Synthesis of novel 6,7-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-8(9H)-ones

Article abstract of DOI:10.1002/jhet.615

A new method was developed for the synthesis of 6,7-dihydro-5H-pyrimido[4, 5-e][1,4]diazepin-8(9H)-one derivatives. The key to construct the pyrimido[4,5-e][1,4]diazepine core is the intramolecular amidation of N-((4-amino-6-chloropyrimidin-5-yl)methyl)-s

Full text of DOI:10.1002/jhet.615

September 2011 Synthesis of Novel 6,7-Dihydro-5H-Pyrimido[4,5-e][1,4]diazepin-
8(9H)-ones
1091
Jinbao Xiang, Xiaowei Hu, Qun Dang,* and Xu Bai*
The Center for Combinatorial Chemistry and Drug Discovery, The School of Pharmaceutical
Sciences and The College of Chemistry, Jilin University, Changchun, Jilin 130021,
People’s Republic of China
*E-mail: qdang@jlu.edu.cn or xbai@jlu.edu.cn
Received May 21, 2010 Revised 13 July 2010; accepted 18 July 2010
DOI 10.1002/jhet.615
Published online 19 May 2011 in Wiley Online Library (wileyonlinelibrary.com).
A new method was developed for the synthesis of 6,7-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-
8(9H)-one derivatives. The key to construct the pyrimido[4,5-e][1,4]diazepine core is the intramolecular
amidation of N-((4-amino-6-chloropyrimidin-5-yl)methyl)-substituted amino acid esters. This methodol-
ogy was validated through the preparation of 13 representative 6,7-dihydro-5H-pyrimido[4,5-e][1,4]dia-
zepin-8(9H)-ones in moderate to good yields.
J. Heterocyclic Chem., 48, 1091 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
The bicyclic pyrimido[4,5-e][1,4]diazepine derivatives
are known as tachykinin receptor antagonists [1], anti-
convulsant agents [2], cysteine protease inhibitors [3],
and raf kinase inhibitors [4]. However, the synthetic
methodologies for pyrimido[4,5-e][1,4]diazepines are
very limited in the literature. We only found the synthe-
sis of one pyrimido[4,5-e][1,4]diazepin-8(9H)-one deriv-
ative by an intramolecular coupling reaction of 2-(((4-
amino-6-(methoxycarbonyl)pyrimidin-5-yl)methyl)(methy-
l)amino)acetic acid as the key step shown in Scheme 1
and the scope of the synthesis was not reported [4].
In our efforts to prepare novel heterocyclic libraries
[5], we have developed a series of methodologies to rap-
idly access various tricyclic and tetracyclic heterocyclic
scaffolds with pyrimidodiazepine as the core [6]. As a
continuing endeavor, we have studied the synthesis of
6,7-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-8(9H)-ones
5 via intramolecular amidation of ester precursors 4,
accessed by the reaction of chloromethylpyrimidine 3
and the ethyl ester of N-substituted amino acids
(Scheme 2). The current procedure involving the direct
amidation cyclization of the ester precursor by a simple
base is complimentary to the literature one [4]. Subse-
quently, a sample library of the representative com-
pounds has been prepared. Herein, the details of investi-
gations are reported.
The synthesis of bicyclic scaffold 5 is depicted in
Scheme 2. Reduction of the formyl group in compound
1 [7] with NaBH4 in MeOH furnished the corresponding
alcohol derivatives 2 in 92% yields. Compound 2 was
treated with SOCl2 to lead to chloromethylpyrimidine 3,
which without further purification, reacted with various
racemic amino acid esters [8] to provide precursors 4 in
high overall yields (Table 1). Treatment of 4 with NaH
in tetrahydrofuran (THF) resulted the ring closure prod-
uct 5 in moderate to good yields.
As shown in Table 1, the ring closure reaction pro-
ceeded slower when the size of R1 and R2 increased
(entries 1–5, entries 9–12). The amidation cyclization
tolerated various side-chain groups in the amino acid
esters, such as alkyl (entries 1–5, 9, 10, 12, and 13;
Table 1), aryl (entries 6 and 11; Table 1), hydrogen
(entry 8; Table 1), and hydroxyethyl groups (entry 7;
Table 1).
