The synthesis of cyclic and acyclic long-chain arylpiperazine derivatives of salicylamide as serotonin receptor ligands

Article abstract of DOI:10.1002/jhet.5570450125

(Chemical Equation Presented) The 1-arylpiperazine series of N-substituted 1,3-benzoxazine-2,4-diones as well as O- and N-substituted salicylamides with an n-propyl chain were synthesized in order to explore the effect of cyclic and acyclic salicylamide moieties on their binding affinity for 5-HT_1A, 5-HT_2A and 5-HT₇ receptor sites. Target compounds 1 and 2 were prepared by a two-step procedure, i.e. by alkylation of 1,3-benzoxazine-2,4-dione or salicylamide with 1,3-dibromopropane and next by condensation of 3-bromopropyl intermediates with arylpiperazines; syntheses of 3-bromopropyl intermediates were performed in solvent-free conditions. Compounds 3 were prepared by hydrolysis of 1. In respect of salicylamide moieties, binding affinities for 5-HT_1A and 5-HT₇ receptors increase according to the rank of derivatives 3 < 1 < 2, for the same arylpiperazines. Regarding 5-HT_2A receptors, increased activity of ligands was changed in reverse order to the affinity for 5-HT_1A, i.e. 2 < 1 < 3. 5-HT_1A and 5-HT₇ receptor binding constants were the highest for the 2-methoxyphenyl ligand 2c, while the 3-chlorophenyl ligand 3b was most active for 5-HT_2A receptors.

Full text of DOI:10.1002/jhet.5570450125

Jan-Feb 2008
209
The Synthesis of Cyclic and Acyclic Long-chain Arylpiperazine
Derivatives of Salicylamide as Serotonin Receptor Ligands
Piotr Kowalski*a, Jolanta Jaꢀkowskaa, Andrzej J. Bojarskib, and Beata Duszyꢁskab
aCracow University of Technology, Institute of Organic Chemistry and Technology, 24 Warszawska Street,
31-155 Kraków, Poland, e-mail: kowapi@usk.pk.edu.pl
bDepartment of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences,
12 Smꢂtna Street, 31-343 Kraków, Poland
Received June 10, 2007
O
O
O
O
O
R
N
NH2
R
R
NH
O
OH
1
2
3
R1
R =
(CH2)3
N
N
R1 = H, m-Cl, o-OCH3
Ki 5-HT1A = 21-743 nM; Ki 5-HT2A = 7.3-699 nM; Ki 5-HT7 = 234-710 nM
The 1-arylpiperazine series of N-substituted 1,3-benzoxazine-2,4-diones as well as O- and N-substituted
salicylamides with an n-propyl chain were synthesized in order to explore the effect of cyclic and acyclic
salicylamide moieties on their binding affinity for 5-HT1A, 5-HT2A and 5-HT7 receptor sites. Target
compounds 1 and 2 were prepared by a two-step procedure, i.e. by alkylation of 1,3-benzoxazine-2,4-dione
or salicylamide with 1,3-dibromopropane and next by condensation of 3-bromopropyl intermediates with
arylpiperazines; syntheses of 3-bromopropyl intermediates were performed in solvent-free conditions.
Compounds 3 were prepared by hydrolysis of 1. In respect of salicylamide moieties, binding affinities for
5-HT1A and 5-HT7 receptors increase according to the rank of derivatives 3 < 1 < 2, for the same
arylpiperazines. Regarding 5-HT2A receptors, increased activity of ligands was changed in reverse order to
the affinity for 5-HT1A, i.e. 2 < 1 < 3. 5-HT1A and 5-HT7 receptor binding constants were the highest for the
2-methoxyphenyl ligand 2c, while the 3-chlorophenyl ligand 3b was most active for 5-HT2A receptors.
J. Heterocyclic Chem., 45, 209 (2008).
O
INTRODUCTION
N
N
Long-chain arylpiperazines with a general structure
presented in Figure 1 are the largest class of 5-HT1A
serotonin receptor ligands [1-4]. An Ar group attached to
N1 of a piperazine moiety is usually a substituted phenyl
or heteroaromatic (one or two rings) system. With regard
to the alkyl chain, two to four methylene groups (n = 0–2)
are optimal for 5-HT1A activity. The terminus usually
contains an amide or an imide function, but neither is
required for high activity, i.e. it may also be a phenyl or
another aromatic group (see Figure 2.).
