 Hz,
H5), 4.43 (t, 2H, J = 4.0 Hz, H6), 6.74 (br s, 2H, deuterium oxide
exchangeable, NH2), 7.25–7.48 (m, 2H, H9 and 10), 7.62 (br d,
2H, J = 8.9 Hz, H8 and 11); FAB–ms: m/z 268 (MH+). Anal.
Calcd for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72. Found: C,
67.02; H, 5.05; N, 15.56.
4-Amino-2-ethyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5-d]pyrimidine (5c). The eluate of benzene–ethyl acetate (1:3
to 1:5) was evaporated in vacuo, and the residue was recrystallized
from acetonitrile to give 5c (61%) as colorless plates, mp 267–
271 ꢀC; IR (potassium bromide): 3420, 3310, 3200 (NH) cmÀ1; 1H
NMR (deuterochloroform): d 1.38 (t, 3H, J =8.0Hz, CH3), 2.89
(q, 2H, J =8.0Hz, CH2CH3), 2.92 (t, 2H, J= 4.0Hz, H5), 4.51
(t, 2H, J= 4.0 Hz, H6), 4.86 (br s, 2H, deuterium oxide
exchangeable, NH2), 7.21–7.45 (m, 2H, H9 and 10), 7.58, 7.62
(each br d, each 1H, J= 7.0, 8.0 Hz, H8 and 11); FAB–ms: m/z 282
(MH+). Anal. Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94.
Found: C, 68.48, H, 5.41; N, 14.93.
67.58; H, 5.09; N, 15.68.
2-Methyl-4-methylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]
oxepino[4,5-d]pyrimidine (6b). Starting material was consumed
after stirring for 7 h, and the precipitated product was recrystallized
from acetonitrile to give 6b (85%) as colorless prisms, mp 248–
250 ꢀC; IR (potassium bromide): 3300, 3260 (NH) cmÀ1; 1H NMR
(deuterochloroform) d 2.67 (s, 3H, CH3), 2.91 (t, 2H, J=4.0Hz,
H5), 3.09 (d, 3H, J= 5.0 Hz, changed to singlet with the addition of
deuterium oxide, NHCH3), 4.49 (t, 2H, J=4.0Hz, H6), 4.72 (br,
1H, deuterium oxide exchangeable, NH), 7.20–7.43 (m, 2H, H9
and 10), 7.55–7.65 (m, 2H, H8 and 11); ESI–ms: m/z 282 (MH+).
Anal. Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found:
C, 68.33; H, 5.40; N, 14.89.
2-Ethyl-4-methylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]
oxepino[4,5-d]pyrimidine (6c).
The reaction was stirred
4-Amino-2-phenyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
for 24h, and the precipitated product was recrystallized from
benzene to give 6c (94%) as colorless needles, mp 233–234 ꢀC;
[4,5-d]pyrimidine (5d).
The eluate of benzene–ethyl acetate
IR (potassium bromide): 3280 (NH) cmÀ1
;
1H NMR
(1:1) was evaporated in vacuo, and the residue was recrystallized
from benzene to give 5d (28%) as a white powder, mp 236–
(deuterochloroform): d 1.40 (t, 3H, J = 8.0 Hz, CH2CH3), 2.92
(t, 2H, J = 4.0 Hz, H5), 2.94 (q, 2H, J = 8.0 Hz, CH2CH3), 3.10
(d, 3H, J = 5.0 Hz, changed to singlet with the addition of
deuterium oxide, NHCH3), 4.48 (t, 2H, J = 4.0 Hz, H6), 4.72
(br, 1H, deuterium oxide exchangeable, NH), 7.18–7.72 (m, 2H,
H9 and 10), 7.55–7.72 (m, 2H, H8 and 11); FAB–ms: m/z 296
(MH+). Anal. Calcd for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23.
Found: C, 68.84; H, 5.89; N, 14.27.
