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5.3.2. 5-(4-Piperazin-1-yl-phenyl)-4,5-dihydro-
isoxazole-3-carboxylic acid ethyl ester (7)
150.66, 150.78, 157.17, 160.16; ESI MS: 453.3 (M þ Na);
HPLC purity: 98%, tR ¼ 6.4 min.
A solution of 6 (0.8 g, 1.98 mmol) in THF/TFA (1:1,
10 mL) was stirred at room temperature for 1 h. The reaction
mixture was concentrated under reduced pressure to give 7
5.4.4. 5-[4-(4-Phenylcarbamoyl-piperazin-1-yl)-
phenyl]-4,5-dihydro-isoxazole-3-carboxylic
acid ethyl ester (8d)
1
(0.552 g) in 92% yield. H NMR (500 MHz, CDCl3): d 1.41
(3H, t, J ¼ 7.1 Hz), 3.22 (1H, dd, J ¼ 9.0, 17.8 Hz), 3.34e
3.42 (4H, br s), 3.43e3.52 (4H, br s), 3.62 (1H, dd,
J ¼ 11.5, 17.8 Hz), 4.39 (2H, q, J ¼ 7.1 Hz), 5.75 (1H, dd,
J ¼ 9.3, 11.5 Hz), 6.95 (2H, d, J ¼ 8.8 Hz), 7.29 (2H, d,
J ¼ 8.5 Hz), 9.62 (2H, br s); 13C NMR (500 MHz, CDCl3):
d 14.15, 41.08, 43.41, 46.71, 62.24, 84.83, 117.31, 127.45,
132.28, 150.23, 151.26, 160.65; ESI MS: 304.2 (M þ 1);
HPLC purity: 98%, tR ¼ 4.7 min.
1
Yield: 95.5%; H NMR (500 MHz, CDCl3): d 1.37 (3H, t,
J ¼ 7.1 Hz), 3.17e3.26 (5H, m), 3.54e3.66 (5H, m), 4.36
(2H, q, J ¼ 7.1 Hz), 5.71 (1H, dd, J ¼ 9.3, 11.5 Hz), 6.67
(1H, s), 6.89 (2H, d, J ¼ 8.5 Hz), 7.04 (1H, t, J ¼ 7.3 Hz),
7.24 (2H, t, J ¼ 8.8 Hz), 7.28 (2H, m), 7.37 (2H, d,
J ¼ 7.6 Hz); 13C NMR (300 MHz, CDCl3): d 13.59, 40.36,
43.36, 48.16, 61.57, 84.57, 115.68, 119.63, 122.73, 126.78,
128.35, 129.87, 138.41, 150.65, 150.71, 154.54, 160.15; ESI
MS: 445.2 (M þ Na); HPLC purity: 96%, tR ¼ 6.0 min.
5.4. General procedure for the synthesis of urea
and carbamate derivatives
5.4.5. 5-[4-(4-Phenethylcarbamoyl-piperazin-1-yl)-
phenyl]-4,5-dihydro-isoxazole-3-carboxylic
acid ethyl ester (8e)
Piperazine TFA salt 7 (1 mmol) was dissolved in anhydrous
dichloromethane, and then triethylamine (4 mmol) was added,
followed by isocyanate or chloroformate (3 mmol). The reaction
mixture was stirred at room temperature overnight and evapo-
rated. The residue was purified by column chromatography.
1
Yield: 82.6%; H NMR (500 MHz, CDCl3): d 1.38 (3H, t,
J ¼ 7.1 Hz), 2.85 (2H, t, J ¼ 6.8 Hz), 3.17 (4H, t,
J ¼ 5.1 Hz), 3.21 (1H, dd, J ¼ 9.3, 17.8 Hz), 3.47 (2H, t,
J ¼ 4.9 Hz), 3.52 (2H, q, J ¼ 6.6 Hz), 3.57 (1H, dd, J ¼ 11.5,
17.8 Hz), 4.37 (2H, q, J ¼ 7.3 Hz), 4.48 (1H, t, J ¼ 5.4 Hz),
5.71 (1H, dd, J ¼ 9.3, 11.2 Hz), 6.89 (2H, d, J ¼ 8.8 Hz),
7.19e7.25 (5H, m), 7.32 (2H, t, J ¼ 7.3 Hz); 13C NMR
(500 MHz, CDCl3): d 13.59, 35.75, 40.36, 41.47, 43.01,
48.12, 61.53, 84.55, 115.65, 125.91, 126.74, 128.08, 128.30,
129.82, 138.76, 150.64, 150.74, 156.90, 160.18; ESI MS:
473.2 (M þ Na); HPLC purity: 98%, tR ¼ 6.1 min.
