2596 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13
Cao et al.
g, 10 mmol) in DMF (85 mL) and H2O (4.16 mL), followed by
addition of K2CO3 (5.53 g, 40.5 mmol). The solution was
warmed to 80 °C for 2 h. The mixture was filtered, and the
filtrate was concentrated in vacuo, dissolved in H2O (100 mL),
extracted with CH2Cl2 (3 × 50 mL), dried (Na2SO4), and
evaporated to give the crude product. Purification by flash
column chromatography (3% CHCl3/MeOH/NH4OH) gave the
pure amide (3.77 g, 100%) as a yellow oil; IR (CHCl3) 1673
(CO) cm-1. The intermediate amide was dissolved in THF (30.8
mL) and added dropwise to a mixture of LAH (0.79 g, 20.8
mmol) in THF (6.21 mL) at 0 °C and stirred overnight at rt.
The mixture was quenched with H2O (0.9 mL), 15% NaOH
(0.9 mL), and H2O (2.7 mL) successively, at 0 °C. The reaction
mixture was filtered, washed with THF, and evaporated to
dryness, to give the crude product, which was purified by flash
column chromatography (3% CHCl3/MeOH/NH4OH) to give the
product as a light yellow oil (2.8 g, 77%). The HCl salt was
made by dissolving the free base in methanolic HCl and was
recrystallized from MeOH/ether; mp 234-236 °C (dec); 1H
NMR δ 1.04 (6H, d, 2 × CH3), 1.55 (2H, t, J ) 11 Hz), 1.78
(2H, t, J ) 7.0 Hz), 2.33 (2H, t, J ) 7.0 Hz), 2.72-2.92 (4H,
m), 3.66 (2H, t, J ) 7.1 Hz, CH2N(PhF)2 ), 6.92-6.95 (8H, m,
aryl-Hs); 13C NMR δ 20.3, 25.0, 50.9, 51.1, 56.0, 61.1, 116.1,
116.4, 122.6, 122.7, 145.0, 156.7, 159.8, 168.1; MS(EI) 359 (M+);
Anal. (C21H27F2N3‚2HCl), C, H, N.
[3-(cis-3,5-Dim eth yl-4-[3-p h en ylp r op yl]-1-p ip er a zin yl)-
p r op yl]-N,N-b is(4-flu or op h en yl)a m in e H yd r ob r om id e
(11). Hydrocinnamic acid (1.84 g, 12.42 mmol) was dissolved
in thionyl chloride (32 mL, 463 mmol), and the solution was
warmed to 50 °C and stirred for 90 min. The excess thionyl
chloride was removed by distillation. The residue was taken
up in toluene (35 mL) and added to a solution of 10 (2.7 g, 7.5
mmol) in toluene (35 mL). The reaction mixture was stirred
at reflux overnight, then extracted with 20% Na2CO3 (3 × 50
mL), washed with brine (50 mL), and dried (Na2SO4). Removal
of the volatiles gave the crude product, which was purified by
flash column chromatography (3% CHCl3/MeOH/NH4OH) to
yield the amide intermediate (3.5 g, 95%) as a yellow oil. The
intermediate amide (3.5 g, 7.13 mmol) was dissolved in THF
(21.47 mL) and added dropwise to a mixture of LAH (0.541 g,
14.26 mmol) in THF (4.33 mL) at 0 °C and stirred overnight
at rt. The mixture was quenched with H2O (0.6 mL), 15%
NaOH (0.6 mL), and H2O (1.8 mL) successively, at 0 °C. The
reaction mixture was filtered and washed with THF and
evaporated to dryness. The crude product was purified by flash
column chromatography (2% CHCl3/MeOH/NH4OH) to give the
product as a light yellow oil (2.5 g, 74%). The HBr salt was
made by dissolving the free base in methanolic HBr and then
recrystallizing from acetone/ether; mp 229.5-230.5 °C; 1H
NMR δ 0.98 (6H, d, J ) 5.9 Hz, 2 × CH3), 1.22-1.25 (2H, m),
1.58-1.80 (4H, m), 2.25-2.29 (2H,m), 2.51-2.54 (2H,m), 2.56-
2.68 (4H,m), 2.78 (2H, t, J ) 7.9 Hz, CH2Ph), 3.64 (2H, t, J )
7.1 Hz, CH2N(PhF)2 ), 6.92-7.36 (13H, m, aryl-Hs); 13C NMR
δ 18.0, 24.6, 33.8, 47.5, 50.7, 53.5, 55.3, 61.4, 115.7, 116.0,
122.2, 122.3, 125.8, 128.3, 128.4; MS(EI) 477 (M+), 218
(+CH2N(PhF)2); Anal. (C30H37F2N3‚2HBr‚H2O), C, H, N.
