Journal of Medicinal Chemistry
ARTICLE
were added to a suspension of 10% Pd/C (17 g) in methanol (1 L) in
argon. The system was flushed with hydrogen, and the mixture was
hydrogenated under a pressure of 40 psi at 84 °C for 5 days. The mixture
was cooled and filtered, and methanol was evaporated. The residue was
treated with a solution of NaOH (25 g) in water (100 mL) and extracted
with dichloromethane (100 mL ꢀ 2). The combined organic layers were
washed with water and brine and dried over Na2SO4. The solvent was
removed in vacuo, and the residue was dissolved in a mixture of THF
(200 mL) and ether (200 mL). A 4 N solution of HCl in dioxane
(53 mL) was added. The formed crystals were separated by filtration to
give 3-[4-(trifluoromethyl)phenyl]-8-azabicyclo[3.2.1]octane hydro-
400 MHz): δ 8.42 (dd, 1H, J = 5.5, 1.0 Hz), 7.98 (d, 1H, J = 8.0 Hz), 7.53
(d, 2H, J = 8.9 Hz), 7.30 (m, 3H), 4.40 (d, 1H, J = 13.7 Hz), 3.91 (s, 3H),
3.49 (d, 1H, J = 13.3 Hz), 2.84 (m, 1H), 2.68 (m, 1H), 2.50 (m, 1H),
2.24 (m, 1H), 1.86 (m, 1H), 1.70 (m, 1H), 1.58 (m, 2H), 1.20 (d, 3H, J =
6.2 Hz). MS (ESþ): m/z 389.2 (Mþ1). UHPLC: 100% (UV), 100%
(ELSD).
1-Methyl-2-((3-(4-(trifluoromethyl)phenyl)-8-azabicyclo[3.2.1]-
octan-8-yl)methyl)-1H-imidazo[4,5-b]pyridine (15). The hydrochlor-
ide salt of the title compound was prepared by reductive amination
method A from 3-[4-(trifluoromethyl)phenyl]-8-azabicyclo[3.2.1]-
octane hydrochloride (10c) and 1-methyl-1H-imidazo[4,5-b]pyridine-
1
1
2-carbaldehyde hydrochloride hydrate (8b). H NMR (CD3OD, 400
chloride (10c) (53.6 g, 70%). H NMR (DMSO-d6, 400 MHz): δ
MHz): δ 8.53 (dd, 1H, J = 5.0, 1.2 Hz), 8.30 (d, 1H, J = 8.3 Hz), 7.79 (d,
2H, J = 8.3 Hz), 7.68 (d, 2H, J = 8.3 Hz), 7.53 (dd, 1H, J = 8.3, 5.0 Hz),
4.78 (m, 1H), 4.45 (m, 2H), 3.95 (s, 3H), 3.46 (m, 1H), 2.80 (m, 4H),
2.28 (m, 2H), 1.88 (m, 2H). MS (APCI): m/z 401.1 (M þ 1). UHPLC:
100% (UV), 100% (ELSD).
2-((3,3-Dimethyl-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-
methyl)-1-methyl-1H-imidazo[4,5-b]pyridine (16). The free base of
the title compound was prepared by reductive amination method A from
3,3-dimethyl-4-(4-(trifluoromethyl)phenyl)piperidine hydrochloride
(10d) and 1-methyl-1H-imidazo[4,5-b]pyridine-2-carbaldehyde hydro-
chloride hydrate (8b). 1H NMR (CD3OD, 400 MHz): δ 8.39 (dd, 1H,
J = 5.5, 1.2 Hz), 8.01 (d, 1H, J = 8.0 Hz), 7.53 (d, 2H, J = 8.9 Hz), 7.35
(m, 3H), 4.03 (s, 3H), 3.87 (s, 2H), 3.00 (d, 1H, J = 8.3 Hz), 2.53 (m,
2H), 2.23 (m, 2H), 2.18 (m, 1H), 1.56 (m, 1H), 0.89 (s, 3H), 0.71 (s,
3H). MS (APCI): m/z 403.4 (M þ 1). UHPLC: 100% (UV), 97%
(ELSD).
