Journal of Medicinal Chemistry
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(2.47 g, 12.88 mmol), NH4OBt (1.96 g, 12.88 mmol), and DIPEA
(2.94 mL, 17.18 mmol). The suspension was stirred at room
temperature for 16 h, diluted with DCM (150 mL), and washed
twice with NH4Cl saturated solution, then with NaHCO3 saturated
solution. The solid in the organic layer was collected by filtration to
give the title compound 4-[(4-chloro-6-phenylpyrimidin-2-ylamino)-
methyl]cyclohexanecarboxylic acid amide (58) (2.1 g, 60%). 1H NMR
(401 MHz, DMSO-d6) δ 8.12 (d, J = 4.64 Hz, 2H), 7.72 (t, J = 5.74
Hz, 1H), 7.47−7.57 (m, 3H), 7.22 (s, 1H), 7.11 (bs, 1H), 6.61 (bs,
1H), 3.24−3.32 (m, 2H)1.96−2.09 (m, 1H), 1.70−1.87 (m, 4H), 1.55
(bs, 1H), 1.22−1.37 (m, 2H), 0.97 (d, J = 7.45 Hz, 2H). HRMS (ESI)
calcd for C18H22ClN4O [M + H]+ 345.1477, found 345.1481.
4-{[4-(2-Methylbenzylamino)-6-phenylpyrimidin-2-
ylamino]methyl}cyclohexanecarboxylic Acid Amide (59). In a
microwave vial, to a solution of 4-[(4-chloro-6-phenylpyrimidin-2-
ylamino)methyl]cyclohexanecarboxylic acid amide (58) (30 mg, 0.09
mmol) in NMP (1 mL), 2-methylbenzylamine (0.021 mL, 0.17 mmol)
and DIPEA (0.087 mL, 0.51 mmol) were added, and the sealed vial
was heated at 220 °C for 15 min. The final solution was directly
purified by preparative HPLC, affording the title compound 4-{[4-(2-
methylbenzylamino)-6-phenylpyrimidin-2-ylamino]methyl}-
cyclohexanecarboxylic acid amide (59) (22.3 mg, 58%). 1H NMR (401
MHz, DMSO-d6) δ 7.80−7.97 (m, 2H), 7.36−7.47 (m, 3H), 7.24−
7.30 (m, 1H), 6.97−7.21 (m, 4H), 6.59 (bs, 2H), 6.50 (bs, 1H), 6.28
(bs, 1H), 4.45−4.54 (m, 2H), 3.04−3.15 (m, 2H), 2.33 (s, 3H), 1.99
(t, J = 12.14 Hz, 1H), 1.60−1.85 (m, J = 12.69 Hz, 4H), 1.48 (bs, 1H),
1.10−1.36 (m, J = 10.86 Hz, 2H), 0.70−0.98 (m, 2H). HRMS (ESI)
calcd for C26H32N5O [M + H]+ 430.2601, found 430.2597.
solution of benzyl-(6-chloro-2-methanesulfonylpyrimidin-4-yl)amine
(0.5 g, 1.68 mmol) in NMP (17 mL), 4-aminomethylcyclohexane-
carboxylic acid ethyl ester (933 mg, 5.04 mmol) and DIPEA (1.15 mL,
6.72 mmol) were added, and the resulting mixture was heated at 180
°C in a sealed microwave vial for 30 min. The mixture was then diluted
with AcOEt (50 mL) and washed with NH4Cl saturated solution. The
organic layers were collected, dried over sodium sulfate, and
evaporated to dryness. The residue was purified by flash chromatog-
raphy (hexane/AcOEt 8:2), yielding 1.1 g (27%) of 4-[(4-
benzylamino-6-chloropyrimidin-2-ylamino)methyl]cyclohexane-
1
carboxylic acid ethyl ester (79). H NMR (401 MHz, DMSO-d6) δ
7.51−7.81 (m, 1H), 7.16−7.40 (m, 5H), 6.77−7.10 (m, 1H), 5.59−
5.86 (m, 1H), 4.35−4.58 (m, 1H), 3.91−4.12 (m, 2H), 2.93−3.07 (m,
2H), 2.03−2.27 (m, 1H), 1.58−1.92 (m, 2H), 1.30−1.51 (m, 1H),
1.04−1.30 (m, 5H), 0.69−1.00 (m, 2H). HRMS (ESI) calcd for
C21H28ClN4O2 [M + H]+ 403.1896, found 403.1885.
