Journal of Medicinal Chemistry
ARTICLE
1
To a mixture of DMPU (0.7 mL) and DMF (2.8 mL) was added
to give the HCl salt of 4 as an off-white solid (175 mg, 42%). H NMR
N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(4-hydroxyphenyl)propana-
(400 MHz, d -DMSO): δ 10.43 (s, 1H), 8.49 (d, J = 5.71 Hz, 1H), 8.21
(d, J = 2.48 Hz, 1H), 7.85 (dd, J = 8.81, 2.45 Hz, 1H), 7.61 (d, J = 8.83
6
1
0
mide (600 mg, 1.75 mmol) and 4-chloro-N-methylpicolinamide (328
t
mg, 1.92 mmol). To this solution was added KO Bu (590 mg, 5.25
Hz, 1H), 7.46 (d, J = 2.27 Hz, 1H), 7.23 (d, J = 8.30 Hz, 1H), 7.16 (dd,
J = 5.73, 2.57 Hz, 1H), 6.99 (d, J = 2.39 Hz, 1H), 6.95 (dd, J = 8.23, 2.51
Hz, 1H), 3.01-2.92 (m, 2H), 2.91-2.72 (m, 6H), 2.19-2.06 (m, 1H),
mmol). The reaction mixture was stirred at 100 °C for 18 h and then
cooled to room temperature, diluted with water, and extracted with
EtOAc and DCM. The combined organic solutions were washed with
þ
and 1.92-1.72 (m, 1H). LC-MS: m/z 504.3/506.3 [M þ H] , 502.4/
-
water and brine, dried over Na
2
SO
4
, filtered, and concentrated to give a
504.3 [M - H] (AA). HRMS: m/z calcd for C H N O ClF ([M þ
2
5
22
3
3
3
þ
brown oil. Purification by column chromatography provided 4-[4-(3-{[4-
chloro-3-(trifluoromethyl)phenyl]amino}-3-oxopropyl)phenoxy]-N-
H]) , 504.12963; found, 504.130179.
General Procedure B1, Amide Bond Formation. 7-({2-[-
(Methylamino)carbonyl]pyridine-4-yl}oxy)-1,2,3,4-tetrahydronaphth-
alene-2-carboxylic acid (400 mg, 1.22 mmol), 5-amino-2-cyanobenzo-
trifluoride (251 mg, 1.35 mmol), EDCI (258 mg, 1.35 mmol), and
DMAP (180 mg, 1.47 mmol) were combined in DCM (10 mL), and the
resulting mixture was stirred overnight at room temperature. The
reaction mixture was concentrated in vacuo, diluted with EtOAc, and
extracted with aqueous 1 N HCl solution. The organic phase was
methylpyridine-2-carboxamide as a colorless solid (100 mg, 12%
1
yield). H NMR (300 MHz, CD
3
OD): δ 10.11 (br s, 0.3H), 8.41
(d, J = 5.6 Hz, 1H), 8.07 (br d, J = 2.2 Hz, 1H), 7.74 (br dd, J = 8.7, 2.1
Hz, 1H), 7.48-7.51 (m, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 8.5
Hz, 2H), 6.98 (dd, J = 5.6, 2.5 Hz, 1H), 3.34 (s, 0.8H), 3.04 (t, J = 7.5
Hz, 2H), 2.92 (s, 3H), 2.71 (t, J = 7.5 Hz, 2H).
4
-[3-(3-{[4-Chloro-3-(trifluoromethyl)phenyl]amino}-3-
oxopropyl)phenoxy]-N-methylpyridine-2-carboxamide
3). A mixture of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(3-hydro-
washed with brine, dried over MgSO , filtered, and concentrated.
