3.2 General procedure for Synthesis of TFMP Derivatives
All derivatives have been synthesized by refluxing equimolar TFMP with a variety of acetophenone, dissolved separately in ethanol/acetone respectively in a RB flask. The RM was refluxed and stirred vigorously for 48 to 72 hours at 75 ºC. The progress of reaction mixture was monitored by using TLC. Solid products were filtered and wash away numerous times with acetone. The resulting products were purified by the process of recrystallization using warm ethanol and diethyl ether/ dichloromethane. The pure product was dry in desiccators using anhydrous calcium sulphate.
3.2.1 6-(2-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}acetyl)-2,4(1H,3H)-pyrimidinedione hydrochloride (1)
Yield: 79%, White crystalline powder, mp: 285 ± 2oC, C24H22NO2BrClF3 (528.7889); Solubility (MeOH, EtOH, DMSO); UV λmax (MeOH) nm: 203, 206, 221, 268, 358; FT-IR υmax (KBr) cm-1: 3381, 2945, 2773, 1714, 1506, 1407, 1324, 1029, 872, 573; EI-MS m/z: 403.1 (M+-HBr), 385.1,278,260.1,207,180,166.1,126.1,82.9; HR-EIMS: 403. 0944 (M+ -HCl,C17H17N3O3ClF3) (Calcd. 403.7832); UV λmax (MeOH) nm: 203, 206, 221, 268, 358; 1H-NMR (MeOD, 300 MHz) δH: 7.92 (d, 1H, J = 2.1 Hz), 7.72 (dd, 1H, J1 = 2.1, J2 = 8.4 Hz), 7.56 (d, 1H, J = 8.4 Hz), 5.64 (s, 1H), 4.57 (s, 1H, H-14, 3.33 (s, 2H), 2.75 (d, 2H, J = 10.8 Hz), 2.63 (m, 2H), 2.18 (m, 2H), 1.70 (d, 2H, J = 12 Hz); 13C-NMR (MeOD, 100 MHz,) δC (ppm): 150.1, 153.4, 98.3, 164.1, 57.5, 48.7, 37.5, 69.3, 148.0, 124.4, 124.2, 128.5, 131.2, 130.8, 131.2.
3.2.2 4-({4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}methyl)-7-methoxy-2H-chromen-2-one hydrobromide (2)
Yield: 88%, White crystalline powder. mp: 281 ± 2oC, C24H26NO3BrClF3 (548.7770), Solubility (MeOH, EtOH, DMSO); UVλmax (MeOH) nm: 322, 279, 251, 223, 211; FT-IR υmax (KBr) cm-1: 3318, 2899,2641, 2568, 1717, 1612, 1472, 1390,1290, 987, 843, 477 EI-MS m/z: 467.1 (M+-HBr), 448, 292, 190, 162, 147, 79.9; HR- EIMS: 467.1475 (M+-HBr, C24H25NO3ClF3) (Calcd. 467.8651); 1H-NMR (MeOD, 300 MHz) δH:7.93 (d, 2H, J = 10.2 Hz) 7.72 (d, IH, J = 8.4 Hz), 7.56 (d, 1H, J = 8.4 Hz), 6.97 (m, 2H), 6.40 (s, 1H), 3.88 (s, 3H), 3.74 (s, 2H), 2.85 (d, 2H, J = 10.8 Hz), 2.70 (t, 2H, J = 10.5 Hz), 2.18 (m, 2H), 1.74 (d, 2H, J = 12.3 Hz); 13C-NMR (MeOD, 100 MHz, ) δC (ppm): 163.6, 156.9, 155.2, 150.5, 150.3, 132.6, 132.6, 131.2, 127.5, 126.3, 125.3, 125.1, 113.7, 113.5, 111.0, 99.4, 71.3, 59.8, 56.3, 50.7, 39.2.
