84
W. Chu et al. / Bioorg. Med. Chem. 13 (2005) 77–87
CH Cl (150mL), washed with saturated NaCl, and
2
3.10 (m, 4H), 2.73 (m, 4H), 2.54 (m, 2H), 2.48 (s, 3H).
Anal. (C H N O S) C, H, N.
2
dried over Na SO . After evaporation of the solvent,
2
4
23 31
3
2
the crude product was purified by chromatography with
CH Cl –MeOH–N(C H ) (10:5:0.5) to afford 11.5g
(
4.10. 4-Chloro-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]-
butyl]benzamide (12d)
2
2
2
5 3
1
87%) of 10 as a colorless oil. H NMR (300MHz,
CDCl ) d 6.99–6.84 (m, 4H), 3.85 (s, 3H), 3.10 (m,
4H), 2.72 (t, J = 6.9Hz, 2H), 2.65 (m, 4H), 2.42 (t,
J = 6.9Hz, 2H), 1.60–1.45 (m, 4H).
3
Compound 12d was prepared according to the proce-
dure for compound 12b except using 6-chloronicotinic
acid, which afford 315mg (52%) of 12d as a white solid;
1
4.7. Thiophene-2-carboxylic acid [4-[4-(2-methoxyphen-
yl)-piperazin-1-yl]-butyl]amide (12a)
mp 126–128ꢁC. H NMR (300MHz, CDCl ) d 8.74 (d,
3
J = 2.4Hz, 1H), 8.08 (dd, J = 8.55Hz, J = 2.7Hz, 1H),
7
.39 (d, J = 8.4Hz, 1H), 7.22 (br, 1H), 7.03–6.84 (m,
A solution of 2-thiophenecarboxylic acid (257mg,
4H), 3.85 (s, 3H), 3.49 (m, 2H), 3.03 (m, 4H), 2.66 (m,
4H), 2.49 (t, J = 6.6Hz, 2H), 1.71 (m, 4H). Anal.
(C H ClN O ) C, H, N.
2
1
.0mmol) in SOCl (1.5mL) was heated to reflux for
2
h. After evaporation of the SOCl , CH Cl (5mL)
2
2
2
21 27
4
2
was added. The solution was added into a solution of
1
0 (440mg, 1.67mmol) in CH Cl (5mL) at 0ꢁC and tri-
4.11. 1H-Indol-2-carboxylic acid [4-[4-(2-methoxyphen-
yl)piperazin-1-yl]-butyl]amide (12e)
2
2
ethylamine (1mL) was added. The mixture was stirred
overnight, then ethyl acetate (75mL) was added, and
the organic layer washed with saturated Na CO
A
solution of indole-2-carboxylic acid (242mg,
1.5mmol) and 10 (395mg, 1.5mmol) in CH Cl
2
3
(
Na SO . After evaporation of the organic layer in
30mL · 2), saturated NaCl (30mL), and dried over
2
2
(15mL) was added to BOP-Cl (420mg, 1.65mmol) at
ambient temperature, then triethylamine (304mg,
3.0mmol) was added. The mixture was stirred over-
night, then ethyl acetate (75mL) was added, the organic
layer washed with saturated Na CO (30mL), saturated
2
4
vacuo, the crude product was purified by chromatogra-
phy with ether–MeOH (10:1) to afford 0.51g (82%) of
1
1
2a as a colorless oil; mp 212–214ꢁC (HCl salt). H
NMR (300MHz, CDCl ) d 7.52 (d, J = 3.75Hz, 1H),
3
2
3
7
(
3
2
.46 (d, J = 4.95Hz, 1H), 7.08 (t, J = 4.2Hz, 1H), 7.01
m, 1H), 6.94 (m, 2H), 6.88 (m, 1H), 6.49 (br, 1H),
NaCl (30mL), and dried over Na SO . After evapora-
2 4
tion of the solvent in vacuo, the crude product was puri-
fied by chromatography with EtOAc–MeOH (5:1) to
afford 352mg (58%) of 12e as a white solid; mp 146–
.88 (s, 3H), 3.49 (m, 2H), 3.12 (m, 4H), 2.70 (m, 4H),
.51 (m, 2H), 1.68 (m, 4H). Anal. (C H N O SÆ2H-
2
0
27
3
2
1
ClÆ0.5H O) C, H, N.
