Page 5 of 7
Journal of Medicinal Chemistry
4-(4-Chlorophenyl)-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)
J = 5.9 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.64-2.55 (m, 8H), 2.31
(s, 3H); 13C-NMR (CDCl3, 200 MHz) δ 161.96, 150.95, 131.64,
110.46, 106.16, 103.79, 67.07, 59.03, 56.31 (2 carbons), 54.86 (2
carbons), 46.74; HR-MS (ESI) Calcd for C13H22N3O (M + H+)
236.1757, Found 236.1751.
1
2
3
4
5
6
7
8
phenyl)pyrimidin-2-amine (2). Microwave-assisted coupling of
2-Chloro-4-(4-chlorophenyl)pyrimidine 8 (23 mg, 0.1 mmol) with
aniline 5 (26 mg, 0.1 mmol) was performed according to the
general procedure. Flash column chromatography of the crude
product on silica gel (CH2Cl2/MeOH = 15:1) afforded 38 mg (90%)
of 2: 1H-NMR (CDCl3, 800 MHz) δ 8.46 (d, J = 5.1 Hz, 1H), 8.01
(d, J = 8.5 Hz, 2H), 7.54 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.22 (t,
J = 8.1 Hz, 1H), 7.17 (s, 1H), 7.11 (d, J = 5.2 Hz, 1H), 7.10 (dd, J
= 8.1, 2.1 Hz, 1H), 6.60 (ddd, J = 8.2, 2.5, 0.9 Hz, 1H), 4.14 (t, J =
5.8 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.81 – 2.40 (m, 8H), 2.34 (s,
3H); 13C NMR (200 MHz, CDCl3) δ 163.69, 160.17, 159.37,
158.82, 140.76, 136.99, 135.55, 129.62, 129.10 (2 carbons), 128.40
(2 carbons), 111.69, 108.78, 108.24, 105.63, 65.92, 57.10 (2
carbons), 54.87 (2 carbons), 53.20, 45.74.
2-Chloro-4-(4-chlorophenyl)pyrimidine (8). To a solution of
2,6-dichloropyrimidine (75 mg, 0.5 mmol), 4-chlorophenylboronic
acid (90 mg, 0.6 mmol), and tetrakispalladium (30 mg, 0.03 mmol)
in THF (2.5 mL), a aqueous solution of Na2CO3 (270 mg, 2.5 mmol
in 2.5 mL water) was added at the room temperature. The reaction
mixture was stirred at 80 °C until the reaction was completed. The
reaction mixture was filtered through a celite pad and extracted
with EtOAc. The combined organic layer was concentrated under
reduced pressure and the residue was purified using flash column
chromatography on silica gel (EtOAc/n-Hexane = 1:4) to afford
102 mg (91%) of chloropyrimidine 8: 1H-NMR (CDCl3, 800 MHz)
δ 8.64 (d, J = 5.4 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 5.2
Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H); 13C-NMR (CDCl3, 200 MHz) δ
165.94, 162.00, 160.06, 138.37, 133.49, 129.46 (2 carbons), 128.73
(2 carbons), 114.89; HR-MS (ESI) Calcd for C10H7Cl2N2 (M + H+)
224.9981, Found 224.9985.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(4-Chlorophenyl)-6-(3-methoxypiperidin-1-yl)-N-(3-(2-(4-
methylpiperazin-1-yl)ethoxy)phenyl)pyrimidin-2-amine
(3).
