Journal of Medicinal Chemistry
Article
2
2
3.37, 11.70. GC-MS (EI) m/z 231 (M+). Anal. (C H N O·1/
(R)-5-(Dipropylamino)-1-propyl-5,6-dihydro-4H-imidazo[4,5,1-ij]-
quinolin-2(1H)-one (15). To the solution of 13 (52 mg, 0.23 mmol)
in DMF (2 mL) was added 1-bromopropane (138 mg, 1.13 mmol)
and K CO (128 mg, 0.92 mmol). The mixture was heated to 65 °C
1
3
17
3
H O) C, H, N.
2
(
R)-5-(Dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-
20
2
(1H)-one (14a). Benzyl chloroformate (639 mg, 3.75 mmol) in dry
2
3
THF (2 mL) was added dropwise at 0 °C under argon to a solution of
1
overnight. The mixture was then filtered after cooling to rt, and the
filtrate was concentrated under vacuum. The residue was purified by
preparative TLC, eluting with 5% CMA to afford 15 (53 mg, 76%).
3 (787 mg, 3.41 mmol) and Et N (1.38 g, 13.6 mmol) in dry THF
3
(
10 mL). The reaction was warmed to rt for 3 h after the addition. The
[α]2 −1.4 (c 0.70, MeOH). H NMR (400 MHz, CDCl ) δ 6.97 (dd,
5
1
mixture was diluted with H O, and the two layers were separated. The
aqueous layer was extracted with CHCl . The combined organic layers
were dried (MgSO ) and concentrated. The residue was purified by
column chromatography (eluting with CHCl /MeOH; 93:7) to afford
benzyl (R)-2-oxo-5-(propylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]-
quinoline-1(2H)-carboxylate (853 mg, 69%). H NMR (400 MHz,
2
D
3
3
J = 7.6, 7.2 Hz, 1H), 6.85 (dd, J = 7.2, 0.8 Hz, 1H), 6.81 (d, J = 7.6 Hz,
1H), 4.17 (ddd, J = 11.6, 4.2, 0.8 Hz, 1H), 3.82 (t, J = 7.4 Hz, 2H),
3.45 (t, J = 11.6 Hz, 1H), 3.29 (m, 1H), 2.90 (m, 2H), 2.53 (m, 4H),
4
3
1
0
.78 (m, 2H), 1.62 (br s, 1H), 1.45 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H),
1
13
.89 (t, J = 7.6 Hz, 6H). C NMR (100 MHz, CDCl ) δ 153.58,
3
CDCl ) δ 7.55−7.50 (m, 3H), 7.42−7.31 (m, 3H), 7.01 (t, J = 7.8 Hz,
3
127.78, 126.28, 120.76, 119.43, 118.96, 105.38, 54.65, 52.81, 42.91,
0.47, 27.02, 22.30, 21.96, 11.68, 11.35. GC-MS (EI) m/z 315(M+).
Anal. (C H N O) C, H, N.
2
3
H), 6.96 (m, 1H), 5.48 (s, 2H), 3.99 (ddd, J = 12.8, 4.0, 1.2 Hz, 1H),
.60 (dd, J = 12.8, 7.0 Hz, 1H), 3.28 (m, 1H), 3.04 (dd, J = 16.0, 4.0
4
19
29
3
Hz, 1H), 2.80−2.61 (m, 3H), 1.56−1.43 (m, 2H), 0.91 (t, J = 7.2 Hz,
H). To a solution of this CBz-protected intermediate (683 mg, 1.87
mmol) in DMF (10 mL) were added K CO (516 mg, 3.74 mmol)
Benzyl (R)-Methyl(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]-
quinolin-5-yl)carbamate (16). N-(Benzyloxycarbonyloxy)succinimide
(386 mg, 1.55 mmol) solution in THF (10 mL) was added dropwise
to the solution of 1 (300 mg, 1.47 mmol) in dry THF (10 mL) at −40
3
2
3
and n-PrBr (460 mg, 3.74 mmol), and the mixture was heated to 65 °C
and stirred overnight. The mixture was then cooled to rt and filtered.
The filtrate was concentrated. The residue was diluted with H O (10
mL) and extracted with EtOAc (3 × 20 mL). The combined organic
layers were dried (MgSO ) and concentrated. The residue was purified
by column chromatography (eluting with CHCl /MeOH; 93:7) to
provide benzyl (R)-5-(dipropylamino)-2-oxo-5,6-dihydro-4H-imidazo-
°
C under an argon atmosphere. The reaction mixture was slowly
2
warmed to rt and stirred overnight. The reaction mixture was then
quenched with 10% sat. NaHCO solution (20 mL) and extracted with
3
4
EtOAc (3 × 10 mL). The organic layers were combined, dried,
concentrated, and purified by column chromatography using 60%
3
EtOAc/hexanes as eluent to provide 498 mg (91%) of oily material.
