Journal of Medicinal Chemistry
Article
and 4-bromo-2,6-difluorophenol (5, 58.2 mg, 0.28 mmol). The reaction
mixture was heated at 120 °C for 12 min in a microwave. An identical
reaction at the same scale was repeated, and the two reactions were
combined. The reaction mixture was partitioned between ethyl acetate
and water. The organic layer was separated, dried over sodium sulfate,
filtered, and concentrated. The crude product (4-(4-chloropyridin-3-
yl)-2,6-difluorophenol, 100 mg, 74% yield) was used in the next
reaction. LCMS (m/z) 242.0, Rt 0.53 min.
To 4-(4-chloropyridin-3-yl)-2,6-difluorophenol (30 mg, 0.12 mmol)
in DME (2 mL) and 2 M sodium carbonate (0.75 mL, 1.50 mmol) were
added (4-hydroxyphenyl)boronic acid (34.3 mg, 0.25 mmol) and 1,1′-
bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (10.1
mg, 0.01 mmol), and the reaction mixture was heated in a microwave
at 130 °C for 20 min. Additional (4-hydroxyphenyl)boronic acid (17.2
mg, 0.12 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]-
dichloropalladium(II)·DCM (10.1 mg, 0.01 mmol) were added. The
reaction mixture was heated at 130 °C for 30 min in a microwave. The
reaction mixture was partitioned between ethyl acetate and water, and
the organic layer was separated, dried over sodium sulfate, filtered, and
concentrated. The residue was purified by reverse phase HPLC to give
30 (5.1 mg, 3% yield) as the TFA salt. 1H NMR (400 MHz, CD3OD) δ
7.47 (m, 2H), 7.59−7.72 (m, 2H), 7.75−7.92 (m, 2H), 8.22−8.39 (m,
1H), 9.26−9.52 (m, 2H), 10.39−10.71 (m, 1H), 11.00−11.33 (m, 1H).
LCMS (m/z) 300.0, Rt 0.46 min, UPLC 1.20 min. HRMS found m/z
300.0837; C17H12NO2F2 requires 300.0836.
Synthesis of 2,6-Difluoro-4-(4-phenylpyridin-3-yl)phenol
(31). To 4-bromo-2,6-difluorophenol (1.20 g, 5.74 mmol) and 4-
chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.38 g,
5.74 mmol) in DME (16 mL) and 2 M sodium carbonate (4.0 mL, 8.00
mmol) was added PdCl2(dppf)·DCM (0.47 g, 0.57 mmol). The reaction
mixture was heated in an oil bath at 100 °C for 3 h. The reaction mixture
was diluted with EtOAc, filtered, and evaporated. The residue was
triturated with DCM, and the solid was filtered and washed with DCM
to provide 4-(4-chloropyridin-3-yl)-2,6-difluorophenol (996 mg, 72%
yield). LCMS (m/z) 241.9, 242.9, 0.53 min.
Compound 31 was synthesized by the same method as 30 to give 20
mg (TFA salt, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ 6.80 (m,
2H), 7.06−7.28 (m, 2H), 7.28−7.47 (m, 6H), 7.48−7.69 (m, 2H),
8.54−8.80 (m, 3H), 10.14−10.62 (m, 1H). LCMS (m/z) 284.0, Rt 0.57
min, UPLC 2.17 min. HRMS found m/z 284.0890; C17H12NOF2
requires 284.0887.
Synthesis of 2,6-Difluoro-4-(4-(tetrahydro-2H-pyran-4-yl)-
pyridin-3-yl)phenol (32). A mixture of 4-(4-chloropyridin-3-yl)-2,6-
difluorophenol (48 mg, 0.20 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.1 mg, 0.24 mmol), Pd-
(dtbpf)Cl2 (12.9 mg, 0.02 mmol), and 2 M Na2CO3 (0.30 mL, 0.60
mmol) in 1,4-dioxane (4 mL) was heated in a microwave at 120 °C for
10 min. The reaction mixture was diluted with ethyl acetate (100 mL)
and washed with sat. NaCl (20 mL). The organic layer was dried over
MgSO4, filtered, and concentrated. The residue was purified by column
chromatography (5% methanol in 1:1 ethyl acetate and heptane) to give
4-(4-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-2,6-difluorophenol (32
mg, 55% yield). LCMS (m/z) 290.0, Rt 0.42 min.