238 ꢀC; IR (potassium bromide): 3470, 3340, 3210 (NH) cmÀ1
;
1H NMR (deuterochloroform): d 3.04 (t, 2H, J = 4.0 Hz, H5),
4.55 (t, 2H, J = 4.0 Hz, H6), 4.92 (s, 2H, deuterium oxide
exchangeable, NH2), 7.20–7.68 (m, 7H, H8, 9, 10, 11 and H3′,
4′, 5′), 8.43–8.53 (m, 2H, H2′ and 6′); FAB–ms: m/z 330 (MH+).
Anal. Calcd for C20H15N3O2: C, 72.94; H, 4.59; N, 12.76.
Found: C, 72.91; H, 4.77; N, 12.86.
4-Amino-2-(4-methylphenyl)-5,6-dihydro[1]benzofuro
4-Methylamino-2-phenyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]
oxepino[4,5-d]pyrimidine (6d). The reaction was stirred for 24h,
and the precipitated product was recrystallized from acetonitrile to
give 6d (82%) as colorless plates, mp 253–255 ꢀC; IR (potassium
[3′,2′:2,3]oxepino[4,5-d]pyrimidine (5e).
The eluate of
n-hexane-ethyl acetate (3:1) was evaporated in vacuo, and the
residue was recrystallized from benzene to give 5e (44%) as
colorless needles, mp 255–258 ꢀC; IR (potassium bromide): 3470,
bromide): 3450 (NH) cmÀ1 1H NMR (deuterochloroform):
;
3340, 3250 (NH) cmÀ1 1H NMR (deuterochloroform): d 2.42
;
d 2.98 (t, 2H, J = 4.0 Hz, H5), 3.22 (d, 3H, J = 5.0 Hz, changed to
singlet with the addition of deuterium oxide, CH3), 4.53 (t, 2H,
J = 4.0Hz, H6), 4.76 (br, 1H, deuterium oxide exchangeable,
NH), 7.22–7.65 (m, 7H, H8, 9, 10, 11 and H3′, 4′, 5′), 8.49–8.61
(m, 2H, H2′ and 6′); FAB–ms: m/z 344 (MH+). Anal. Calcd for
(s, 3H, CH3), 3.03 (t, 2H, J = 4.2 Hz, H5), 4.54 (t, 2H, J = 4.2 Hz,
H6), 4.91 (s, 2H, deuterium oxide exchangeable, NH2), 7.22–7.46
(m, 4H, H8, 9 and H3′, 5′), 7.60, 7.64 (each d, each 1H, J = 8.1,
8.3 Hz, H8 and 11), 8.38 (br d, 2H, J = 8.1 Hz, H2′ and 6′);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

666
K. Okuda, J. Takano, T. Hirota, K. Sasaki, Y. Nishina, and H. Ishida
Vol 51
C21H17N3O2: C, 73.45; H, 4.99; N, 12.24. Found: C, 73.16; H,
5.15; N, 12.13.
4-Methylamino-2-(4-methylphenyl)-5,6-dihydro[1]benzofuro
7d (73%) as colorless needles, mp 183–185 ꢀC; 1H NMR
(deuterochloroform): d 3.07 (s, 6H, 2Â NCH3), 3.23 (t, 2H,
J = 4.0Hz, H5), 4.51 (t, 2H, J = 4.0 Hz, H6), 7.20–7.68 (m, 7H,
H8, 9, 10, 11 and H3′, 4′, 5′), 8.52–8.63 (m, 2H, H2′ and 6′);
FAB–ms: m/z 358 (MH+). Anal. Calcd for C22H19N3O2: C, 73.93;
H, 5.36; N, 11.76. Found: C, 74.06; H, 5.51; N, 11.83.
[3′,2′:2,3]oxepino[4,5-d]pyrimidine (6e).
