Clozapine-Like Mixed Activities at Receptors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21 4665
7.81 (s, 1H, CH-5). MS m/z 442 (M+, 12), 247 (base). Anal.
(C26H23ClN4O) C, H, N.
6.94-7.06 (m, 4H, ArH), 7.11 (s, 1H, CH-5), 7.19-7.36 (m, 10H,
ArH). MS m/z 428 (M+, 2), 233 (base). Anal. (C26H25ClN4) C,
H, N.
1-[(1,2-Dip h en yl-1H-im id a zol-4-yl)ca r bon yl]-4-(4-ch lo-
r op h en yl)p ip er a zin e (12g). TLC (AcOEt/petroleum ether,
7:3) Rf ) 0.69. IR 1625, 1547 cm-1. 1H NMR (CDCl3): δ 3.23-
3.28 (m, 4H, 2 × CH2), 3.96 (m, 2H, CH2), 4.61 (m, 2H, CH2),
6.87 (d, J ) 8.8 Hz, 2H, ArH), 7.20-7.41 (m, 12H, ArH), 7.81
1-(3-Ch lor op h en yl)-4-[(1,2-d ip h en yl-1H-im id a zol-4-yl)-
m eth yl]p ip er a zin e (1f). TLC (CHCl3/CH3OH, 9.5:0.5) Rf )
1
0.46. IR (KBr): 1594 cm-1. H NMR (CDCl3): δ 2.76-2.81 (m,
4H, 2 × CH2), 3.23-3.27 (m, 4H, 2 × CH2), 3.68 (s, 2H, CH2),
6.76-6.88 (m, 4H, ArH), 7.11 (s, 1H, CH-5), 7.15-7.36 (m, 10H,
ArH). MS m/z 428 (M+, 3), 233 (base). Anal. (C26H25ClN4) C,
H, N.
(s, 1H, CH-5). MS m/z 442 (M+, 15), 247 (base). Anal. (C26H23
-
ClN4O) C, H, N.
1-[(1,2-Diph en yl-1H-im idazol-4-yl)car bon yl]-4-(2-eth oxy-
p h en yl)p ip er a zin e (12o). TLC (AcOEt/petroleum ether, 7:3)
Rf ) 0.63. IR (KBr): 1612, 1542 cm-1. 1H NMR (CDCl3): δ 1.49
(t, J ) 6.6 Hz, 3H, CH3), 3.20 (m, 4H, 2 × CH2), 4.0 (m, 2H,
CH2), 4.13 (q, J ) 6.6 Hz, 2H, CH2O), 4.62 (m, 2H, CH2), 6.86-
6.96 (m, 4H, ArH), 7.26-7.42 (m, 10H, ArH), 7.80 (s, 1H, CH-
5). MS m/z 452 (M+, 29), 247 (base). Anal. (C28H28N4O2) C, H,
N.
{[1,2-Bis(4-flu or op h en yl)-1H-im id a zol-4-yl]ca r bon yl}-
4-(2-eth oxyp h en yl)p ip er a zin e (12r ). TLC (AcOEt/petro-
leum ether, 7:3) Rf ) 0.61. IR (KBr): 1615, 1540 cm-1. 1H NMR
(CDCl3): δ 1.49 (t, J ) 6.6 Hz, 3H, CH3), 3.19 (m, 4H, 2 ×
CH2), 3.99 (m, 2H, CH2), 4.12 (q, J ) 6.6 Hz, 2H, CH2O), 4.57
(m, 2H, CH2), 6.66-7.40 (m, 12H, ArH), 7.75 (s, 1H, CH-5).
MS m/z 488 (M+, 48), 283 (base). Anal. (C28H26F2N4O2) C, H,
N.