In summary, we have prepared a representative
library of pyrimido[4,5-e][1,4]diazepin-8(9H)-ones from
a simple aminopyrimidinealdehyde precursor and amino
acid esters. The key reaction in this synthetic protocol is
the base-effected intramolecular aminolysis of amino
acid esters. This new procedure complements existing
method for the synthesis of pyrimido[4,5-e][1,4]diaze-
pin-8(9H)-one derivatives.
C
V
2011 HeteroCorporation

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J. Xiang, X. Hu, Q. Dang, and X. Bai
Vol 48
Scheme 1. Synthesis of pyrimido[4,5-e][1,4]diazepin-8(9H)-one.
EXPERIMENTAL
cated by TLC, the volatiles were removed in vacuo. The resi-
due was partitioned between water (5 mL) and EtOAc (3 ꢁ
5 mL). The combined organic layers were washed with saturated
aqueous NH4Cl (6 mL) and brine (5 mL), dried over Na2SO4,
concentrated in vacuo, and purified by flash chromatography
(CH2Cl2/EtOAc, 30:1–5:1, v/v) to afford the desired product 4.
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(methyl)
amino)acetate 4.1. 486 mg (94%). mp: 102–104ꢀC. 1H-NMR
d 8.25 (s, 1H), 4.23 (q, 2H, J ¼ 7.2), 3.67 (s, 2H), 3.31 (s,
2H), 2.29 (s, 3H), 1.30 (t, 3H, J ¼ 7.2). MS (ESI): m/z 258.9
[M þ Hþ].
General consideration. Dichloromethane (CH2Cl2) was
dried with CaH2 and distilled. Methanol (MeOH) was dried
with Na and distilled. Acetonitrile (CH3CN) was dried with
CaH2 and distilled. THF was dried with P2O5 and distilled
from sodium before usage. All other commercial reagents were
used as received without additional purification. Melting point
was uncorrected. Mass spectra and HPLC data were recorded
on an LC/MS system with ELSD. The 1H-NMR data were
obtained on a 300-MHz NMR spectrometer with TMS as the
internal standard and CDCl3 as solvent unless otherwise stated.
Multiplicities are indicated as the following: s, singlet; d, dou-
blet; t, triplet; q, quartet; m, multiplet; dd, doubled doublet;
and br, broad. Coupling constants (J values) were noted are
quoted in hertz.
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(butyl)
amino)acetate 4.2. 366 mg (61%). mp: 79–81ꢀC. 1H-NMR d
8.23 (s, 1H), 4.21 (q, 2H, J ¼ 7.2), 3.74 (s, 2H), 3.31 (s, 2H),
2.45 (t, 2H, J ¼ 7.2), 1.46–1.36 (m, 2H), 1.32–1.18 (m, 5H),
0.83 (t, 3H, J ¼ 7.2). MS (ESI): m/z 300.9 [M þ Hþ].
Preparation of (4-amino-6-chloropyrimidin-5-yl)methanol
2. NaBH4 (1.2 g, 30.08 mmol) was added to a stirred solution
of compound 1 (3.235 g, 20.53 mmol) in MeOH (80 mL) at
0ꢀC. After an additional 10 min, the reaction mixture was
allowed to warm to room temperature. After complete con-
sumption of the starting material 1, as indicated by TLC, the
volatiles were removed in vacuo and the residue was parti-
tioned between water (8 mL) and EtOAc (6 ꢁ 8 mL). The
combined organic layers were washed with saturated aqueous
NH4Cl (5 mL) and brine (5 mL), dried over Na2SO4, concen-
trated in vacuo, and purified by flash chromatography (petro-
leum ether/EtOAc, 10:1–5:1, v/v) to afford 3.0 g (92%) of 2
Ethyl
2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(cyclo-
hexyl)amino)acetate 4.3. 470 mg (72%). mp: 97–99ꢀC. 1H-
NMR d 8.23 (s, 1H), 4.20 (q, 2H, J ¼ 7.2), 3.82 (s, 2H), 3.32
(s, 2H), 2.35–2.28 (m, 1H), 1.85–1.75 (m, 4H), 1.63–1.59 (m,
1H), 1.29 (t, 3H, J ¼ 7.2), 1.19–1.00 (m, 5H). MS (ESI): m/z
326.9 [M þ Hþ].