The reaction was
stirred for 96 h, and the precipitated product was recrystallized
from acetonitrile to give 6e (81%) as colorless prisms, mp
236–237 ꢀC; IR (potassium bromide): 3430 (NH) cmÀ1
;
1H
4-Dimethylamino-2-(4-methylphenyl)-5,6-dihydro[1]benzofuro
NMR (deuterochloroform): d 2.43 (s, 3H, 4′-CH3), 2.97 (t, 2H,
J = 4.0 Hz, H5), 3.20 (d, 3H, J = 5.0 Hz, changed to singlet with
the addition of deuterium oxide, NHCH3), 4.52 (t, 2H,
J = 4.0 Hz, H6), 4.75 (br, 1H, deuterium oxide exchangeable,
NH), 7.22–7.45 (m, 4H, H9, 10 and H3′, 5′), 7.56–7.65 (m, 2H,
H8 and 11), 8.47 (d, 2H, J=8.0Hz, H2′ and 6′); FAB–ms: m/z358
(MH+). Anal. Calcd for C22H19N3O2: C, 73.93; H, 5.36; N, 11.76.
Found: 74.19; H, 5.53; N, 11.70.
General procedure for the preparation of 2-substituted
4-dimethylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5-d]pyrimidines (7a–e). Fifty percent aqueous dimethylamine
(10 mL) was added to a solution of 4a–e (4a: 120 mg, 4b–e:
200 mg) in THF (2.0 mL), and the reaction was stirred at room
temperature for the times required for completion of the reaction, as
determined by TLC. After evaporation of solvent in vacuo, ice
water was added to the residue. In the case of 7a, 7d, and 7e, the
precipitated solid was collected on a filter and recrystallized from a
suitable solvent. In the case of 7b and 7c, the mixture was extracted
with ethyl acetate (50 mL Â 3). The combined organic layer was
washed with sat. brine, dried over anhydrous magnesium sulfate,
and evaporated in vacuo. The residue was recrystallized from a
suitable solvent.
[3′,2′:2,3]oxepino[4,5-d]pyrimidine (7e).
The reaction was
stirred for 24 h, and the product was recrystallized from acetonitrile
1
to give 7e (76%) as colorless needles, mp 184–187 ꢀC; H NMR
(deuterochloroform): d 2.43 (s, 3H, 4′-CH3), 3.06 (s, 6H, 2Â
NCH3), 3.22 (t, 2H, J=4.0Hz, H5), 4.50 (t, 2H, J=4.0Hz, H6),
7.20–7.46 (m, 4H, H9, 10 and H3′, 5′), 7.60, 7.64 (each d, each
1H, each J= 8.0 Hz, H8 and 11), 8.45 (d, 2H, J=8.0Hz, H2′ and
6′); FAB–ms: m/z372 (MH+). Anal. Calcd C23H21N3O2: C, 74.37;
H, 5.70; N, 11.31. Found: C, 74.48; H, 5.65; N, 10.93.
General procedure for the preparation of 2-substituted
4-ethylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5:d]pyrimidines (8a–e).
Seventy percent aqueous
ethylamine (10 mL) was added to a solution of 4 (4a: 100mg, 4b–e:
200 mg) in 2.0 mL of solvent (4a–c, e: THF, 4d: 1,4-dioxane), and
the reaction was stirred at the temperature and time described in the
succeeding texts for the specific examples. After disappearance of
starting material as judged by TLC analysis, the mixture was
evaporated in vacuo. Ice water (50 mL) was added to the residue,
and the precipitated solid was collected by filtration and
recrystallized from a suitable solvent.
4-Ethylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5-d]pyrimidine (8a).
The reaction was stirred at room
4-Dimethylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]oxepino
[4,5-d]pyrimidine (7a). The reaction was stirred for 1 h, and the
product was recrystallized from n-hexane to give 7a (97%) as
temperature for 7.5 h, and the product was recrystallized
from benzene to give 8a (60%) as colorless prisÀm1s, mp 268–
270 ꢀC; IR (potassium bromide): 3260 (NH) cm
;
1H NMR
1
colorless plates, mp 182–183 ꢀC; H NMR (deuterochloroform):
(deterochloroform): d 1.03 (t, 3H, J = 7.0 Hz, CH3), 2.94 (t, 2H,
J = 4.0Hz, H5), 3.58 (qd, 2H, J = 7.0, 5.0 Hz, changed to quartet
with the addition of deuterium oxide, NCH2CH3), 4.52 (t, 2H,
J = 4.0Hz, H6), 4.75 (br t, 1H, J = 5.0 Hz, deuterium oxide
exchangeable, NH), 7.25, 7.40 (each br dd, each 1H, each J = 7.0,
8.0 Hz, H9 and 10), 7.57, 7.62 (each br d, each J = 8.0 Hz, H8 and
11), 8.68 (s, 1H, H2); FAB–ms: m/z 282 (MH+). Anal. Calcd for
C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.43; H,
5.41; N, 14.89.