3.2.3 4-[4-chloro-3-(trifluoromethyl)phenyl]-1-[2-(1, 3-dioxan-2-yl) ethyl]-4-piperidinol hydrobromide (3)
Yield: 80%, White crystalline powder, mp: 213 ± 2oC, C18H24NO3ClBrF3 (474.7400); Solubility (MeOH, EtOH, DMSO); UVλmax (MeOH) nm: 223, 266, 344, 387; FT-IR υmax (KBr) cm-1: 3741, 3292, 2931, 2435, 1831, 1743, 1647, 1319, 982, 662, 503; EI-MS m/z: 393 (M+-HBr), 374, 336, 307, 292, 274, 261,251, 201,101, 87; HR- EIMS: 393.1317 (M+ -HBr C18H23NO3ClF3) (Calcd. 393.8281); 1H-NMR (MeOD, 300 MHz) δH: 7.93 (s, 1H), 7,74 (d, 1H, J = 8.4 Hz), 7.65 (d, 1H, J = 8.4 Hz), 7.30 (m, 2H), 6.96 (m, 3H), 4.15 (t, 2H, J = 5.7 Hz), 3.58 (6H, m), 2.37 (m, 4H), 2.03 (d, 2H, J = 14.1 Hz); 13C-NMR (MeOD, 100 MHz,) δC (ppm): 148.4, 132.0, 131.4, 130.5, 128.3, 124.7, 124.1, 68.4, 66.0, 52.0, 49.1, 35.5, 30.3, 25.2.
3.2.4 4-[4-chloro-3-(trifluoromethyl)phenyl]-1-[2-(2, 5, 5-trimethyl-1, 3-dioxan-2-yl) ethyl]-4-piperidinol hydrobromide (4)
Yield: 75%, White crystalline powder, mp: 244 ± 2oC, C22H30NO3ClBrF3 (516.8197), Solubility (MeOH, EtOH, DMSO); UVλmax (MeOH) nm: 268.2, 352, 389; IR υmax (KBr) cm-1 3446, 3062, 2893, 2655, 435, 1747, 1580, 1480, 1387, 1129, 971, 905, 823, 658, 431; EI-MS m/z: 435.2 (M+-HBr), 350.1, 292.1, 274.1, 235, 201, 129, 100.1; HR-EIMS: 435.1782 (M+ -HBr, C22H29NO3ClF3) (Calcd. 435.9078); 1H-NMR (MeOD, 300 MHz) δH: 7.93 (d, 1H, J = 1.6 Hz), 7.73 (d, 1H, J = 8.0 Hz), 7.64 (d, 1H, J = 8.8 Hz), 3.75 (d, 2H, J = 11.6 Hz), 3.55 (br. s, 2H), 3.476 (m, 6H), 2.32 (t, 2H, J = 11.6 Hz), 2.17 (t, 2H, J = 11.6 Hz), 2.17 (t, 2H, J = 8.0 Hz), 2.00 (d, 2H, J = 14.0 Hz), 1.48 (s, 3H), 10.11 (s, 3H), 0.82 (s, 3H); 13C-NMR (MeOD, 100 MHz,) δC (ppm): 148.3, 131.5, 131.5, 130.5, 129.0, 128.3, 124.0, 97.3, 69.2, 68.3, 48.4, 35.4, 35.4, 33.0, 22.4, 21.9, 20.3.