4-(4-(3,6-Dihydro-2H-pyran-4-yl)pyridin-3-yl)-2,6-difluorophenol
(22 mg, 0.08 mmol) was dissolved in MeOH (2 mL), and Pd/C (8.1
mg) was added. The flask was fitted with a 3-way stopcock, and the flask
was evacuated under vacuum and then filled with H2. The reaction was
stirred under H2 overnight, and then the reaction was flushed with N2.
The solid was removed by filtration, and the filtrate was concentrated
under reduced pressure. The crude product was purified by reverse-
phase HPLC to give 32 as the TFA salt (1.5 mg, 5% yield). 1H NMR
(400 MHz, CD3OD) δ 1.67 (d, J = 12.91 Hz, 2H), 1.78−1.94 (m, 3H),
3.07−3.19 (m, 2H), 3.37 (dd, J = 11.74, 10.37 Hz, 2H), 3.98(dd, J =
11.54, 3.72 Hz, 2H), 6.97−7.09 (m, 2H), 7.94 (d, J = 6.06 Hz, 1H), 8.57
(s, 1H), 8.67 (d, J = 5.87 Hz, 1H). LCMS (m/z) 292.0, Rt 0.42 min;
UPLC 1.01 min. HRMS found m/z 292.1151; C16H16NO2F2 requires
292.1149.
olan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (184 mg, 0.60
mmol), Pd(dtbpf)Cl2 (32.4 mg, 0.05 mmol), and Na2CO3 (2 M, 0.75
mL, 1.5 mmol) in 1,4-dioxane (5 mL) was stirred in microwave at 120
°C for 10 min. The reaction mixture was diluted with ethyl acetate (100
mL) and washed with sat. NaCl (20 mL). The organic layer was dried
over MgSO4, filtered, and concentrated. The residue was purified by
column chromatography (5% methanol in 1:1 ethyl acetate and
heptane) to give tert-butyl 4-(3-(3,5-difluoro-4-hydroxyphenyl)pyridin-
4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (145 mg, 75% yield).
LCMS (m/z) 389.3, Rt 0.66 min.
tert-Butyl 4-(3-(3,5-difluoro-4-hydroxyphenyl)pyridin-4-yl)-5,6-di-
hydropyridine-1(2H)-carboxylate (125 mg, 0.32 mmol) was dissolved
in MeOH (5 mL), and Pd/C (68.5 mg, 0.06 mmol) was added. The flask
was fitted with a 3-way stopcock, and the flask was evacuated under
vacuum and then filled with H2. The reaction was stirred under H2 for 4
h, and then the reaction was flushed with N2. The solid was removed by
filtration, and the filtrate was concentrated to give the crude tert-butyl 4-
(3-(3,5-difluoro-4-hydroxyphenyl)pyridin-4-yl)piperidine-1-carboxy-
late (105 mg, yield 84%) which was used directly in the next reaction.
LCMS (m/z) 391.1, Rt 0.68 min.
A mixture of tert-butyl 4-(3-(3,5-difluoro-4-hydroxyphenyl)pyridin-
4-yl)piperidine-1-carboxylate (70 mg, 0.18 mmol) in DCM (4 mL) and
TFA (1 mL) was stirred at rt for 2 h. The solvents were removed, and the
crude product was purified by reverse phase HPLC to 33 as the TFA salt
(45 mg, 62% yield). 1H NMR (400 MHz, CD3OD) δ 2.00 (d, J = 6.85
Hz, 5H), 2.69−2.94 (m, 4H), 3.00 (br. s., 3H), 3.18 (br. s., 2H), 3.44 (d,
J = 12.52 Hz, 3H), 6.88−7.12 (m, 2H), 7.76 (br. s., 2H), 8.54 (s, 1H),
8.67 (br. s., 2H); LCMS (m/z) 291.1, Rt 0.25 min, UPLC 0.32 min.