R = H; 5-HT1A, Ki = 38 nM [6]
5-HT2A, Ki = 40 nM [6]
N
R
R = Cl; 5-HT1A, Ki = 29 nM [6]
5-HT2A, Ki = 25 nM [6]
H
N
N
N
OCH3
O
N
N
5-HT1A, Ki = 1.3 nM [7]
O
OCH3
Ar
terminus
N
N
5-HT1A, Ki = 7.0 nM [8]
5-HT7, Ki = 43.5 nM [8]
n
F
Figure 1. The general chemical structure of long-chain arylpiperazines.
O
N
OCH3
Serotonin (5-hydroxytryptamine, 5-HT) is an important
neurotransmitter that mediates a wide variety of sensory,
motor, and cortical functions through multiple 5-HT
receptor subtypes [5]. It is generally accepted that 5-HT1A
receptors are involved in psychiatric disorders, such as
anxiety and depression [9,10].
5-HT1A, Ki = 3.4 nM [7]
N
Figure 2. Selected long-chain arylpiperazine derivatives and their
binding data for 5-HT1A, 5-HT2A and 5-HT7 serotonin receptors [6-8].

210
P. Kowalski, J. Jaꢀkowska, A. J. Bojarski and B. Duszyꢁska
Vol 45
dione (1) and O- (2), as well as N-substituted (3)
salicylamides (Figure 3). The influence of the above
terminus on receptor affinities was studied for three
classic arylpiperazines with a propylene linker a–c.
Some currently widely used drugs (buspirone [11],
ziprasidone [12], aripiprazol [13]) are effective 5-HT1A
ligands, belonging to the arylpiperazine class. The high
sequence homology of 5-HT1A receptor binding sites with
other serotonin receptor subtypes [14-16] causes that
long-chain arylpiperazines are investigated also as 5-HT2A
and 5-HT7 receptor ligands (Figure 2).
RESULTS AND DISCUSSION
Synthesis. Compounds 1a–c and 2a–c were prepared
by a two-step procedure by alkylation of 1,3-benzoxazine-
2,4-dione (1) or salicylamide (2) with 1,3-dibromo-
propane (4), and next, condensation of 3-bromopropyl
intermediates 5 or 6 with 1-phenylpiperazine (7), 1-(3-
chlorophenyl)piperazine (8), and 1-(2-methoxyphenyl)-
piperazine (9) (Scheme 1).
In comparison with the previously described method
[6,19,21], the alkylation of 1 was performed in the
absence of a solvent at an ambient temperature using 3
equivalents of 4, K2CO3 and tetrabutylammonium
bromide (TBAB) as a catalyst. In the above conditions,
the reaction was completed in ca. 30 min. and the yield of
5 was 92%. The usefulness of the solvent-free protocol to
synthesize N-alkyl derivatives of 1,3-benzoxazine-2,4-
dione was confirmed by experimental results on their N-
benzylation, N-ethylation, and N-(ꢀ-halogenation) (Table
1). In all the cases, the reaction occurred in a few minutes,
with the high yield.
In consequence of an our sustained interest in 5-HT1A,
5-HT2A and 5-HT7 serotonin receptor ligands, we found a
number of active long-chain arylpiperazine derivatives of
benzoxazinone, benzoxazolinone, quinazolinone,
phthalazinedione, pyridazinedione, benzoxazolindione
and others [6,17-23]. Their affinity, selectivity, and
function towards the particular type of the receptor were
affected by relatively small structure modifications in
either terminal fragments or a chain bridge.
O
O
O
X
O
N
NH2
X
NH
X
O
O
OH
3: X = H
1: X = H
2: X = H
(CH2)3
N
N
N
1a, 2a, 3a: X =
Cl
A
solvent-free alkylation procedure was also
(CH2)3
(CH2)3
N
N
1b, 2b, 3b: X =
1c, 2c, 3c: X =
applied to synthesize O-(3-bromopropyl)salicylamide
(6) (Scheme 1). In that case, however, progress of the
reaction of 1,3-dibromopropane (4) with salicylamide (2)
was observed only after heating on a water bath.
N
H3CO
The synthesis of amides 3 was based on literature
reports describing that under alkali conditions 1,3-
benzoxazin-2,4-dione and its N-methyl derivative
underwent hydrolysis to the corresponding salicylamides
[27,28]. In our experiment, the parent substances in
synthesis of the compounds 3 were the N-substituted
derivatives 1. The optimization of hydrolysis conditions
showed that the highest yield of 3 was obtained using a
5% water solution of sodium hydroxide (Scheme 2).