3.2.5 4-[4-chloro-3-(trifluoromethyl)phenyl]-1-[2-(1, 3-dioxolan-2-yl) ethyl]-4-piperidinol hydrobromide (5)
Yield: 73%, White crystalline powder, mp: 193 ± 2oC, C17H22NO3ClBrF3 (460.7134), Solubility (MeOH, EtOH, DMSO), UVλmax (MeOH) nm: 199.8, 222, 270, 389; FT-IR υmax (KBr) cm-1: 3446, 2937, 2655, 2433, 1580, 1480, 1387, 1323, 1217, 1031,905, 658, 431, EI-MS m/z: 379.2 (M+-HBr), 279.1, 261.1, 207, 201, 167, 112 ,81.9, 153, 139, 124, 110, 83, 70, 55; HR-EI-MS: 379.1156 (M+ -HBr,C17H21NO3ClF3) (Calcd. 379.8015); 1H-NMR (MeOD, 300 MHz) δH: 7.92 (s, 1H), 7.73 (d, 1H, J = 8.4 Hz), 7.64 (d, 1H, J = 8.4 Hz), 5.00 (t, 1H, J = 3.0 Hz), 4.03 (m, 2H), 3.93 (m, 2H), 3.55 (s, 2H), 3.47 (m, 4H), 2.32 (m, 2H), 2.21 (m, 2H), 2.00 (d, 2H, J = 14 Hz); 13C-NMR (MeOD, 100 MHz, ) δC (ppm): 148.1, 132.8, 132.0, 131.1, 126.2, 125.6, 125.3, 102.6, 69.1, 66.2, 54.2, 50.2, 35.6, 29.3.
3.2.6 4-[4-chloro-3-(trifluoromethyl)phenyl]-1-phenethyl-4-piperidinol hydrobromide (6)
Yield: 86%, White crystalline powder, mp: 191 ± 2oC, C20H22NOBrClF3 (463.0525), Solubility (methanol, ethanol, DMSO); UV λmax (MeOH) nm: 221.2, 265.8, 390; EI-MS m/z: 384 (M+-HBr), 364.1, 212, 194, 184, 158, 135, 116.4, 89, 63; FT-IR υmax(KBr) cm-1: 3737, 3342, 2925, 2564, 1742, 1645, 1456, 1319, 1178,1033, 725, 546; HR-FABMS: 384.123{[M + H]+ -HBr C20H22NOClF3}(Calcd. 384.843); 1H-NMR (MeOD, 300 MHz)δH: 7.78 (s,1H),7.74 (m, 2H), 7.24 (m, 5H), 5.83 (s,1H), 3.54 (s,2H), 3.30(s, 2H), 3.03 (t, 4H, J = 15.3 Hz), 2.26 (t, 2H, J = 14.1 Hz), 1.86 (d, 2H, J = 14.1 Hz); 13C-NMR (MeOD, 100 MHz) δ (ppm): 138.3, 132.8, 131.9, 131.1, 129.9, 129.8, 126.2, 125.2, 122.6, 64.6, 59.4, 50.1, 36.8, 32.1.
3.2.7 2-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}-1-(4-methoxyphenyl)-1-ethanone hydrobromide (7)
Yield: 80.5%, White crystalline powder, mp: 275 ± 3oC, C21H22NO3BrClF3 (508.7562 a.m.u), Solubility (methanol, ethanol, DMSO), UV λmax (MeOH) nm: 203, 278, 390 FT-IR υmax (KBr) cm-1: 3742, 3285, 2929, 2568, 1683, 1467, 1319, 1138, 622; EI-MS m/z: 428 (M+-HBr), 408, 292, 274, 207, 210, 135, 121.1, 56.1; HR- EI-MS: 428.1230 (M+-Br, C21H 22NO3ClF3) (Calcd. 428); 1H-NMR (MeOD, 300 MHz) δH: (ppm): 8.01 (m, 2H), 7.76 (d, 1H, J = 7.74 Hz), 7.64 (d, 2H, J = 8.4 Hz), 7.09 (d, 2H, J = 8.8 Hz,), 3.90 (s, 3H,), 3.62(d, 4H, J = 12.9 Hz), 2.48 (s,2H), 1.98 (d, 2H, J = 14 Hz); 13C-NMR (MeOD, 100 MHz) δC (ppm): 190.3, 166.7, 139.3, 133.1, 131.9, 131.3, 130.0, 129.2, 126.1, 125.5, 122.5, 115.4, 69.9, 61.2, 52.6, 51.3, 35.0, 25.0.