d 3.00 (s, 6H, 2Â NCH3), 3.19 (t, 2H, J = 4.0 Hz, H5), 4.48 (t,
2H, J = 4.0 Hz, H6), 7.26, 7.40 (each br dd, each 1H, J = 7.0,
8.0 Hz, H9 and 10), 7.57, 7.63 (each br d, each 1H, J = 8.0 Hz, H8
and 11), 8.74 (s, 1H, H2); FAB–ms: m/z 282 (MH+). Anal. Calcd
for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.61;
H, 5.46; N, 14.97.
2-Methyl-4-dimethylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]
oxepino[4,5-d]pyrimidine (7b).
The reaction was stirred for
1 h, and the product was recrystallized from n-hexane to give
7b (71%) as colorless needles, mp 157–159 ꢀC; 1H NMR
(deuterochloroform): d 2.69 (s, 3H, 2-CH3), 2.97 (s, 6H, 2Â
NCH3), 3.16 (t, 2H, J = 4.0 Hz, H5), 4.46 (t, 2H, J = 4.0 Hz,
H6), 7.25, 7.39 (each br dd, each 1H, J = 6.9, 8.3 Hz, H9 and
10), 7.58, 7.62 (each br d, each 1H, J = 8.3, 6.9 Hz, H8 and 11);
ESI–ms: m/z 296 (MH+). Anal. Calcd for C17H17N3O2: C,
69.14; H, 5.80; N, 14.23. Found: C, 69.07; H, 5.79; N, 13.96.
2-Ethyl-4-dimethylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]
4-Ethylamino-2-methyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]
oxepino[4,5-d]pyrimidine (8b).
The reaction was stirred at
room temperature for 18h, and the product was recrystallized
from acetonitrile to give 8b (79%) as colorless needles, mp 269–
272 ꢀC; IR (potassium bromide): 3280 (NH) cmÀ1 1H NMR
;
(deuterochloroform): d 1.29 (t, 3H, J = 7.0 Hz, CH2CH3), 2.65 (s,
3H, 2-CH3), 2.90 (t, 2H, J = 4.0 Hz, H5), 3.58 (qd, 2H, J = 7.0,
5.0 Hz, changed to quartet with the addition of deuterium oxide,
NCH2CH3), 4.49 (t, 2H, J = 4.0 Hz, H6), 4.57 (br s, 1H, deuterium
oxide exchangeable, NH), 7.20–7.32 (m, 1H, H9), 7.38 (br dd,
1H, J = 8,0, 7.0Hz, H10), 7.55–7.65 (m, 2H, H8 and 11); ESI–
ms: m/z 296 (MH+). Anal. Calcd for C17H17N3O2: C, 69.14; H,
5.80; N, 14.23. Found: C, 69.31; H, 5.80; N, 14.22.
oxepino[4,5-d]pyrimidine (7c).
The reaction was stirred for
6 h, and the product was recrystallized from n-hexane to give 7c
(84%) as colorless prisms, mp 100–101 ꢀC; 1H NMR
(deuterochloroform): d 1.39 (t, 3H, J = 7.6 Hz, CH2CH3), 2.98 (s,
6H, 2Â NCH3), 3.00 (q, 2H, J = 7.6Hz, CH2CH3), 3.15 (t, 2H,
J = 4.2 Hz, H5), 4.46 (t, 2H, J = 4.2 Hz, H6), 7.20–7.23 (m, 2H,
H9 and 10), 7.56–7.64 (m, 2H, H8 and 11); FAB–ms: m/z 310
(MH+). Anal. Calcd for C18H19N3O2: C, 69.88; H, 6.19; N, 13.58.
Found: C, 70.06; H, 6.20; N, 13.86.