Microwave-assisted coupling of 2-chloro-4-(4-chlorophenyl)-6-(3-
methoxypiperidin-1-yl)pyrimidine 11 (34 mg, 0.1 mmol) with
aniline 5 (26 mg, 0.1 mmol) was performed according to the
general procedure. Flash column chromatography of the crude
product on silica gel (CH2Cl2/MeOH = 9:1) afforded 49 mg (91%)
of 3: 1H-NMR (CDCl3, 800 MHz) δ 7.90 (d, J = 8.5 Hz, 2H), 7.53
(t, J = 2.3 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.16 (t, J = 8.1 Hz,
1H), 7.06 – 7.04 (m, 1H), 6.92 (s, 1H), 6.53 (ddd, J = 8.1, 2.4, 0.8
Hz, 1H), 6.42 (s, 1H), 4.21 (br s, 1H), 4.12 (t, J = 5.9 Hz, 2H), 3.91
(br s, 1H), 3.41 (s, 3H), 3.35 – 3.25 (m, 3H), 2.80 (t, J = 5.9 Hz,
2H), 2.61 (br s, 4H), 2.46 (br s, 4H), 2.28 (s, 3H), 2.08 – 2.00 (m,
1H), 1.89 – 1.80 (m, 1H), 1.58 – 1.52 (m, 2H); 13C-NMR (CDCl3,
200 MHz) δ 163.43, 163.20, 159.78, 159.33, 141.60, 137.25,
135.74, 129.35, 128.74 (2 carbons), 128.20 (2 carbons), 111.34,
107.94, 105.29, 91.03, 74.87, 65.95, 57.25, 56.40, 55.08 (2
carbons), 53.63 (2 carbons), 48.13, 46.04, 44.78, 30.12, 22.51; HR-
MS (ESI) Calcd for C29H38ClN6O2 (M + H+) 537.2739, Found
537.2751.
3-Methoxypiperidine (10). To a suspension of NaH (60 mg, 2
mmol) in THF (10 mL), a solution of hydroxide 9 (201 mg, 1 mmol)
in THF (4 mL) was dropwise added at room temperature. The
reaction mixture was stirred for 30 min and a solution of
iodomethane (0.18 mL, 3 mmol) in THF (1 mL) was added. After
completion of the reaction, the reaction mixture was quenched with
saturated NH4Cl aqueous solution and extracted with EtOAc. The
combined organic layer was dried over MgSO4 and concentrated
under reduced pressure. The residue was purified using flash
column chromatography on silica gel (EtOAc/n-Hexane = 1:3) to
afford 215 mg (100%) of tert-butyl 3-methoxypiperidine-1-
carboxylate: 1H-NMR (CDCl3, 300 MHz) δ 4.0-3.64 (m, 2H), 3.56
(d, J = 11.7 Hz, 1H), 3.35 (s, 3H), 3.22-3.12 (m, 1H), 3.10-2.88
(m,1H), 1.98-1.83 (m, 1H), 1.74-1.68 (m, 1H), 1.43 (s, 9H), 1.41-
1.34 (m, 1H), 1.26-1.14 (m, 1H); 13C NMR (200 MHz, CDCl3) δ
154.94, 79.50, 74.83, 50.90, 37.09, 31.93, 29.70, 28.43 (3 carbons),
3-(2-(4-Methylpiperazin-1-yl)ethoxy)aniline (5). To a solution
of chloride 4 (5.49 g, 27 mmol) in DMF (30 mL), 1-
methylpiperazine (9.15 mL, 82 mmol), K2CO3 (18.80 g, 136 mmol),
and tetrabutylammonium iodide (15.10 g, 41 mmol) were added at
room temperature, and the reaction mixture was stirred at 100 °C.
