RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2017, 350, e1600377
M. N. Aboul-Enein et al.
Archiv der Pharmazie
2-(4-Benzylpiperazin-1-yl)-1-(4-(7-chloroquinolin-4-yl)-
piperazin-1-yl)ethanone (4o)
(m, 4H, piperazine), 6.84–6.85 (d, J ¼ 3.0 Hz, 1HAr), 7.12–7.20
(m, 4HAr), 7.46–7.48 (d, J ¼ 6.0 Hz, 1HAr), 7.96–7.98 (d, J ¼ 6.0
Hz, 1HAr), 8.08 (s, 1HAr), 8.75–8.76 (d, J ¼ 3.0 Hz, 1HAr). 13C-
NMR 125 MHz (CDCl3) d ppm 21.63, 42.25, 46.21, 52.62, 53.51,
53.61, 62.16, 63.20, 109.81, 122.37, 125.38, 127.05, 129.45,
129.55, 129.66, 135.33, 135.64, 137.22, 150.70, 152.46, 157.02,
168.91. ESI HRMS (m/z) for C27H32ClN5O, calcd. 477.22954,
found 478.23087 (Mþþ1). Anal. calcd. C, 67.84; H, 6.75; N,
14.65. Found C, 68.02; H, 6.82; N, 14.83.
Yield 71%, buff powder, m.p. 171°C. IR (KBr cmꢀ1): 1639.20
(CO amide). 1H-NMR 500 MHz (CDCl3) d ppm 2.55 (m, 8H,
piperazine), 3.17 (m, 4H, piperazine), 3.26 (s, 2H, COCH2N),
3.55 (s, 2H, PhCH2N), 3.90 (m, 4H, piperazine), 6.82–6.84 (d,
J ¼ 3.0 Hz, 1HAr), 7.31–7.32 (m, 5HAr), 7.44–7.46 (d, J ¼ 6.0 Hz,
1HAr), 7.93–7.99 (d, J ¼ 6.0 Hz, 1HAr), 8.07–8.09 (d, J ¼ 6.0 Hz,
1HAr), 8.73–8.75 (d, J ¼ 6.0 Hz, 1HAr). 13C-NMR 125 MHz (CDCl3)
d ppm 41.74, 45.62, 52.08, 52.27, 52.89, 61.35, 62.80, 109.29,
121.83, 124.88, 126.54, 127.28, 128.30, 128.92, 129.54, 135.14,
137.36, 150.07, 151.89, 156.91, 168.31. ESI HRMS (m/z) for
1-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-2-(4-(4-
methoxybenzyl)piperazin-1-yl)ethanone (4s)
C
26H30ClN5O, calcd. 463.21389, found 464.20662 (Mþþ1).
Yield 56%, dark yellow oil. IR (KBr cmꢀ1): 1643.05 (CO amide)
1H-NMR 500 MHz (CDCl3) d ppm 2.633 (br s, 8H, piperazine),
3.155–3.189 (m, 4H, piperazine), 3.266 (s, 2H, COCH2N), 3.591
(s, 2H, PhCH2N), 3.774–3.834 (m, 4H, piperazine), 3.858 (s, 3H,
OCH3), 6.823–6.848 (m, 3HAr), 7.211–7.228 (d, J ¼ 8.6 Hz, 2HAr),
7.437–7.454 (d, J ¼ 8.6 Hz, 1HAr), 7.911–7.928 (d, J ¼ 8.6 Hz,
1HAr), 8.056–8.062 (d, J ¼ 2.9 Hz, 1HAr), 8.733–8.742 (d,
J ¼ 4.8 Hz, 1HAr). 13C-NMR 125 MHz (CDCl3) d ppm 41.77,
45.54, 52.13, 52.24, 52.66, 55.37, 60.89, 61.58, 109.34, 113.868,
121.824, 124.92, 126.38, 127.38, 128.65, 131.18, 135.47,
149.74, 151.59, 151.72, 156.80, 159.30, 168.18. ESI HRMS (m/
z) for C27H32ClN5O2, calcd. 493.22445, found 494.21948
(Mþþ1). Anal. calcd. C, 65.64; H, 6.53; N, 14.18. Found C,
65.82; H, 6.60; N, 14.36.
Anal. calcd. C, 67.30; H, 6.52; N, 15.09. Found C, 67.51; H, 6.73;
N, 15.30.
2-(4-(4-Chlorobenzyl)piperazin-1-yl)-1-(4-(7-
chloroquinolin-4-yl)piperazin-1-yl)ethanone (4p)
Yield 58%, dark yellow oil. IR (KBr cmꢀ1): 1644.98 (CO amide).
1H-NMR 500 MHz (CDCl3) d ppm 2.560 (br s, 8H, piperazine),
3.140–3.184 (m, 4H, piperazine), 3.245 (s, 2H, COCH2N), 3.444 (s,
2H, PhCH2N), 3.792–3.859 (m, 4H, piperazine), 6.519 (s, 1HAr),
6.541 (s, 1HAr), 6.806–6.815 (d, J ¼ 4.6 Hz, 1HAr), 7.253 (s, 1HAr),
7.274 (s, 1HAr), 7.412–7.429 (d, J ¼ 8.6 Hz, 1HAr), 7.901–7.920 (d,
J ¼ 9.5 Hz, 1HAr), 8.0312 (s, 1HAr), 8.706–8.716 (d, J ¼ 4.8 Hz,
1HAr). 13C-NMR 125 MHz (CDCl3) d ppm 41.99, 45.66, 52.10,
52.83, 60.96, 61.88, 109.47, 121.75, 123.71, 124.92, 126.77,
128.85, 129.76, 130.98, 132.52, 135.48, 149.85, 151.86, 156.68,
167.93. ESI HRMS (m/z) for C26H29Cl2N5O, calcd. 463.21389,
found 464.20662(Mþþ1). Anal. calcd. C, 62.65; H, 5.86; N, 14.05.
