Journal of Medicinal Chemistry
Article
15% EtOAc in hexanes) afforded 33.5 g (88%) of the title compound.
(d, 1H), 7.08 (m, 1H), 7.13 (m, 1H), 7.32−7.40 (m, 4H), 7.58 (d,
1H), 7.69 (dd, 1H), 8.31 (d, 1H), 8.46 (s, 1H). [M + H]+: m/z
calculated 648; observed 648
3-[3-tert-Butylsulfanyl-1-[4-(6-methoxypyridin-3-yl)benzyl]-
5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-
propionic Acid (11j). For step 3, 2-chloromethyl-5-methylpyridine
hydrochloride (16c) was used as the alkylating agent at 55 °C for 24 h.
1H NMR (CDCl3) δ 1.22 (s, 9H), 1.27 (s, 6H), 2.35 (s, 3H), 3.33 (s,
2H), 3.95 (s, 3H), 5.21 (s, 2H), 5.43 (s, 2H), 6.76 (d, 1H), 6.82 (m,
3H), 6.99 (d, 1H), 7.33 (m, 3H), 7.49 (d, 1H), 7.56 (dd, 1H), 7.68
(dd, 1H), 8.28 (d, 1H), 8.47 (s, 1H). [M + H]+: m/z calculated 624;
observed 624.
1H NMR (CDCl3) δ 1.16 (t, 3H), 1.21 (s, 6H), 1.25 (s, 9H), 1,31 (s,
12H), 3.25 (s, 2H), 4.04 (q, 2H), 4.69 (s, 1H), 5.37 (s, 2H), 6.65 (dd,
1H), 6.76 (d, 2H), 6.96 (d, 1H), 7.17 (d, 1H), 7.67 (d, 2H). [M +
H]+: m/z calculated 566; observed 566.
Step 2: 3-{3-tert-Butylsulfanyl-5-hydroxy-1-[4-(6-methoxy-
pyridin-3-yl)benzyl]-1H-indol-2-yl}-2,2-dimethylpropionic
Acid Ethyl Ester (13, R2 = 6-Methoxypyridin-3-yl). To a solution
of 12 (25.3 g, 44.8 mmol) in a mixture of 1,2-dimethoxyethane (300
mL) and water (150 mL) were added potassium carbonate (15.5 g,
112.1 mmol) and 5-bromo-2-methoxypyridine (10.9 g, 58.0 mmol).
The mixture was degassed via sparging with nitrogen gas for 30 min
and tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and
heated at 80 °C under nitrogen for 24 h. The reaction mixture was
reduced in volume in vacuo and diluted in EtOAc and washed with
water. The aqueous phase was extracted with EtOAc, and the
combined organic phases were dried (MgSO4), filtered, and
evaporated in vacuo. The residue was purified using silica gel
chromatography (0−20% EtOAc in hexanes) to yield 23.7 g (96%)
of the title compound as a colorless foam. 1H NMR (CDCl3) δ 1.17 (t,
3H), 1.23 (s, 6H), 1.28 (s, 9H), 3.29 (s, 2H), 3.97 (s, 3H), 4.04 (q,
2H), 5.40 (s, 2H), 6.70 (dd, 1H), 6.79 (d, 1H), 6.85 (d, 2H), 7.20 (d,
1H), 7.37 (d, 2H), 7.72 (dd, 1H), 8.31 (d, 1H).
3-[3-tert-Butylsulfanyl-1-[4-(6-methoxypyridin-3-yl)benzyl]-
5-(6-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-
propionic Acid (11k). For step 3, 16d was used as the alkylating
1
agent using catalytic TBAI in DMF as solvent at 50 °C. H NMR
(CDCl3) δ 1.24 (s, 15H), 2.81 (s, 3H), 3.34 (s, 2H), 3.95 (s, 3H), 5.45
(s, 2H), 5.54 (s, 2H), 6.78 (d, 1H), 6.88 (m, 3H), 7.07 (d, 1H), 7.35
(m, 4H), 7.71 (m, 2H), 7.95 (m, 1H), 8.32 (s, 1H). [M + H]+: m/z
calculated 624; observed 624.
