3.3. General procedure for the preparation of compounds 4–23
A mixture of 4-(4-phenylpiperazine-1-yl)benzonitrile (3, 10 mmol, 2.66 g) in dichloromethane (250 mL) and methanol (25 mL) was saturated with HCl gas and the reaction medium was left at room temperature for 24 hours. The precipitate was filtered and thoroughly washed with ether. Without further purification the crude imidate 4 (3 mmol, 1.0 g) was treated with the appropriate amine in refluxing methanol for 1 hour. A precipitate was obtained either by cooling or by addition of ether.
4-(4-Phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (5). Prepared by treatment of the crude imidate 4 with ammonia (15 mmol, 2.5 mL of a 7 N methanolic solution) in refluxing ethanol (10 mL) for 1 hour. The precipitate obtained after cooling was filtered and washed with ether and water. Yield: 64%. M.p.: >300 °C; 1H-NMR (DMSO-d6): 9.2 (br, 2H), 9.0 (br, 2H), 7.8 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.3 (t, 4H, J = 5 Hz) ppm; IR: 3,073, 2,834, 1,658, 1,607, 1,698, 1,494 cm-1; C17H20N4·HCl (316.15). Calc.: C, 63.68; H, 6.63; N, 17.47. Found: C, 64.03; H, 6.23; N, 17.37.
N-Methyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (6). Prepared by treatment of the crude compound 4 with methylamine (15 mmol, 1.8 mL of an ethanolic solution at 33%) in ethanol (10 mL) at reflux for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 57%. M.p.: >300 °C; 1H-NMR (DMSO-d6): 9.7 (br, 1H), 9.3 (br, 1H), 9.0 (br, 1H), 7.8 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.3 (t, 4H, J = 5 Hz), 3.0 (s, 3H) ppm; IR: 3,441, 3,056, 1,666, 1,505, 1,446, 1,367, 1,236 cm-1; C18H22N4·HCl (330.16). Calc.: C, 65.34; H, 7.01; N, 16.93. Found: C, 65.52; H, 6.99; N, 16.96.
N-Ethyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (7). Prepared by treatment of the crude imidate 4 with ethylamine (15 mmol, 7.5 mL of a 2 M methanolic solution) in refluxing methanol (10 mL) for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 47%. M.p.: 280–284 °C; 1H- NMR (DMSO-d6): 8.8 (br, 3H), 7.8 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (q, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.2 (t, J = 7 Hz, 3H) ppm; IR: 3,051, 2,840, 1,672, 1,604, 1,505, 1,387, 1,235 cm-1; C19H24N4·HCl (344.18). Calc.: C, 66.17; H, 7.31; N, 16.25. Found: C, 65.87; H, 7.27; N, 15.99.
N-Propyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (8). Prepared by treatment of the crude imidate 4 with propylamine (15 mmol, 1.2 mL) in refluxing ethanol (10 mL) for 1 hour. The precipitate obtained after cooling was filtered and washed with ether and water. Yield: 53%. M.p.: 275–280 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.8 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (q, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.7 (m, 2H, J = 7 Hz), 0.9 (t, 3H, J = 7 Hz); IR: 3,052, 2,970, 2,872, 1,670, 1,505, 1,452, 1,361, 1,234 cm-1; C20H26N4·HCl (358.19). Calc.: C, 66.93; H, 7.58; N, 15.61. Found: C, 66.99; H, 7.33; N, 15.39.
N-Isopropyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (9). Prepared by treatment of the crude imidate 4 with isopropylamine (15 mmol, 1.3 mL) in refluxing ethanol (10 mL) for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 67%. M.p.: >300 °C; 1H-NMR (DMSO-d6): 8.7 (br, 3H), 7.8 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 4.1 (m, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.3 (t, 4H, J = 5 Hz), 1.3 (d, 6H, J = 5 Hz); IR: 3,410, 3,051, 2,971, 1,666, 1,601, 1,505, 1,385, 1,234 cm-1; C20H26N4·HCl (358.19). Calc.: C, 66.93; H, 7.58; N, 15.61. Found: C, 67.02; H, 7.63; N, 15.57.
N-Butyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (10). Prepared by treatment of the crude imidate 4 with butylamine (15 mmol, 1.3 mL) in refluxing ethanol (10 mL) for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 32%. M.p.: 280–284 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.8 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (t, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.6 (m, 2H, J = 7 Hz), 1.4 (m, 2H, J = 7 Hz), 0.9 (t, 3H, J = 7 Hz); IR: 3,229, 3,091, 2,951, 1,665, 1,614, 1,520, 1,497, 1,386, 1,225 cm-1; C21H28N4·HCl (372.21). Calc.: C, 67.63; H, 7.84; N, 15.02. Found: C, 67.59; H, 7.85; N, 15.03.
