R. Jahan et al. / European Journal of Medicinal Chemistry 126 (2017) 550e560
557
vacuum filtration and washed with ice cold water (2 ꢂ 50 mL). The
filtrate was extracted with ethyl acetate and the solvent was
removed under reduced pressure to yield solid diazepine 4. The
MeOH in CH
(2.1 g) in 84% yield: M.p ¼ >260 C (decomp.); H NMR (300 MHz,
CDCl
2 2
Cl ] to furnish the phenolic ethyl ester 6 as a solid
ꢀ
1
3
)
d
1.44 (t, 3H, J ¼ 7.1 Hz), 2.19e2.42 (m, 3H), 3.55e3.64 (m,
ꢀ
combined solids were dried in a vacuum oven at 80 C for 4 h. The
2H), 3.81e3.89 (m, 1H), 4.42 (q, 2H, J ¼ 7.1 Hz), 4.82 (d, 1H,
ꢀ
25
yield of 4 was 96% (37.9 g): M.p ¼ 214e216 C; [
a
]
D
¼ þ444.40 (c
J ¼ 7.3 Hz), 7.13 (dd,1H, J ¼ 8.7 Hz, 2.6 Hz), 7.27e7.31 (m,1H), 7.85 (s,
1
13
1
2
3
%, in CH
2
Cl
2
); H NMR (300 MHz, CDCl
3
)
d
1.82e2.01 (m, 3H),
1H), 7.91 (d, 1H, J ¼ 2.6 Hz), 9.22 (s, 1H); C NMR (75 MHz, CDCl
3
)
.50e2.51 (m, 1H), 3.40e3.49 (m, 1H), 3.56e3.63 (m, 1H), 3.78 (s,
H), 4.07e4.10 (m, 1H), 7.07 (d, 1H, J ¼ 8.7 Hz), 7.13 (dd, 1H,
d 14.3, 24.4, 28.4, 46.9, 53.8, 61.2, 117.5, 120.8, 124.9, 125.2, 127.7,
þ
129.5, 136.0, 137.2, 157.6, 162.8, 164.6; HRMS (ESI) (M þ H) , calcd.
J ¼ 8.7 Hz, 3.0 Hz), 7.26 (d, 1H, J ¼ 3.0 Hz), 10.30 (bs, 1H). The
spectral data were identical to the reported values [27]. This ma-
terial was employed directly in the next step.
for C17
H
18
N
3
O
4
328.1292; Found 328.1293.
2
4.1.6. (S)-Ethyl-7-( H
3
)-methoxy-9-oxo-11,12,13,13a-tetrahydro-
9
H-benzo[e]imidazo[5,1-c]pyrrolo-[1,2-a][1,4]diazepine-1-
carboxylate (5a)
To a solution of phenol 6 (1.5 g, 4.6 mmol) in CH
CO (3 g, 9.2 mmol) was added and the mixture stirred at rt for
30 min. Then CD I (2.3 mL, 36.8 mmol) was added slowly and the
4
.1.4. (S)-Ethyl-7-methoxy-9-oxo-11,12,13,13a-tetrahydro-9H-
benzo[e]imidazo[5,1-c]pyrrolo[1,2-a][1,4]diazepine-1-carboxylate
5)
2 2
Cl (30 mL),
(
Cs
2
3
A well dried reaction flask was evacuated completely and
flushed with argon. The flask was then charged with diazepine 4
3
reaction mixture was stirred at rt for 24 h. After completion of the
reaction the mixture was quenched with cold water and extracted
(
37 g, 150.2 mmol) in dry THF (800 mL). The turbid solution was
ꢀ
cooled to ꢁ20 C. Potassium tert-butoxide (33.7 g, 300.4 mmol) was
added to the flask and the solution was stirred at rt for 1 h. Diethyl
chlorophosphate (43.4 mL, 300.4 mmol) was then slowly added to
with CH
and dried (Na
pressure and the residue was purified by flash column chroma-
