C. Lamberth et al. / Bioorg. Med. Chem. 22 (2014) 3922–3930
3927
J = 2.0 Hz), 8.54 (d, 1H, J = 2.2 Hz), 9.06 (d, 1H, J = 2.1 Hz). LC-MS:
R = 1.94 min; MS: m/z = 268 [M] , 269 [M+1] .
t
4.1.5. 2-(3-Bromo-8-methylquinolin-6-yloxy)-N-prop-2-ynyl-
butyramide (9)
+
+
Lithium hydroxide hydrate (0.2 g, 5.3 mmol) was added to a solu-
tion of 2-(3-bromo-8-methylquinolin-6-yloxy)-butyric acid methyl
ester (8, 1.5 g, 4.4 mmol) in a mixture of 11 ml of tetrahydrofuran
and 11 ml of water at 0 °C The reaction mixture was stirred for 2 h
at 0 °C and then warmed to room temperature. The tetrahydrofuran
was evaporated under reduced pressure and 1 N hydrochloric acid
wasaddedto theremainingmixtureuntilpH1 wasreached. Thepre-
cipitate formed was filtered and dried in a vaccum oven at 50 °C to
deliver 2-(3-bromo-8-methyl-quinolin-6-yloxy)-butyric acid. This
intermediate was dissolved in 30 ml of N,N-dimethylformamide
and triethylamine (1.5 g, 15 mmol), 1-hydroxy-7-azabenzotriazole
(0.9 g, 6.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(1.2 g, 6.5 mmol) and propargylamine (0.4 g, 6.5 mmol) were added
consecutively. The reaction mixture was stirred for 16 h at room
temperature, then diluted with ethyl acetate and extracted with
brine, saturated aqueous sodium bicarbonate solution and water.
The organic layer was dried over magnesium sulfate and evaporated
under reduced pressure, the residue was crystallized with t-butyl
methyl ether to deliver 2-(3-bromo-8-methylquinolin-6-yloxy)-N-
4
.1.2. 3-Bromo-6-methoxy-8-methylquinoline (6)
,2,3-Tribromopropanal (50.0 g, 0.18 mol) was slowly added to a
suspension of 4-methoxy-2-methylaniline (5, 25.0 g, 0.18 mol) in
2
3
6
00 ml of glacial acetic acid. The reaction mixture was stirred for
h atroomtemperature, thendilutedwith ethylacetateandwashed
with water, brine and 2 N sodium hydroxide solution, subsequently
dried over magnesium sulfate and evaporated under reduced pres-
sure. The residuewas purifiedby chromatographyonsilica gel, using
ethyl acetate and heptane as eluents to yield 3-bromo-6-methoxy-
8
-methylquinoline (6, 20.5 g, 81 mmol, 45%). 1H NMR (CDCl
3
):
d = 2.73 (s, 3H), 3.90 (s, 3H), 6.82 (d, 1H, J = 2.0 Hz), 7.21 (d, 1H,
J = 2.1 Hz), 8.17 (d, 1H, J = 1.9 Hz), 8.76 (d, 1H, J = 2.0 Hz). LC-MS:
R = 1.99 min; MS: m/z = 254 [M] , 255 [M+1] .
t
+
+
4
.1.3. 3-Bromo-8-methylquinolin-6-ol (7)
From 4: reduced iron powder (15 g, 0.27 mol) was added in por-
tions to a suspension of 3-bromo-8-methyl-6-nitroquinoline (4,
2
3
0.6 g, 77 mmol) in a mixture of 400 ml of ethanol and 2 ml of
7% aqueous hydrochloric acid at room temperature. The reaction
prop-2-ynylbutryramide (9, 0.7 g, 1.9 mmol, 43%). Mp 174–178 °C
1
mixture was heated to reflux for 2 h, during which the color of the
suspension changed from grey–yellow to red–brown. The reaction
mixture was cooled to 40 °C, filtered through Celite, the filtrate
was diluted with ethanol, treated with silica gel and concentrated
under reduced pressure. The residue was purified by chromatogra-
phy on silica gel, using ethyl acetate and dichloromethane as eluents
to deliver 6-amino-3-bromo-8-methylquinoline. This intermediate
was suspended in a mixture of 125 ml of 85% aqueous phosphoric
acid and 12 ml of water and heated in a tantalum pressure vessel
to 180 °C for 72 h. Subsequently, the mixture was cooled to room
temperature and poured on water. 30% Aqueous sodium hydroxide
was added to this solution until pH 2–4 was reached. The precipitate
formed was filtered, washed with cold water and dried to give 3-
(%). H NMR (CDCl
3
): d = 1.00 (t, 3H, J = 7.2 Hz), 1.92–2.03 (m, 2H),
2.11 (d, 1H, J = 2.4 Hz), 2.78 (s, 3H), 3.93 (dd, 1 H, J = 2.3 Hz,11.0 Hz),
4.06 (dd, 1H, J = 2.4 Hz, 10.8 Hz), 4.59 (t, 1H, J = 7.5 Hz), 6.45 (br s,
1H), 6.76 (d, 1H, J = 2.0 Hz), 7.22 (d, 1H, J = 2.1 Hz), 8.09 (d, 1H,
t
J = 2.2 Hz), 8.72 (d, 1H, J = 2.1 Hz). LC-MS: R = 0.97 min; MS:
+
+
m/z = 363 [M+1] , 364 [M+2] .