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(phene-
thyl)amino)acetate 4.4. 586 mg (84%). mp: 74–75ꢀC. 1H-
NMR d 8.20 (s, 1H), 7.27–7.19 (m, 3H), 7.07 (d, 2H, J ¼
6.9), 4.22 (q, 2H, J ¼ 7.2), 3.79 (s, 2H), 3.39 (s, 2H), 2.76 (s,
4H), 1.30 (d, 3H, J ¼ 7.2). MS (ESI): m/z 348.8 [M þ Hþ].
1
as a white solid. mp: 179–180ꢀC. H-NMR (DMSO-d6) d 8.12
(s, 1H), 4.50 (s, 2H). MS (ESI): m/z 159.8 [M þ Hþ].
Scheme 2. Synthesis of 6,7-disubstituted pyrimido[4,5-e][1,4]diazepin-
8(9H)-ones.
General procedure for the synthesis of 4-aminopyrimi-
dine precursors 4. SOCl2 (0.58 mL, 8 mmol) was added
dropwise to a stirred solution of 2 (318 mg, 2 mmol) in
CH2Cl2 (7 mL) at 0ꢀC. After being stirred for an additional 10
min, the reaction mixture was allowed to warm to room tem-
perature. After starting material 2 was completely consumed,
as indicated by TLC, the volatiles were removed in vacuo to
afford crude product 3. MS (ESI): m/z 177.7 [M þ Hþ]. The
crude 3 was dissolved in CH3CN (8 mL), followed by addition
of amino acid ester hydrochloride (2.4 mmol) and DIPEA
(1.22 mL, 7 mmol) dropwise at 0ꢀC. The reaction mixture was
stirred for 10 min and allowed to warm to room temperature.
After starting material 3 was consumed completely, as indi-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis of Novel 6,7-Dihydro-5H-pyrimido[4,5-e][1,4]diazepin-8(9H)-ones
1093
Table 1
Preparation of pyrimido[4,5-e][1,4]diazepin-8(9H)-ones.
Intermediate 4
Product 5
Entry
R1
R2
Time (h)
Yield (%)a
Time (h)
Yield (%)
1
2
Me
n-Bu
Cyclohexyl
PhCH2CH2
H
H
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
5
8
94
61
72
84
80
53
70
74
64
70
86
84
77
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
1.5
3
70
76
80
77
64
45
44b
36b
67
47
49
72
63
3
4
H
H
11
12
9
3.5
6
5
PhCH2
Ph
Hydroxyethyl
H
H
6.5
11
20
1.3
5
6
7
H
H
13
18
9
8
9
H
Me
Me
Me
Me
Me
i-Pr
Ph
PhCH2
4.9
9
5.9
10
11
12
13
4.10
4.11
4.12
4.13
10
12
8
5.10
5.11
5.12
5.13
10
12
4
A(CH2)3A
5
1
a Overall yield (two steps) from alcohol 2.
b NaH of 2.2 equiv. was used.
(q, 1H, J ¼ 6.0), 3.16–2.97 (m, 2H), 2.31 (s, 3H), 1.30 (t, 3H,
J ¼ 7.2). MS (ESI): m/z 348.9 [M þ Hþ].
dine-2-carboxylate 4.13. 438 mg (77%). mp: 61–62ꢀC. 1H-
NMR d 8.22 (s, 1H), 4.27–4.17 (m, 2H), 3.78 (q, 2H, J ¼
13.2), 3.26 (q, 1H, J ¼ 7.2), 2.98–2.92 (m, 1H), 2.39 (q, 1H,
J ¼ 9.0), 2.30–2.20 (m, 1H), 1.96–1.76 (m, 3H), 1.30 (t, 3H,
J ¼ 6.9). MS (ESI): m/z 284.9 [M þ Hþ].
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(benzyl)
amino)acetate 4.5. 535 mg (80%). mp: 43–45ꢀC. 1H-NMR d
8.24 (s, 1H), 7.33–7.22 (m, 5H), 4.17 (q, 2H, J ¼ 6.9), 3.82
(s, 2H), 3.57 (s, 2H), 3.26 (s, 2H), 1.25 (t, 3H, J ¼ 7.2). MS
(ESI): m/z 334.9 [M þ Hþ].