5.4.1. 5-[4-(4-Isopropylcarbamoyl-piperazin-1-yl)-phenyl]-
4,5-dihydro-isoxazole-3-carboxylic acid ethyl ester (8a)
1
Yield: 91.1%; H NMR (500 MHz, CDCl3): d 1.20 (6H, d,
J ¼ 6.6 Hz), 1.41 (3H, t, J ¼ 7.1 Hz), 3.21e3.26 (5H, m),
3.53e3.63 (5H, m), 4.02 (1H, m), 4.29 (1H, d, J ¼ 6.6 Hz),
4.39 (2H, q, J ¼ 7.1 Hz), 5.74 (1H, dd, J ¼ 9.0, 11.2 Hz),
6.95 (2H, d, J ¼ 8.3 Hz), 7.27 (2H, d, J ¼ 8.5 Hz); 13C NMR
(500 MHz, CDCl3): d 14.17, 23.49, 40.96, 42.71, 43.44,
48.92, 62.17, 85.07, 116.45, 127.36, 151.23, 156.97, 160.73;
ESI MS: 411.3 (M þ Na); HPLC purity: 99%, tR ¼ 5.6 min.
5.4.6. 4-[4-(3-Ethoxycarbonyl-4,5-dihydro-isoxazol-5-yl)-
phenyl]-piperazine-1-carboxylic acid methyl ester (9a)
1
Yield: 76.3%; H NMR (500 MHz, CDCl3): d 1.38 (3H, t,
5.4.2. 5-[4-(4-Propylcarbamoyl-piperazin-1-yl)-
phenyl]-4,5-dihydro-isoxazole-3-carboxylic
acid ethyl ester (8b)
J ¼ 7.1 Hz), 3.10e3.25 (5H, m), 3.53e3.67 (5H, m), 3.73
(3H, s), 4.37 (2H, q, J ¼ 7.1 Hz), 5.71 (1H, dd, J ¼ 9.8,
11.0 Hz), 6.91 (2H, d, J ¼ 8.5 Hz), 7.24 (2H, d, J ¼ 8.3 Hz);
13C NMR (500 MHz, CDCl3): d 14.17, 40.93, 43.59, 49.01,
52.76, 62.15, 85.12, 116.54, 127.32, 130.54, 151.22, 151.48,
155.87, 160.74; ESI MS: 384.1 (M þ Na); HPLC purity:
98%, tR ¼ 5.8 min.
1
Yield: 97.8%; H NMR (500 MHz, CDCl3): d 0.93 (3H, t,
J ¼ 7.1 Hz), 1.38 (3H, t, J ¼ 7.1 Hz), 1.49e1.60 (2H, m),
3.10e3.28 (7H, m), 3.46e3.64 (5H, m), 4.37 (2H, q,
J ¼ 7.1 Hz), 4.55 (1H, br s), 5.71 (1H, t, J ¼ 10.0 Hz), 6.90
(2H, d, J ¼ 8.1 Hz), 7.23 (2H, d, J ¼ 8.1 Hz); 13C NMR
(500 MHz, CDCl3): d 11.42, 14.17, 23.46, 40.92, 42.71,
43.60, 48.71, 62.15, 85.16, 116.22, 127.34, 130.31, 151.23,
151.33, 157.71, 160.74; ESI MS: 411.3 (M þ Na); HPLC pu-
rity: 100%, tR ¼ 5.6 min.
5.4.7. 4-[4-(3-Ethoxycarbonyl-4,5-dihydro-isoxazol-5-yl)-
phenyl]-piperazine-1-carboxylic acid ethyl ester (9b)
Yield: 89.1%; 1H NMR (500 MHz, CDCl3): d 1.27 (3H, t),
1.38 (3H, t), 3.16 (4H, t, J ¼ 4.9 Hz), 3.21 (1H, dd, J ¼ 9.3,
17.8 Hz), 3.57 (1H, dd, J ¼ 11.5, 17.6 Hz), 3.63 (4H, t,
J ¼ 4.9 Hz), 4.17 (2H, q, J ¼ 7.1 Hz), 4.37 (2H, q,
J ¼ 7.1 Hz), 5.71 (1H, dd, J ¼ 9.3, 11.2 Hz), 6.91 (2H, d,
J ¼ 8.8 Hz), 7.24 (2H, d, J ¼ 8.8 Hz); 13C NMR (500 MHz,
CDCl3): d 14.17, 14.70, 40.93, 43.51, 49.03, 61.56, 62.15,
85.14, 116.52, 127.32, 130.49, 151.22, 151.52, 155.49,
160.75; ESI MS: 398.3 (M þ Na); HPLC purity: 96%,
tR ¼ 6.1 min.
5.4.3. 5-[4-(4-Hexylcarbamoyl-piperazin-1-yl)-phenyl]-4,
5-dihydro-isoxazole-3-carboxylic acid ethyl ester (8c)
1
Yield: 100%; H NMR (500 MHz, CDCl3): d 0.91e0.97
(3H, t), 1.22e1.41 (9H, m), 1.40e1.58 (2H, m), 3.16e3.27
(7H, m), 3.48e3.61 (5H, m), 4.36 (2H, q, J ¼ 7.1 Hz), 4.58
(1H, t), 5.71 (1H, dd, J ¼ 9.5, 11.0 Hz), 6.90 (2H, d,
J ¼ 8.5 Hz), 7.23 (2H, d, J ¼ 8.8 Hz); 13C NMR (300 MHz,
CDCl3): d 13.45, 13.58, 22.01, 26.08, 29.69, 31.01, 40.35,
40.50, 43.07, 48.15, 61.52, 84.57, 115.63, 126.74, 129.74,