Journal of Medicinal Chemistry
Article
with DCM and washed with sat. NaHCO3. The organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The residue
was purified by prep-TLC (DCM/acetone = 3/1) to afford 40 (25 mg,
reduced pressure. The residue was purified by flash column
chromatography (hexane only and then to ethyl acetate/hexane = 1/
8) to afford 67 (290 mg, 70%) as a colorless oil. 1H NMR (CDCl3, 600
MHz) δ 8.09 (d, J = 5.8 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 6.68 (dd, J =
5.8, 2.3 Hz, 1H), 3.79 (d, J = 7.1 Hz, 2H), 1.23−1.16 (m, 1H), 0.64−
0.57 (m, 2H), 0.34−0.27 (m, 2H). 13C NMR (CDCl3, 150 MHz) δ
166.60, 152.51, 150.18, 110.11, 109.86, 73.22, 9.75, 3.31. ESI-MS
184.1: ([M + H]+).
1
quantitative yield) as a colorless amorphous compound. H NMR
(CDCl3, 600 MHz) δ 8.58−8.49 (m, 2H), 8.04−7.98 (m, 1H), 7.89 (s,
1H), 7.72 (s, 1H), 7.39 (s, 1H), 7.22 (d, 2H), 7.02 (d, 2H), 6.33 (d,
1H), 6.06 (s, 1H), 4.53 (s, 1H), 3.49−3.34 (m, 2H), 3.09−2.93 (m,
2H), 2.29−2.08 (m, 5H), 1.50−1.32 (m, 2H). 13C NMR (CDCl3, 600
MHz) δ 180.08, 163.60, 162.32, 153.96, 146.08, 144.68, 144.42, 136.39,
130.18, 123.11, 120.88, 120.09 (q, 1JC−F = 254.4 Hz), 113.87, 107.03,
50.75, 48.68, 31.17, 11.26. HRMS calculated for C24H25F3N5O2S [M +
H]+ 504.1681, found 504.1677.
2-Chloro3-methyl-4-{4-(trifluoromethoxy)phenyloxy}-
pyridine (75). To a solution of 4-(trifluoromethoxy)phenol (60 mg,
0.34 mmol) in dry DMF (0.2 mL) was slowly added 60% sodium
hydride in mineral oil (14 mg, 0.34 mmol) at 0 °C. The mixture was
warmed to room temperature and stirred for 20 min. To the he reaction
mixture was added 2,4-dichloro-3-methylpyridine (64) (50 mg, 0.31
mmol). The reaction mixture was stirred at 120 °C, and the reaction
was stirred overnight. The reaction mixture was concentrated under
reduced pressure. The residue was purified by prep-TLC (ethyl
acetate/hexane = 1/10) to afford 75 (59 mg, 63%) as a colorless oil. 1H
NMR (CDCl3, 600 MHz) δ 8.08 (d, J = 5.6 Hz, 1H), 7.31−7.26 (m,
2H), 7.11−7.06 (m, 2H), 6.56 (d, J = 5.6 Hz, 1H), 2.40 (s, 3H). 13C
NMR (CDCl3, 150 MHz) δ 163.81, 153.36, 153.00, 147.60, 146.19,
(R)-N-3-Pyridyl-N′-(1-[3-chloro-4-{3-chloro-4-
(trifluoromethoxy)phenoxy}pyridine-2-yl]piperidin-3-yl)-
thiourea (49). To a solution of 99 (20 mg, 38 μmol) in DCM (0.2 mL)
was added 4 N HCl in dioxane (0.2 mL) in a dropwise fashion, and the
mixture was stirred for 2 h at room temperature. The mixture was dried
under N2 stream. The residue was dissolved in DCM with iPr2NEt (27
μL, 0.15 mmol), and pyridine-3-isothiocyanate (5.7 mg, 42 μmol) was
added. The mixture was stirred overnight at room temperature. The
mixture was diluted with DCM and washed with sat. NaHCO3. The
organic layer was dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by prep-TLC (DCM/acetone = 3/1)
1
123.13, 122.74, 121.55, 120.53 (q, JC−F = 255.5 Hz), 110.16, 12.58.
ESI-MS 304.0: ([M + H]+).