2-Ethyl-4-ethylamino-5,6-dihydro[1]benzofuro[3′,2′:2,3]
oxepino[4,5-d]pyrimidine (8c).
The reaction was stirred at
room temperature for 70 h, and the product was recrystallized
from acetonitrile to give 8c (66%) as colorless prisms, mp 217–
220 ꢀC; IR (potassium bromide): 3270 (NH) cmÀ1 1H NMR
;
(deuterochloroform): d 1.29 (t, 3H, J= 7.2Hz, NCH2CH3), 1.38
(t, 3H, J = 7.6Hz, 2-CH2CH3), 2.90 (t, 2H, J= 4.2Hz, H5), 2.92
(q, 2H, J= 7.6Hz, 2-CH2CH3), 3.59 (qd, 2H, J =7.2, 5.3 Hz,
4-Dimethylamino-2-phenyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]
oxepino[4,5-d]pyrimidine (7d).
The reaction was stirred for
2.5 h, and the product was recrystallized from acetonitrile to give
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis and Antiplatelet Evaluation of 2,4-Disubstituted
667
5,6-Dihydro[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]pyrimidines
change to quartet with the addition of deuterium oxide, NCH2CH3),
4.49 (t, 2H, J= 4.2Hz, H6), 4.61 (br t, 1H, J = 5.3 Hz, deuterium
oxide exchangeable, NH), 7.18–7.28 (m, 1H, H9), 7.37 (br dd,
1H, J =8.5, 7.0Hz, H10), 7.55–7.62 (m, 2H, H8 and 11); FAB–
and 11); FAB–ms: m/z 312 (MH+). Anal. Calcd for C17H17N3O3:
C, 65.58; H, 5.50; N, 13.50. Found: C, 65.58; H, 5.53; N, 13.59.
2-Ethyl-4-(2-hydroxyethylamino)-5,6-dihydro[1]benzofuro
[3′,2′:2,3]oxepino[4,5-d]pyrimidine (9c).
The reaction was
ms:
m/z 310 (MH+). Anal. Calcd for C18H19N3O2: C, 69.88;
refluxed for 2 h to produce 9c (69%) as pale yellow needles, mp
196–197 ꢀC; IR (potassium bromide): 3310, 3150 (NH, OH)
H, 6.19; N, 13.58. Found: C, 69.95; H, 6.25; N, 13.67.
4-Ethylamino-2-phenyl-5,6-dihydro[1]benzofuro[3′,2′:2,3]
cmÀ1 1H NMR (deuterochloroform): d 1.38 (t, 3H, J=8.0Hz,
;
oxepino[4,5-d]pyrimidine (8d).
The reaction was stirred at
CH3), 2.92 (q, 2H, J=8.0Hz, CH2CH3), 2.94 (t, 2H, J=4.0Hz,
H5), 3.62 (t, 1H, J = 5.0 Hz, deuterium oxide exchangeable, NH or
OH), 3.68–3.90 (m, 4H, NCH2CH2O), 4.50 (t, 2H, J=4.0 Hz, H6),
5.26 (br t, 1H, J= 5.0 Hz, deuterium oxide exchangeable, NH or
OH), 7.20–7.45 (m, 2H, H9 and 10), 7.57, 7.61 (each d, each 1H,
each J= 8.0 Hz, H8 and 11); FAB–ms: m/z 326 (MH+). Anal.
Calcd for C18H19N3O3: C, 66.45; H, 5.89; N, 12.91. Found: C,
66.49; H, 5.91; N, 13.14.
80 ꢀC for 8.5 h and the product was recrystallized from acetonitrile
to give 8d (81%) as colorless plates, mp 244–247 ꢀC; IR (potassium
1
bromide): 3460 (NH) cmÀ1; H NMR (deuterochloroform): d 1.36
(t, 3H, J=7.0Hz, CH3), 2.98 (t, 2H, J= 4.0 Hz, H5), 3.72 (m, 2H,
changed to quartet with the addition of deuterium oxide, NCH2CH3),
4.54 (t, 2H, J= 4.0 Hz, H6), 4.69 (br t, 1H, J= 6.0 Hz, deuterium
oxide exchangeable, NH), 7.15–7.66 (m, 7H, H8, 9, 10, 11 and H3′,
4′, 5′), 8.49–8.61 (m, 2H, H2′ and 6′); FAB–ms: m/z358 (MH+).