N-Pentyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (11). Prepared by treatment of the crude imidate 4 with pentylamine (15 mmol, 1.7 mL) in refluxing ethanol (10 mL) for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 30%. M.p.: 285–290 °C. 1H NMR (DMSO-d6): 9.3 (br, 3H), 7.7 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (t, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.6 (m, 2H, J = 7 Hz), 1.3 (m, 4H), 0.9 (t, 3H, J = 7 Hz). IR: 3063, 2957, 2857, 1662, 1603, 1505, 1451, 1386, 1336, 1231 cm-1. C22H30N4·1.2 HCl (386,22). Calc.: C, 67.02; H, 7.98; N, 14.21. Found: C, 66.88; H, 8.04; N, 14.45.
N-(3-Methylbutyl)l 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (12). Prepared by treatment of the crude imidate with 3-methylbutylamine (15 mmol, 1.7 mL) in refluxing ethanol (10 mL) for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 63%. M.p.: >300 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.8 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (t, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.7 (m, 1H), 1.6 (m, 2H), 0.9 (d, 6H, J = 7 Hz); IR: 3,063, 2,957, 2,857, 1,662, 1,603, 1,505, 1,451, 1,386, 1,336, 1,231 cm-1; C22H30N4·HCl (386.22). Calc.: C, 68.28; H, 8.07; N, 14.48. Found: C, 68.08; H, 7.84; N, 14.22.
N-(2-Methylbutyl)l 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (13). Prepared by treatment of the crude imidate 4 with 2-methylbutylamine (15 mmol, 1.8 mL) in refluxing ethanol (10 mL) for 1 hour. The precipitate obtained after cooling was filtered and washed with ether and water. Yield: 35%. M.p.: >300 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.8 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (d, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.8 (m, 1H), 1.2 (m, 2H), 0.9 (t, 3H, J = 7 Hz), 0.9 (d, 3H, J = 6 Hz); IR: 3,024, 2,960, 2,844, 1,671, 1,604, 1,515, 1,450, 1,387, 1,230 cm-1; C22H30N4·1.1 HCl (386.22). Calc.: C, 67.65; H, 8.03; N, 14.34. Found: C, 67.44; H, 7.80; N, 14.11.
N-(1-Ethylpropyl) 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (14). Prepared by treatment of the crude imidate 4 with 1-ethylpropylamine (15 mmol, 1.8 mL) in refluxing ethanol (10 mL) for 1 hour. The precipitate obtained after cooling was filtered and washed with ether and water. Yield: 61%. M.p.: >300 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.8 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.8 (m, 1H), 3.5 (t, 4H, J = 5 Hz), 3.3 (t, 4H, J = 5 Hz), 1.6 (m, 4H), 0.9 (t, 6H, J = 7 Hz); IR: 3,074, 2,966, 2,935, 2,880, 1,666, 1,600, 1,505, 1,231 cm-1; C22H30N4·HCl (386.22). Calc.: C, 68.28; H, 8.07; N, 14.48. Found: C, 68.15; H, 8.08; N, 14.46.
N-Hexyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (15). The compound was prepared by treatment of the crude imidate 4 with hexylamine (15 mmol, 2.0 mL) in refluxing ethanol (10 mL) for 1 hour. The precipitate obtained after cooling was filtered and washed with ether and water. Yield: 42%. M.p.: 285–290 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.7 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (t, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.6 (m, 2H, J = 7 Hz), 1.3 (m, 6H), 0.9 (t, 3H, J = 7 Hz); IR: 3,050, 2,956, 2,931, 1,669, 1,505, 1,451, 1,387, 1,232 cm-1; C23H32N4·1.1 HCl (400.24). Calc.: C, 68.27; H, 8.25; N, 13.85. Found: C, 68.31; H, 8.19; N, 13.98.
N-Heptyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (16). Prepared by treatment of the crude imidate 4 with heptylamine (15 mmol, 2.2 mL) in refluxing ethanol (10 mL) for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 43%. M.p.: 290–294 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.7 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (t, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.6 (m, 2H, J = 7 Hz), 1.3 (m, 8H), 0.9 (t, 3H, J = 7 Hz); IR: 3,078, 2,956, 2,926, 1,661, 1,505, 1,387, 1,387, 1,234 cm-1; C24H34N4·1.1 HCl (414.26). Calc.: C, 68.85; H, 8.45; N, 13.38. Found: C, 69.20; H, 8.09; N, 13.47.
N-Octyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (17). Prepared by treatment of the crude imidate 4 with octylamine (15 mmol, 2.5 mL) in refluxing ethanol (10 mL) for 1 hour. The precipitate obtained after cooling was filtered and washed with ether and water. Yield: 43%. M.p.: 280–284 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.7 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (t, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.6 (m, 2H, J = 7 Hz), 1.3 (m, 10H), 0.9 (t, 3H, J = 7 Hz); IR: 3,062, 2,923, 2,853, 1,662, 1,607, 1,505, 1,386, 1,232 cm-1; C25H36N4·HCl (428.27). Calc.: C, 69.99; H, 8.69; N, 13.06. Found: C, 69.94; H, 8.68; N, 13.04.