3.2.8 2-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}-1-(2-naphthyl)-1-ethanone hydrobromide (8)
Yield: 79%, White crystalline powder, mp: 285 ± 2oC, C24H22NO2BrClF3 (528.7889); Solubility (MeOH, EtOH, DMSO); UV λmax (MeOH) nm: 199.8, 222, 250.2, 279, 338.2; FT-IRυmax (KBr) cm-1: 3740, 3442, 2929, 2657, 1836, 1685, 1627, 1399, 1177, 1137, 1035, 816, 750, 473; EI-MS m/z: 448 (M+HBr), 428, 291.9, 274, 257, 201, 178, 155, 127, 79.9; HR-EIMS: 448.1313 (MH+-HBr ,C24H22N2OClF3) (Calcd. 448.8849); 1H-NMR (MeOD, 300 MHz) δH: 8.69 (s, 1H), 8.04 (m, 4H), 7.80 (m, 4H), 5.20 (s, 2H), 3.70 (d, 4H, J = 13.8 Hz), 2.59 (m, 2H), 2.02 (d, 2H, J = 14.1 Hz); 13C-NMR (MeOD, 100 MHz,) δC (ppm): 196.2, 150.0, 134.6, 133.9, 132.9, 132.8, 132.6, 131.6, 131.5, 130.3, 128.9, 126.3, 69.9, 61.2, 51.0, 35.6.
3.2.9 1-(1-adamantyl)-2-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}-1-ethanone hydrobromide (9)
Yield: 79%, White crystalline powder, mp: 285 ± 2oC, C24H22NO2BrClF3 (528.7889), Solubility (MeOH, EtOH, DMSO); UV λmax (MeOH) nm: 271, 385, 389.6 FT-IR υmax (KBr) cm-1: 3315.6, 2917, 2856, 1709, 1582, 449, 1320, 1212, 1143, 985, 833, EIMS m/z: 456 (M+-HBr), 436,292, 294, 274, 257, 232, 208, 201, 178, 135, 107, 93.1, 79.1,56; HR- FABMS: 456.1905 {M + H]+ -HBr C24H30NO2ClF3} Calcd. 456.9484; 1H-NMR (MeOD, 300 MHz) δH: 7.93 (d, J = 2.1 Hz), 7.72 (dd, 1H, J1 = 2.1 Hz, J2 = 8.4 Hz), 7.58 (m, 1H), 3.54 (m, 2H), 2.79 (d, 2H, J = 10.2 Hz), 2.61 (m, 2H), 2.22 (m, 2H), 2.03 (br.s, 3H), 1.87 (m, 7H), 1.71 (m, 5H); 13C-NMR (MeOD, 100 MHz) δC (ppm): 207.5, 147.0, 130.4, 130.4, 129.2, 126.5, 124.7, 67.7, 59.8, 49.1, 44.9, 36.6, 35.7, 34.6, 27.0.
3.2.10 3-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}-1-phenyl-1-propanone hydrochloride (10)
Yield: 83%, White crystalline powder, mp: 220 ± 2oC, C21H22nNO2Cl2F3 (447.0979), Solubility (MeOH, EtOH, DMSO). 434; UVλmax (MeOH) nm: 201, 223, 243, 290, 302, 312, 316, 329. FT-IR υmax (KBr) cm-1: 3902, 3731, 3449, 2423, 3253, 2932, 2802, 2586, 2126, 1985, 1686, 1773, 1686, 1582, 1322, 1031, 668; EI-MS m/z: 411 (M+-HBr), 306.1, 292, 279.1, 260.9, 251.0, 232.1, 207, 179.1, 144, 132.1, 105; HR-EIMS: 411.1185 (M+ -HCl, C21H22nNO2Cl2F3 (Calcd. 411.8449); 1H-NMR (MeOD, 300 MHz) δH: 10.59 (s, 1H), 8.04 (s, 1H), 8.01 (d, 1H, J = 1.2 Hz),7.91 (s, 1H),7.75 (m, 3H), 7.59 (m, 2H), 5.84 (s, 1H), 3.70 (s, 2H), 3.51 (m, 6H), 2.49 (s, 1H) 1.86 (d, 2H, J = 13.8); 13C-NMR-(MeOD, 100 MHz) δC (ppm): 197.7, 148.3, 136.3, 133.4, 132.3, 131.4, 130.2, 128.8, 128.4, 128.4, 128.4, 124.7, 68.6, 51.7, 48.5, 34.2, 23.9.