Anal. Calcd for C22H19N3O2: C, 73.93; H, 5.36; N, 11.76. Found:
C, 73.99; H, 5.48; N, 12.05.
4-(2-Hydroxyethylamino)-2-phenyl-5,6-dihydro[1]benzofuro
[3′,2′:2,3]oxepino[4,5-d]pyrimidine (9d).
The reaction was
refluxed for 6 h to produce 9d (96%) as pale yellow needles, mp
228–229 ꢀC; IR (potassium bromide): 3400, 3310 (NH, OH)
cmÀ1 1H NMR (deuterochloroform): d 3.00 (t, 2H, J = 4.0 Hz,
;
4-Ethylamino-2-(4-methylphenyl)-5,6-dihydro[1]benzofuro
[3′,2′:2,3]oxepino[4,5-d]pyrimidine (8e).
The reaction was
H5), 3.51 (br s, 1H, deuterium oxide exchangeable, NH or OH),
3.80–3.98 (m, 4H, NCH2CH2O), 4.54 (t, 2H, J = 4.0 Hz, H6), 5.24
(t, 1H, J= 5.0 Hz, deuterium oxide exchangeable, NH or OH),
7.20–7.68 (m, 7H, H8, 9, 10, 11 and H3′, 4′, 5′), 8.44–8.53 (m,
2H, H2′ and 6′); FAB–ms: m/z 374 (MH+). Anal. Calcd for
C22H19N3O3: 70.76; H, 5.13; N, 11.25. Found: C, 70.98; H, 5.29;
stirred at 60 ꢀC for 24 h, and the product was recrystallized from
cyclohexane to give 8e (72%) as colorless platÀes1, mp 208–
211 ꢀC; IR (potassium bromide): 3460 (NH) cm
;
1H NMR
(deuterochloroform): d 1.35 (t, 3H, J = 7.0Hz, CH2CH3), 2.42
(s, 3H, 4′-CH3), 2.96 (t, 2H, J=4.0Hz, H5), 3.63–3.79 (m, 2H,
changed to quartet with the addition of deuterium oxide, NCH2CH3),
4.53 (t, 2H, J= 4.0 Hz, H6), 4.65 (br t, 1H, J= 5.0 Hz, deuterium
oxide exchangeable, NH), 7.21–7.44 (m, 4H, H9, 10 and H3′, 5′),
7.57–7.64 (m, 2H, H8 and 11), 8.45 (br d, 2H, J=8.0Hz, H2′ and
6′); FAB–ms: m/z372 (MH+). Anal. Calcd for C23H21N3O2: 74.37;
H, 5.70; N, 11.31. Found: C, 74.52; H, 5.70; N, 10.93.
N, 11.33.
4-(2-Hydroxyethylamino)-2-(4-methylphenyl)-5,6-dihydro
[1]benzofuro[3′,2′:2,3]oxepino[4,5-d]pyrimidine (9e). The
reaction was refluxed for 21h to produce 9e (86%) as colorless
plates, mp 241–244 ꢀC; IR (potassium bromide): 3470, 3380 (NH,
1
OH) cmÀ1: H NMR (deuterochloroform): d 2.42 (s, 3H, CH3),
2.99 (t, 2H, J = 4.0 Hz, H5), 3.63 (br s, 1H, deuterium oxide
exchangeable, NH or OH), 3.80–3.99 (m, 4H, NCH2CH2O), 4.53
(t, 2H, J = 4.0Hz, H6), 5.22 (t, 1H, J = 5.0 Hz, deuterium oxide
exchangeable, NH or OH), 7.21–7.46 (m, 4H, H9, 10 and H3′,
5′), 7.59, 7.63 (each d, each 1H, each J = 8.0 Hz, H8 and 11), 8.38
(d, 2H, J = 8.0 Hz, H2′ and 6′); FAB–ms: m/z 388 (MH+). Anal.