Gen er a l P r oced u r e for P r ep a r a tion of 1-[(1,2-Dip h e-
n yl-1H-im idazol-4-yl)m eth yl]-4-piper azin es 1a-r . The syn-
thesis of 1-[(1,2-diphenyl-1H-imidazol-4-yl)methyl]-4-phe-
nylpiperazine (1a ) is described as a general procedure. To a
solution of carboxamide 12a (0.71 g, 1.74 mmol) in anhydrous
THF (30 mL) at room temperature, 2 M borane-methyl sulfide
complex (2.55 mL, 5.1 mmol) was slowly added. The resulting
mixture was refluxed for 1.5 h and then allowed to cool at room
temperature. The solution was acidified with 1 N HCl and
refluxed for 15 min. The cooled reaction mixture was neutral-
1-(4-Ch lor op h en yl)-4-[(1,2-d ip h en yl-1H-im id a zol-4-yl)-
m eth yl]p ip er a zin e (1g). TLC (CHCl3/CH3OH, 9.5:0.5) Rf )
1
0.40. IR (KBr): 1596 cm-1. H NMR (CDCl3): δ 2.80 (m, 4H, 2
× CH2), 3.21 (m, 4H, 2 × CH2), 3.68 (s, 2H, CH2), 6.82-6.86
(m, 3H, ArH), 7.11 (s, 1H, CH-5), 7.17-7.36 (m, 11H, ArH).
MS m/z 428 (M+, 3), 233 (base). Anal. (C26H25ClN4) C, H, N.
1-[(1,2-Dip h en yl-1H -im id a zol-4-yl)m et h yl]-4-(2-flu o-
r op h en yl)p ip er a zin e (1h ). TLC (CHCl3/CH3OH, 9.5:0.5) Rf
) 0.43. IR (KBr): 1598 cm-1. 1H NMR (CDCl3): δ 2.84 (m, 4H,
2 × CH2), 3.12-3.15 (m, 4H, 2 × CH2), 3.71 (s, 2H, CH2), 6.95-
7.07 (m, 4H, ArH), 7.11 (s, 1H, CH-5), 7.17-7.39 (m, 10H,
ArH). MS m/z 412 (M+, 3), 233 (base). Anal. (C26H25FN4) C, H,
N.
1-[(1,2-Dip h en yl-1H -im id a zol-4-yl)m et h yl]-4-(4-flu o-
r op h en yl)p ip er a zin e (1i). TLC (CHCl3/CH3OH, 9.5:0.5) Rf
1
) 0.33. IR (KBr): 1595 cm-1. H NMR (CDCl3): δ 2.79-2.83
(m, 4H, 2 × CH2), 3.15-3.20 (m, 4H, 2 × CH2), 3.69 (s, 2H,
CH2), 6.89-6.95 (m, 4H, ArH), 7.11 (s, 1H, CH-5), 7.23-7.37-
(m, 10H, ArH). MS m/z 412 (M+, 1), 233 (base). Anal. (C26H25
-
FN4) C, H, N.
1-[(1,2-Dip h en yl-1H-im id a zol-4-yl)m eth yl]-4-[3-(tr iflu o-
r om eth yl)p h en yl]p ip er a zin e (1j). TLC (CHCl3/CH3OH, 9.5:
0.5) Rf ) 0.33. IR (KBr): 1603 cm-1. 1H NMR (CDCl3): δ 2.79-
2.84 (m, 4H, 2 × CH2), 3.27-3.31 (m, 4H, 2 × CH2), 3.69 (s,
2H, CH2), 7.04-7.08 (m, 3H, ArH), 7.11 (s, 1H, CH-5), 7.20-
7.40 (m, 11H, ArH). MS m/z 462 (M+, 2), 233 (base). Anal.