Found C, 62.83; H, 5.93; N, 14.21.
1-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-2-(4-(3,4,5-
trimethoxybenzyl)piperazin-1-yl)ethanone (4t)
Yield 55%, dark yellow oil. IR (KBr cmꢀ1): 1641.13 (CO
amide). 1H-NMR 500 MHz (CDCl3): d ppm 2.585 (br s, 8H,
piperazine), 3.134–3.176 (m, 8H, piperazine), 3.482 (s, 2H,
COCH2N), 3.801 (m, 11H, PhCH2N & (OCH3)3), 6.519 (s, 2HAr),
6.798–6.810 (d, J ¼ 5.75 Hz, 1HAr), 7.399–7.416 (d, J ¼ 8.6 Hz,
1HAr), 7.888–7.905 (d, J ¼ 8.6 Hz, 1HAr), 8.0221 (s, 1HAr),
8.697–8.706 (d, J ¼ 4.75 Hz, 1HAr). 13C-NMR 125 MHz (CDCl3):
d 41.75, 45.58, 52.10, 52.60, 52.99, 56.16, 60.93, 62.75, 106.18,
109.34, 121.79, 124.95, 126.73, 128.63, 132.34, 135.39,
137.16, 149.74, 151.73, 153.16, 156.76, 168.10. ESI HRMS
(m/z) for C29H36ClN5O4, calcd. 553.24558, found 554.34191
(Mþþ1). Anal. calcd. C, 62.86; H, 6.55; N, 12.64. Found C,
63.04; H, 6.42; N, 12.82.
2-(4-(4-Bromobenzyl)piperazin-1-yl)-1-(4-(7-
chloroquinolin-4-yl)piperazin-1-yl)ethanone (4q)
Yield 71%, buff crystals from ethyl acetate, m.p. 184°C. IR (KBr
cmꢀ1): 1651.73 (CO amide). 1H-NMR 500 MHz (CDCl3) d ppm
2.463–2.549 (m, 8H, piperazine), 3.149–3.172 (t, J ¼ 4.4 Hz, 4H,
piperazine), 3.250 (s, 2H, COCH2N), 3.436 (s, 2H, PhCH2N),
3.889–3.922 (m, 4H, piperazine), 6.825–6.837 (d, J ¼ 4.8 Hz,
1HAr), 7.171–7.192 (d, J ¼ 8.4 Hz, AB system, 2HAr), 7.401–7.423
(d, J ¼ 8.8 Hz, AB system, 2HAr), 7.455–7.461 (d, J ¼ 2.4 Hz,
1HAr), 7.940–7.962 (d, J ¼ 8.8 Hz, 1HAr), 8.053–8.058 (d, J ¼ 2
Hz, 1HAr), 8.734–8.746 (d, J ¼ 4.8 Hz, 1HAr). 13C-NMR 125 MHz
(CDCl3) d ppm 41.71, 45.68, 52.88, 53.00, 53.88, 61.61, 62.12,
109.28, 120.84, 121.88, 124.85, 126.51, 129.05, 130.71, 131.33,
135.08, 137.20, 150.18, 151.97, 156.44, 168.30. ESI HRMS (m/z)
Synthesis of 1-(un)substituted-benzylpiperazines 5o–t
To a solution of the appropriate benzylchloride (40 mmol) in
ethanol (30 mL), anhydrous piperazine (8.73 g, 400 mmol) was
added. The mixture was refluxed under stirring for 8 h, then
ethanol was evaporated under vacuum. To the residue an
aqueous solution of Na2CO3 (10%, 50 mL) was added, and
extracted with ethyl acetate (3 ꢁ 20 mL). The organic layer was
washed with brine (30 mL), separated, dried (anhydrous
Na2SO4) and evaporated under reduced pressure; then the
residue was crystallized from petroleum ether (40:60) to
afford 5o–t.
for
C26H29BrClN5O, calcd. 541.12440, found 544.12256
(Mþþ 3). Anal. calcd. C, 57.72; H, 5.38; N, 12.90. Found C,
57.70; H, 5.46; N, 13.02.
1-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-2-(4-(4-
methylbenzyl)piperazin-1-yl)ethanone (4r)
Yield 73%, buff powder, m.p. 184°C. IR (KBr cmꢀ1): 1654.62
(CO amide). 1H-NMR 500 MHz (CDCl3) d ppm 2.35 (s, 3H,
PhCH3), 2.50–2.56 (m, 8H, piperazine), 3.18–3.22 (m, 4H,
piperazine), 3.26 (s, 2H, COCH2N), 3.48 (s, 2H, PhCH2N), 3.91
ꢃ 1-Benzylpiperazine (5o) [23], colorless oil used as such,
77.5% yield.
ß 2017 Deutsche Pharmazeutische Gesellschaft
(10 of 12) e1600377