N-Dodecyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (18). Prepared by treatment of the crude imidate 4 with dodecylamine (15 mmol, 3.5 mL) in refluxing ethanol (10 mL) for 1 hour. The precipitate obtained after cooling was filtered and washed with ether and water. Yield: 51%. M.p.: 275–280 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.7 (d, 2H, J = 9 Hz), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 9 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (t, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 1.6 (m, 2H, J = 7 Hz), 1.4 (m, 18H), 0.9 (t, 3H, J = 7 Hz); IR: 3,047, 2,920, 2,850, 1,668, 1,608, 1,515, 1,466, 1,387, 1,233 cm-1; C29H44N4·HCl (484.33). Calc.: C, 71.79; H, 9.35; N, 11.55. Found: C, 71.77; H, 9.34; N, 11.57.
N-Benzyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (19). Prepared by treatment of the crude imidate 4 with benzylamine (15 mmol, 1.6 mL) in refluxing ethanol (10 mL) for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 67%. M.p.: 290–295 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.7 (d, 2H, J = 8 Hz), 7.4 (m, 5H), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 8 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 4.7 (s, 2H), 3.5 (t, 4H, J = 5 Hz), 3.3 (t, 4H, J = 5 Hz); IR: 3,033, 2,359, 1,665, 1,516, 1,497, 1,452, 1,388, 1,230 cm-1; C24H26N4·HCl (406.19). Calc.: C, 70.83; H, 6.69; N, 13.77. Found: C, 70.77; H, 6.66; N, 13.76.
N-Phenethyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (20). Prepared by treatment of the crude imidate 4 with phenethylamine (15 mmol, 1.9 mL) in refluxing ethanol (10 mL) at for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 64%. M.p.: >300 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.7 (d, 2H, J = 8 Hz), 7.4 (m, 5H), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 8 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.7 (t, 2H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.3 (t, 4H, J = 5 Hz), 3.0 (t, 2H, J = 7Hz); IR: 3,051, 1,605, 1,671, 1,498, 1,452, 1,383, 1,231 cm-1; C25H28N4·0.8 HCl (420.21). Calc.: C, 72.58; H, 7.02; N, 13.54. Found: C, 72.71; H, 6.89; N, 13.35.
N-(3-Phenylpropyl) 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (21). Prepared by treatment of the crude imidate 4 with 3-phenylpropylamine (15 mmol, 2.1 mL) in reluxing ethanol (10 mL) for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 51%. M.p.: 250–255 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.7 (d, 2H, J = 8 Hz), 7.4 (m, 5H), 7.3 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 8 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.5 (t, 4H, J = 5 Hz), 3.4 (t, 2H, J = 7 Hz), 3.3 (t, 4H, J = 5 Hz), 2.7 (m, 2H), 1.9 (m, 2H); IR: 3,073, 1,658, 1,607, 1,505, 1,232 cm-1; C26H30N4·HCl (434.22). Calc.: C, 71.79; H, 7.18; N, 12.88. Found: C, 71.81; H, 7.2; N, 12.86.
N-(4-Fluorobenzyl) 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (22). Prepared by treatment of the crude imidate 4 with 4-fluorobenzylamine (15 mmol, 1.7 mL) in refluxing ethanol (10 mL) for 1 hour. After cooling, the precipitate obtained by addition of ether was filtered and washed with water. Yield: 58%. M.p.: 280–285 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.8 (d, 2H, J = 8 Hz), 7.3 (m, 4H), 7.2 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 8 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 4.7 (s, 2H), 3.6 (t, 4H, J = 5 Hz), 3.3 (t, 4H, J = 5 Hz); IR: 3,039, 1,666, 1,600, 1,515, 1,385, 1,234 cm-1; C24H25FN4·HCl (424.18). Calc.: C, 67.83; H, 6.17; N, 13.18. Found: C, 67.82; H, 6.18; N, 13.17.
N-2-(4-Fluorophenyl)ethyl 4-(4-phenylpiperazine-1-yl)benzenecarboximidamide hydrochloride salt (23). The compound was obtained by treatment of the crude imidate 4 with 2-(4-fluorophenyl)-ethylamine (15 mmol, 2.0 mL) in reluxing ethanol (10 mL) for 1 hour. After cooling, a precipitate was obtained by pouring ether into the solution. The solid was filtered and washed with water. Yield: 64%. M.p.: >300 °C; 1H-NMR (DMSO-d6): 9.3 (br, 3H), 7.7 (d, 2H, J = 8 Hz), 7.3 (m, 4H), 7.2 (t, 2H, J = 7 Hz), 7.1 (d, 2H, J = 8 Hz), 7.0 (d, 2H, J = 7 Hz), 6.8 (t, 1H, J = 7 Hz), 3.7 (t, 2H, J = 7 Hz), 3.6 (t, 4H, J = 5 Hz), 3.3 (t, 4H, J = 5 Hz), 3.2 (t, 2H, J = 7 Hz); IR: 3,040, 1,672, 1,604, 1,511, 1,463, 1,452, 1,385, 1,231, 1,206, 1,160 cm-1; C25H27FN4·HCl (438.20). Calc.: C, 68.40; H, 6.43; N, 12.76. Found: C, 68.41; H, 6.39; N, 12.79.