Journal of Medicinal Chemistry
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General Procedure C. The ester (1.0 equiv) was dissolved in a 1:1
MeOH/2 N NaOH solution. The reaction was stirred at 50 °C for 5−
18 h. The mixture was concentrated under reduced pressure, and water
was added. The pH of the solution was adjusted to ∼4 to 5 with a 6 N
HCl solution. The aqueous solution was then extracted with CH2Cl2
or a mixture of CH2Cl2/MeOH (9:1). The combined organic extracts
were dried (Na2SO4 or MgSO4), filtered, and concentrated under
reduced pressure. The crude material was purified by flash column
chromatography on silica gel or by recrystallization.
General Procedure D. The secondary amine (1.1 equivs) was
dissolved in CH3CN (concentration ∼0.1 M). DIPEA (1.5 equivs)
followed by a halide reagent (1.0 equiv) were added. The reaction was
heated at 50−75 °C for 18 h. The mixture was concentrated under
reduced pressure, and CH2Cl2 and saturated aqueous NaHCO3 were
added. The aqueous layer was extracted with CH2Cl2, and the
combined organic extracts were dried (Na2SO4 or MgSO4), filtered,
and concentrated under reduced pressure. The crude material was
purified by flash column chromatography or by radial chromatography
on silica gel.
(R)-4-((6-Methyl-5-((4-(2-oxo-5-phenyl-3-(tetrahydro-2H-
pyran-4-yl)imidazolidin-1-yl)piperidin-1-yl)methyl)pyridin-2-
yl)oxy)benzoic Acid (6d). A mixture of 6-bromo-2-methylpyridine-
3-carboxaldehyde (4.00 g, 20.0 mmol), 4-hydroxybenzoic acid methyl
ester (3.80 g, 25.0 mmol), and K2CO3 (1.73 g, 12.5 mmol) in DMF
(30 mL) was heated at 130 °C for 2 h. The mixture was cooled to
room temperature, and DMF was removed. Aqueous workup and
purification by flash chromatography on silica gel (CH3OH/CH2Cl2,
1:50 in v/v) afforded methyl 4-((5-formyl-6-methylpyridin-2-yl)oxy)-
benzoate as a white solid (3.20 g, 59%). 1H NMR (300 MHz, CDCl3)
δ 2.72 (s, 3H), 3.93 (s, 3H), 6.86 (d, 1 H, J= 8.4 Hz), 7.20−7.25 (m,
2H), 8.08−8.15 (m, 3H), 10.25 (s, 1H). Following general procedure
A, (R)-1-cyclohexyl-4-phenyl-3-(piperidin-4-yl)imidazolidin-2-one 10b
(R1Ph, R2 = 4-THP) and the above aldehyde provided (R)-methyl
4-((6-methyl-5-((4-(2-oxo-5-phenyl-3-(tetrahydro-2H-pyran-4-yl)-
imidazolidin-1-yl)piperidin-1-yl)methyl)pyridin-2-yl)oxy)benzoate,
which was treated under general procedure C to afford 6d as a white
solid (164 mg, 51% over two steps). 1H NMR (300 MHz, CD3OD) δ
1.32 (dq, 1H, J= 12.0, 3.6 Hz), 1.48 (br d, 1H, J= 12.0 Hz), 1.60−1.80
(m, 5H), 1.95−2.20 (m, 3H), 2.39 (s, 3H), 2.78 (d, 1H, J = 11.4 Hz),
2.94 (d, 1H, J = 11.l Hz), 3.13 (m, 1H), 3.40−3.60 (m, 5H), 3.77 (t,
1H, J = 9.0 Hz), 3.93 (m, 3H), 4.73 (m, 1H), 6.69 (d, 1H, J= 8.1 Hz),
7.07 (d, 2H, J= 8.7 Hz), 7.30−7.40 (m, 5H), 7.64 (d, 1H, J = 8.4 Hz),
8.01 (d, 2H, J= 8.7 Hz). 13C NMR (75 MHz, CD3OD) δ 20.71, 28.44,
29.82 (2C), 30.14, 48.57, 49.44, 52.08, 52.85, 53.05, 56.74, 57.98,
67.18, 67.27, 109.02, 119.53 (2C), 125.88, 127.02 (2C), 128.46,
129.03 (2C), 130.67, 131.50 (2C), 142.62, 142.91, 157.37, 158.09,
160.87, 162.01, 171.02. ES−MS m/z 571 [M + H]+. Anal. Calcd. for
C33H38N4O5·0.7CH2Cl2·0.3NH3: C, 63.38; H, 6.45; N, 9.87. Found:
C, 63.20; H, 6.60; N, 9.85.
m/z 605 [M + H]+. Anal. Calcd. for C33H37N4ClO5·0.6CH2C12: C,
61.51; H, 5.87; N, 8.54. Found: C, 61.56; H, 5.82; N, 8.44.