3.2.11 4-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}-1-phenyl-1-butanone hydrochloride (11)
Yield: 73%, White crystalline powder, mp: 223 ± 2oC, C22H24NO2Cl2F3 (462.3321), Solubility (MeOH, EtOH, DMSO); UVλmax (MeOH) nm: 202, 242, 270, 302, 316, 319, 324, 336; IR υmax (KBr) cm-1: 3286, 2950, 2894, 2653, 1680, 1480, 1319, 1120, 984, 834, 652, 517; EIMS m/z: 425 (M+-HBr), 405.9, 374.9, 304.9, 291.9, 273.9, 256.8, 200, 178.9, 105, 98; HR- EIMS: 425.136 (M+ -HCl, C22H23NO2ClF3) (Calcd. 425.8715); 1H-NMR (MeOD, 300 MHz) δH: 8.03 (s, 1H), 8.01 (d, 1H, J = 1.5 Hz), 7.92 (d, 1H, J = 2.1 Hz), 7.72 (dd, J = 1.8 Hz, J = 8.4 Hz), 7.64 (m, 2H), 7.53 (m, 2H), 3.41 (d, 2H, J = 9.9 Hz), 3.23 (t, 4H, J = 12.0 Hz), 3.11 (t, 2H, J = 7.8 Hz), 2.29 (m, 4H), 1.09 (m, 2H); 13C-NMR (MeOD, 100 MHz,) δC (ppm): 198.6, 148.0,136.4, 133.2, 131.6, 131.2, 130.4, 129.1, 128.7, 127.8, 124.0, 124.0, 68.1, 55.3, 48.2, 35.2, 34.7.
3.2.12 4-[4-chloro-3-(trifluoromethyl)phenyl]-1-(3-phenoxypropyl)-4-piperidinol hydrobromide (12)
Yield: 80%, White crystalline powder, mp: 179 ± 2oC, C21H24NO2ClBrF3 (494.7727); Solubility (MeOH, EtOH, DMSO); UVλmax (MeOH) nm: 201, 221, 270, 277, 302, 324; FT-IR υmax (KBr) cm-1: 3447, 3422, 3284, 2924, 2649, 2432, 1782, 1598, 1321, 1125, 766, 427; EI-MS m/z: 413.2 (M+-HBr), 306, 394.2, 320.1, 292.1, 274.1, 276.1, 261.1, 207, 201.1, 179, 107, 94; HR- EIMS: 413.1380 (M+ -HBr, C21H23NO2ClF3) (Calcd. 413.1369); 1H-NMR (MeOD, 300 MHz) δH: 7.93 (s, 1H), 7.74 (d, 1H, J = 8.4 Hz), 7.65 (d, 1H, J = 8.4 Hz), 7.30 (m, 2H), 6.96 (m, 3H), 4.15 (t, 2H, J = 5.7 Hz), 3.58 (6H, m), 2.37 (m, 4H), 2.03 (d, 2H, J = 14.1 Hz); 13C-NMR (MeOD, 100 MHz) δC (ppm): 159.9, 148.0, 132.8, 132.1, 131.1, 148.0, 126.2, 125.4, 122.6, 122.2, 115.5, 69.2, 65.8, 50.2, 49.8, 36.5, 25.5.