752
M. I. El-Gamal et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 745–754
3-(4-Chloro-3-methoxyphenyl)-N-(2-(2,6-
dimethylmorpholino)ethyl)-4-(pyridin-4-yl)-1H-pyrazole-
1-carboxamide Id
3-(4-Chloro-3-methoxyphenyl)-4-(pyridin-4-yl)-N-(2-
(pyrrolidin-1-yl)ethyl)-1H-pyrazole-1-carboxamide Ii
It was purified by flash column chromatography (silica gel, ethyl
acetate). Yield 67%; mp: 244–2478C; IR (KBr) [cmꢂ1]: 3439, 3093,
1729, 1603, 1543, 1522, 1497, 1459, 1245, 1140, 1059, 1035; 1H-
NMR (CDCl3) d 1.84 (t, 4H, J ¼ 5.4 Hz), 2.62 (t, 4H, J ¼ 5.3 Hz), 2.78
(t, 2H, J ¼ 6.1 Hz), 3.31 (t, 2H, J ¼ 6.0 Hz), 3.74 (s, 3H), 7.03 (d, 1H,
J ¼ 1.9 Hz), 7.11 (dd, 1H, J ¼ 1.9 Hz, J ¼ 8.1 Hz), 7.24 (d, 1H,
J ¼ 8.0 Hz), 7.37 (d, 2H, J ¼ 5.9 Hz), 7.89 (brs, 1H), 8.44 (s, 1H),
8.57 (d, 2H, J ¼ 6.0 Hz); MS m/z: 428.9 (Mþ þ 3), 427.9 (Mþ þ 2),
426.9 (Mþ þ 1).
It was purified by flash column chromatography (silica gel, ethyl
acetate). Yield 79%; mp: 87–898C; IR (KBr) [cmꢂ1]: 3208, 3098,
2975, 1733, 1600, 1583, 1524, 1465, 1408, 1338, 1252, 1148,
1092, 1074; 1H-NMR (CDCl3) d 1.18 (d, 6H, J ¼ 6.3 Hz), 1.85 (t,
2H, J ¼ 10.1 Hz), 2.62 (t, 2H, J ¼ 6.1 Hz), 2.78 (d, 2H, J ¼ 11.4 Hz),
3.58 (q, 2H, J ¼ 5.8 Hz), 3.68 (t, 2H, J ¼ 5.9 Hz), 3.78 (s, 3H), 7.00
(d, 1H, J ¼ 1.8 Hz), 7.06 (brs, 1H), 7.22 (dd, 1H,
J ¼ 1.9 Hz, J ¼ 8.0 Hz), 7.37 (d, 2H, J ¼ 4.5 Hz), 7.68 (d, 1H,
J ¼ 7.9 Hz), 8.44 (s, 1H), 8.57 (d, 2H, J ¼ 4.4 Hz); 13C-NMR
(CDCl3) d 158.7, 153.8, 152.9, 143.4, 134.9, 134.0, 132.5, 127.1,
126.7, 125.0, 124.5, 115.8, 75.4, 62.8, 60.0, 59.6, 55.4, 40.6, 22.7;
MS m/z: 473.0 (Mþ þ 3), 472.0 (Mþ þ 2), 471.0 (Mþ þ 1).
General procedure for preparation of compounds IIa–i
To a solution of compound Ia–i (0.1 mmol) in methylene
chloride (3 mL), BF3 ꢃ Me2S (0.13 g, 1 mmol) was added dropwise
at room temperature under N2 and the reaction mixture was
stirred at the same temperature for 48 h. The mixture was
quenched with saturated aqueous NaHCO3. Ethyl acetate
(3 mL) was added and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate (3 ꢁ 2 mL). The
combined organic layer extracts were washed with brine and
dried over anhydrous Na2SO4. The organic solvent was evapo-
rated under reduced pressure and the residue was obtained.