Figure 3. Structures of the investigated compounds 1a,b,c–3a,b,c.
In the present paper we explored the effect of
salicylamide moieties in serotonin receptor ligands of the
long-chain arylpiperazine family on their binding affinity
for 5-HT1A, 5-HT2A and 5-HT7 receptor sites. Both cyclic
and acyclic derivatives of the salicylamide were chosen,
i.e. the N-substituted derivatives of 1,3-benzoxazine-2,4-
Scheme 1
O
O
O
HN
N Ar (7-9)
(CH2)3Br
Br(CH2)3Br
(4)
N
NH
1a-c
2a-c
K2CO3 / KI / DMF
K2CO3 / TBAB
O
O
O
5
6
1
O
O
O
HN
N Ar (7-9)
Br(CH2)3Br
(4)
NH2
OH
NH2
K2CO3 / TBAB
(CH2)3Br
K2CO3 / KI / DMF
2

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The synthesis of cyclic and acyclic long-chain arylpiperazine
211
Table 1
Synthesis of N-alkyl derivatives of 1,3-benzoxazine-2,4-dione (5, 15–19) in solvent-free conditions.
O
O
R
O
R-X (4, 10-14)
N
NH
K2CO3 / TBAB
O
O
O
1
5, 15-19
Molar ratio
imide : R-X
Compound
R-X
Yield, %
Mp, °C
Recryst. solvent
Br(CH2)3-Br, 4
C6H5CH2-Cl, 10
CH3CH2-Br, 11
Br(CH2)2-Br, 12
Br(CH2)4-Br, 13
Br(CH2)5-Br, 14
5
1 : 3
92
93
70
91
84
85
102-103
methanol
methanol
methanol
methanol
propan-1-ol
acetone-water
15
16
17
18
19
1 : 1.2
1 : 1.2
1 : 3
1 : 3
1 : 3
133-135 [a]
109-111 [b]
113-115 [c]
64-66
81-83
[a] ref. 24, mp 133–134 °C. [b] ref. 25, mp 110–112 °C. [c] ref. 26, mp 111–112 °C.
Scheme 2
The binding affinity for 5-HT1A receptors of the
compounds studied clearly depends on the structure of a
terminus amide, as well as on nature of a phenyl attached
to the piperazine ring (Table 2). In respect of salicylamide
moieties, the binding affinity for 5-HT1A receptors
increased in the following order: 3 < 1 < 2 for the same
arylpiperazines. In the case of compounds with the same
salicylamide motif, the affinity was changed in order:
phenyl (a) < 3-chlorophenyl (b) < 2-methoxyphenyl (c)
piperazine derivatives. Thus compound 2c turned out to
be the most active 5-HT1A receptor ligand.
O
(CH2)3
N
N Ar
N
5% NaOH
O
O
O
1a-c
(CH2)3
NH
OH
N
N Ar
3a-c
The influence of the salicylamide fragment on 5-HT7
receptor activity was similar to that found for 5-HT1A
sites; however, it was investigated for O-(2-methoxy-
phenyl)piperazine derivatives only, and the observed Ki
values were within a moderate range.
The structure of the obtained compounds was
confirmed by infrared and H nmr spectra, and in some
1
cases by comparison of their physical properties to those
described in the literature. For biological experiments,
bases 1a–c, 2a–c and 3a–c were converted into hydro-
chloride salts. Their physicochemical properties and
binding affinities for 5-HT1A, 5-HT2A and 5-HT7 receptors
are collected in Table 2.
Regarding 5-HT2A receptors, the increase of ligands
activity in respect of salicylamide moieties was in reverse
order, i.e. 2 < 1 < 3, obviously, for the same aryl-
piperazine (Table 2). Compounds with the 3-chlorophenyl
group attached to the piperazine ring (b) were the most
active, whereas the 2-methoxyphenyl fragment was
detrimental for 5-HT2A receptors activity. The highest
binding constant (Ki = 7.3 nM), detected for the N-(3-
chlorophenyl)piperazine derivative of acyclic salicyl-
amide (3b), distinguished it as a selective 5-HT2A/5-HT1A
agent.
Receptor Binding Assays. Radioligand studies with
native 5-HT1A and 5-HT2A receptors were conducted
according to the methods previously described by us [29].