4
(
Purification by column chromatography (SiO , elution with 0-50%
2
xyphenyl)propanamide [585 mg, 1.70 mmol, prepared as described
above using 3-(3-hydroxyphenyl)propanoic acid and 4-chloro-
EtOAc in hexanes) provided 4-{[7-({[4-cyano-3-(trifluoromethyl)ph-
enyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-meth-
1
0
1
3-(trifluoromethyl)aniline], 4-chloro-N-methylpicolinamide
(318
ylpyridine-2-carboxamide as a white powder (480 mg, 79%). H NMR
mg, 1.87 mmol), and Cs CO (7.76 g, 8.5 mmol) in DMF (3.4 mL)
2
3
(400 MHz, CDCl
(m, 1H), 8.22 (d, J = 4.9 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 8.03 (dd, J =
.5, 1.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.06
d, J = 8.3 Hz, 1H), 7.00 (dd, J = 5.6, 2.5 Hz, 1H), 6.81 (dd, J = 8.2, 2.3
3
): δ 9.30 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.25-8.18
was heated at 100 °C overnight. The reaction mixture was concentrated
and diluted with EtOAc. The organic solution was washed with brine,
8
(
dried over MgSO
by column chromatography (SiO
as a white solid (10 mg, 1% yield). H NMR (400 MHz, CD OD): δ
4
, filtered, and concentrated. The residue was purified
2
, 0-30% EtOAc in hexanes) to give 3
Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 3.05-2.97 (m, 4H), 2.88 (dd, J = 16.9,
3.4 Hz, 2H), 2.77-2.60 (m, 2H), 2.22-2.13 (m, 1H), and 2.01-1.89
1
3
8
7
7
2
.39 (d, J = 5.58 Hz, 1H), 8.03 (d, J = 2.43 Hz, 1H), 7.74-7.66 (m, 1H),
.50 (dd, J = 8.12, 5.65 Hz, 2H), 7.40 (d, J = 7.86 Hz, 1H), 7.22 (d, J =
.68 Hz, 1H), 7.06 (s, 1H), 7.03-6.96 (m, 2H), 3.05 (t, J = 7.48, 7.48 Hz,
(m, 1H).
4-{[7-({[4-(Aminomethyl)-3-(trifluoromethyl)phenyl]ami-
no}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-
methylpyridine-2-carboxamide (18). 4-{[7-({[4-Cyano-3-(trifl-
uoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-
yl]oxy}-N-methylpyridine-2-carboxamide (200 mg, 0.4 mmol) was dis-
H), 2.93 (s, 3H), and 2.71 (t, J = 7.46, 7.46 Hz, 2H). LCMS: m/z 478.3
þ
[M þ H] (AA).
General Procedure A1, Biaryl Ether Bond Formation. A
mixture of 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
solved in 7.0 M NH in MeOH solution. To this solution was added
Raney 2800 nickel (50% v/v slurry in water, approx 2 mL), and the mix-
3
10
(8.00 g, 41.6 mmol), 4-chloro-N-methylpicolinamide (8.58 g, 50.3
mmol), and cesium carbonate (40.7 g, 125 mmol) in DMF (150 mL)
was heated at 100 °C overnight. The reaction was cooled to room temp-
erature and concentrated under vacuum. The resulting slurry was diluted
with water and acidified with 1 N HCl solution to pH 3. The mixture was
allowed to stand at room temperature, and a precipitate formed. This preci-
pitate was isolated by filtration, washed well with water, and thoroughly
dried to give 7-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)-1,2,3,4-
ture was stirred under an atmosphere of hydrogen gas for 5 h. The
reaction mixture was filtered through a pad of Celite, and the filtrate was
concentrated. Purification by column chromatography [SiO , elution
2
with 0-5% MeOH (with 1% NH OH) in DCM] provided 18 as a white
4
solid. This material was taken up in DCM and treated with 1 N HCl in
Et O. The solution was concentrated to give the HCl salt of 18 as a white
2
1
6
solid (110 mg, 52%). H NMR (300 MHz, d -DMSO): δ 10.73 (s, 1H),
tetrahydronaphthalene-2-carboxylic acid as a white solid (12.10 g, 89%).