(R)-4-((6-Ethyl-5-((4-(2-oxo-5-phenyl-3-(tetrahydro-2H-
pyran-4-yl)imidazolidin-1-yl)piperidin-1-yl)methyl)pyridin-2-
yl)oxy)benzoic Acid (6h). Following general procedure A, (R)-4-
phenyl-3-(piperidin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-
one 10b (R1Ph, R2 = 4-THP) and t-butyl 4-((6-ethyl-5-
formylpyridin-2-yl)oxy)benzoate provided (R)-t-butyl 4-((6-ethyl-5-
((4-(2-oxo-5-phenyl-3-(tetrahydro-2H-pyran-4-yl)imidazolidin-1-yl)-
piperidin-1-yl)methyl)pyridin-2-yl)oxy)benzoate, which was treated
under general procedure B to afford 6h as a white powder (71 mg,
59% over two steps). 1H NMR (300 MHz, CDCl3) δ 1.11 (t, 3H, J =
7.5 Hz), 1.25−1.42 (m, 2H), 1.66 (m, 5H), 2.14−2.28 (m, 3H), 2.88
(br, s, 1H), 3.08 (m, 2H), 3.48−3.81 (m, 5H), 4.01 (m, 3H), 4.59 (t,
1H, J = 7.5 Hz), 6.62 (d, 1H, J = 9.0 Hz), 7.05−7.26 (m, 5H), 7.14 (d,
2H, J = 9.0 Hz), 7.65 (br s, 1H), 8.02 (br s, 2H). 13C NMR (75 MHz,
CDCl3) δ 13.74, 28.01, 30.20, 30.52, 48.74, 49.14, 51.52, 52.96, 56.33,
57.64, 67.53, 67.62, 109.12, 120.24, 122.03, 127.09, 128.39, 128.72,
129.30, 131.97, 142.66, 142.88, 158.56, 160.33, 161.79, 162.07, 170.32.
ES−MS m/z 585 [M + H]+. Anal. Calcd. for C33H40N4O5·0.5CH2Cl2:
C, 66.07; H, 6.59; N, 8.93. Found: C, 66.02; H, 6.65; N, 8.91.
(R)-4-((5-((4-(2-Oxo-5-phenyl-3-(tetrahydro-2H-pyran-4-yl)-
imidazolidin-1-yl)piperidin-1-yl)methyl)pyridin-2-yl)thio)-
benzoic Acid (6i). 2-Bromo-5-methyl-pyridine (2.23 g, 13.0 mmol),
4-mercaptobenzoic acid (333 mg, 2.16 mmol), and K2CO3 (597 mg,
4.32 mmol) were heated at 200 °C for 2 h. The mixture was
partitioned between H2O (70 mL) and diethyl ether (20 mL). The
aqueous phase was extracted with diethyl ether (20 mL) and then
acidified to pH 3 with 10% HCl (aq). The aqueous phase was
extracted with 10% MeOH/CH2Cl2 (4 × 20 mL), and the combined
organic layers were dried (MgSO4) and concentrated to give a yellow
solid (412 mg). A solution of the yellow solid from above (412 mg)
and H2SO4 (0.11 mL) in MeOH (16 mL) was heated to reflux for 15 h
and then concentrated. The residue was dissolved in CH2Cl2 (15 mL),
washed with H2O (5 mL) and saturated NaHCO3 (aq) (10 mL), dried
(MgSO4), and concentrated. Purification by chromatography on silica
gel (0−5% EtOAc/CH2Cl2) gave methyl 4-((5-methylpyridin-2-
yl)thio)benzoate as colorless crystals (280 mg, 50% over two steps),
which was added to a mixture of NBS (231 mg, 1.30 mmol) and
benzoyl peroxide (39 mg, 0.16 mmol) in CCl4 (2.7 mL), heated to
reflux for 4 h, and filtered and concentrated. Purification by
chromatography on silica gel (1% EtOAc/CH2Cl2) gave methyl 4-
((5-(bromomethyl)pyridin-2-yl)thio)benzoate as colorless crystals
1
(161 mg, 44%). H NMR (300 MHz, CDCl3) δ 3.94 (s, 3H), 4.43
(s, 2H), 7.05 (d, 1H, J= 8.4 Hz), 7.56 (dd, 1H, J = 8.4, 2.4 Hz), 7.61
(dd, 2H, J= 6.6, 1.8 Hz), 8.06 (dd, 2H, J= 6.8, 1.7 Hz), 8.45 (d, 1H, J=
2.1 Hz). Following general procedure D, (R)-1-cyclohexyl-4-phenyl-3-
(piperidin-4-yl)imidazolidin-2-one 10b (R1Ph, R2 = 4-THP) (80
mg, 0.24 mmol) and methyl 4-((5-(bromomethyl)pyridin-2-yl)thio)-
benzoate (75 mg) in CH3CN (4 mL) afforded (R)-methyl 4-((5-((4-
(2-oxo-5-phenyl-3-(tetrahydro-2H-pyran-4-yl)imidazolidin-1-yl)-
piperidin-1-yl)methyl)pyridin-2-yl)thio)benzoate as a white foam (105
mg, 81%). Following general procedure C, the ester prepared above
(105 mg. 0.18 mmol) afforded 6i as a white precipitate (64 mg, 62%).
