Journal of Medicinal Chemistry
Article
was purified by flash column chromatography (SiO2), eluting with a
gradient of EtOAc to 15% MeOH in EtOAc to yield 27 as a yellow
syrup (0.039 g, 41%), which was used without further characterization.
This compound was diluted with anhydrous MeOH (6 mL), and
anhydrous K2CO3 (0.031 g, 0.022 mmol) was added. The mixture was
heated at reflux for 2 h 15 min, cooled, and concentrated. The residue
was diluted with EtOAc (10 mL), and 3 mL each of H2O and sat. aq.
NaCl was added. The layers were separated, the aqueous layer was
extracted with EtOAc (3 × 4 mL), and the combined organic layers
were washed with sat. aq. NaCl (4 mL), dried over anhydrous sodium
sulfate, and concentrated. The residue was diluted with CH2Cl2 (5
mL), filtered to remove particulate matter, and reconcentrated.
Methanolic HCl (∼1.4 M, 3 mL) was added, the mixture was stirred
for 5 min, and ether (30 mL) was added slowly until a white
precipitate formed. This solid was collected and dried to afford the title
compound as a white microcrystalline solid (0.029 g, 28% based on
was added, followed by 3 mL of a 2:1 mixture of CHCl3/MeOH and
anhydrous sodium sulfate (∼0.5 g). The mixture was stirred rapidly at
room temperature for 90 min, after which glacial acetic acid (10 μL)
was added. After a total of 4 h, the amine appeared to be consumed by
TLC, and the mixture was filtered to remove the sodium sulfate. The
filtrate was concentrated, and the oily residue was diluted in MeOH (5
mL). NaBH4 (0.020 g, 0.523 mmol) was added, and the mixture was
stirred for 40 min at room temperature. The mixture was concentrated
and partitioned between EtOAc and H2O (10 mL of each). The layers
were separated, and the aqueous layer was extracted with EtOAc (10
mL). The organic layer was washed with H2O and sat aq. NaCl (20
mL each), dried over anhydrous sodium sulfate, and concentrated. The
residue was purified by flash column chromatography (SiO2), eluting
with a gradient of EtOAc to 20% MeOH in EtOAc to yield the
intermediate acetamide as a yellow syrup (0.052 g, 72%, confirmed by
MS). This compound was immediately diluted in MeOH (5 mL), and
K2CO3 (0.021 g, 0.154 mmol) was added. The mixture was heated at
vigorous reflux for 2 h, cooled, and concentrated, and the resulting
residue was diluted with EtOAc (20 mL) and washed with H2O (10
mL). The aqueous layer was extracted with EtOAc (2 × 10 mL), and
the combined organic layers were washed with sat. aq. NaCl (10 mL)
and dried over anhydrous sodium sulfate. Concentration afforded a
white solid, which was diluted with methanolic HCl (∼1.4 M, 3 mL)
and stirred for 10 min. The addition of ether (50 mL) resulted in the
precipitation of a solid that was collected, washed with ether (20 mL)
and dried in vacuo to yield the title compound as a white solid (0.043
g, 54% from 48): mp 282−284 °C. 1H NMR (500 MHz; DMSO-d6):
δ 14.24 (s, 1 H), 9.62 (s, 2 H), 9.16 (br s, 1 H), 8.35 (d, J = 9.4 Hz, 1
H), 8.19 (br s, 1 H), 7.80 (d, J = 0.7 Hz, 1 H), 7.71−7.67 (m, 2 H),
7.52−7.48 (m, 2 H), 7.42 (d, J = 7.7 Hz, 1 H), 7.30−7.26 (m, 1 H),
7.12 (d, J = 9.3 Hz, 1 H), 4.22 (s, 2 H), 3.17−3.14 (m, 4 H). 13C NMR
(126 MHz; DMSO-d6): δ (162.9 + 160.9, 1 C), 154.0 (1 C), 142.8 (1
C), (134.62 + 134.56, 1 C), 134.0 (1 C), 133.3 (1 C), (130.76 +
130.70, 1 C), 128.3 (1 C), (126.24 + 126.22, 1 C), 121.0 (1 C), 117.7
(1 C), (116.96 + 116.79, 1 C), (115.90 + 115.74, 1 C), 114.0 (1 C),
49.2 (1 C), 47.2 (1 C), 30.8 (1 C); one of the aminoquinoline carbons
is not visible because of baseline broadening; ESIMS m/z (rel.
intensity) 296 (MH+,100). HRMS calcd for C18H18FN3, 295.1485;
found, 295.1486.