(C27H25F3N4) C, H, N.
ized with
a saturated aqueous solution of NaHCO3 and
extracted with CH2Cl2. The organic layer was washed with
water, dried, and evaporated in vacuo. The residue was
purified by flash silica gel chromatography, eluting with
CHCl3/CH3OH (9.5:0.5) to give a colorless oil, which was dried
under vacuum to give 1a (0.6 g, 88%). This compound crystal-
lized on standing as white crystals of 1a ; mp 99-100 °C
(ether). TLC (CHCl3/CH3OH, 9.5:0.5) Rf ) 0.47. IR (KBr): 1599
cm-1. 1H NMR (CDCl3): δ 2.79-2.84 (m, 4H, 2 × CH2), 3.23-
3.28 (m, 4H, 2 × CH2), 3.69 (s, 2H, CH2), 6.61-6.96 (m, 3H,
ArH), 7.11 (s, 1H, CH-5), 7.19-7.41 (m, 12H, ArH). MS m/z
394 (M+, 1), 233 (base). Anal. (C26H26N4) C, H, N.
1-[(1,2-Dip h en yl-1H-im id a zol-4-yl)m eth yl]-4-[4-(tr iflu o-
r om eth yl)p h en yl]p ip er a zin e (1k ). TLC (CHCl3/CH3OH, 9.5:
0.5) Rf ) 0.37. IR (KBr): 1607 cm-1. 1H NMR (CDCl3): δ 2.80-
2.84 (m, 4H, 2 × CH2), 3.28-3.33 (m, 4H, 2 × CH2), 3.70 (s,
2H, CH2), 7.05-7.40 (m, 14H, ArH and CH-5). MS m/z 462
(M+,1), 233 (base). Anal. (C27H25F3N4) C, H, N.
[(1,2-Dip h en yl-1H-im id a zol-4-yl)m eth yl]-4-(2-p yr id yl)-
p ip er a zin e (1l). TLC (CHCl3/CH3OH, 9.5:0.5) Rf ) 0.32. IR
1
(KBr): 1591 cm-1. H NMR (CDCl3): δ 2.74-2.79 (m, 4H, 2 ×
CH2), 3.58-3.63 (m, 4H, 2 × CH2), 3.69 (s, 2H, CH2), 6.58-
6.67 (m, 3H, ArH), 7.12 (s, 1H, CH-5), 7.20-7.50 (m, 10H,
ArH), 8.19 (d, J ) 4.0 Hz, 1H, ArH). MS m/z 395 (M+, 3), 233
(base). Anal. (C25H25N5) C, H, N.
1-[(1,2-Dip h en yl-1H -im id a zol-4-yl)m et h yl]-4-(2-m et h -
oxyp h en yl)p ip er a zin e (1b). TLC (CHCl3/CH3OH, 9.5:0.5) Rf
1
) 0.26. IR (KBr): 1591 cm-1. H NMR (CDCl3): δ 2.88-2.90
1-Ben zyl-4-[(1,2-d iph en yl-1H-im ida zol-4-yl)m eth yl]p ip -
er a zin e (1m ). TLC (CHCl3/CH3OH, 9.5:0.5) Rf ) 0.21. IR
(m, 4H, 2 × CH2), 3.14-3.16 (m, 4H, 2 × CH2), 3.75 (s, 2H,
CH2), 3.86 (s, 3H, OCH3), 6.95-6.98 (m, 4H, ArH), 7.15 (s, 1H,
CH-5), 7.23-7.40 (m, 10H, ArH). MS m/z 424 (M+, 3), 233
(base). Anal. (C27H28N4O) C, H, N.
1
(KBr): 1596 cm-1. H NMR (CDCl3): δ 2.55 (m, 4H, 2 × CH2),
2.68 (m, 4H, 2 × CH2), 3.52 (s, 2H, CH2), 3.64 (s, 2H, CH2),
7.06 (s, 1H, CH-5), 7.16-7.33 (m, 15H, ArH). MS m/z 408 (M+,
3), 233 (base). Anal. (C27H28N4) C, H, N.