4-[(4-Chloro-6-phenylaminopyrimidin-2-ylamino)methyl]-
cyclohexanecarboxylic Acid Ethyl Ester (80). To a solution of (6-
chloro-2-methylsulfanylpyrimidin-4-yl)phenylamine (78) (100 mg,
0.40 mmol) in DCM (4 mL), m-chloroperoxybenzoic acid (55% in
weight) (257 mg, 0.82 mmol) was added, and the resulting suspension
was stirred at room temperature for 20 h. The mixture was washed
with NaHCO3 saturated solution (3 × 50 mL), and the organic layers
were collected, dried over sodium sulfate, and evaporated to dryness
affording (6-chloro-2-methanesulfonylpyrimidin-4-yl)phenylamine
(101 mg, 90%) that was used without further purification. To a
solution of (6-chloro-2-methanesulfonylpyrimidin-4-yl)phenylamine
(101 mg, 0.36 mmol) in NMP (1.8 mL), 4-aminomethyl-cyclohexane-
carboxylic acid ethyl ester (200 mg, 1.08 mmol) and DIPEA (0.25 mL,
1.44 mmol) were added, and the resulting mixture was heated at 180
°C in a sealed microwave vial for 30 min. The final solution was
diluted with AcOEt (10 mL) and washed with NH4Cl saturated
solution. The organic layers were collected, dried over sodium sulfate,
and evaporated to dryness. The residue was purified by flash
chromatography (hexane/AcOEt 8:2) yielding 23 mg (15%) of the
title compound 4-[(4-chloro-6-phenylaminopyrimidin-2-ylamino)-
By analogous procedure, starting from 4-[(4-chloro-6-phenyl-
pyrimidin-2-ylamino)methyl]cyclohexanecarboxylic acid amide (58)
and using the appropriate benzylamine, compounds 60−75 were
prepared with a 40% average yield (see Scheme 2 and Supporting
Information, p S23).
Benzyl-(6-chloro-2-methylsulfanylpyrimidin-4-yl)amine
(77). A solution of 4,6-dichloro-2-methylsulfanylpyrimidine (76) (1 g,
5.13 mmol) in EtOH (10 mL) was treated with benzylamine (0.615
mL, 5.64 mmol) and DIPEA (1.75 mL, 10.25 mmol) and heated at
150 °C in a sealed microwave vial for 30 min. The resulting mixture
was dried, dissolved in DCM (50 mL), and washed twice with NH4Cl
saturated solution. The organic layer was collected and dried over
sodium sulfate and the solvent evaporated to dryness affording the title
compound benzyl-(6-chloro-2-methylsulfanylpyrimidin-4-yl)amine
1
methyl]cyclohexanecarboxylic acid ethyl ester (80). H NMR (401
MHz, DMSO-d6) δ 8.02 (bs, 1H), 7.85 (d, J = 7.57 Hz, 2H), 7.75 (bs,
2H), 6.25 (s, 1H), 3.95−4.12 (m, 2H), 2.94−3.07 (m, 2H), 2.03−2.28
(m, 1H), 1.58−1.90 (m, 2H), 1.32−1.51 (m, 1H), 1.04−1.32 (m, 5H),
0.68−1.05 (m, 2H). HRMS (ESI) calcd for C20H26ClN4O2 [M + H]+
389.1739, found 389.1742.