1
21) after drying in vacuo: mp 250−252 °C (dec). H NMR (500
MHz; DMSO-d6): δ 14.44 (s, 1 H), 9.50 (s, 2 H), 9.30 (br s, 1 H),
8.39 (d, J = 9.2 Hz, 1 H), 8.30 (br s, 1 H), 7.98 (d, J = 8.2 Hz, 1 H),
7.86 (s, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 7.35 (td, J = 8.0, 6.4 Hz, 1 H),
7.15 (d, J = 9.3 Hz, 1 H), 7.10−7.02 (m, 3 H), 4.32 (t, J = 5.5 Hz, 2
H), 2.95−2.90 (m, 2 H), 2.70 (t, J = 7.6 Hz, 2 H), 2.00 (quintet, J =
7.7 Hz, 2 H). 13C NMR (126 MHz; DMSO-d6): δ (163.2 + 161.3, 1
C), 154.6 (1 C), (143.67 + 143.61, 1 C), 142.6 (1 C), 136.6 (1 C),
(130.32 + 130.25, 1 C), 129.0 (1 C), 126.4 (1 C), (124.47 + 124.45, 1
C), 120.9 (1 C), 118.7 (1 C), (115.08 + 114.91, 1 C), 114.5 (1 C),
(112.95 + 112.78, 1 C), 49.3 (1 C), 46.0 (1 C), 31.5 (1 C), 26.7 (1 C);
one of the aminoquinoline carbons is not visible due to baseline
broadening; ESIMS m/z (rel. intensity) 310 (MH+, 100). HRMS calcd
for C19H20FN3, 309.1641; found, 309.1645.
6-[(3-Fluorophenethylamino)methyl]quinolin-2-amine Di-
hydrochloride (10). Anhydrous Cs2CO3 (0.090 g, 0.288 mmol)
was diluted in anhydrous DMF (5 mL), and amine 22 (0.040 g, 0.288
mmol) was added. The mixture was stirred for 30 min at room
temperature before compound 46 (0.070 g, 0.250 mmol) was added
dropwise as a solution in anhydrous DMF (2 mL). The resultant
suspension was stirred for 16 h at room temperature and concentrated,
the residue was partitioned between EtOAc and H2O (5 mL each),
and the layers were separated. The aqueous layer was extracted with
EtOAc (2 × 5 mL), and the organic layers were washed with sat. aq.
NaCl (5 mL), dried over anhydrous sodium sulfate, and concentrated.
The residue was purified by flash column chromatography (SiO2),
eluting with a gradient of EtOAc to 10% MeOH in EtOAc to yield the
intermediate acetamide as a yellow syrup (0.040 g, 47%, confirmed by
MS). This syrup was dissolved in MeOH (5 mL), and K2CO3 (0.026
g, 0.148 mmol) was added. The mixture was heated at reflux for 2 h,
cooled to room temperature, and concentrated. The residue was
partitioned between EtOAc (5 mL) and sat. aq. NaCl/H2O (4:1, 5
mL). The layers were separated, and the aqueous layer was extracted
with EtOAc (2 × 5 mL). The combined organic phase was washed
with sat aq. NaCl (4 mL), dried over anhydrous sodium sulfate, and
concentrated. The resulting residue was diluted in CH2Cl2 (5 mL) and
filtered to remove particulate matter, and methanolic HCl (∼1.4 M, 3
mL) was added. After 10 min, ether (20 mL) was added, and a
precipitate formed. This was collected and dried to yield the title
compound as a cream-colored powder (0.036 g, 38% from 46: mp
277−278 °C). 1H NMR (500 MHz; DMSO-d6): δ 14.35 (s, 1 H), 9.58
(s, 2 H), 9.28 (br s, 1 H), 8.37 (d, J = 9.5 Hz, 1 H), 8.32 (br s, 1 H),
8.05 (s, 1 H), 7.96 (d, J = 8.6 Hz, 1 H), 7.78 (d, J = 8.5 Hz, 1 H), 7.39
(td, J = 7.8, 6.4 Hz, 1 H), 7.16−7.09 (m, 4 H), 4.29 (s, 2 H), 3.20−
3.19 (m, 2 H), 3.05 (t, J = 8.1 Hz, 2 H). 13C NMR (126 MHz; DMSO-
d6): δ (163.2 + 161.2, 1 C), 154.4 (1 C), 142.8 (1 C), (140.11 +
140.05, 1 C), 135.9 (1 C), 134.2 (1 C), 130.59 (1 C), (130.58 +
130.52, 1 C), 128.6 (1 C), (124.83 + 124.81, 1 C), 120.5 (1 C), 117.6
(1 C), (115.53 + 115.36, 1 C) 114.5 (1 C), (113.69 + 113.52, 1 C),
49.2 (1 C), 47.0 (1 C), 31.0 (1 C). ESIMS m/z (rel. intensity) 296
(MH+, 100). HRMS calcd for C18H18FN3, 295.1485; found, 295.1490.