1
[
4,5,1-ij]quinoline-1(2H)-carboxylate (356 mg) in 46% yield.
H
1
H NMR (400 MHz, CDCl ) δ 10.23 (br, 1H), 7.36 (m, 5H), 6.95 (m,
3
NMR (400 MHz, CDCl ) δ 7.54−7.50 (m, 3H), 7.42−7.31 (m, 3H),
3
2
=
H), 6.84 (d, J = 7.8 Hz, 1H), 5.18 (s, 2H), 4.65 (m, 1H), 4.12 (dd, J
11.6, 4.8 Hz, 1H), 3.71 (m, 1H), 3.13 (dd, J = 15.6, 11.2 Hz, 1H),
7.02−6.94 (m, 2H), 5.48 (s, 2H), 4.14 (ddd, J = 12.0, 4.8, 0.8 Hz, 1H),
3.41 (t, J = 11.8 Hz, 1H), 3.24 (m, 1H), 2.96−2.81 (m, 2H), 2.60−
2.44 (m, 4H), 1.52−1.40 (m, 4H), 0.89 (t, J = 7.2 Hz, 6H). This
2
.86 (s, 3H), 3.00−2.84 (m, 1H).
Benzyl (R)-Methyl(2-oxo-1-propyl-1,2,5,6-tetrahydro-4H-
intermediate (330 mg, 0.81 mmol) was dissolved in EtOH (10 mL) in
a Parr bottle, and Pd/C (10%, 50 mg) was added. The mixture was
hydrogenolyzed at an initial pressure of 50 psi for 5 h. The mixture was
then filtered over Celite. The filtrate was concentrated, and the residue
was purified by column chromatography (eluting with 10% CMA) to
imidazo[4,5,1-ij]quinolin-5-yl)carbamate (17a). 1-Bromopropane
(90 mg, 0.73 mmol) was added to the reaction mixture of 16 (122
mg, 0.36 mmol) and K CO (504 mg, 3.66 mmol) in acetone (5 mL)
2
3
and stirred at reflux for 20 h. The reaction mixture was filtered,
concentrated, and purified using flash chromatography with 10%
2
2
give pure product 14a (179 mg) in 81% yield. [α] −4.25 (c 0.6,
24
D
acetone/CHCl as eluent to provide 138 mg (93%) of 17a. [α]
1
3
D
CHCl ). H NMR (400 MHz, CDCl ) δ 10.20 (br, 1H), 6.98−6.91
1
3
3
+
41.4 (c 0.58, MeOH). H NMR (400 MHz, CDCl ) δ 7.36 (br, 5H),
3
(
m, 2H), 6.85 (d, J = 6.8 Hz, 1H), 4.18 (ddd, J = 11.6, 4.0, 0.8 Hz,
6
.99 (ddd, J = 7.6, 7.2, 0.8 Hz, 1H), 6.84 (m, 2H), 5.18 (s, 2H), 4.65
(br, 1H), 4.13 (dd, J = 12.0, 4.8 Hz, 1H), 3.82 (t, J = 7.2 Hz, 2H), 3.73
m, 1H), 3.14 (dd, J = 15.6, 7.2 Hz, 1H), 2.94 (m, 4H), 1.78 (m, 2H),
1
2
H), 3.46 (t, J = 11.4 Hz, 1H), 3.31 (m, 1H), 2.97−2.83 (m, 2H),
13
.60−2.46 (m, 4H), 1.45 (m, 4H), 0.90 (t, J = 7.2 Hz, 6H). C NMR
(
(
100 MHz, CDCl ) δ 155.26, 127.33, 126.27, 121.32, 119.66, 119.11,
3
0
.97 (dt, J = 7.6, 0.8 Hz, 3H).
1
07.35, 54.74, 52.81, 40.39, 26.74, 22.30, 11.69. GC-MS (EI) m/z 273
Benzyl (R)-Methyl(2-oxo-1-butyl-1,2,5,6-tetrahydro-4H-imidazo-
4,5,1-ij]quinolin-5-yl)carbamate (17b). NaH (60% in mineral oil,
(
M+). Anal. (C H N O·0.25 H O) C, H, N.
16
23
3
2
[
(
R)-5-(Propylamino)-1-propyl-5,6-dihydro-4H-imidazo[4,5,1-ij]-
3
0 mg, 0.75 mmol) was washed with hexane (3 × 1 mL) and then
quinolin-2(1H)-one (14b). Compound 13 (60 mg, 0.26 mmol) was
dissolved in DMF (2 mL), and to the solution was added 1-
bromopropane (62 mg, 0.52 mmol) and K CO (72 mg, 0.52 mmol).
suspended in dry THF. To this suspension was added 16 (168 mg, 0.5
mmol) in dry THF, and the mixture was stirred at rt for 30 min. 1-
Bromobutane (137 mg, 1.0 mmol) was added, and the mixture was
2
3
The mixture was heated to 40 °C for 48 h. The mixture was filtered
after cooling to rt, and the filtrate was concentrated under vacuum.