3-(4-Chloro-3-methoxyphenyl)-N-(2-(4-methylpiperazin-
1-yl)ethyl)-4-(pyridin-4-yl)-1H-pyrazole-1-carboxamide Ie
It was purified by flash column chromatography (silica gel, ethyl
acetate). Yield 44%; mp: 247–2498C; 1H-NMR (DMSO-d6) d 2.28 (s,
3H), 2.36–2.51 (m, 8H), 2.63 (t, 2H, J ¼ 5.9 Hz), 3.17 (t, 2H,
J ¼ 6.0 Hz), 3.77 (s, 3H), 6.97 (d, 1H, J ¼ 2.0 Hz), 7.17 (dd, 1H,
J ¼ 1.9 Hz, J ¼ 7.9 Hz), 7.29 (d, 1H, J ¼ 8.0 Hz), 7.46 (d, 2H,
J ¼ 5.4 Hz), 7.95 (brs, 1H), 8.25 (s, 1H), 8.49 (d, 2H, J ¼ 5.2 Hz);
MS m/z: 457.9 (Mþ þ 3), 456.9 (Mþ þ 2), 455.9 (Mþ þ 1).
3-(4-Chloro-3-hydroxyphenyl)-N-(2-(dimethylamino)ethyl)-
4-(pyridin-4-yl)-1H-pyrazole-1-carboxamide IIa
It was purified by flash column chromatography (silica gel, ethyl
acetate then switching to ethyl acetate/methanol 4:1 v/v). Yield
43%; m.p.: 276–2778C; IR (KBr) [cmꢂ1]: 3392, 3128, 2970, 2925,
1730, 1612, 1593, 1514, 1418, 1346, 1293, 1207, 1155, 1004; 1H-
NMR (DMSO-d6) d 2.37 (s, 6H), 2.68 (t, 2H, J ¼ 6.9 Hz), 3.60 (t, 2H,
J ¼ 6.7 Hz), 6.88 (d, 1H, J ¼ 2.0 Hz), 6.91 (dd, 1H,
J ¼ 8.1 Hz, J ¼ 2.1 Hz), 7.08 (d, 1H, J ¼ 8.0 Hz), 7.36 (d, 2H,
J ¼ 5.9 Hz), 8.04 (brs, 1H), 8.42 (d, 2H, J ¼ 6.1 Hz), 8.61 (s, 1H);
13C-NMR (DMSO-d6) d 153.1, 149.8, 147.7, 141.6, 140.8, 138.3,
134.6, 134.2, 122.1, 120.3, 119.8, 116.2, 113.4, 56.5, 46.3, 37.1;
MS m/z: 388.97 (Mþ þ 3), 387.96 (Mþ þ 2), 386.96 (Mþ þ 1).
N-(2-(4-Acetylpiperazin-1-yl)ethyl)-3-(4-chloro-
3-methoxyphenyl)-4-(pyridin-4-yl)-1H-pyrazole-
1-carboxamide If
It was purified by flash column chromatography (silica gel, ethyl
acetate then switching to ethyl acetate/methanol 4:1 v/v). Yield
66%; mp: 247–2488C; IR (KBr) [cmꢂ1]: 3454, 3094, 3000, 1722,
1703, 1603, 1543, 1522, 1497, 1410, 1262, 1245, 1140, 1099,
1059, 1035; 1H-NMR (CD3OD) d 2.10 (s, 3H), 2.48–2.60 (m, 6H),
3.32 (t, 2H, J ¼ 5.0 Hz), 3.52 (t, 4H, J ¼ 4.1 Hz), 3.77 (s, 3H), 7.08 (d,
1H, J ¼ 2.0 Hz), 7.24 (dd, 1H, J ¼ 2.0 Hz, J ¼ 7.9 Hz), 7.36 (d, 1H,
J ¼ 8.0 Hz), 7.55 (d, 2H, J ¼ 6.0 Hz), 8.54 (d, 2H, J ¼ 6.1 Hz), 8.60
(s, 1H); MS m/z: 486.0 (Mþ þ 3), 485.0 (Mþ þ 2), 484.0 (Mþ þ 1).