148ꢁC. H NMR (300MHz, CDCl ) d 9.34 (br, 1H),
2
3
7.66 (d, J = 8.1Hz, 1H), 7.46 (d, J = 8.4Hz, 1H), 7.30
(t, J = 7.5Hz, 1H), 7.16 (t, J = 7.2Hz, 1H), 7.02 (m,
4.8. 4-Dimethylamino-N-[4-[4-(2-methoxyphenyl)piper-
azin-1-yl]-butyl]benzamide (12b)
1H), 6.95 (m, 2H), 6.88 (m, 2H), 6.66 (br, 1H), 3.88 (s,
3
H), 3.55 (m, 2H), 3.15 (m, 4H), 2.72 (m, 4H), 2.53 (t,
J = 6.9Hz, 2H), 1.73 (m, 4H). Anal. (C H N O Æ0.25-
A solution of 4-(dimethylamino)benzoic acid (207mg,
.25mmol) in CH Cl (5mL) was added to ethyl chloro-
2
4
30
4
2
1
H O) C, H, N.
2
2
2
formate (142mg, 1.31mmol) at À5ꢁC, then triethylamine
132mg, 1.31mmol) was added. The reaction mixture
was stirred for 15min at À5ꢁC, then a solution of 10
300mg, 1.14mmol) in CH Cl (5mL) was added. The
(
4.12. Quinoxaline-2-carboxylic acid [4-[4-(2-methoxy-
phenyl)piperazin-1-yl]-butyl]amide (12f)
(
2
2
mixture was stirred overnight at ambient temperature,
then ethyl ether (75mL) was added, washed with satu-
rated Na CO (25mL · 2), saturated NaCl (25mL),
Compound 12f was prepared according to the procedure
for compound 12e except using 2-quinoxaline-carboxy-
lic acid, which afford 287mg (45%) of 12f as a white
2
3
1
and dried over Na SO . After evaporation of the solvent
solid; mp 157–159ꢁC. H NMR (300MHz, CDCl ) d
2
4
3
in vacuo, the crude product was purified by chromatog-
raphy with ether–MeOH (10:2) to afford 229mg (49%) of
9.69 (s, 1H), 8.19 (m, 1H), 8.11 (m, 2H), 7.90–7.81 (m,
2H), 7.01–6.84 (m, 4H), 3.86 (s, 3H), 3.60 (q,
J = 6.3Hz, 2H), 3.12 (m, 4H), 2.69 (m, 4H), 2.51 (t,
J = 7.2Hz, 2H), 1.75 (m, 4H). Anal. (C H N O ) C,
1
1
2b as a white solid; mp 126–128ꢁC. H NMR (300MHz,
CDCl ) d 7.68 (d, J = 9.0Hz, 2H), 7.00 (m, 1H), 7.92 (m,
3
24 29
5
2
2
H), 6.86 (m, 1H), 6.66 (d, J = 9.0Hz, 2H), 6.39 (br, 1H),
H, N.
3
.86 (s, 3H), 3.47 (m, 2H), 3.11 (m, 4H), 3.01 (s, 6H), 2.68
m, 4H), 2.49 (m, 2H), 1.67 (m, 4H). Anal.
(
(
4.13. Benzofuran-2-carboxylic acid [4-[4-(2-methoxyphen-
yl)piperazin-1-yl]-butyl]amide (12g)
C H N O Æ0.5H O) C, H, N.
2
4
34
4
2
2
4.9. N-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]-butyl]-4-
methylsulfanylbenzamide (12c)
Compound 12g was prepared according to the proce-
dure for compound 12b except using 2-benzofuran-carb-
oxylic acid, which afford 402mg (66%) of 12g as a white
1
Compound 12c was prepared according to the proce-
dure for compound 12b except using 4-(methylthio)ben-
zoic acid, which afford 404mg (65%) of 12c as a white
solid; mp 120–122ꢁC. H NMR (300MHz, CDCl ) d
3
7.67 (m, 1H), 7.48 (m, 1H), 7.46 (m, 1H), 7.40 (m,
1H), 7.29 (m, 1H), 7.03–6.85 (m, 5H), 3.87 (s, 3H),
3.53 (q, J = 6.0Hz, 2H), 3.14 (m, 4H), 2.71 (m, 4H),
2.50 (t, J = 6.9, 2H), 1.71 (m, 4H). Anal.
(C H N O ) C, H, N.
1
solid; mp 153–155ꢁC. H NMR (300MHz, CDCl ) d
3
7
1
.69 (d, J = 8.4, 2H), 7.21 (d, J = 8.7Hz, 2H), 7.98 (m,
H), 6.92–6.85 (m, 4H), 3.86 (s, 3H), 3.48 (m, 2H),
2
4
29
3
3