9.15 (br, s, 2H), 7.68 (s 4H), 3.95 (m, 2H), 3.40 (m, 1H), 2.45 (m, 2H),
2.20 (m, 2H), 1.88 (m, 2H), 1.55 (m, 2H). MS (ESþ):m/z256.1 (M þ 1).
UHPLC: 96% (UV), 98% (ELSD).
3,3-Dimethyl-4-(4-(trifluoromethyl)phenyl)piperidine Hydrochlor-
ide (10d). The title compound was prepared by the method described
in the synthesis of 10c. 1H NMR (CD3OD, 400 MHz): δ 7.56 (d, 2H, J =
7.9 Hz), 7.35 (d, 2H, J = 7.9 Hz), 3.18 (m, 1H), 2.6-2.75 (m, 4H), 2.18
(m, 1H), 1.50 (m, 1H), 0.88 (s, 3H), 0.74 (s, 3H). MS (ESþ): m/z 299.2
(M þ CH3CN).
1-((1-Methyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-4-(4-(trifluoro-
methyl)phenyl)piperidin-3-ol (13). The free base of the title com-
pound was prepared by reductive amination method A from trans-
4-(4-(trifluoromethyl)phenyl)piperidin-3-ol (10a) and 1-methyl-1H-
imidazo[4,5-b]pyridine-2-carbaldehyde hydrochloride hydrate (8b).
1
The trans-diastereomer: H NMR (CD3OD, 400 MHz): δ 8.37 (dd,
1H, J = 3.3, 1.2 Hz), 8.0 (m, 1H), 7.50-7.70 (m, 3H), 7.42 (d, 2H, J =
8.4 Hz), 7.32 (m, 1H), 3.97 (s, 3H), 3.93 (s, 2H), 3.78 (m, 1H), 3.12
(m, 1H), 2.91 (m, 1H), 2.78 (m, 1H), 2.68 (m, 1H), 2.52 (m, 1H), 2.25
(m, 1H), 2.10 (m, 1H), 1.80 (m, 1H). MS (APCI): m/z 391.1 (M þ 1).
UHPLC: 95% (UV), 86% (ELSD).
1-Methyl-2-((cis-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidin-
1-yl)methyl)-1H-imidazo[4,5-b]pyridine (17a)
Step 1. 4-Bromo-3-methylpyridine (1.36 g, 7.89 mmol), 4-trifluoro-
methylphenyl boronic acid (1.50 g, 7.89 mmol), sodium bicarbonate
(2.65 g, 31.6 mmol), and tetrakis (triphenylphosphine) palladium(0)
(912 mg, 0.79 mmol) were combined in DME (40 mL) and H2O
(10 mL) under N2 at room temperature. The reaction mixture was then
heated to reflux at 85 °C for 17 h. After it was cooled to room
temperature, the mixture was diluted by water and extracted with ethyl
acetate. The organic layers were combined and washed with water and
brine and dried over anhydrous Na2SO4. The solvent was removed in
vacuo, and the residue was purified by flash chromatography (silica gel,
30% EtOAc in hexanes) to give 1.42 g (76% yield) of 3-methyl-
4-(4-(trifluoromethyl)phenyl)pyridine as a viscous oil. 1H NMR
(CDCl3, 400 MHz): δ 8.52 (s, 1H), 8.47 (d, 1H, J = 5 Hz), 7.69 (d,
2H, J = 8.3 Hz), 7.42 (d, 2H, J = 7.9 Hz), 7.10 (d, 1H, J = 5 Hz), 2.24 (s,
3H). MS (ESþ): m/z 238.1 (M þ 1). The free base was dissolved in
CH2Cl2 (10 mL), and 4 N HCl in dioxane was added (2 mL). The
mixture was stirred at room temperature for 10 min, and the solvent was
concentrated in vacuo. The resulting solid was suspended in cold ethyl
ether and filtered to yield 1.58 g of the hydrochloride salt as a white solid,
which was used in the next step.