3-{3-tert-Butylsulfanyl-5-(5,6-dimethylpyridin-2ylmethoxy)-
1-[4-(6-methoxypyridin-3-yl)benzyl]-1H-indol-2-yl}-2,2-dime-
thylpropionic Acid (11n). For step 3, compound 26 was used as the
1
alkylating agent at 35 °C for 12 h. H NMR (CDCl3) δ 1.22 (s, 9H),
Step 3: 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxypyridin-3-yl)-
benzyl]-5-(quinoxalin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dime-
thylpropionic Acid Ethyl Ester. To the phenol isolated in step 2
(1.62 g, 2.96 mmol) in MeCN (45 mL) were added cesium carbonate
(2.89 g, 8.87 mmol) and 2-chloromethylquinoxaline (15, 0.58 g, 3.25
mmol), and the suspension was stirred at ambient temperature for 12
h. The reaction mixture was partitioned between CH2Cl2 and water,
and the organic phase was separated, washed with water, dried
(MgSO4), filtered, and evaporated in vacuo. The residue was purified
using silica gel chromatography (ISCO, 0−5% EtOAc in CH2Cl2) to
1.26 (s, 6H), 2.28 (s, 3H), 2.53 (s, 3H), 3.33 (s, 2H), 3.95 (s, 3H),
5.18 (s, 2H), 5.43 (s, 2H), 6.76 (s, 1H), 6.85 (m, 3H), 7.03 (d, 1H),
7.32 (m, 4H), 7.42 (d, 1H), 7.69 (dd, 1H), 8.30 (d, 1H). [M + H]+:
m/z calculated 638; observed 638.
3-{3-tert-Butylsulfanyl-5-(5-chloropyridin-2-ylmethoxy)-1-
[4-(6-methoxypyridin-3-yl)benzyl]-1H-indol-2-yl}-2,2-dime-
thylpropionic Acid (11o). For step 3, compound 27 was used as the
1
alkylating agent with catalytic TBAI in DMF as solvent for 12 h. H
NMR (CDCl3) δ 1.22 (s, 9H), 1.27 (s, 6H), 3.35 (s, 2H), 3.96 (s, 3H),
5.24 (s, 2H), 5.45 (s, 2H), 6.78 (d, 1H), 6.87 (m, 3H), 7.08 (d, 1H),
7.30 (d, 1H), 7.37 (d, 2H), 7.54 (d, 1H), 7.69 (m, 2H), 8.30 (d, 1H),
8.57 (d, 1H). [M + H]+: m/z calculated 644; observed 644.
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afford 1.84 g (90%) of the title ester as a colorless solid. H NMR
(CDCl3) δ 1.15 (s, 9H), 1.17 (t, 3H), 1.23 (s, 6H), 3.29 (s, 2H), 3.96
(s, 3H), 4.05 (q, 2H), 5.43 (s, 2H), 5.50 (s, 2H), 6.78 (d, 1H), 6.85 (d,
2H), 6.94 (dd, 1H), 7.10 (d, 1H), 7.37 (m, 3H), 7.72 (dd, 1H), 7.78
(m, 2H), 8.11 (m, 2H), 8.31 (d, 1H), 9.14 (s, 1H).
3-[3-tert-Butylsulfanyl-1-[4-(6-methoxypyridin-3-yl)benzyl]-
5-(5-methoxypyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dime-
thylpropionic Acid (11p). For step 3, compound 18 was used as the
Step 4: 3-{-3-tert-Butylsulfanyl-1-[4-(6-methoxypyridine-3-
yl)benzyl]-5-(quinoxalin-2-ylmethoxy)-1H-indol-2-yl}-2,2-di-
methylpropionic Acid. To the ester isolated in step 3 (150 mg, 0.22
mmol) in a mixture of THF (4 mL), MeOH (1.3 mL), and water (1.3
mL) was added LiOH·H2O (45 mg, 1.07 mmol), and the solution was
heated at 60 °C for 4 h. Upon completion of the reaction the mixture
was diluted with EtOAc and water, solid citric acid was added to attain
an aqueous pH of ∼3, and the aqueous phase was extracted with
EtOAc. The organic phase was washed with water, dried (MgSO4),
filtered, and evaporated in vacuo to yield 140 mg (97%) of the title
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alkylating agent with catalytic TBAI and DMF as solvent for 12 h. H
NMR (CDCl3) δ 1.22 (s, 9H), 1.26 (s, 6H), 3.86 (s, 3H), 3.94 (s, 3H),
5.18 (s, 2H), 5.43 (s, 2H), 6.75 (d, 1H), 6.84 (m, 3H), 7.02 (d, 1H),
7.23 (dd, 1H), 7.32 (m, 3H), 7.49 (d, 1H), 7.68 (dd, 1H), 8.29 (d,
1H), 8.32 (d, 1H).). [M + H]+: m/z calculated 641; observed 641.