propyl]diphenylamine11 (0.53 g, 1.64 mmol) and 3,4-dichlo-
rophenylacetic acid (0.56 g, 2.71 mmol). After coupling and
reduction (0.43 g, 53%), the amine was converted to the HCl
salt and was recrystallized from acetone; mp 221-224 °C; 1H
NMR δ 1.11 (6H, d, J ) 6.1 Hz, 2 × CH3), 1.64-1.88 (4H, m),
2.32 (2H, t, J ) 7.2 Hz), 2.61-2.78 (6H, m), 2.92-2.98 (2H,
m), 3.75 (2H, t, J ) 7.3 Hz, CH2N(PhF)2 ), 6.91-7.36 (13H, m,
aryl-Hs); 13C NMR δ 18.0, 24.5, 28.8, 49.6, 50.0, 53.3, 55.2,
61.2, 120.8, 121.0, 127.9, 129.1, 130.3, 130.4, 140.8, 147.9; MS-
(EI) 495 (M+); Anal. (C29H35N3Cl2‚2HCl‚0.5H2O), C, H, N.
[3-(1-P ip e r a zin yl)p r op yl]-N ,N -b is(4-flu or op h e n yl)-
a m in e h yd r och lor id e (15) was prepared as described for 10
from 14 (5.2 g, 15.3 mmol), using piperazine (1.32 g, 15.3
mmol). After coupling and reduction (1.96 g, 39% from 14),
the amine was converted to the HCl salt and recrystallized
from acetone/ether; mp 216-218 °C (dec) 1H NMR δ 1.72-
1.80 (2H, m CH2), 2.17-2.37 (4H, m), 2.86-2.89 (6H, m), 3.67
(2H, t, J ) 7.2 Hz, CH2N(PhF)2 ), 6.92-7.00 (8H, m, aryl-Hs);
13C NMR δ 24.9, 25.1, 46.4, 51.0, 55.0, 56.6, 116.1, 116.4, 122.6,
122.7, 144.9, 145.0, 156.7, 160.0, 167.1; MS(EI) 331(M+); Anal.
(C19H23F2N3‚2HCl‚0.5H2O), C, H, N.
[3-(4-[3-p h en ylp r op yl]-1-p ip er a zin yl)p r op yl]-N,N-bis-
(4-flu or op h en yl)a m in e h yd r obr om id e (16) was prepared
as described for 11 from 15 (0.49 g, 1.48 mmol) and hydrocin-
namic acid (0.37 g, 2.46 mmol). After coupling and reduction
(0.67 g, 90%, from 15), the amine was converted to the HBr
salt in methanolic HBr and recrystallized from acetone/MeOH;
mp 235-236 °C (dec); 1H NMR δ 1.60-1.84 (4H,m), 2.17-2.65
(14H, m), 3.66 (2H, t, J ) 7.0 Hz, CH2N(PhF)2 ), 6.9-7.3 (13H,
m, aryl-Hs); 13C NMR δ 25.1, 29.0, 34.1, 51.1, 53.6, 55.9, 58.4,
116.1, 116.4, 122.6, 122.7, 126.1, 128.7, 128.8, 142.5, 144.9,
156.7, 159.8, 168.0; MS(EI) 449(M+) 218 (+CH2N(PhF)2); Anal.
(C28H33F2N3‚2HBr), C, H, N.
[3-(4-Benzyl-1-piperazinyl)propyl]-N,N-bis(4-fluorophen-
yl)a m in e h yd r obr om id e (17) was prepared as described for
12 from 15 (0.49 g, 1.48 mmol) and benzoyl chloride (0.29 mL,
2.50 mmol). After coupling and reduction (0.57 g, 91%, from
15), the amine was converted to HBr salt and recrystallized
1
from acetone/ether. mp 74-76 °C; H NMR δ 1.76 (2H, m, J
) 7.2 Hz, CH2), 2.14-2.46 (10H, m), 3.51 (1H, s, NCH2-aryl),
3.65 (2H, t, J ) 7.2 Hz, CH2N(PhF)2 ), 7.25-7.32 (13H, m,
aryl-Hs); 13C NMR δ 15.6, 25.1, 25.7, 51.1, 53.5, 53.6, 55.9,
63.5, 116.1, 116.4, 122.6, 122.7, 127.4, 128.6, 129.6, 138.4,
144.9, 145.0, 156.7, 159.8; MS(EI) 421(M+), 218 (+CH2N(PhF)2);
Anal. (C26H29F2N3‚HBr‚0.5H2O), C, H, N.