1H NMR (300 MHz, CDCl3) δ 1.48 (br s, 1H), 1.64−1.74 (m, 4H),
1.86−1.90 (m, 1H), 2.53 (br s, 2H), 2.72 (br s, 1H), 3.12−3.21 (m,
2H), 3.43−3.52 (m, 4H), 3.70 (t, 1H, J = 9.3 Hz), 3.83−4.20 (m, 6H),
4.61−4.65 (m, 1H), 6.98 (d, 1H, J = 6.0 Hz), 7.19−7.31 (m, 6H), 7.60
(d, 2H, J = 8.1 Hz), 8.01 (d, 2H, J = 8.1 Hz), 8.30 (s, 1H). 13C NMR
(75 MHz, CDCl3) δ 25.7, 27.3, 29.8, 30.1, 48.3, 48.9, 49.3, 51.5, 53.5,
55.7, 67.1, 67.2, 122.0, 126.7, 128.6, 129.2, 131.0, 132.1, 134.4, 135.4,
140.0, 141.8, 151.1, 159.7, 162.5, 168.5. ES−MS m/z 573 [M + H]+.
Anal. Calcd. for C32H36N4O4S·1.6CH2Cl2: C, 56.95; H, 5.58; N, 7.91.
Found: C, 56.91; H, 5.90; N, 8.00.
(R)-4-((5-((4-(5-(3-Chlorophenyl)-2-oxo-3-(tetrahydro-2H-
pyran-4-yl)imidazolidin-1-yl)piperidin-1-yl)methyl)-6-methyl-
pyridin-2-yl)oxy)benzoic Acid (6e). Following general procedure
A, (R)-4-(3-chlorophenyl)-3-(piperidin-4-yl)-1-(tetrahydro-2H-pyran-
4-yl)imidazolidin-2-one 10b (R1Ph-3-Cl, R2 = 4-THP) and methyl
4-((5-formyl-6-methylpyridin-2-yl)oxy)benzoate provided (R)-methyl
4-((5-((4-(5-(3-chlorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-
imidazolidin-1-yl)piperidin-1-yl)methyl)-6-methylpyridin-2-yl)oxy)-
benzoate, which was treated under general procedure C to afford 6e as
1
a white solid (368 mg, 88% over two steps). H NMR (300 MHz,
CD3OD) δ 1.42 (dq, 1H, J = 12.6, 3.9 Hz), 1.50−1.80 (m, 6H), 2.05
(dq, 1H, J = 12.6, 3.6 Hz), 2.30 (m, 2H), 2.41 (s, 3H), 2.93 (d, 1H, J =
11.7 Hz), 3.05 (d, 1H, J = 11.7 Hz), 3.11 (m, 1H), 3.47 (t, 2H, J= 11.7
Hz), 3.55 (m, 1H), 3.63 (s, 2H), 3.78 (t, 1H, J = 9.3 Hz), 3.94 (m,3H),
4.56 (m, 1H), 6.75 (d, 1H, J = 8.1 Hz), 7.10 (d, 2H, J = 8.4 Hz), 7.30−
7.42 (m, 4H), 7.69 (d, 1H, J= 8.4 Hz), 8.03 (d, 2H, J= 8.7 Hz). 13C
NMR (75 MHz, CD3OD) δ 22.48, 28.01, 30.27, 30.31, 30.44, 48.64,
49.19, 51.49, 53.07 (2C), 55.68, 58.16, 67.59 (2C), 109.31, 120.14
(2C), 125.27, 126.94, 128.03, 128.97, 130.65, 132.10 (2C), 135.22,
142.94, 144.99, 157.38, 158.77, 160.24, 161.99, 169.83, 174.11. ES−S
(R)-4-((6-Methyl-5-((4-(2-oxo-5-phenyl-3-(tetrahydro-2H-
pyran-4-yl)imidazolidin-1-yl)piperidin-1-yl)methyl)pyridin-2-
yl)oxy)benzamide (6k). A mixture of 6-bromo-2-methylpyridine-3-
carboxaldehyde (1.00 g, 5.00 mmol), 4-hydroxybenzonitrile (0.596 g.
5.00 mmol), and K2CO3 (0.414 g, 3.00 mmol) in DMF (10 mL) was
heated at 130 °C for 1 h. The mixture was cooled to room
M
dx.doi.org/10.1021/jm401101p | J. Med. Chem. XXXX, XXX, XXX−XXX