4.1.6. 2-(3-Bromo-8-methylquinolin-6-yloxy)-2-
methylsulfanyl-acetic acid methyl ester (10)
Methyl 2-chloro-2-(methylsulfanyl)acetate (11 g, 73 mmol) and
milled potassium carbonate (42.5 g, 0.3 mol) were consecutively
added to a suspension of 3-bromo-8-methylquinolin-6-ol (7,
14.5 g, 61 mmol) in 200 ml of N,N-dimethylformamide. The reac-
tion mixture was stirred for 2 h at 60 °C, then cooled to room tem-
perature and diluted with ethyl acetate. The organic layer was
washed with water, dried over magnesium sulfate and evaporated
under reduced pressure. The residue was purified by chromatogra-
phy on silica gel, using ethyl acetate and hexane as eluents to
deliver 2-(3-bromo-8-methylquinolin-6-yloxy)-2-methylsulfanyl-
acetic acid methyl ester (10, 15.5 g, 43 mmol, 71%). 1H NMR
1
bromo-8-methylquinolin-6-ol (7, 12.3 g, 52 mmol, 67%). H NMR
(
DMSO-d
6
): d = 2.64 (s, 3H), 6.99 (d, 1H, J = 2.1 Hz), 7.22 (d, 1H,
J = 2.1 Hz), 8.47 (d, 1H, J = 2.2 Hz), 8.69 (d, 1H, J = 2.3 Hz), 10.13 (s,
+
+
1
H). LC-MS: R
From 6: a mixture of 3-bromo-6-methoxy-8-methylquinoline
6, 14.0 g, 55 mmol) in 250 ml of 48% hydrobromic acid was slowly
t
= 1.78 min; MS: m/z = 238 [M] , 239 [M+1] .
(
heated to 110 °C and kept at this temperature for 20 h. Subse-
quently, the reaction mixture was cooled to room temperature
and filtered. The residue was washed with water, taken up in sat-
urated aqueous sodium bicarbonate solution and filtered again.
The remainder was washed with water and dried in high vacuum
(CDCl
6.96 (d, 1H, J = 2.2 Hz), 7.36 (d, 1H, J = 2.1 Hz), 8.18 (d, 1H,
J = 2.0 Hz), 8.80 (d, 1H, J = 2.1 Hz). LC-MS: R = 2.04 min; MS:
3
): d = 2.23 (s, 3H), 2.74 (s, 3H), 3.87 (s, 3H), 5.72 (s, 1H),
t
+
+
m/z = 358 [M+1] , 359 [M+2] .
to afford 3-bromo-8-methylquinolin-6-ol (7, 11.1 g, 47 mmol,
1
8
4%). H NMR and LC-MS were identical to those obtained from 4.
4.1.7. 2-(3-Bromo-8-methylquinolin-6-yloxy)-2-
methylsulfanyl-acetic acid (11)
4
.1.4. 2-(3-Bromo-8-methylquinolin-6-yloxy)-butyric acid
2 N sodium hydroxide (21 ml, 42 mmol) was added to a suspen-
sion of 2-(3-bromo-8-methylquinolin-6-yloxy)-2-methylsulfanyl-
acetic acid methyl ester (10, 10 g, 28 mmol) in 65 ml of ethanol.
The reaction mixture was stirred for 1 h at room temperature, then
cooled to 0 °C and acidified with 2 N hydrochloric acid until pH 2
was reached. The resulting precipitate was filtered and dried in a
dessicator to obtain 2-(3-bromo-8-methylquinoline-6-yloxy)-2-
methylsulfanyl-acetic acid (11, 9.6 g, 28 mmol, 100%). 1H NMR
methyl ester (8)
Potassium carbonate (8.7 g, 63 mmol) was added to a solution
of 3-bromo-8-methylquinolin-6-ol (7, 5.0 g, 21 mmol) in 70 ml of
N,N-dimethylformamide. After the addition of methyl 2-bromobu-
tyrate (7.1 g, 38 mmol), the reaction mixture was stirred for 16 h at
room temperature. Subsequently the mixture was filtered and the
filtrate was diluted with ethyl acetate. This organic phase was
washed with water and brine, dried over magnesium sulfate and
evaporated under reduced pressure. The residue was purified by
chromatography on silica gel, using ethyl acetate and cyclohexane
as eluents to yield 2-(3-bromo-8-methylquinolin-6-yloxy)-butyric
(DMSO-d
6
): d = 2.17 (s, 3H), 2.68 (s, 3H), 6.06 (s, 1H), 7.32 (d, 1H,
J = 2.1 Hz), 7.47 (d, 1H, J = 2.0 Hz), 8.54 (d, 1H, J = 2.1 Hz), 8.83 (d,
+
1H, J = 2.2 Hz). LC-MS: R
[M+2] .
t
= 1.95 min; MS: m/z = 344 [M+1] , 345
+
acid methyl ester (8, 6.5 g, 19 mmol, 91%). 1H NMR (CDCl
d = 1.04 (t, 3H, J = 7.3 Hz), 1.99 (q, 2H, J = 7.1 Hz), 2.68 (s, 3H),
.70 (s, 3H), 4.63 (t, 1H, J = 7.7 Hz), 6.65 (d, 1H, J = 2.3 Hz), 7.22
d, 1H, J = 2.2 Hz), 8.06 (d, 1H, J = 2.1 Hz), 8.68 (d, 1H, J = 2.1 Hz).
):
3
4.1.8. 2-(3-Bromo-8-methylquinolin-6-yloxy)-N-tert-butyl-2-
methylsulfanyl-acetamide (12)
Triethylamine (1.5 g, 15 mmol), 1-hydroxy-7-azabenzotriazole
(2.0 g, 15 mmol), 1-ethyl-3-(3-dimethylamino-propyl)carbodiim-
3
(
+
+
t
LC-MS: R = 1.12 min; MS: m/z = 340 [M+1] , 341 [M+2] .