3-(4-Chloro-3-hydroxyphenyl)-N-(2-(diethylamino)ethyl)-
4-(pyridin-4-yl)-1H-pyrazole-1-carboxamide IIb
It was purified by flash column chromatography (silica gel, ethyl
acetate then switching to ethyl acetate/methanol 6:1 v/v). Yield
55%; mp: 220–2228C; IR (KBr) [cmꢂ1]: 3393, 3126, 2970, 1730,
1610, 1593, 1513, 1417, 1344, 1293, 1206, 1155, 1003; 1H-NMR
(CD3OD) d 1.14 (t, 6H, J ¼ 7.0 Hz), 2.76 (q, 4H, J ¼ 7.1 Hz), 2.84 (t,
2H, J ¼ 6.6 Hz), 3.45 (t, 2H, J ¼ 6.5 Hz), 6.87 (d, 1H, J ¼ 1.9 Hz),
6.90 (dd, 1H, J ¼ 8.0 Hz, J ¼ 1.9 Hz), 7.05 (d, 1H, J ¼ 8.1 Hz), 7.38
(d, 2H, J ¼ 5.8 Hz), 8.49 (d, 2H, J ¼ 5.9 Hz), 8.64 (s, 1H); MS m/z:
416.97 (Mþ þ 3), 415.97 (Mþ þ 2), 414.97 (Mþ þ 1).
3-(4-Chloro-3-methoxyphenyl)-N-(2-(piperidin-1-yl)ethyl)-
4-(pyridin-4-yl)-1H-pyrazole-1-carboxamide Ig
It was purified by flash column chromatography (silica gel, ethyl
acetate). Yield 80%; mp: 150–1528C; IR (KBr) [cmꢂ1]: 3326, 2937,
1722, 1603, 1522, 1497, 1458, 1245, 1140, 1098, 1058, 1034; 1H-
NMR (DMSO-d6) d 1.35–1.46 (m, 6H), 2.29 (t, 4H, J ¼ 6.9 Hz), 2.64 (t,
2H, J ¼ 6.0 Hz), 3.08 (t, 2H, J ¼ 5.8 Hz), 3.76 (s, 3H), 6.96 (d, 1H,
J ¼ 2.1 Hz), 7.11 (dd, 1H, J ¼ 2.0 Hz, J ¼ 8.1 Hz), 7.28 (d, 1H,
J ¼ 8.0 Hz), 7.36 (d, 2H, J ¼ 4.9 Hz), 8.22 (s, 1H), 8.48 (d, 2H,
J ¼ 4.6 Hz); MS m/z: 443.0 (Mþ þ 3), 442.0 (Mþ þ 2), 441.0 (Mþ þ 1).
3-(4-Chloro-3-hydroxyphenyl)-N-(2-morpholinoethyl)-4-
(pyridin-4-yl)-1H-pyrazole-1-carboxamide IIc
3-(4-Chloro-3-methoxyphenyl)-N-(2-(2-methylpiperidin-
It was purified by flash column chromatography (silica gel, ethyl
acetate then switching to ethyl acetate/methanol 6:1 v/v). Yield
42%; mp: 220–2228C; IR (KBr) [cmꢂ1]: 3382, 3129, 2920, 1732,
1611, 1562, 1497, 1437, 1352, 1295, 1193, 1148, 1116; 1H-NMR
(DMSO-d6) d 2.42–2.51 (m, 6H), 3.44 (t, 2H, J ¼ 6.2 Hz), 3.56 (t, 4H,
J ¼ 4.1 Hz), 7.00 (d, 1H, J ¼ 2.0 Hz), 7.31-7.38 (m, 3H), 7.48 (d, 1H,
J ¼ 8.0 Hz), 8.52 (d, 2H, J ¼ 6.0 Hz), 8.75 (s, 1H); MS m/z: 430.91
(Mþ þ 3), 429.91 (Mþ þ 2), 428.91 (Mþ þ 1).
1-yl)ethyl)-4-(pyridin-4-yl)-1H-pyrazole-1-carboxamide Ih
It was purified by flash column chromatography (silica gel, ethyl
acetate). Yield 68%; mp: 219–2218C; 1H-NMR (CDCl3) d 1.07 (d, 3H,
J ¼ 6.2 Hz), 1.54–1.63 (m, 6H), 2.33–2.61 (m, 5H), 3.30 (t, 2H,
J ¼ 5.1 Hz), 3.79 (s, 3H), 6.98 (d, 1H, J ¼ 2.1 Hz), 7.10 (dd, 1H,
J ¼ 2.0 Hz, J ¼ 8.0 Hz), 7.23 (d, 1H, J ¼ 7.9 Hz), 7.38 (d, 2H,
J ¼ 6.0 Hz), 8.23 (s, 1H), 8.54 (d, 2H, J ¼ 5.8 Hz); MS m/z:
457.01 (Mþ þ 3), 456.08 (Mþ þ 2), 455.07 (Mþ þ 1).
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