tography [silica gel, 2% CH OH in CH Cl ] to furnish ester 5a as a
solid (1.36 g) in 86% yield: M.p ¼ 195e196 C; [
2
Cl
2
. The combined organic layer was washed with brine
2
SO ). The solvent was removed under reduced
4
ꢀ
the reaction mixture at ꢁ20 C and it was allowed to stir at rt over a
3
2
2
ꢀ
25
period of 2e3 h. The cloudy reaction mixture became a clear golden
a
]
D
¼ þ20.00 (c
1
brown solution. After complete consumption of the starting ma-
2 2 3
0.5%, in CH Cl ); H NMR (300 MHz, CDCl ) d
1.46 (t, 3H, J ¼ 7.1 Hz),
ꢀ
terial 4 (TLC), the reaction was cooled to ꢁ20 C, afterwhich ethyl
2.17e2.36 (m, 3H), 3.54e3.63 (m, 2H), 3.77e3.84 (m, 1H), 4.43 (q,
2H, J ¼ 7.1 Hz), 4.77 (d, 1H, J ¼ 7.3 Hz), 7.16 (dd, 1H, J ¼ 8.8 Hz,
2.8 Hz), 7.33 (d, 1H, J ¼ 8.8 Hz), 7.60 (d, 1H, J ¼ 2.8 Hz), 7.82 (s, 1H);
isocyanoacetate (32.8 mL, 300.4 mmol) and potassium tert-but-
oxide (33.7 g, 300.4 mmol) were added. The reaction mixture was
stirred at rt for 8 h. The reaction was quenched with a saturated aq
13
3
C NMR (75 MHz, CDCl ) d 14.3, 24.3, 28.3, 46.5, 53.4, 61.1, 114.4,
solution of NaHCO
pressure and the aq layer was extracted with CH
The combined organic layer was separated and washed with brine
400 mL) and dried (Na SO ). The CH Cl was removed under
3
(80 mL). The THF was removed under reduced
119.7, 124.5, 126.0, 127.6, 130.5, 135.8, 137.6, 159.3, 162.8, 163.7;
þ
2
2
Cl (300 mL X 3).
2
HRMS (ESI) (M þ H) , calcd. for C18
17 3 3 4
H H N O 345.1637; Found
13
345.1635. The C-D signal was not observed due to long relaxation
time, line broadening, reduced NOE effect and spin-spin coupling.
(
2
4
2
2
reduced pressure and the dark brown pasty liquid residue, which
resulted, was washed with ether to yield the crude ethyl ester 5.
4.1.7. (S)-tert-Butyl-7-methoxy-9-oxo-11,12,13,13a-tetrahydro-9H-
benzo[e]imidazo[5,1-c]pyrrolo[1,2-a][1,4]diazepine-1-carboxylate
(7)
This crude solid was recrystallized from CH
2
Cl
2
to yield ethyl ester 5
ꢀ
as a pure white solid in 60% (30.85 g) yield: M.p ¼ 195e197 C; (Lit.
ꢀ
25
1
report: 175e176 C) [27]; [
300 MHz, CDCl
1.44 (t, 3H, J ¼ 7.2 Hz), 2.15e2.31 (m, 3H),
.49e3.61 (m, 2H), 3.75e3.85 (m, 1H), 3.91 (s, 3H), 4.41 (q, 2H,
J ¼ 7.2 Hz), 4.75 (d, 1H, J ¼ 6.9 Hz), 7.15 (dd, 1H, J ¼ 8.9 Hz, 3.0 Hz),
a
]
D
¼ þ18.00 (c 0.5%, in CH
2
Cl
2
); H NMR
A flame dried round bottom flask was charged with dry THF
(30 mL) and lithium rod (excess, cut into small pieces) was added.