Ethyl
1-((4-amino-6-chloropyrimidin-5-yl)methyl)pyrroli-
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(phenyl)
amino)acetate 4.6. 341 mg (53%). mp: 134–135ꢀC. 1H-NMR
d 8.20 (s, 1H), 7.28–7.22 (m, 2H), 6.98–6.92 (m, 3H), 4.51 (s,
2H), 4.23 (q, 2H, J ¼ 7.2), 3.93 (s, 2H), 1.29 (t, 3H, J ¼ 7.2).
MS (ESI): m/z 320.8 [M þ Hþ].
General procedure for the synthesis of 6,7-dihydro-5H-
pyrimido[4,5-e][1,4]diazepin-8(9H)-ones 5. NaH (0.84 mmol
or 1.54 mmol, 60% dispersion in oil) was added to a stirred
solution of compound 4 (0.7 mmol) in THF (4 mL) at 0ꢀC
under dry N2. The reaction mixture was stirred for 10 min and
allowed to warm to room temperature. After starting material
4 was consumed completely, as indicated by TLC, saturated
aqueous NH4Cl was added to quench the reaction. The mixture
was concentrated in vacuo and partitioned between water (4
mL) and EtOAc (3 ꢁ 5 mL). The combined organic layers
were washed with saturated aqueous NH4Cl (4 mL) and brine
(4 mL), dried over Na2SO4, concentrated in vacuo, and puri-
fied by flash chromatography (CH2Cl2/EtOAc, 10:1–5:1, v/v)
to afford the desired product 5.
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(2-hydroxy-
ethyl)amino)acetate 4.7. 404 mg (70%). mp: 109–111ꢀC. 1H-
NMR (DMSO-d6) d 8.12 (s, 1H), 4.11 (q, 2H, J ¼ 7.2), 3.77
(s, 2H), 3.48–3.39 (m, 4H), 2.61 (t, 2H, J ¼ 5.4), 1.20 (t, 3H,
J ¼ 7.2). MS (ESI): m/z 288.8 [M þ Hþ].
Ethyl 2-((4-amino-6-chloropyrimidin-5-yl)methylamino)ace-
tate 4.8. 362 mg (74%). mp: 95–97ꢀC. 1H-NMR d 8.25 (s,
1H), 4.24 (q, 2H, J ¼ 7.2), 3.96 (s, 2H), 3.46 (s, 2H), 2.24 (br,
1H), 1.30 (t, 3H, J ¼ 7.2). MS (ESI): m/z 244.8 [M þ Hþ].
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(methyl)
amino)propanoate 4.9. 349 mg (64%). mp: 75–76ꢀC. 1H-
NMR d 8.24 (s, 1H), 4.22 (q, 2H, J ¼ 7.2), 3.75 (s, 2H), 3.41
(q, 1H, J ¼ 7.2), 2.25 (s, 3H), 1.38–1.29 (m, 6H). MS (ESI):
m/z 272.9 [M þ Hþ].
4-Chloro-6-methyl-6,7-dihydro-5H-pyrimido[4,5-e][1,4]dia-
zepin-8(9H)-one 5.1. 104 mg (70%). mp: 177–179ꢀC. 1H-
NMR d 9.11 (s, 1H), 8.66 (s, 1H), 4.15 (s, 2H), 3.80 (s, 2H),
2.55 (s, 3H). MS (ESI): m/z 212.8 [M þ Hþ].
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(methyl)
1
amino)-3-methylbutanoate 4.10. 421 mg (70%). Oil. H-NMR
6-Butyl-4-chloro-6,7-dihydro-5H-pyrimido[4,5-e][1,4]diaze-
pin-8(9H)-one 5.2. 136 mg (76%). mp: 144–146ꢀC. 1H-NMR
(DMSO-d6) d 8.59 (s, 1H), 4.07 (s, 2H), 3.70 (s, 2H), 2.56–
2.50 (m, 2H), 1.45–1.21 (m, 4H), 0.86 (t, 3H, J ¼ 7.2). MS
(ESI): m/z 254.9 [M þ Hþ].
d 8.25 (s, 1H), 4.29–4.21 (m, 2H), 3.79 (d, 2H, J ¼ 2.4), 2.84
(d, 1H, J ¼ 9.6), 2.25 (s, 3H), 2.22–2.14 (m, 1H), 1.33 (t, 3H,
J ¼ 7.2), 1.00 (d, 3H, J ¼ 6.6), 0.92 (d, 3H, J ¼ 6.6). MS
(ESI): m/z 300.9 [M þ Hþ].