After completion of the reaction, the reaction mixture was
quenched with water, and extracted with EtOAc. The organic layer
was concentrated under reduced pressure, and the residue was
purified using flash column chromatography on silica gel
(CH2Cl2/MeOH = 3:1) to afford 7.20 g (100%) of 1-methyl-4-(2-
22.69; HR-MS (ESI) Calcd for C7H14NO3 (M - C4H8 + H+)
160.0968, Found 160.0965. To tert-butyl 3-methoxypiperidine-1-
carboxylate (187 mg, 1 mmol), a 4.0 M solution of HCl in dixoane
(2 mL) was added, and the reaction mixture was stirred at room
temperature until the reaction was completed. The reaction mixture
was concentrated under reduced pressure, diluted with EtOAc, and
saturated NaHCO3 aqueous solution. The organic layer was
separated and concentrated. The residue (115 mg, 100%) was used
for the next step without further purification. 1H-NMR (CDCl3, 800
MHz) δ 6.63 (s, 1H), 3.63 (dq, J = 6.9, 3.5 Hz, 1H), 3.38 (s, 3H),
3.27 (dq, J = 10.6, 3.7 Hz, 1H), 3.18-3.11 (m, 1H), 3.06 (d, J = 8.6
Hz, 1H), 2.98 (dt, J = 13.6, 7.1 Hz, 1H), 2.02 (ddq, J = 11.3, 7.6,
3.6 Hz, 1H), 1.89 (ddt, J = 12.2, 7.7, 3.6 Hz, 1H), 1.81 (m, 1H),
1.66 (dtd, J = 12.1, 7.8, 3.5 Hz, 1H); 13C NMR (200 MHz, CDCl3)
δ 71.50, 55.59, 45.55, 43.02, 26.46, 18.68; HR-MS (ESI) Calcd for
C6H14NO (M + H+) 116.1070, Found 116.1068.
1
(3-nitrophenoxy)ethyl)piperazine: H-NMR (CDCl3, 400 MHz) δ
7.79 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 2.3 Hz, 1H), 7.39 (t, J = 8.2
Hz, 1H), 7.20 (dd, J = 8.0, 2.4 Hz, 1H), 4.15 (t, J = 5.8 Hz, 2H),
2.83 (t, J = 5.7 Hz, 2H), 2.63-2.50 (m, 8H), 2.30 (s, 3H); 13C-NMR
(CDCl3, 200 MHz) δ 160.75, 159.33, 129.91, 121.76, 115.87,
108.90, 66.71, 56.90, 55.00 (2 carbons), 53.58 (2 carbons), 45.99;
HR-MS (ESI) Calcd for C13H20N3O3 (M + H+) 266.1499, Found
266.1499.
To
a
solution
of
1-methyl-4-(2-(3-
nitrophenoxy)ethyl)piperazine (1.10 g, 4 mmol) in EtOH, Tin(II)
chloride dihydrate (2.80 g, 13 mmol) was added at the room
temperature, and the reaction mixture was stirred under reflux
conditions. After completion of the reaction, the reaction mixture
was concentrated under reduced pressure. The residue was diluted
with EtOAc and saturated NaOH aqueous solution. The mixture
was filtered through a pad of celite and extracted with a mixture of
isopropylalcohol and chloroform (1:4). The organic layer was
washed with brine, dried over MgSO4, and concentrated. The
residue was purified using flash column chromatography on silica
gel (CH2Cl2/MeOH = 3:1) to afford 880 mg (90%) of aniline 5: 1H-
NMR (CDCl3, 400 MHz) δ 7.02 (d, J = 8.0 Hz, 1H), 6.36-6.30 (m,
1H), 6.28 (td, J = 8.1, 2.1 Hz, 1H), 6.22 (t, J = 2.2 Hz, 1H), 4.05 (t,
2-Chloro-4-(4-chlorophenyl)-6-(3-methoxypiperidin-1-yl)
pyrimidine (11). To
a
solution of 2,4-dichloro-6-(4-
mmol) in EtOH,
chlorophenyl)pyrimidine18 (446 mg,
2
diisopropylethylamine (0.6 mL, 3 mmol) and piperidine 7 (198 mg,
2 mmol) were added at room temperature. After completion of
reaction, the reaction mixture was concentrated under reduced
pressure. The residue was purified using flash column
chromatography on silica gel (EtOAc/n-Hexane = 1:3) to afford
419 mg (72%) of chloropyrimidine 9: 1H-NMR (CDCl3, 300 MHz)
δ 7.88 (dt, J = 8.6, 2.6 Hz, 2H), 7.40 (dt, J = 8.6, 2.6 Hz, 2H), 6.72
(s, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.80-3.58 (m, 2H), 3.55-3.47 (m,
1H), 3.39 (s, 3H), 3.38-3.32 (m, 1H), 2.02-1.93 (m, 1H), 1.92-1.80
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