1-[(1,2-Dip h en yl-1H -im id a zol-4-yl)m et h yl]-4-(3-m et h -
oxyp h en yl)p ip er a zin e (1c). TLC (CHCl3/CH3OH, 9.5:0.5) Rf
1-[(1,2-Diph en yl-1H-im idazol-4-yl)m eth yl]-4-m eth ylpip-
er a zin e (1n ). TLC (CHCl3/CH3OH, 9.5:0.5) Rf ) 0.32. IR
1
) 0.31. IR (KBr): 1598 cm-1. H NMR (CDCl3): δ 2.77-2.82
(m, 4H, 2 × CH2), 3.23-3.26 (m, 4H, 2 × CH2), 3.72 (s, 2H,
CH2), 3.81 (s, 3H, OCH3), 6.39-6.57 (m, 4H, ArH), 7.11 (s, 1H,
CH-5), 7.16-7.36 (m, 10H, ArH). MS m/z 424 (M+, 1), 233
(base). Anal. (C27H28N4O) C, H, N.
1
(KBr): 1598 cm-1. H NMR (CDCl3): δ 2.32 (s, 3H, N-CH3),
2.56 (m, 4H, 2 × CH2), 2.71 (m, 4H, 2 × CH2), 3.66 (s, 2H,
CH2), 7.10 (s, 1H, CH-5), 7.17-7.39 (m, 10H, ArH). MS m/z
332 (M+, 6), 233 (base). Anal. (C21H24N4) C, H, N.
1-[(1,2-Dip h en yl-1H -im id a zol-4-yl)m et h yl]-4-(4-m et h -
oxyp h en yl)p ip er a zin e (1d ). TLC (CHCl3/CH3OH, 9.5:0.5) Rf
1-[(1,2-Dip h en yl-1H-im id a zol-4-yl)m eth yl]-4-(2-eth oxy-
p h en yl)p ip er a zin e (1o). TLC (CHCl3/CH3OH, 9.5:0.5) Rf )
1
) 0.30. IR (KBr): 1598 cm-1. H NMR (CDCl3): δ 2.80-2.84
0.44. IR (KBr): 1596 cm-1 1H NMR (CDCl3): δ 1.45 (t, J )
.
(m, 4H, 2 × CH2), 3.13-3.16 (m, 4H, 2 × CH2), 3.70 (s, 3H,
OCH3), 3.76 (s, 2H, CH2), 6.87 (d, J ) 9.2 Hz, 2H, ArH), 6.92
(d, J ) 9.6 Hz, 2H, ArH), 7.12 (s, 1H, CH-5), 7.19-7.40 (m,
10H, ArH). MS m/z 424 (M+, 8), 233 (base). Anal. (C27H28N4O)
C, H, N.
6.8 Hz, 3H, CH3), 2.86 (m, 4H, 2 × CH2), 3.18 (m, 4H, 2 ×
CH2), 3.71 (s, 2H, CH2), 4.06 (q, J ) 7.0 Hz, 2H, CH2O), 6.62-
6.96 (m, 4H, ArH), 7.12 (s, 1H, CH-5), 7.19-7.41 (m, 10H,
ArH). MS m/z 438 (M+, 3), 233 (base). Anal. (C28H30N4O) C,
H, N.
1-(2-Ch lor op h en yl)-4-[(1,2-d ip h en yl-1H-im id a zol-4-yl)-
m eth yl]p ip er a zin e (1e). TLC (CHCl3/CH3OH, 9.5:0.5) Rf )
1-{[1,2-Bis(4-flu or op h en yl)-1H-im id a zol-4-yl]m eth yl}-
4-p h en ylp ip er a zin e (1p ). TLC (CHCl3/CH3OH, 9.5:0.5) Rf )
1
1
0.46. IR (KBr): 1598 cm-1. H NMR (CDCl3): δ 2.81-2.86 (m,
0.26. IR (KBr): 1598 cm-1. H NMR (CDCl3): δ 2.77-2.82 (m,
4H, 2 × CH2), 3.15-3.19 (m, 4H, 2 × CH2), 3.71 (s, 2H, CH2),
4H, 2 × CH2), 3.23-3.28 (m, 4H, 2 × CH2), 3.67 (s, 2H, CH2),