The residue was purified by preparative TLC, eluting with 5% CMA to
stirred at rt overnight. The mixture was quenched with H O, extracted
2
with CHCl , dried (MgSO ), and concentrated. The residue was
3
4
afford 14b (55 mg, 78%) as an oil. [α]2 −14.4 (c 0.55, MeOH). H
4
D
1
purified by column chromatography, eluting with hexane/ethyl acetate
1
(
1:1) to afford 115 mg (68%) of 17b. H NMR (400 MHz, CDCl ) δ
NMR (400 MHz, CDCl ) δ 6.98 (dd, J = 8.0, 7.6 Hz, 1H), 6.85 (dd, J
3
3
7.33 (br, 5H), 6.97 (m, 1H), 6.83 (m, 2H), 5.18 (s, 2H), 4.63 (br,
1H), 4.13 (dd, J = 12.0, 4.4 Hz, 1H), 3.85 (t, J = 7.6 Hz, 2H), 3.74 (m,
1H), 3.12 (dd, J = 15.6, 7.6 Hz, 1H), 2.93 (m, 4H), 1.74 (m, 2H), 1.40
=
7.6, 0.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.10 (ddd, J = 12.0, 4.4,
1
.2 Hz, 1H), 3.82 (m, 2H), 3.55 (dd, J = 12.0, 8.0 Hz, 1H), 3.28 (m,
H), 3.05 (dd, J = 15.6, 4.4 Hz, 1H), 2.72 (m, 3H), 1.78 (m, 2H), 1.50
1
(
(
m, 2H), 0.97 (t, J = 7.6 Hz, 3H), 0.92 (t, J = 7.6 Hz, 3H); 13C NMR
(m, 2H), 0.95 (t, J = 7.6 Hz, 3H).
(
R)-5-(Methylamino)-1-propyl-5,6-dihydro-4H-imidazo[4,5,1-ij]-
100 MHz, CDCl ) δ 153.57, 127.82, 126.24, 120.98, 119.55, 117.44,
3
quinolin-2(1H)-one (18a). Compound 17a (100 mg, 0.26 mmol) and
1
05.63, 51.61, 49.29, 43.53, 42.93, 31.70, 23.44, 21.97, 11.68, 11.36.
Pd/C (10%, 20 mg) in absolute EtOH (5 mL) was hydrogenolyzed
GC-MS (EI) m/z 273 (M+). Anal. (C H N O·1/4H O) C, H, N.
16
23
3
2
(50 psi) for 5 h. TLC showed that the reaction was complete. The
(
R)-5-[Methyl(propyl)amino]-5,6-dihydro-4H-imidazo[4,5,1-ij]-
quinolin-2(1H)-one (14c). Compound 14c was synthesized from 1
and 1-bromopropane in 73% yield using the same procedure as for
1
mixture was filtered over Celite. The filtrate was concentrated, and the
residue was purified by preparative TLC, eluting with 5% CMA to
4b. [α]2 −6.6 (c 0.29, MeOH). H NMR (400 MHz, CDCl ) δ 10.0
5
1
25
1
provide 58 mg (90%) of 18a. [α]
(400 MHz, CDCl
−12.9 (c 1.00, MeOH). H NMR
D
3
D
(
4
s, 1H), 6.94 (m, 2H), 6.85 (d, J = 7.2 Hz, 1H), 4.22 (ddd, J = 12.0,
.4, 1.2 Hz, 1H), 3.53 (dd, J = 12.0 6.6 Hz, 1H), 3.11 (m, 1H), 2.95
3
) δ 6.98 (dd, J = 7.6, 7.6 Hz, 1H), 6.85 (dd, J = 7.6,
0.8 Hz, 1H), 6.82 (dd, J = 7.6, 0.8 Hz, 1H), 4.06 (ddd, J = 12.0, 4.0, 0.8
Hz, 1H), 3.82 (m, 2H), 3.64 (dd, J = 12.0, 6.8 Hz, 1H), 3.23 (m, 1H),
3.07 (dd, J = 16.0, 4.0 Hz, 1H), 2.78 (dd, J = 16.0, 7.2 Hz, 1H), 2.54
(s, 3H),1.77 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
(
3
1
m, 2H), 2.57 (m, 2H), 2.42 (s, 3H), 1.54 (m, 2H), 0.91 (t, J = 7.6 Hz,
H). 13C NMR (100 MHz, CDCl ) δ 155.06, 127.35, 126.12, 121.39,
3
19.69, 118.63, 107.35, 57.40, 56.11, 39.98, 38.22, 27.10, 20.93, 11.70.
GC-MS (EI) m/z 245 (M+). Anal. (C H N O·1/2H O) C, H, N.
CDCl ) δ 153.61, 127.83, 126.13, 121.06, 119.62, 117.13, 105.72,
14
19
3
2
3
K
J. Med. Chem. XXXX, XXX, XXX−XXX