Dry tert-butanol (2.6 mL, 27.1 mmol) was added to the above flask
(
3
3
) d
ꢀ
at rt and the mixture which resulted was heated to 45e50 C under
13
7
.32 (d, 1H, J ¼ 8.9 Hz), 7.59 (d, 1H, J ¼ 3.0 Hz), 7.82 (s, 1H); C NMR
Ar until the tert-butanol reacted completely. This freshly prepared
lithium tert-butoxide solution was transferred carefully with a
cannula to another flame dried round bottom flask charged with
(
75 MHz, CDCl 14.3, 24.3, 28.4, 46.6, 53.4, 55.8, 61.2, 114.5, 119.7,
3
) d
1
24.6, 126.0, 127.3, 130.6, 135.8, 137.6, 159.4, 162.6, 163.7; HRMS
þ
ꢀ
(
ESI) (M þ Na) , calcd. for C18
19
H N
3
O
4
Na 364.1273; Found
ester 5 (1.0 g, 2.71 mmol) and stirred at 50 C under Ar for 30 min.
3
64.1279. The spectral data were identical to the reported values
After the completion of the reaction (TLC, silica gel), the flask was
[27]. This material was employed directly in the next step.
cooled to rt and the THF removed under reduced pressure. Ice water
(10 mL) was added to the residue and it was then extracted with
4
.1.5. (S)-Ethyl-7-hydroxy-9-oxo-11,12,13,13a-tetrahydro-9H-benzo
EtOAc. The organic layer was washed with water (2 ꢂ 10 mL) and
brine (15 mL). The solvent was removed under reduced pressure
and the residue was purified by flash column chromatography
[silica gel, EtOAc/hexane (7:3)] to yield tert-butyl ester (XHE-III-74)
[e]imidazo[5,1-c]pyrrolo[1,2-a][1,4]diazepine-1-carboxylate (6)
In an oven dried round bottom flask, dry CH
2
Cl
2
(50 mL) was
ꢀ
added and cooled to 0 C. Then AlCl
nethiol (4.5 mL, 60.8 mmol) were added to the above flask slowly at
0
3
(3 g, 22.8 mmol) and etha-
ꢀ
ꢀ
7 as a solid (0.72 g) in 67% yield: M.p ¼ 115e117 C (119e121 C)
ꢀ
25 1
C. The ice bath was removed and the reaction was allowed to
dissolved completely, ester 5 (2.6 g,
[27]; [
d
a
]
D
¼ þ36.00 (c 0.5%, in CH
2 2 3
Cl ); H NMR (300 MHz, CDCl )
warm up to rt. After the AlCl
3
1.63 (s, 9H), 2.14e2.28 (m, 3H), 3.47e3.61 (m, 2H), 3.74e3.81 (m,
7
2
.62 mmol) was added to the mixture at rt and it was stirred for
4 h under Ar. The reaction time will vary with the scale of the
1H), 3.90 (s, 3H), 4.73 (d, 1H, J ¼ 6.9 Hz), 7.14 (dd, 1H, J ¼ 8.8 Hz,
3.0 Hz), 7.30 (d, 1H, J ¼ 8.8 Hz), 7.57 (d, 1H, J ¼ 3.0 Hz), 7.83 (s, 1H);
1
3
reaction. After completion of the reaction (TLC, silica gel), the so-
3
C NMR (75 MHz, CDCl ) d 24.3, 28.2, 28.3, 46.7, 53.4, 55.9, 81.9,
lution was poured onto ice and was acidified using an aq 2N HCl
114.5, 119.7, 124.6, 126.1, 128.9, 130.5, 135.6, 136.5, 159.4, 162.2,
þ
solution. The solution was extracted 7 times with CH
2
Cl
2
and 4
23 3 4
163.8; HRMS (ESI) (M þ Na) , calcd. for C20H N O Na 392.1586;
times with EtOAc separately. Since the product was soluble in
water, the extraction procedure was carried out until there was no
more product observed in the aqueous layer (TLC, silica gel). The
Found 392.1574. The spectral data were identical to the reported
values [27].
combined organic layer was washed with brine and dried (Na
The solvent was removed under reduced pressure and the residue
was purified by flash column chromatography on [silica gel, 4%
2
SO
4
).
4.1.8. (S)-7-Methoxy-9-oxo-11,12,13,13a-tetrahydro-9H-benzo[e]
imidazo[5,1-c]pyrrolo[1,2-a][1,4]di-azepine-1-carboxylic acid (9)
The ester 5 (2.12 g, 6.21 mmol) was dissolved in a mixture of