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(methyl)
amino)-2-phenylacetate 4.11. 575 mg (86%). mp: 97–99ꢀC.
1H-NMR d 8.23 (s, 1H), 7.41–7.35 (m, 5H), 4.27–4.08 (m,
3H), 3.78–3.61 (m ,2H), 2.03 (s, 3H), 1.20 (t, 3H, J ¼ 7.2).
MS (ESI): m/z 334.8 [M þ Hþ].
4-Chloro-6-cyclohexyl-6,7-dihydro-5H-pyrimido[4,5-e][1,4]dia-
1
zepin-8(9H)-one 5.3. 157 mg (80%). mp: 212–214ꢀC. H-NMR
(DMSO-d6) d 8.56 (s, 1H), 4.12 (s, 2H), 3.75 (s, 2H), 3.38 (s,
1H), 1.74–1.70 (m, 4H), 1.53–1.51 (m, 1H), 1.22–1.13 (m,
5H). MS (ESI): m/z 280.9 [M þ Hþ].
Ethyl 2-(((4-amino-6-chloropyrimidin-5-yl)methyl)(methyl)
amino)-3-phenylpropanoate 4.12. 585 mg (84%). mp: 57–
60ꢀC. 1H-NMR d 8.18 (s, 1H), 7.34–7.18 (m, 5H), 4.32–4.14
(m, 2H), 4.01 (d, 1H, J ¼ 13.8), 3.76 (d, 1H, J ¼ 13.8), 3.59
4-Chloro-6-phenethyl-6,7-dihydro-5H-pyrimido[4,5-e][1,4]dia-
1
zepin-8(9H)-one 5.4. 164 mg (77%). mp: 110–111ꢀC. H-NMR
(DMSO-d6) d 8.59 (s, 1H), 7.26–7.19 (m, 5H), 4.11 (s, 2H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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J. Xiang, X. Hu, Q. Dang, and X. Bai
Vol 48
3.75 (s, 2H), 2.81–2.74 (m, 4H). MS (ESI): m/z 302.8 [M þ
Hþ].
1H), 2.70–2.59 (m, 2H), 2.22–2.08 (m, 1H), 1.93–1.90 (m,
2H). MS (ESI): m/z 238.9 [M þ Hþ].
6-Benzyl-4-chloro-6,7-dihydro-5H-pyrimido[4,5-e][1,4]diaze-
pin-8(9H)-one 5.5. 129 mg (64%). mp: 168–170ꢀC. 1H-NMR
(DMSO-d6) d 98.62 (s, 1H), 7.36–7.24 (m, 5H), 4.02 (s, 2H),
3.74 (s, 4H). 3.43 (s, 1H). MS (ESI): m/z 288.9 [M þ Hþ].
4-Chloro-6-phenyl-6,7-dihydro-5H-pyrimido[4,5-e][1,4]diaze-
pin-8(9H)-one 5.6. 86 mg (45%). mp: 246–248ꢀC. 1H-NMR
(DMSO-d6) d 8.52 (s, 1H), 7.22–7.17 (m, 2H), 6.77–6.71 (m,
3H), 4.88 (s, 2H), 4.57 (s, 2H). MS (ESI): m/z 274.8 [M þ
Hþ].
Acknowledgment. This work was supported by National Natu-
ral Science Foundation of China (No. 90713008), National Sci-
ence & Technology Major Project ‘‘Key New Drug Creation and
Manufacturing Program’’ of China (No. 2009ZX09501-010), and
Changchun Discovery Sciences, Ltd.
REFERENCES AND NOTES
4-Chloro-6-(2-hydroxyethyl)-6,7-dihydro-5H-pyrimido[4,5-e]
[1,4]diazepin-8(9H)-one 5.7. 75 mg (44%). mp: 213–214ꢀC.
1H-NMR (DMSO-d6) d 8.14 (s, 1H), 4.28 (t, 2H, J ¼ 4.5),
3.58 (s, 2H), 2.66 (t, 4H, J ¼ 4.5). MS (ESI): m/z 242.8 [M þ
Hþ].