6-[2-(3-Fluorobenzylamino)ethyl]quinolin-2-amine Dihydro-
chloride (11). Amine 48 (0.050 g, 0.218 mmol) was dissolved in
anhydrous CHCl3 (3 mL), and aldehyde 30 (0.034 g, 0.274 mmol)
6-[(3-Fluorophenethylamino)ethyl]quinolin-2-amine Dihy-
drochloride (12). To a solution of 48 (0.074 g, 0.321 mmol) in
7:1 CHCl3/MeOH (8 mL), aldehyde 35 (0.049 g, 0.353 mmol) was
added, followed by glacial AcOH (7 μL) and anhydrous MgSO4
(approx 0.5 g). The mixture was stirred at room temperature for 20
min and then cooled to 0 °C. Sodium triacetoxyborohydride (0.082 g,
0.385 mmol) was added in one portion, and the mixture was slowly
warmed to room temperature over 50 min, then diluted with CH2Cl2
(10 mL). The mixture was filtered, the filtrate was washed with sat. aq.
NaHCO3 (2 × 20 mL), and the aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). The combined organic layers were washed with
sat. aq. NaCl (10 mL) and dried over anhydrous sodium sulfate. The
solution was concentrated, and the residue was purified by flash
column chromatography (SiO2), eluting with a gradient of EtOAc to
20% MeOH in EtOAc to yield the intermediate acetamide as a sticky
syrup (0.039 g, 34%) that was immediately dissolved in MeOH (3
mL). K2CO3 (0.023 g, 0.167 mmol) was added, and the mixture was
heated to vigorous reflux for 1 h 50 min. The mixture was cooled and
concentrated, and the residue was partitioned between EtOAc (10
mL) and 1:1 H2O/sat. aq. NaCl (4 mL). The layers were separated,
and the aqueous layer was extracted with EtOAc (2 × 4 mL). The
combined organic layers were washed with sat. aq. NaCl (4 mL), dried
over anhydrous sodium sulfate, and concentrated to yield a sticky
residue that was diluted with CH2Cl2 (3 mL) and filtered to remove
particulate matter. Methanolic HCl (∼1.4 M, 2 mL) was added, the
mixture was stirred for 10 min and concentrated, and the residue was
recrystallized from 1:1 MeOH/ether (1 mL) to yield the product as a
pale tan hygroscopic solid (0.025 g, 21% based on 48): mp 223−226
1
°C (dec). H NMR (500 MHz; DMSO-d6): δ 14.37 (s, 1 H), 9.35−
9.23 (m, 3 H), 8.36 (d, J = 9.4 Hz, 1 H), 8.30 (br s, 1 H), 7.83 (s, 1
H), 7.73−7.69 (m, 2 H), 7.42−7.38 (m, 1 H), 7.18−7.09 (m, 4 H),
1523
dx.doi.org/10.1021/jm401838x | J. Med. Chem. 2014, 57, 1513−1530