HRMS found m/z 291.1307; C16H17N2OF2 requires 291.1309.
Synthesis of 2,6-Difluoro-4-(4-isopropylpyridin-3-yl)phenol
(34). To a mixture of 4-(4-chloropyridin-3-yl)-2,6-difluorophenol (50
mg, 0.21 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-
dioxaborolane (174 mg, 1.04 mmol) in 2 M sodium carbonate (1.04
mL, 2.07 mmol) and dioxane (2.1 mL) was added Pd(dtbpf)Cl2 (22.9
mg, 0.03 mmol). The reaction mixture was heated in a microwave at 120
°C for 15 min. The reaction mixture was diluted with ethyl acetate, dried
over MgSO4, filtered, and concentrated. The crude 2,6-difluoro-4-(4-
(prop-1-en-2-yl)pyridin-3-yl)phenol (51.2 mg) was used in the next
reaction. LCMS (m/z) 248.0, Rt 0.51 min.
The crude 2,6-difluoro-4-(4-(prop-1-en-2-yl)pyridin-3-yl)phenol
(51.2 mg, 0.21 mmol) was dissolved in MeOH (4.1 mL) and then
purged with N2 for 5 min. Pd/C (22.0 mg, 0.02 mmol) was added, and
the reaction was placed under an atmosphere of H2 and stirred overnight
at rt. The reaction was then flushed with N2. The reaction mixture was
filtered through a pad of Celite and then concentrated. The residue was
purified by reverse phase HPLC to give 34 as a TFA salt (8.8 mg, 17%
yield). 1H NMR (400 MHz, CD3OD) δ 1.17 (d, J = 7.04 Hz, 6H), 3.16
(t, J = 6.85 Hz, 1H), 6.90−6.96 (m, 2H), 7.88 (d, J = 5.87 Hz, 1H), 8.48
(s, 1H), 8.58 (d, J = 6.26 Hz, 1H). LCMS (m/z) 250.1, Rt 0.52 min;
UPLC 1.63 min. HRMS found m/z 250.1041; C14H14NOF2 requires
250.1043.
Synthesis of 2,6-Difluoro-4-(4-(m-tolyl)pyridin-3-yl)phenol
(35). To 4-(4-chloropyridin-3-yl)-2,6-difluorophenol (40 mg, 0.166
mmol) (for synthesis see 30, step 1) in DME (2 mL) and 2 M sodium
carbonate (0.5 mL, 1.0 mmol) were added m-tolylboronic acid (33.8 mg,
0.248 mmol) and Pd(dtbpf)Cl2 (10.8 mg, 0.017 mmol). The reaction
mixture was heated in a microwave at 120 °C for 12 min. The reaction
mixture was partitioned between ethyl acetate and water, and the
organic layer was separated, dried over sodium sulfate, filtered, and
concentrated. The residue was purified by reverse phase HPLC to give
35 (14 mg, 28% yield) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ
2.22 (s, 3H), 6.61−6.96 (m, 3H), 6.98−7.26 (m, 3H), 7.38−7.62 (m,
1H), 8.40−8.79 (m, 2H), 10.11−10.54 (m, 1H). LCMS (m/z) 298.0, Rt
0.65 min, UPLC 2.32 min. HRMS found m/z 298.1046; C18H14NOF2
requires 298.1043.
Synthesis of 2,6-Difluoro-4-(4-(3-methoxyphenyl)pyridin-3-
yl)phenol (36). Compound 36 was synthesized by the same method as
35 as a TFA salt (13.2 mg, TFA salt, 25% yield). 1H NMR (400 MHz,
DMSO-d6) δ 3.67 (s, 3H), 6.58−7.04 (m, 5H), 7.11−7.37 (m, 1H),
7.46−7.65 (m, 1H), 8.51−8.77 (m, 2H), 10.13−10.55 (m, 1H). LCMS
Synthesis of 2,6-Difluoro-4-(4-(piperidin-4-yl)pyridin-3-yl)-
phenol (33). A mixture of 4-(4-chloropyridin-3-yl)-2,6-difluorophenol
(120 mg, 0.49 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
L
J. Med. Chem. XXXX, XXX, XXX−XXX