3-{3-tert-Butylsulfanyl-5-(5-carbamoylpyridin-2-ylmethoxy)-
1-[4-(6-methoxypyridin-3-yl)benzyl]-1H-indol-2-yl}-2,2-dime-
thylpropionic Acid (11q). For step 3, compound 19 was used as the
1
alkylating agent with catalytic TBAI and DMF as solvent for 12 h. H
1
NMR (DMSO-d6) δ 1.14 (s, 15H), 3.26 (s, 2H), 3.89 (s, 3H), 5.24 (s,
2H), 5.56 (s, 2H), 6.92 (m, 4H), 7.11 (d, 1H), 7.38 (d, 1H), 7.58 (d,
2H), 7.66 (d, 1H), 7.99 (dd, 1H), 8.30 (dd, 1H), 8.46 (d, 1H), 9.10
(d, 1H). [M + H]+: m/z calculated 654; observed 654.
compound. H NMR (CDCl3) δ 1.15 (s, 9H), 1.26 (s, 6H), 3.33 (s,
2H), 3.95 (s, 3H), 5.45 (s, 2H), 5.49 (s, 2H), 6.76 (d, 1H), 6.85 (d,
2H), 6.94 (dd, 1H), 7.10 (d, 1H), 7.38 (m, 3H), 7.70 (dd, 1H), 7.78
(m, 2H), 8.11 (m, 2H), 8.30 (d, 1H), 9.14 (s, 1H). [M + H]+: m/z
calculated 661; observed 661.
The following compounds were prepared according to route B
using the intermediate prepared from step 2 (Scheme 1, R2 = 6-
methoxy-pyridin-3-yl).
3-[3-tert-Butylsulfanyl-1-[4-(6-methoxypyridin-3-yl)benzyl]-
5-(5-methylpyrazin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-
propionic Acid (11r). For step 3, compound 14 was used as the
1
alkylating agent. H NMR (CDCl3) δ 1.22 (s, 9H), 1.26 (s, 6H), 2.58
(s, 3H), 3.34 (s, 2H), 3.95 (s, 3H), 5.27 (s, 2H), 5.45 (s, 2H), 6.77 (d,
1H), 6.87 (m, 3H), 7.08 (d, 1H), 7.33 (m, 3H), 7.70 (dd, 1H), 8.30
(d, 1H), 8.46 (s, 1H), 8.71 (s, 1H). [M + H]+: m/z calculated 625;
observed 625.
The following compounds were prepared according to route B but
varying the cross-coupling partner in step 2 as described and using
compound 16c as the alkylating agent in step 3.
3-[3-tert-Butylsulfanyl-1-[4-(3-methoxypyridin-3-yl)benzyl]-
5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl}-2,2-dimethyl-
propionic Acid (11w). For step 2, 2-bromo-3-methoxypyridine was
used in the cross-coupling reaction. 1H NMR (CDCl3) δ 0.98 (s, 6H),
1.05 (s, 9H), 2.29 (s, 3H), 3.20 (s, 2H), 3.61 (s, 3H), 5.15 (s, 2H),
5.34 (s, 2H), 6.74 (m, 3H), 6.89 (d, 1H), 7.08 (m, 2H), 7.22 (m, 1H),
7.41 (m, 2H), 7.59 (d, 2H), 8.11 (s, 1H), 8.39 (s, 1H). [M + H]+: m/z
calculated 624; observed 624.
3-[3-tert-Butylsulfanyl-1-[4-(6-methoxypyridin-3-yl)benzyl]-
5-(quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpro-
pionic Acid (11a). For step 3, 2-chloromethylquinoline hydro-
chloride was used as the alkylating agent with catalytic TBAI and DMF
1
as solvent. H NMR (CDCl3) δ 1.16 (s, 15H), 3.32 (s, 2H), 3.95 (s,
3H), 5.43 (s, 4H), 6.77 (d, 1H), 6.84 (d, 2H), 6.90 (dd, 1H), 7.07 (d,
1H), 7.36 (m, 3H), 7.54 (m, 1H), 7.70 (dd, 1H), 7.74 (d, 2H), 7.81
(d, 1H), 8.11 (d, 1H), 8.17 (d, 1H), 8.30 (d, 1H). [M + H]+: m/z
calculated 660; observed 660.
3-{3-tert-Butylsulfanyl-5-(1H-indol-2-ylmethoxy)-1-[4-(6-me-
thoxypyridin-3-yl)benzyl]-1H-indol-2-yl}-2,2-dimethylpro-
pionic Acid (11g). For step 3, 2-chloromethylindole-1-carboxylic
1
acid tert-butyl ester (28) was used as the alkylating agent. H NMR
(CDCl3) δ 1.23 (s, 9H), 1.26 (s, 6H), 3.34 (s, 2H), 3.95 (s, 3H), 5.27
(s, 2H), 5.44 (s, 2H), 6.53 (s, 1H), 6.76 (d, 1H), 6.85 (m, 3H), 7.07
8026
dx.doi.org/10.1021/jm2008369|J. Med. Chem. 2011, 54, 8013−8029