Briefly, in 5-HT1A assays, rat hippocampal membranes,
[3H]-8-OH-DPAT (106 Ci/mmol, NEN Chemicals) and
10 μM of 5-HT (for non–specific binding) were used,
whereas in 5-HT2A assays, rat cortical membranes, [3H]-
ketanserin (67.0 Ci/mmol, PerkinElmer) and methyl-
sergide (1 μM) were employed. 5-HT7 binding assays
were performed on membranes from HEK 293 cells,
stably expressing the human 5-HT7(b) receptor according
to the procedure described by Thomas et al. [30]. [3H]-5-
CT (93.0 Ci/mmol, Amersham) was used as a radioligand,
while the non-specific binding was defined in the
presence of 10 μM of 5-HT.
The present results confirm the importance of both the
salicylamide motif and N1-aryl fragment for the
modulation of serotonin 5-HT1A, 5-HT2A and 5-HT7
activity. The most striking effect was observed for O-
substituted derivatives 2, whose 5-HT1A affinities were
reinforced compared to N-substituted analogues 3, with
simultaneous decrease in the 5-HT2A binding constants

212
P. Kowalski, J. Jaꢀkowska, A. J. Bojarski and B. Duszyꢁska
Vol 45
Table 2
Physical properties of compounds 1a-c, 2a-c, and 3a-c and their binding affinities to 5-HT1A, 5-HT2A and 5-HT7 receptors.
Base
Mp, °C
Ki (nM)
5-HT2A
Hydrochloride,
mp, °C
Compound
Yield, %
Recryst. solvent
5-HT1A
5-HT7
1a
1b
1c
2a
2b
2c
3a
3b
3c
70 [a]
68 [d]
56
74
65
57
68
61
55
124-127
97-99
acetonitrile
acetone
methanol
methanol
methanol
233-236 [b]
211-214 [e]
212-215
207-110
228-229
195-198
192-194
193-194 [g]
176-179 [i]
402 [c]
126 [c]
46
143
77
49 [c]
18 [c]
417
641
402
699
32
7.3
322
–
–
–
324
–
–
234
–
–
719
–
104-105
144-146
176-178
143-145
114-116
96-98 [f]
125-6 [h]
acetone
acetonitrile/water
methanol
21
743
191
130
12 [j]
–
propan-2-ol
buspirone
ritanserin
methiothepin
1.1 [k]
–
–
–
2.7 [l]
[a] ref. 17, Yield 67 %. [b] ref. 17, mp 234-236 °C. [c] data taken from ref. 17. [d] ref. 17, Yield 53 %. [e] ref. 17, mp 215-217 °C. [f]
ref. 31, mp 105 °C. [g] ref. 31, mp 193 °C. [h] ref. 31, mp 77 °C. [i] ref. 31, mp 176 °C. [j] ref. 24,32-35, Ki = 9–29 nM. [k] ref. 36, 37
Ki = 0.56 nM, [l] ref. 30, Ki = 3.2 nM.
3-(4-bromobutyl)-2H-1,3-benzoxazine-2,4(3H)-dione (18).
1H nmr: ꢀ 2.10-2.46 (m, 4H, CH2-CH2), 3.46 (t, 2H, CH2-Br),
4.09 (t, 2H, CH2-N-imide), 7.23-8.15 (m, 4H, ArH). Anal. Calcd.
for C12H12BrNO3 (298.13): C, 48.34; H, 4.06; N, 4.70. Found: C,
48.46; H, 4.11; N, 4.94.
3-(5-bromopentyl)-2H-1,3-benzoxazine-2,4(3H)-dione (19).
1H nmr: ꢀ 1.52-2.02 (m, 6H, CH2-CH2-CH2), 3.42 (t, 2H, CH2-
Br), 4.06 (t, 2H, CH2-N-imide), 7.23-8.15 (m, 4H, ArH). Anal.
Calcd. for C13H14BrNO3 (312.16): C, 50.02; H, 4.52; N, 4.49.
Found: C, 49.86; H, 4.50; N, 4.33.
EXPERIMENTAL
Melting points were determined on a Böetius melting point
apparatus and are uncorrected. Elemental analyses were
performed on Perkin Elmer 2400 analyzer and the results are
within ±0.4% of the calculated values. Infrared spectra were
recorded as pressed KBr discs on a Bio-Rad FTS 175B
spectrometer. 1H NMR spectra were taken on Tesla 587A
(80MHz) spectrometer in CDCl3 solution, using TMS as an
internal standard; the chemical shifts are given in ppm (ꢀ). The
reactions and purifications were monitored by tlc (uv detection)
on aluminum sheets coated with silica gel 60 F254 (Merck)
using chloroform/methanol (90:10) mixture as eluent. All
starting materials were purchased from commercial sources
(Sigma-Aldrich and Merck) and were used without further
purification.
Synthesis of 2-(3-bromopropoxy)benzamide (6).
A
powdered mixture of 1.37 g (0.01 mol) of salicylamide (2)
4.14 g (0.03 mol) of anhydrous potassium carbonate, 0.32 g
(0.001 mol) of TBAB were placed in vessel. Next, 3
equivalents of 6.06 g of 1,3-dibromopropane (4) was added,
and the mixture was stirred by spatula for ca. 1 minute. The
reaction mixture was heated during 60 minutes on boiling
water bath, and after cooling was poured into 100 mL of
water. The precipitate was extracted with chloroform. After
evaporation of the solvent, the crude product was purified by
crystallization from methanol to give 6 in 58% yield, mp
126–129 °C (mp. 126–128 °C [38]).
General procedure for the synthesis of 1a–c and 2a–c. A
mixture of 0.01 mol of 5 or 6, 0.01 mol of the respective amines
7–9, 0.02 mol of anhydrous potassium carbonate (when a
hydrochloride salt of an amine was used, an equivalent of
potassium carbonate was also added), and a few crystals (~0.01
g) of potassium iodide in 20 mL of dimethylformamide were
stirred with a magnetic stirrer at room temperature for 40 hours.
Them, the reaction mixture was poured into 100–150 mL of
water, and the precipitate was either colleted by filtration or
extracted with chloroform. The crude products were purified by
crystallization. The yields and physical properties of 1a–c and
2a–c are shown in Table 2. Compounds 1a and 1b have been
described previously [17].
General procedure for the synthesis of N-alkyl derivatives
of 1,3-benzoxazine-2,4-dione (5, 15–19).
A powdered
mixture of 1.63 g (0.01 mol) of 1,3-benzoxazine-2,4-dione
(1), 4.14 g (0.03 mol) of anhydrous potassium carbonate and
0.32 g (0.001 mol) of TBAB was placed in a vessel. Then, 3
equivalents of dibromoalkanes 4, 12–14, or 1.2 equivalents of
alkyl halides 10, 11 were added, respectively; the mixture was
stirred with a spatula for ca. 1 minute. The reaction mixture
was left at an ambient temperature. During 10–15 minutes,
the mixture was warmed up spontaneously up to a temp. of
40–60 °C, and after another 15–20 minutes the temperature
fell, which signified that the reaction was completed. The
reaction mixture was poured into 100 mL of water. In the case
of compound 5 and 17–19, the precipitate was extracted with
chloroform, and after evaporation of the solvent, crude
products were purified by crystallization (Table 1).
Compounds 15 and 16 were collected by filtration and were
recrystallized from methanol (Table 1).
3-(3-bromopropyl)-2H-1,3-benzoxazine-2,4(3H)-dione (5).
1H nmr: ꢀ 2.14-2.48 (m, 2H, CH2), 3.47 (t, 2H, CH2-Br), 4.20 (t,
2H, CH2-N-imide), 7.26-8.15 (m, 4H, ArH). Anal. Calcd. for
C11H10BrNO3 (284.11): C, 46.50; H, 3.55; N, 4.93. Found: C,
46.68; H, 3.51; N, 4.74.
3-{3-[4-(2-Methoxyphenyl)piperazin-1-yl)propyl]-2H-1,3-
benzoksazyno-2,4(3H)-dion (1c). Base; ir (KBr): ꢁ 750, 1244,
1
1351, 1469, 1504, 1702, 1760, 2820, 2958 cm-1; H nmr: ꢀ 1.78-
2.12 (m, 2H, CH2), 2.48-2.70 (m, 6H, CH2-N-pip, 2CH2-pip),

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The synthesis of cyclic and acyclic long-chain arylpiperazine
213
2.88-2.98 (m, 4H, 2CH2-pip), 3.83 (s, 3H, OCH3), 4.17 (t, 2H,
CH2-N-imide), 6.81-8.14 (m, 8H, ArH). Anal. Calcd. for
C22H25N3O4 · 2HCl · 0.5H2O (477.38): C, 55.35; H, 5.91; N,
8.80. Found: C, 55.72; H, 5.99; N, 8.59.
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1
3173, 3379 cm-1; H nmr: ꢁ 1.93-2.24 (m, 2H, CH2), 2.51-2.68
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2-{3-[4-(3-Chlorophenyl)piperazin-1-yl]propoxy}benz-
amide (2b). Base; ir (KBr): ꢀ 760, 1150, 1240, 1592, 1664,
2823, 2930, 3168, 3377 cm-1; 1H nmr: ꢁ 2.04-2.28 (m, 2H, CH2),
2.64-2.86 (m, 6H, CH2-N-pip, 2CH2-pip), 3.17-3.30 (m, 4H,
2CH2-pip), 4.24 (t, 2H, CH2-O), 5.86 (s, 1H, NH2), 6.87-7.58 (m,
7H, ArH), 7.86 (s, 1H, NH2), 8.21(d, 1H, ArH). Anal. Calcd. for
C20H24ClN3O2 · 2HCl · 0.5H2O (455.81): C, 52.70; H, 5.97; N,
9.22. Found: C, 53.06; H, 5.82; N, 8.87.
2-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propoxy}benz-
amide (2c). Base; ir (KBr): ꢀ 771, 1150, 1236, 1594, 1663,
2830, 2940, 3173, 3454 cm-1; 1H nmr: ꢁ 2.05-2.28 (m, 2H, CH2),
2.57-2.77 (m, 6H, CH2-N-pip, 2CH2-pip), 3.07-3.19 (m, 4H,
2CH2-pip), 3.87 (s, 3H, OCH3), 4.24 (t, 2H, CH2-O), 5.92 (s, 1H,
NH2), 6.91-7.58 (m, 7H, ArH), 7.86 (s, 1H, NH2), 8.22 (m, 1H,
ArH). Anal. Calcd. for C21H27N3O3 · 2HCl (442.38): C, 57.02; H,
6.61; N, 9.50. Found: C, 56.91; H, 6.63; N, 9.41.
General procedure for the hydrolysis of 1a–c to 3a–c.
Compound 1a–c (0.5 g) was heated 10-15 minutes in 10 mL
middle boiling 5% water solution of sodium hydroxide until the
reaction mixture becomes clear. After cooling the reaction
mixture was neutralized with 10% hydrogen chloride to neutral
pH. Precipitate was collected by filtration and recrystallized
from appropriate solvent. The yields and physical properties of
3a–c are collected in the Table 2.
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Duszyꢀska, B.; Bojarski, A. J.; Fruziꢀski, A.; Karolak-Wojciechowska,
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N-{3-[4-(Phenyl)piperazin-1-yl]propyl}-2-hydroxybenz-
amide (3a). Base; ir (KBr): ꢀ 755, 1240, 1494, 1597, 1643,
2830, 2957, 3188, 3437 cm-1; 1H nmr: ꢁ 1.67-1.97 (m, 2H, CH2),
2.58-2.76 (m, 6H, CH2-N-pip, 2CH2-pip), 3.19-3.32 (m, 4H,
2CH2-pip), 3.60 (t, 2H, CH2-N-amide), 6.55-7.53 (m, 9H, ArH),
8.70 (s, 1H, NH), 12.60 (s, 1H, OH). Anal. Calcd. for
C20H25N3O2·HCl· 0.5H2O (384.90): C, 62.41; H, 7.07; N, 10.92.
Found: C, 62.28; H, 7.02; N, 11.03.
N-{3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl}-2-hydroxy-
benzamide (3b). Base; ir (KBr): ꢀ 759, 1237, 1489, 1596, 1641,
2835, 2943, 3197 cm-1; 1H nmr: ꢁ 1.83-1.97 (m, 2H, CH2), 2.67-
2.74 (m, 6H, CH2-N-pip, 2CH2-pip), 3.19-3.31 (m, 4H, 2CH2-
pip), 3.56 (t, 2H, CH2-N-amide), 6.56-7.48 (m, 8H, ArH),
8,63 (s, 1H, NH), 12,59 (s, 1H, OH). Anal. Calcd. for
C20H24ClN3O2·2HCl (446.80): C, 53.76; H, 5.87; N, 9.40. Found:
C, 53.75; H, 5.92; N, 9.25.
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1
1596, 1643, 2823, 2945, 3188, 3431 cm-1; H nmr: ꢁ 1.84-1.98
(m, 2H, CH2), 2.64-2.83 (m, 6H, CH2-N-pip, 2CH2-pip), 3.13-
3.24 (m, 4H, 2CH2-pip), 3.52 (t, 2H, CH2-N-amide), 3.87 (s, 3H,
OCH3), 6.65-7.63 (m, 8H, ArH), 9,00 (s, 1H, NH), 12,60 (s, 1H,
OH). Anal. Calcd. for C21H27N3O3·2HCl (442.38): C, 57.02; H,
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