[3-(4-[3-Hydr oxy-3-ph en ylpr opyl]-1-piper azin yl)pr opyl]-
N,N-b is(4-flu or op h en yl)a m in e H yd r ob r om id e (19). A
solution of 15 (750 mg, 2.27 mmol) in acetone (4.54 mL) was
added to a stirred solution of 3-chloropropiophenone (556 mg,
3.30 mmol) in acetone (5.67 mL). The reaction was stirred
overnight (12-18 h) at rt. After removing the solvent, the
residue was extracted with CHCl3 (3 × 100 mL) and aq NH4-
OH (20%, 100 mL), dried (MgSO4), and concentrated. The
crude ketone was purified by flash column chromatography
(2% CHCl3/MeOH/NH4OH) to give the pure product as a yellow
oil. The ketone 18 was reduced with LAH (0.131 g, 3.45 mmol)
in THF to give the crude product which was converted to the
HBr salt in methanolic HBr and was recrystallized from
[3-(cis-3,5-Dim eth yl-4-[2-(3,4-d ich lor op h en yl)eth yl]-1-
p ip er a zin yl)p r op yl]-N,N-bis(4-flu or op h en yl)a m in e h y-
d r och lor id e (12) was prepared as described for 11 from 10
(0.59 g, 1.64 mmol) using 3,4-dichlorophenylacetic acid (0.56
g, 2.71 mmol). After coupling and reduction (0.6 g, 69% from
15), the amine was converted to the HCl salt. The product was
recrystallized from acetone/ether; mp 211-213 °C (dec) 1H
NMR δ 1.12 (6H, d, J ) 6.0 Hz, 2 × CH3), 1.61-1.85 (4H, m),
2.31 (2H, t, J ) 7.1 Hz), 2.61-2.77 (6H, m), 2.92-2.98 (2H,
m), 3.66 (2H, t, J ) 7.2 Hz, CH2N(PhF)2), 6.88-7.00 (7H, m,
aryl-Hs), 7.25 (2H, d, J ) 9.06 Hz, aryl-Hs), 7.35 (2H,d, J )
8.2 Hz, aryl-Hs); 13C NMR δ 18.1, 24.7, 29.1, 49.8, 50.7, 53.5,
55.3, 61.3, 115.8, 116.1, 122.3, 122.4, 128.0, 130.4, 130.5, 144.6;
MS(EI) 531 (M+), 218 (+CH2N(PhF)2); Anal. (C29H33F2N3Cl2‚
2HCl‚H2O), C, H, N.
1
acetone (784 mg, 74%, from 15); mp 184-185 °C; H NMR δ
1.75-1.88 (4H, m), 2.17-2.74 (12H, m),3.67 (2H, t, J ) 7.1
Hz, CH2N(PhF)2 ), 4.93 (1H, t, J ) 5.5 Hz, CHO), 6.88-7.36
(13H, m, aryl-Hs); 13C NMR δ 25.1, 34.0, 51.0, 53.6, 55.8, 57.4,
116.1, 116.4, 122.6, 122.7, 125.9, 127.3, 128.6, 144.9, 145.0,
145.2, 156.7, 160.0; Anal. (C28H33F2N3O‚HBr), C, H, N.
Sin gle-Cr ysta l X-r a y Diffr a ction An a lysis of 11. C30H39
-
F2N3 2(Br)- FW ) 639.46, monoclinic space group P21/c, a
) 14.997(1), b ) 7.365(1), c ) 28.823(1) Å, â ) 105.089(1)°, V
) 3073.8(1) Å3, Z ) 4, Fcalc ) 1.382 mg mm-3, λ(Cu KR) )
1.54178 Å, µ ) 3.623 mm-1, F(000) ) 1312, T ) 293 K.
2+
A colorless 0.20 × 0.12 × 0.06 mm crystal was used for data
collection with a Bruker SMART27 6K CCD detector on a
Platform goniometer. The Rigaku rotating Cu anode source
was equipped with an incident beam Gobel mirrors. Lattice
parameters were determined using SAINT27 from 2706 reflec-
[3-(cis-3,5-Dim eth yl-4-[2-(3,4-d ich lor op h en yl)eth yl]-1-
p ip er a zin yl)p r op yl]d ip h en yla m in e h yd r och lor id e (13)
was prepared as in 12 from [3-(cis-3,5-dimethyl-1-piperazinyl)-