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1
one 5.8. 51 mg (36%). mp: 168–170ꢀC. H-NMR (DMSO-d6)
d 8.54 (s, 1H), 4.01 (s, 2H), 3.67 (s, 2H). MS (ESI): m/z 198.8
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[M þ Hþ].
4-Chloro-6,7-dimethyl-6,7-dihydro-5H-pyrimido[4,5-e][1,4]
diazepin-8(9H)-one 5.9. 106 mg (67%). mp: 166–168ꢀC. 1H-
NMR (DMSO-d6) d 8.62 (s, 1H), 4.14 (d, 1H, J ¼ 16.8), 3.98
(d, 1H, J ¼ 17.1), 3.68 (q, 1H, J ¼ 6.9), 2.32 (s, 3H), 1.21 (d,
3H, J ¼ 6.9). MS (ESI): m/z 226.8 [M þ Hþ].
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4-Chloro-7-isopropyl-6-methyl-6,7-dihydro-5H-pyrimido[4,5-
e][1,4]diazepin-8(9H)-one 5.10. 83 mg (47%). mp: 224–
1
226ꢀC. H-NMR (DMSO-d6) d 8.61 (s, 1H), 4.00 (q, 2H, J ¼
16.8), 3.11 (d, 1H, J ¼ 9.9), 2.37 (s, 3H), 1.89–1.81 (m, 1H),
0.96 (d, 3H, J ¼ 6.6), 0.87 (d, 3H, J ¼ 6.6). MS (ESI): m/z
254.7[M þ Hþ].
4-Chloro-6-methyl-7-phenyl-6,7-dihydro-5H-pyrimido[4,5-e]
[1,4]diazepin-8(9H)-one 5.11. 99 mg (49%). mp: 202–203ꢀC.
1H-NMR (DMSO-d6) d 8.66 (s, 1H), 7.36–7.26 (m, 5H), 4.53
(s, 1H), 3.95 (q, 2H, J ¼ 15.9), 2.39 (s, 3H). MS (ESI): m/z
288.9 [M þ Hþ].
[7] Gomtsyan, A.; Didomenico, S.; Lee, C.-H.; Matulenko, M.
A.; Kim, K.; Kowaluk, E. A.; Wismer, C. T.; Mikusa, J.; Yu, H.;
Kohlhaas, K.; Jarvis, M. F.; Bhagwat, S. S. J Med Chem 2002, 45,
3639.
7-Benzyl-4-chloro-6-methyl-6,7-dihydro-5H-pyrimido[4,5-e]
[1,4]diazepin-8(9H)-one 5.12. 152 mg (72%). mp: 177–179ꢀC.
1H-NMR (DMSO-d6) d 8.60, (s, 1H), 7.27–7.15 (m, 5H), 4.00
(s, 1H), 3.97 (s, 2H), 3.38 (s, 1H), 3.08–3.03 (m, 1H), 2.89–
2.81 (m, 1H), 2.36 (s, 3H). MS (ESI): m/z 302.9 [M þ Hþ].
4-Chloro-7,8,9,9a-tetrahydro-5H-pyrimido[4,5-e]pyrrolo[1,2-a]
[1,4]diazepin-10(11H)-one 5.13. 105 mg (63%). mp: 169–
[8] (a) Coggins, J. R.; Benoiton, N. L. Can J Chem 1971, 49,
1968; (b) Cheung, S. T.; Benoiton, N. L. Can J Chem 1977, 55, 906;
(c) Stodulski, M.; Mlynarski, J. Tetrahedron: Asymmetry 2008, 19,
970; (d) Chen, L.; Yang, S.; Zhang, J.; Zhang, Z. US Patent
20,080,081,810, 2008; (e) Ho, B. A.; Cridera, M.; Stablesb, J. P. Eur
J Med Chem 2001, 36, 265; (f) Flynn, G, A.; Beighht, D, W. US Pat-
ent 5,329,012, 1994.
1
170ꢀC. H-NMR d 8.77 (br, 1H), 8.63 (s, 1H), 4.33 (d, 1H, J
¼ 16.5), 3.87 (d, 1H, J ¼ 16.5), 3.41 (s, 1H), 3.28–3.24 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet