S. Hayashi et al. / European Journal of Medicinal Chemistry 55 (2012) 228e242
237
(44.0 mL) was added trifluoroacetic acid (TFA) (133 mL) at 0 ꢀC under
N2. The mixture was stirred at 0 ꢀC under N2 for 30 min, allowed to
room temperature, stirred for 2 h, then concentrated in vacuo. The
residue was dissolved in CH2Cl2 (150 mL)eH2O (150 mL). The organic
layer was separated, dried over anhydrous MgSO4, and concentrated
in vacuo to afford 7.15 g of the title product (rac)-2 in 99% yield as
25% aqueous ammonia ¼ 10:1:0.5) was performed to afford 71.9 mg
of the title product 5b in 87% yield. 1H NMR (300 MHz, CDCl3)
8.28
d
(0.4H, d, 8.25 Hz, Ar H that is a peak for an amide-bond conformer),
7.26e7.08 (2.6H, m, Ar H including a peak for an amide-bond
conformer), 6.99 (1H, ddd, J ¼ 7.32 Hz, J ¼ 7.14 Hz, J ¼ 1.11 Hz, Ar
H), 5.47e5.44 (0.6H, CHeCO that is a peak for an amide-bond
conformer), 5.21 (0.4H, d, 8.61 Hz, CHeCO that is a peak for an
amide-bond conformer), 3.72e1.76 (23H, m, NCH(CH2)2, CH2, and
N(CH3)2), 1.69e1.38 (8H, m, CH2). Monocitrate of compound 5b: IR
(KBr): 3396, 2943, 1653, 1597, 1483, 1406, 1271, 1123, 1061, 989, 760,
a slight brownish-white solid. 1H NMR (270 MHz, CDCl3)
d 7.08e7.03
(2H, m, Ar H), 6.80e6.70 (2H, m, Ar H), 4.57 (1H, dd, J ¼ 10.7 Hz,
J¼ 5.62Hz,CH), 3.50(1H, dd, J¼ 15.7 Hz, J¼ 10.7 Hz, CH2), 3.16(1H, dd,
J ¼ 15.7 Hz, J ¼ 5.62 Hz, CH2), 3.07 (3H, s, NCH3), 2.99 (3H, s, NCH3).
598 cmꢃ1
(C24H36N4O2$C6H8O7) C, H, N.
.
MS (ESI positive) m/z: [M
þ
H]þ 413.28. Anal.
4.1.2.3. 1-Acryloyl-N,N-dimethylindoline-(2RS)-2-carboxamide
[(rac)-3]. To a stirred solution of N,N-dimethylindoline-(2RS)-2-
carboxamide (rac)-2 (7.150 g, 37.58 mmol) in dry CH2Cl2 (140 mL)
was added dry Et3N (13.1 mL, 94.0 mmol) at room temperature
under N2. The mixture was cooled to 0 ꢀC, then acryloyl chloride
(3.70 mL, 45.1 mmol) was added. The reaction mixture was stirred
at 0 ꢀC under N2 for 2 h, then poured into saturated aqueous
NaHCO3 (150 mL) at 0 ꢀC. The mixture was stirred at 0 ꢀC for 15 min,
then the organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (100 mL ꢂ 2). The organic layers were
combined, dried over anhydrous MgSO4, and concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel, hexane/acetone ¼ 1:1) followed by recrystallization from
AcOEtehexane to afford 5.335 g of the title product (rac)-3 in 58%
yield as a yellowish-white solid. 1H NMR (300 MHz, DMSO-d6)
4.1.5. 1-{3-[4-(2-Ethoxyphenyl)piperazin-1-yl]propanoyl}-N,N-
dimethylindoline-(2RS)-2-carboxamide (5c)
A solution of 1-(2-ethoxyphenyl)piperazine monohydrochloride
(SigmaeAldrich, 48.6 mg, 0.200 mmol), compound (rac)-3
(48.9 mg, 0.200 mmol), and dry Et3N (72.5
mL, 0.52 mmol) in
anhydrous THF (3.0 mL) was stirred at 60 ꢀC under N2 for 36 h,
cooled to room temperature, then concentrated in vacuo. PTLC
purification (silica gel, CH2Cl2/MeOH ¼ 20:1) was performed to
afford 61.1 mg of the title product 5c in 68% yield. 1H NMR
(300 MHz, CDCl3)
d
8.61 (0.4H, d, J ¼ 7.50 Hz, Ar(indoline) H that is
a peak for an amide-bond conformer), 7.29e6.83 (7.6H, m, Ar H
including Ar(indoline) H that is a peak for an amide-bond
conformer), 5.49e5.46 (0.6H, m, CHeCO that is a peak for an
amide-bond conformer), 5.26e5.23 (0.4H, m, CHeCO that is a peak
for an amide-bond conformer), 4.07 (2H, q, 6.96 Hz, OCH2CH3),
3.75e1.70 (20H, m, CH2 and N(CH3)2), 1.46 (3H, t, J ¼ 6.96 Hz,
OCH2CH3). Monocitrate of compound 5c: IR (KBr): 3410, 2932,1728,
1655, 1501, 1485, 1404, 1248, 1121, 1042, 984, 935, 754, 598,
d
8.20 (1H, d, J ¼ 8.40 Hz, Ar H), 7.21e7.16 (2H, m, Ar H), 7.03e6.98
(1H, m, Ar H), 6.37e6.21 (2H, m, CH2]CH(CO) and CH2]CH(CO)),
5.76e5.68 (2H, m, CH2]CH(CO) and CHeCON(CH3)2), 3.68 (1H, dd,
J ¼ 17.1 Hz, J ¼ 11.1 Hz, CH2), 3.11 (3H, s, NCH3), 3.03 (1H, d,
J ¼ 18.3 Hz, CH2), 2.84 (3H, s, NCH3). MS (EI direct) m/z: Mþ 244.
536 cmꢃ1
(C26H34N4O3$C6H8O7) C, H, N.
.
MS (ESI positive) m/z: [M
þ
H]þ 451.26. Anal.
4.1.3. N,N-Dimethyl-1-[3-(4-o-tolylpiperidin-1-yl)propanoyl]
indoline-(2RS)-2-carboxamide (5a)
A solution of 4-o-tolylpiperidine hydrochloride (Arch, 52.9 mg,
0.250 mmol), compound (rac)-3 (61.7 mg, 0.252mmol), and dry Et3N
4.1.6. N,N-Dimethyl-1-[3-(4-phenylpiperazin-1-yl)propanoyl]
indoline-(2RS)-2-carboxamide (5d)
A solution of 1-phenylpiperazine (Tokyo Chemical Industry,
32.4 mg, 0.200 mmol), compound (rac)-3 (48.9 mg, 0.200 mmol),
(91
m
L, 0.65 mmol) in anhydrous THF (3.0 mL) was stirred at 60 ꢀ
C
under N2 for 36 h, cooled to room temperature, then concentrated in
vacuo. PTLC purification (silica gel, CH2Cl2/MeOH ¼ 10:1) was per-
formed to afford70.9 mgof the title product 5a in 68% yield as a solid.
and dry Et3N (45 mL, 0.32 mmol) in anhydrous THF (3.0 mL) was
stirred at 60 ꢀC under N2 for 36 h, cooled to room temperature, then
concentrated in vacuo. PTLC purification (silica gel, CH2Cl2/
MeOH ¼ 20:1) was performed to afford 41.2 mg of the title product
1H NMR (270 MHz, CDCl3)
d
8.31 (0.4H, d, J ¼ 7.72 Hz, Ar(indoline) H
that is a peak for an amide-bond conformer), 7.30e7.06 (6.6H, m, Ar
H including Ar(indoline) H that is a peak for an amide-bond
conformer), 7.03e6.97 (1H, m, Ar(indoline) H), 5.50e5.45 (0.6H,
m, CHeCO that is a peak for an amide-bond conformer), 5.26e5.21
(0.4H, m, CHeCO that is a peak for an amide-bond conformer),
3.75e2.47 (15H, m, AreCH, CH2, and N(CH3)2), 2.29e2.11 (2H, m,
CH2), 2.34 (3H, s, AreCH3),1.87e1.74 (4H, m, CH2). General procedure
of monocitrate formation. A solution of compound 5a (70.9 mg,
0.169 mmol) and one equivalent of citric acid (32.5 mg, 0.169 mmol)
in dry MeOH (15.0 mL)edry CH2Cl2 (12.0 mL) was stirred at room
temperature under N2 for 2 h, and then concentrated in vacuo. The
residue was solidified from dry CH2Cl2edry hexane. After removing
solvent in vacuo, the solid was collected and dried under vacuum at
60 ꢀC for 2 h to afford 93.1 mg of monocitrate of compound 5a as
awhite solid: IR (KBr): 3398, 2932,1724,1655,1485,1406,1261,1123,
756, 598 cmꢃ1. Anal. (C26H33N3O2$C6H8O7) C, H, N.
5d in 51% yield. 1H NMR (300 MHz, CDCl3)
d 8.31e8.28 (0.4H, m,
Ar(indoline) H that is a peak for an amide-bond conformer),
7.29e6.83 (8.6H, m, Ar H including Ar(indoline) H that is a peak for
an amide-bond conformer), 5.49e5.46 (0.6H, m, CHeCO that is
a peak for an amide-bond conformer), 5.24e5.21 (0.4H, m, CHeCO
that is a peak for an amide-bond conformer), 3.73e1.80 (20H, m,
CH2 and N(CH3)2). Monocitrate of compound 5d: IR (KBr): 3418,
2932, 1728, 1655, 1599, 1485, 1402, 1250, 1124, 982, 928, 758, 696,
596, 581 cmꢃ1. MS (ESI positive) m/z: [M þ H]þ 407.22. Anal.
(C24H30N4O2$C6H8O7) C, H, N.
4.1.7. N,N-Dimethyl-1-[3-(4-pyrazin-2-ylpiperazin-1-yl)propanoyl]
indoline-(2RS)-2-carboxamide (5e)
A
solution of 1-(2-pyrazinyl)piperazine (Chess, 32.8 mg,
0.200 mmol), compound (rac)-3 (48.9 mg, 0.200 mmol), and dry
Et3N (45 mL, 0.32 mmol) in anhydrous THF (3.0 mL) was stirred at
4.1.4. 1-[3-(1,40-Bipiperidin-10-yl)propanoyl]-N,N-dimethylindoline-
60 ꢀC under N2 for 36 h, cooled to room temperature, then
concentrated in vacuo. PTLC purification (silica gel, CH2Cl2/
MeOH ¼ 20/1/) was performed to afford 70.1 mg of the title product
(2RS)-2-carboxamide (5b)
A
solution of 1,40-bipiperidine (SigmaeAldrich, 33.7 mg,
0.200 mmol), compound (rac)-3 (48.9 mg, 0.200 mmol), and dry
5e in 86% yield. 1H NMR (300 MHz, CDCl3)
d 8.30 (0.4H, d,
Et3N (45
m
L, 0.32 mmol) in anhydrous THF (3.0 mL) was stirred at
J ¼ 8.40 Hz, Ar(indoline) H that is a peak for an amide-bond
conformer), 8.13 (1H, m, pyrazine H), 8.06 (1H, dd, J ¼ 2.55 Hz,
J ¼ 1.47 Hz, pyrazine H), 7.85 (1H, d, J ¼ 2.58 Hz, pyrazine H),
60 ꢀC under N2 for 36 h, cooled to room temperature, then
concentrated in vacuo. PTLC purification (silica gel, CH2Cl2/MeOH/