1
(77) (1.24 g, 90%). H NMR (401 MHz, DMSO-d6) δ 8.21−8.32
4-[(4-Phenyl-6-phenylaminopyrimidin-2-ylamino)methyl]-
cyclohexanecarboxylic Acid (50). In a microwave vial, to a solution
of 4-[(4-chloro-6-phenylaminopyrimidin-2-ylamino)methyl]-
cyclohexanecarboxylic acid ethyl ester (80) (20 mg, 0.05 mmol 0.11
mmol) in a predegassed mixture of dioxane/water (3:1, 0.6 mL),
Cs2CO3 (50 mg, 0.16 mmol), phenylboronic acid (20 mg, 0.16 mmol),
and Pd(dppf)Cl2 (1 mg, 0.0012 mmol) were added. The sealed vial
was heated in a microwave at 100 °C for 20 min. The upper phase of
the final bilayer system (dioxane) was transferred and dried. The
residue was dissolved in DCM and eluted with DCM on a prepacked
silica cartridge (0.5 g of silica). The volatiles were removed under
reduced pressure, and the residue was dissolved in THF/water/MeOH
2:2:1 (2 mL) and treated with LiOH·H2O (3.2 mg, 0.07 mmol). The
resulting mixture was stirred at room temperature for 24 h, treated
with HCl 1 N (0.07 mL, 0.07 mmol), and evaporated to dryness. The
residue was dissolved in DMSO (1 mL), filtered, and purified by
preparative HPLC, affording the title compound 4-[(4-phenyl-6-
phenylaminopyrimidin-2-ylamino)methyl]cyclohexanecarboxylic acid
(50) (5 mg, 24%).1H NMR (401 MHz, DMSO-d6) δ 10.43 (bs,
1H), 8.08 (bs, 1H), 7.86 (d, J = 7.57 Hz, 2H), 7.75 (bs, 2H), 7.65 (bs,
3H), 7.42 (t, J = 7.45 Hz, 2H), 7.19 (bs, 1H), 6.60 (bs, 1H), 2.08−2.21
(m, 1H), 1.94 (d, J = 10.25 Hz, 2H), 1.83 (d, J = 11.11 Hz, 2H), 1.64
(bs, 1H), 1.17−1.36 (m, 2H), 0.94−1.13 (m, 2H). HRMS (ESI) calcd
for C24H27N4O2 [M + H]+ 403.2129, found 403.2140.
(m, 1H), 7.29−7.39 (m, 4H), 7.23−7.27 (m, 1H), 6.28 (s, 1H), 4.50−
4.59 (m, 2H), 2.39 (s, 3H). HRMS (ESI) calcd for C12H13ClN3S [M +
H]+ 266.0513, found 266.0514.
(6-Chloro-2-methylsulfanylpyrimidin-4-yl)phenylamine (78).
A solution of 4,6-dichloro-2-methylsulfanylpyrimidine (76) (500 mg,
2.56 mmol) in EtOH (5 mL) was treated with aniline (0.257 mL, 2.82
mmol) and DIPEA (0.6 mL, 3.5 mmol) and heated at 120 °C in a
sealed microwave vial for 2 h with the cooling function activated. The
resulting mixture was dried, dissolved in DCM (50 mL), and washed
twice with NH4Cl saturated solution. The organic layer was collected
and dried over sodium sulfate. The residue was purified by flash-
chromatography (DCM), yielding 558 mg (87%) of the title
compound (6-chloro-2-methylsulfanylpyrimidin-4-yl)phenylamine
1
(78). H NMR (401 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.59 (d, J =
7.93 Hz, 2H), 7.36 (t, J = 7.93 Hz, 2H), 7.08 (t, J = 7.38 Hz, 1H), 6.49
(s, 1H), 2.48 (s, 3H). HRMS (ESI) calcd for C11H11ClN3S [M + H]+
252.0357, found 252.0359.
4-[(4-Benzylamino-6-chloropyrimidin-2-ylamino)methyl]-
cyclohexanecarboxylic Acid Ethyl Ester (79). To a solution of
benzyl-(6-chloro-2-methylsulfanylpyrimidin-4-yl)amine (77) (1.1 g,
4.14 mmol) in DCM (42 mL), m-chloroperoxybenzoic acid (55% in
weight) (2.66 g, 8.48 mmol) was added, and the resulting suspension
was stirred at room temperature for 20 h. The mixture was washed
with NaHCO3 saturated solution (3 × 50 mL) and the organic layers
were collected, dried over sodium sulfate, and evaporated to dryness,
affording benzyl-(6-chloro-2-methanesulfonylpyrimidin-4-yl)-amine
(1.12 g, 91%), that was used without further purification. To a
4-[(4-Benzylamino-6-chloropyrimidin-2-ylamino)methyl]-
cyclohexanecarboxylic Acid Amide (81). 4-[(4-Benzylamino-6-
chloropyrimidin-2-ylamino)methyl]cyclohexanecarboxylic acid ethyl
ester (79) (1.4 g, 3.47 mmol) was dissolved in THF/water/MeOH
J
dx.doi.org/10.1021/jm501313x | J. Med. Chem. XXXX, XXX, XXX−XXX