Calcd for C23H21N3O3: C, 71.30; H, 5.46; N, 10.85. Found: C,
71.20; H, 5.57; N, 10.95.
General procedure for the preparation of 2-substituted
4-(2-hydroxyethylamino)-5,6-dihydro[1]benzofuro[3′,2′:2,3]
oxepino[4,5-d]pyrimidines (9a–e).
2-Aminoethanol (10 eq.)
was added to a solution of 4 (4a: 300mg, 4b–e: 200 mg) in dry
1,4-dioxane (5.0 mL), and the mixture was refluxed until TLC
analysis indicated the consumption of starting material. The solvent
was evaporated in vacuo, and ice water (50 mL) was added to the
residue. The precipitated solid was collected by filtration and
recrystallized from acetonitrile to give 9a–e.
1,2,4,5-Tetrahydro[1]benzofuro[2′,3′:6,7]oxepino[4,5-e]
imidazo[1,2-c]pyrimidine (10).
Compound 9a (150 mg,
4-(2-Hydroxyethylamino)-5.6-dihydro[1]benzofuro[3′,2′:2,3]
0.505 mmol) was added to phosphoryl chloride (4.0 mL), and the
mixture was stirred at 80ꢀC for 5 h. After evaporation of excess
phosphoryl chloride in vacuo, ice water (50 mL) was added to the
residue, and the solution was then neutralized with sodium
bicarbonate. The resulting precipitation was filtered off and
recrystallized from ethanol–water to give 4a (80.0mg, 57%) as
yellow needles, mp 207–209 ꢀC; 1H NMR (DMSO-d6): d 2.99
(t, 2H, J = 4.0 Hz, H4), 3.81, 4.12 (each td, each 2H, J = 10.0,
2.0 Hz, H1 and 2), 4.40 (t, 2H, J = 4.0 Hz, H5), 7.28 (td, 1H,
J = 7.0, 1.0 Hz, H8), 7.42 (td, 1H, J = 7.0, 1.0 Hz, H9), 7.54–7.63
(m, 2H, H7 and 10), 8.04 (s, 1H, H13); FAB–ms: m/z 280 (MH+).
Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N, 15.05. Found:
C, 68.53; H, 4.86; N, 14.82.
oxepino[4,5-d]pyrimidine (9a).
7.5 h to produce, after workup, 9a (95%) as pale yellow nÀee1dles,
mp 237 ꢀC; IR (potassium bromide): 3300 (NH, OH) cm 1H
The reaction was refluxed for
;
NMR (DMSO-d6): d 3.04 (t, 2H, J=4.0Hz, H5), 3.41–3.60
(m, 4H, NCH2CH2O), 4.47 (t, 2H, J=4.0Hz, H6), 4.74 (t, 1H,
J= 5.0 Hz, deuterium oxide exchangeable, NH or OH), 7.11 (br
t, 1H, J= 4.5 Hz, deuterium oxide exchangeable, NH or OH),
7.27–7.50 (m, 2H, H9 and 10), 7.58–7.66 (m, 2H, H8 and 11), 8.40
(s, 1H, H2); FAB–ms: m/z298 (MH+). Anal. Calcd for C16H15N3O3:
C, 64.64; H, 5.09; N, 14.13. Found: C, 64.62; H, 5.10; N, 14.04.
4-(2-Hydroxyethylamino)-2-methyl-5,6-dihydro[1]benzofuro
[3′,2′:2,3]oxepino[4,5-d]pyrimidine (9b).