1
to afford 49 (12 mg, 57%) as a colorless amorphous compound. H
tert-Butyl [1-{4-(Cyclopropylmethyloxy)pyridin-2-yl}-
piperidin-4-yl]carbamate (82). A solution of 67 (80 mg, 0.44
mmol), tert-butyl (piperidin-4-yl)carbamate (440 mg, 2.2 mmol), and
potassium carbonate (120 mg, 0.87 mmol) in dry DMSO (1 mL) was
stirred at 120 °C for 24 h. The mixture was diluted with DCM and
filtered through a pad of silica with ethyl acetate. The eluent was
concentrated under reduced pressure and the residue was purified by
flash column chromatography (hexane only and then to hexane/ethyl
acetate = 1/10 to 1/2) to afford 82 (40 mg, 26%) as a white solid. 1H
NMR (CDCl3, 600 MHz) δ 7.99 (d, J = 5.8 Hz, 1H), 6.20 (dd, J = 5.8,
2.1 Hz, 1H), 6.11 (d, J = 2.1 Hz, 1H), 4.54−4.42 (m, 1H), 4.14 (dt, J =
13.9, 3.6 Hz, 2H), 3.79 (d, J = 7.0 Hz, 2H), 3.72−3.60 (m, 1H), 2.93
(ddd, J = 13.8, 11.6, 2.7 Hz, 2H), 2.04−1.94 (m, 2H), 1.49−1.34 (m,
11H), 1.28−1.18 (m, 1H), 0.68−0.60 (m, 2H), 0.37−0.29 (m, 2H).
13C NMR (CDCl3, 150 MHz) δ 166.79, 161.26, 155.28, 149.22, 101.22,
NMR (CDCl3, 600 MHz) δ 8.56 (s, 1H), 8.46 (dd, J = 4.8, 1.5 Hz, 1H),
7.83 (s, 2H), 7.62 (s, 1H), 7.54 (s, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.30
(dd, J = 8.1, 4.7 Hz, 1H), 7.20 (dd, J = 8.9, 2.8 Hz, 1H), 7.13 (d, J = 8.9
Hz, 1H), 6.09 (d, J = 5.6 Hz, 1H), 4.76−4.06 (m, 1H), 3.79−2.81 (m,
4H), 2.35 (s, 1H), 1.70 (s, 3H). 13C NMR (CDCl3, 150 MHz) δ 179.99,
160.68, 160.52, 148.64, 147.93, 146.65, 146.59, 146.03, 133.71, 132.51,
127.86, 124.50, 124.07, 123.31, 121.16, 120.42 (q, 1JC−F = 257.0 Hz),
111.95, 106.05, 53.32, 51.10, 50.68, 28.23, 21.97. HRMS calculated for
C23H20Cl2F3N5O2S [M + H]+ 558.0745, found 558.0755.
tert-Butyl [1-{3-Chloro-5-methylpyridin-2-yl}piperidin-4-yl]-
carbamate (56). A solution of 2,3-dichloro-5-(methyl)pyridine (53)
(200 mg, 1.23 mmol), tert-butyl (piperidin-4-yl)carbamate (2.5 g, 12
mmol), and Cu powder (8 mg) in DMF (4 mL) was stirred for 18 h at
120 °C. The mixture was diluted with DCM and filtered through a silica
pad (ethyl acetate/hexane = 1:1 as an eluent). The eluent was
concentrated under reduced pressure. The residue was purified by flash
column chromatography (hexane only, then ethyl acetate/hexane =
1:10 to 1:3) to afford 56 (150 mg, 37%) as a yellow amorphous
compound. 1H NMR (CDCl3, 600 MHz) δ 7.92 (d, J = 1.9 Hz, 1H),
7.35 (d, J = 2.0 Hz, 1H), 4.59 (d, J = 8.2 Hz, 1H), 3.65−3.52 (m, 3H),
2.84 (ddd, J = 13.2, 11.3, 2.5 Hz, 2H), 2.16 (s, 3H), 2.01−1.94 (m, 2H),
1.52 (dtd, J = 12.6, 11.0, 3.9 Hz, 2H), 1.34 (s, 9H). 13C NMR (CDCl3,
150 MHz) δ 156.82, 155.22, 145.71, 139.31, 127.76, 122.72, 79.20,
48.47, 47.83, 32.60, 28.46, 17.15. ESI-MS 326.1: ([M + H]+).
92.77, 79.46, 72.48, 48.29, 44.72, 32.21, 28.52, 10.13, 3.33. ESI-MS
348.2: ([M + H]+).