8.86 (dd, J = 9.32, 4.51 Hz, 1H), 8.60 (bs, 2H), 8.51 (d, J = 5.69 Hz, 1H),
8.21 (d, J = 1.72 Hz, 1H), 7.94 (d, J = 8.54 Hz, 1H), 7.73 (d, J = 8.50 Hz,
1H), 7.44 (d, J = 2.40 Hz, 1H), 7.24 (d, J = 8.28 Hz, 1H), 7.18 (dd, J =
5.67, 2.52 Hz, 1H), 7.02 (d, J = 2.16 Hz, 1H), 6.97 (dd, J = 8.20, 2.37 Hz,
1H), 4.14-4.03 (m, 2H), 2.99-2.92 (m, 2H), 2.91-2.81 (m, 3H), 2.78
(d, J = 4.76 Hz, 3H), 2.18-2.06 (m, 1H), and 1.90-1.72 (m, 1H). LC-
1
H NMR (400 MHz, d
.8 Hz, 1H), 12.30 (s, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.20 (d, J = 8.3
Hz, 1H), 7.13 (dd, J = 5.6, 2.6 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.94
dd, J = 8.3, 2.6 Hz, 1H), 2.93 (d, J = 5.4 Hz, 1H), 2.83 (ddd, J = 9.4,
.8, 3.6 Hz, 1H), 2.72 (s, 1H), 2.16-2.06 (m, 1H), and 1.81-1.68
m, 1H).
-{[7-({[4-Chloro-3-(trifluoromethyl)phenyl]amino}car-
6
-DMSO): δ 8.48 (d, J = 5.6 Hz, 1H), 8.76 (d, J =
4
(
7
(
þ
-
MS: m/z 499.4 [M þ H] , 497.4 [M - H] (FA).
4
General Procedure B2, Amide Bond Formation. 7-(2-Acet-
amidopyridin-4-yloxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
(1.00 mg, 3.06 mmol), DIPEA (1.60 mL, 9.19 mmol), and HATU (1.75
g, 4.60 mmol) were combined in DMF (30 mL), and the solution was
stirred for 30 min. tert-Butyl [4-amino-2-(trifluoromethyl)benzyl]-
carbamate (889 mg, 3.06 mmol) was added, and the resulting mixture
was stirred overnight at room temperature. Water was added to the
reaction mixture, and the resulting precipitate was isolated by filtration,
washed well with water and hexane, and dried under vacuum. Purifica-
bonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methyl-
pyridine-2-carboxamide (4). 4-Chloro-3-(trifluoromethyl)aniline
(160 mg, 0.817 mmol), 7-({2-[(methylamino)carbonyl]pyridine-4-
yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (254 mg,
0
0
.778 mmol), EDCI (149 mg, 0.778 mmol), and DMAP (114 mg,
.943 mmol) were suspended in DCM (2.74 mL) in a microwave vial.
The vial was sealed, and the reaction mixture was subjected to micro-
wave irradiation at 60 °C for 5 min. Water and DCM were added to the
reaction mixture, and the phases were separated. The organic phase was
tion by column chromatography (SiO , elution with 20-80% EtOAc in
2
dried over MgSO , filtered, and concentrated. Purification by column
hexane) provided tert-butyl [3-{[((2S)-7-{[2-(acetylamino)pyridin-4-
4
chromatography (SiO , elution with 10-50% EtOAc in hexanes)
provided 210 mg of desired product. This material was taken up in
yl]oxy}-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}-5-(trifluo-
romethyl)benzyl]carbamate as an off white solid (1.21 g, 66%) H NMR
2
1
DCM and treated with 1 N HCl in Et O. The solution was concentrated
(300 MHz, CDCl
3
): δ 8.20 (s, 1H), 8.05 (d, J = 6.1 Hz, 1H), 7.83
2
1
842
dx.doi.org/10.1021/jm101479y |J. Med. Chem. 2011, 54, 1836–1846