1-Methyl-2-((cis-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidin-
1-yl)methyl)-1H-imidazo[4,5-b]pyridine (14)
Step 1. 4-Bromo-2-methylpyridine (209 mg, 1.16 mmol), 4-trifluor-
omethylphenyl boronic acid (221 mg, 1.16 mmol), sodium bicarbonate
(293 mg, 3.48 mmol), and tetrakis (triphenylphosphine) palladium(0)
(18.4 mg, 0.012 mmol) were combined in DME (10 mL) and H2O
(2 mL) under N2 at room temperature. The reaction mixture was then
heated to reflux at 85 °C for 17 h. After it was cooled to room
temperature, the mixture was diluted by water and extracted with ethyl
acetate (50 mL ꢀ 2). The combined organic layer was washed with
water and brine and dried over anhydrous Na2SO4. The solvent was
removed in vacuo, and the residue was purified by flash chromatography
(silica gel, 30% EtOAc in hexanes) to give 240 mg of 2-methyl-
4-(4-(trifluoromethyl)phenyl)pyridine as a viscous oil. The residue
was then dissolved in CH2Cl2 (5 mL), and 4 N HCl in dioxane was
added (1 mL). The mixture was stirred at room temperature for 10 min,
and the solvent was concentrated in vacuo. The resulting solid was
suspended in cold ethylether and filtered to yield 250 mg of 2-methyl-
4-(4-(trifluoromethyl)phenyl)pyridine hydrochloride salt as pure white
solid. MS (APCI): m/z 238.3 (M þ 1).
Step 2. 2-Methyl-4-(4-(trifluoromethyl)phenyl)pyridine hydrochloride
salt (1.27 g, 4.68 mmol) was dissolved in ethanol (20 mL), and platinum-
(IV) oxide (50 mg) was added. The mixture was then shaken on a Parr
shaker under hydrogen (45 psi) at 50 °C overnight. The reaction mixture
was then filtered through a pad of Celite, and the cake was rinsed several
times with methanol. The filtrate was evaporated in vacuo to give 1.25 g of
cis-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidine hydrochloride salt
(18a) as a white solid. MS (APCI): m/z 244.1 (M þ 1).
Step 2. 2-Methyl-4-(4-(trifluoromethyl)phenyl)pyridine hydrochlor-
ide salt (250 mg, 0.92 mmol) was dissolved in methanol (10 mL), and
platinum(IV) oxide (20 mg) was added. The mixture was then shaken
on a Parr shaker under hydrogen (45 psi) at 50 °C for 5 h. The reaction
mixture was then filtered through a pad of Celite, and the cake was rinsed
several times with methanol. The filtrate was evaporated in vacuo to give
253 mg of 2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine hydro-
chloride salt (10b) as a white solid. MS (APCI): m/z 244.3 (M þ 1).
Step 3. The free base of the title compound was prepared by reductive
amination method A with 2-methyl-4-(4-(trifluoromethyl)phenyl)-
piperidine hydrochloride salt (10b) and 1-methyl-1H-imidazo[4,5-b]-
pyridine-2-carbaldehyde hydrochloride hydrate (8b). 1H NMR (CDCl3,
Step 3. The free base of the title compound was prepared by reductive
amination method A with cis-3-methyl-4-(4-(trifluoromethyl)phenyl)-
piperidine hydrochloride salt (18a) and 1-methyl-1H-imidazo[4,5-
b]pyridine-2-carbaldehyde hydrochloride hydrate (8b). 1H NMR
(CDCl3, 400 MHz): δ 8.52 (dd, 1H, J = 5.0, 1.7 Hz), 7.65 (d, 1H,
J = 8.0 Hz), 7.52 (d, 2H, J = 8.3 Hz), 7.23 (m, 2H), 7.18 (m, 1H), 3.92
1736
dx.doi.org/10.1021/jm101414h |J. Med. Chem. 2011, 54, 1724–1739