tert-Butyl (1-[3-Methyl-4-{4-(trifluoromethoxy)phenoxy}-
pyridine-2-yl]piperidin-4-yl)carbamate (90). A solution of 75
(120 mg, 0.37 mmol), tert-butyl(piperidin-4-yl)carbamate (300 mg, 1.5
mmol), and potassium carbonate (80 mg, 0.56 mmol) in dry DMSO
(0.2 mL) was stirred at 120 °C for 1 h. The mixture was diluted with
DCM and filtered through a pad of silica with ethyl acetate. The eluent
was concentrated under reduced pressure and the residue was purified
by prep-TLC (ethyl acetate/hexane = 1/7) to afford 90 (64 mg, 37%)
as a white solid. 1H NMR (CDCl3, 600 MHz) δ 8.01 (d, J = 5.6 Hz, 1H),
7.22−7.17 (m, 2H), 7.03−6.98 (m, 2H), 6.32 (d, J = 5.6 Hz, 1H), 4.57
(d, J = 8.1 Hz, 1H), 3.71−3.59 (m, 1H), 3.44−3.36 (m, 2H), 2.96−2.86
(m, 2H), 2.19 (s, 3H), 2.09−2.00 (m, 2H), 1.56 (dtd, J = 12.6, 10.9, 3.8
Hz, 2H), 1.44 (s, 9H). 13C NMR (CDCl3, 150 MHz) δ 164.26, 163.12,
155.32, 154.04, 146.12, 145.40, 122.86, 120.75, 120.57 (q, 1JC−F = 256.1
Hz), 114.83, 107.07, 79.41, 49.13, 47.96, 32.94, 28.39, 11.50. ESI-MS
468.1: ([M + H]+).
tert-Butyl [1-{3-Chloro-5-(trifluoromethyl)pyridin-2-yl}-
piperidin-3-yl]carbamate (61a). A solution of 2,3-dichloro-5-
trifluoromethylpyridine (54) (200 mg, 0.93 mmol), tert-butyl
(piperidin-3-yl)carbamate (220 mg, 1.1 mmol), and potassium
carbonate (130 mg, 0.93 mmol) in dry DMF (0.5 mL) was stirred at
100 °C overnight. The mixture was diluted with DCM and filtered
through a pad of silica with ethyl acetate. The eluent was concentrated
under reduced pressure and the residue was purified by flash column
chromatography (ethyl acetate/hexane = 1/8 to 1/3) to afford 61a
(350 mg, 99%) as a white solid. 1H NMR (CDCl3, 600 MHz) δ 8.33 (s,
1H), 7.70 (d, J = 2.3 Hz, 1H), 5.14−4.79 (m, 1H), 3.89−3.03 (m, 5H),
1.87−1.74 (m, 2H), 1.74−1.50 (m, 2H), 1.39 (s, 9H). 13C NMR
(R)-tert-Butyl (1-[3-Chrolo-4-{2-chloro-4-(trifluoromethoxy)-
phenoxy}pyridine-2-yl]piperidin-3-yl)carbamate (99). A solu-
tion of 8119 (120 mg, 0.37 mmol), (R)-tert-butyl (piperidin-3-
yl)carbamate (150 mg, 0.74 mmol), and potassium carbonate (61
mg, 0.44 mmol) in dry DMSO (0.3 mL) was stirred at 100 °C for 3 h.
The mixture was diluted with DCM and filtered through a pad of silica
with ethyl acetate. The eluent was concentrated under reduced pressure
and the residue was purified by prep-TLC (ethyl acetate/hexane = 1/3)
(CDCl3, 150 MHz) δ 160.52, 155.21, 142.98, 135.96, 123.35 (q, 1JC−F
=
2
269.9 Hz), 121.47, 120.16 (q, JC−F = 33.2 Hz), 79.25, 53.80, 49.51,
46.52, 29.99, 28.42, 22.54. ESI-MS: 380.1 ([M + H]+).
2-Chloro-4-(cyclopropylmethoxy)pyridine (67). To a solution
of 2-cyclopropylmethanol (160 mg, 2.3 mmol) in dry DMF (1 mL) was
slowly added 60% sodium hydride in mineral oil (91 mg, 2.3 mmol) at 0
°C. The mixture was warmed to room temperature and stirred for 20
min. The reaction mixture was added 4-fluoropyridine (62) (300 mg,
2.3 mmol). The reaction mixture was stirred at 90 °C, and the reaction
was stirred overnight. The reaction mixture was concentrated under
1
to afford 99 (91 mg, 47%) as a white solid. H NMR (CDCl3, 600
MHz) δ 8.00 (d, J = 5.6 Hz, 1H), 7.39 (d, J = 2.8, 1H), 7.18 (dd, J = 8.9,
2.8, 1H), 7.13 (d, J = 9.0 Hz, 1H), 6.19 (d, J = 5.6 Hz, 1H), 5.33−4.89
(m, 1H), 3.97−3.65 (m, 1H), 3.51−3.08 (m, 4H), 1.92−1.59 (m, 4H),
1.44 (s, 9H). 13C NMR (CDCl3, 150 MHz) δ 161.17, 160.46, 155.40,
148.96, 146.38, 146.30, 127.78, 124.03, 123.07, 121.09, 120.42 (q, 1JC−F
K
J. Med. Chem. XXXX, XXX, XXX−XXX