The reaction was
refluxed for 19 h to produce 9b (80%) as colorless needles, mp
220–223 ꢀC; IR (potassium bromide): 3430, 3270 (NH, OH)
cmÀ1; 1H NMR (deuterochloroforrm): d 2.65 (s, 3H, CH3), 2.94 (t,
2H, J= 4.0 Hz, H5), 3.65–3.90 (m, 4H, NCH2CH2O), 4.50 (t, 2H,
J= 4.0 Hz, H6), 4.69 (br s, 1H, deuterium oxide exchangeable, NH
or OH), 5.23 (br t, 1H, J = 5.0 Hz, deuterium oxide exchangeable,
NH or OH), 7.17–7.43 (m, 2H, H9 and 10), 7.55–7.67 (m, 2H, H8
Measurement of platelet aggregation. Preparation of platelet
rich plasma was performed according to the method described
previously [12]. Synthetic compounds 4–10 25 mL (60% DMF
solution) and 1 M Tris–HCl buffer (pH 7.4) 25 mL were added to
the platelet rich plasma described earlier (250 mL) and preincubated
at 37 ꢀC. This was followed 2 min later by the addition of 50 mL of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

668
K. Okuda, J. Takano, T. Hirota, K. Sasaki, Y. Nishina, and H. Ishida
Vol 51
[7] Nagamatsu, T.; Hantani, Y.; Sasaki, K.; Ohtomo, H.;
Nakayama, T.; Hirota, T. J Heterocycl Chem 1993, 30, 233.
[8] Sasaki, K.; Sekiya, Y.; Nagamatsu, T.; Ohtomo, H.;
Nakayama, T.; Hirota, T. J Heterocycl Chem 1991, 28, 503.
[9] Nagamatsu, T.; Tsurubayashi, S.; Sasaki, K.; Hirota, T.
Synthesis 1991, 303.
[10] Nagamatsu, T.; Kinoshita, K.; Sasaki, K.; Nakayama, T.;
Hirota, T. J Heterocyclic Chem 1991, 28, 513.
[11] Sasaki, K.; Hirota, T.; Arimoto, Y.; Satoh, Y.; Ohtomo, H.;
Nakayama, T. J Heterocycl Chem 1990, 27, 1771.
the aggregating agent (collagen, final concentration 14.3 mg/mL).
Platelet aggregation was measured by continuous recording of light
transmission at 650 nm through plasma for 10–15 min with the use
of an aggregometer (Aggrecoder II PA-3220, Kyoto Daiichi
Kagaku Co. Ltd., Kyoto, Japan). Aspirin was used as a positive
control. All compounds were used at a 25 mM final concentration.
The inhibition rate was calculated from an aggregation response
according to the method already described [12].
[12] Hirota, T.; Sasaki, K.; Ohtomo, H.; Uehara, A.; Nakayama, T.
Heterocycles 1990, 31, 153.
Acknowledgments. The authors are grateful to the SC-NMR
Laboratory of Okayama University for 200 MHz 1H NMR
experiments. They also thank Ms. Hiromi Ohtomo (Laboratory of
Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences,
Okayama University), Prof. Taiji Nakayama (deceased) (Faculty
of Pharmaceutical Sciences, Okayama University) for their
experimental assistance, and Dr K. L. Kirk (NIDDK, NIH) for
helpful comments on the manuscript.
[13] Cheng, S.; Zhang, X.; Wang, W.; Zhao, M.; Zheng, M.;
Chang, H. W.; Wu, J.; Peng, S. Eur J Med Chem 2009, 44, 4904.
[14] Zhang, X.; Wang, W.; Cheng, S.; Zhao, M.; Zheng, M.;
Chang, H. W.; Wu, J.; Peng, S. Bioorg Med Chem 2010, 18, 1536.
[15] Hsieh, P.-W.; Chang, Y.-T.; Chuang, W. Y.; Shih, H.-C.;
Chiang, S.-Z.; Wu, C.-C. Bioorg Med Chem 2010, 18, 7621.
[16] Ihmaid, S.; Al-Rawi, J.; Bradley, C. Eur J Med Chem 2010,
45, 4934.
[17] Wang, H.; Peng, L.; Zhao, M.; Liu, J.; Zhang, X.; Wang, Y.;
Wu, J.; Li, L.; Peng, S. Bioorg Med Chem 2011, 19, 871.
[18] Yao, K.; Zhao, M.; Zhang, X.; Wang, Y.; Li, L.; Zheng, M.;
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REFERENCES AND NOTES
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[20] Crystallographic data for the structure of 4d have been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication numbers CCDC 833649. Copies of the data
can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: +44 01223 336033 or e-mail:
deposit@ccdccamacuk].
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet