Synthesis of N-[2-(1-piperidinyl)ethyl]benzamides

Article abstract of DOI:10.1248/cpb.50.129

Novel benzamide derivatives, A-[1-(aminocarbonyl)-2-(1-piperidinyl)ethyl] benzamides (4 and 5), were prepared from the reaction of N-piperidinoalanine (6) as the starting material.

Full text of DOI:10.1248/cpb.50.129

January 2002
Notes
Chem. Pharm. Bull. 50(1) 129—132 (2002)
129
Synthesis of N-[2-(1-Piperidinyl)ethyl]benzamides
Fumiko FUJISAKI,* Nobuhiro ABE, and Kunihiro SUMOTO
Faculty of Pharmaceutical Science, Fukuoka University, Nanakuma, Jonann-ku, Fukuoka 814–0180, Japan.
Received July 30, 2001; accepted October 12, 2001
Novel benzamide derivatives, N-[1-(aminocarbonyl)-2-(1-piperidinyl)ethyl]benzamides (4 and 5), were pre-
pared from the reaction of b-piperidinoalanine (6) as the starting material.
Key words b-piperidinoalanine; benzamide derivative; Mannich base; mixed anhydride; pivaloyl chloride; Schotten–Baumann
reaction
In the course of our studies on the chemistry of enamino- step without further purification. Treatment of compound 8
ketones,1) we synthesized some enamino-ketone Mannich with carboxylic acids in the presence of dicyclohexylcarbodi-
base derivatives depicted by the general formula 1 (Chart 1), imide (DCC) gave the desired benzamide derivative 4. In a
and found that most had strong opioid analgesic activity.2) similar manner, the reaction of 9 with carboxylic acids af-
Among the derivatives synthesized, compound 1a or 1b forded corresponding benzamide derivatives 5a—d. Since no
showed higher analgesic acitivity than that of morphine, and reaction of 7 with piperidine occurred,4) alternative amidation
both compounds had various pharmacological activities such of the target compound 5e was investigated and we found
as sedative, antitussive, or anticonvulsant activities. These re- that a method via mixed anhydride was efficient. Thus the re-
sults suggested that 1a or 1b can interact with a variety of re- action of 6 with benzoyl chloride under Schotten–Baumann
ceptors in the central nervous system. On the basis of those reaction conditions gave N-[(1-carboxy)-2-(1-piperidinyl)-
studies, we attempted the chemical modification of the proto- ethyl]benzamide 10 in good yield. The reactant of 10 with
type compound 1 as shown in Chart 2. Thus the alicyclic pivaloyl chloride, giving a corresponding mixed anhydride,
moiety (part A enclosed in the dotted lines in 1) was re- was allowed to react with piperidine to provide the desired 5e
moved and the vinylogous amide moiety was divided into in 50% yield. Using this procedure, compound 5a was also
two amide moieties (parts B and C in structure 2), leading to obtained from 10 and pyrrolidine in 63% yield (see Chart 3).
the malonodiamide Mannich base 2. However, the synthe- This method via mixed anhydride was also applicable for the
sized compounds 2 were unstable. Therefore we planned to preparation of 4 and 5b—d and provides a new synthetic
synthesize the Mannich base 3 in which the anilide moiety procedure for this class of compounds. The results are sum-
(part C in 2) was replaced with a benzamide group. This marized in Table 1.5)
molecule 3 bears a marked structural resemblance to some
The molecules of 4 and 5 synthesized above have frame-
dopamine antagonists. In this paper, we report the synthesis works similar to those of tiapride6) and metoclopramide7)
of novel benzamide derivatives (4 and 5 in Chart 3) with the
general structure 3.
Results and Discussion
For the preparation of the target compounds 4 and 5 start-
ing from b-piperidinoalanine 6, two rational synthetic path-
ways via amidation of this amino acid are possible. The effi-
cient synthesis of starting material 6 and related compounds
has already been reported.3) To begin, we attempted the pro-
cedure via amidation of the carboxylic acid functionality.
Thus treatment of 6 with methanolic hydrogen chloride gave
the corresponding amino acid methyl ester 7 in excellent
yield. The ester dihydrochloride 7 was reacted with methyl-
amine and pyrrolidine to give corresponding amides 8 and 9
Chart 1
(87 and 72% yield, respectively), which were used in next
Chart 2
To whom correspondence should be addressed. e-mail: fujisaki@cis.fukuoka-u.ac.jp
© 2002 Pharmaceutical Society of Japan

130
Vol. 50, No. 1
Chart 3
Table 1. Preparation of N-[(1-Aminocarbonyl)-2-(1-piperidinyl)ethyl]benzamides 4 and 5
R1
Analysis (%) Calcd (Found)
Compd.
no.
mp (°C)
(Solvent)
Formula
FAB-MS
(MHϩ)
X
–N
C
C
H
N
4a
4b
4c
4d
5a
H
–NHCH3
–NHCH3·
–NHCH3
–NHCH3
139—142
(AcOEt)
183 (dec.)
(H2O)
154—155
(CH3CN)
138—141
(AcOEt)
216—218 (dec.)
(CH3CN)
C16H23N3O2
290
369
350
380
330
66.41
(66.51
48.23
(48.10
61.87
(61.95
60.14
(59.96
62.37
(62.14
8.01
8.03
6.67
6.61
7.79
7.71
7.7
7.90
7.71
7.76
14.52
14.54)
13.23
13.20)
12.03
12.04)
11.07
11.04)
11.48
11.63)
2-OCH3, 4-NH2,
5-Cl
3,4-OCH3
C17H25ClN4O3
·HCl·H2O
C18H27N3O4
3,4,5-OCH3
H
C19H29N3O5
C19H27N3O2
·HCl
5b
5c
2-OCH3, 4-NH2,
5-Cl
3,4-OCH3
175—177
(Acetone)
106—112
(AcOEt)
159—162
(CH3CN)
161–162
(CH3CN)
C20H29ClN4O3
C21H31N3O4
C22H33N3O5
C20H29N3O2
409
390
420
344
58.74
(58.76
64.76
(64.46
62.99
(62.90
69.94
(69.86
7.15
7.18
8.02
8.03
7.93
7.84
8.51
8.50
13.7
13.63)
10.79
10.52)
10.02
10.15)
12.23
12.21)
5d
5ea)
3,4,5-OCH3
H
a) This compound was obtained by the method via mixed anhydride, other compounds were obtained by the method via ester 7.
(Chart 4), which are clinically useful dopamine receptor an-
tagonists. Molecular model examination of these com-
pounds8) suggested the possibility that compounds 4 and 5
may interact with the dopamine receptor. Further synthetic
applications and pharmacological evaluations of the com-
pounds synthesized are under investigation to find a new can-
didate with potent dopamine antagonist activity.
Chart 4
Experimental
Melting points were uncorrected. Infrared (IR) spectra were measured
with a Shimadzu FTIR-8100 spectrometer. 1H- (500 MHz) and 13C- (125
MHz) NMR spectra were obtained with a JEOL JNM A-500. Chemical
shifts were expressed as d ppm downfield from an internal tetramethylsilane
(TMS) signal (0 ppm) or sodium 3-(trimethylsilyl)propionic 2,2,3,3-d4 acid
(TSP) signal (0 ppm) (in D2O) for 1H-NMR, and the carbon signal of the

January 2002
131
corresponding solvent [CDCl3 (77.0 ppm), DMSO-d6 (39.5 ppm)], and TSP
CH2Cl2. The filtrate was extracted three times with 1 N HCl and the extract
(0 ppm) (in D2O) for 13C-NMR, respectively. The signal assignments were was washed with CH2Cl2. The aqueous solution was made basic with anhy-
1
1
confirmed with H–1H correlation spectroscopy (COSY), H–13C heteronu- drous K2CO3 and the resulting precipitate was extracted with CH2Cl2. The
clear multiple quantum coherence (HMQC), and 1H–13C heteronuclear mul- extract was washed with brine, dried over anhydrous MgSO4, and concen-
tiple bond connectivity (HMBC) spectra. FAB-MS were obtained with a trated in vacuo to give 4a (0.76 g, 49%) which was recrystallized from
JEOL JMS-HX110 mass spectrometer. Yield and physical data (MS, analy- AcOEt to afford colorless prisms. IR (KBr): 3315, 3265, 1674, 1630 cmϪ1
.
sis) for compounds 4 and 5 are summarized in Table 1. Other spectroscopic 1H-NMR (CDCl3) d: 1.47—1.50 (2H, m, 4-CH2 of piperidine ring), 1.57—
data are recorded below. 1.62 (4H, m, 3,5-CH2 of piperidine ring), 2.42—2.57 (2H, m, 2-CH2 of
Methyl a-Amino-1-piperidinepropanoate Dihydrochloride (7) piperidine ring), 2.47 [1H, dd, Jϭ13,10 Hz, –NHCH(CONϭ)CHHNϭ],
Methanolic HCl (10%) was added to a solution of 6 in anhydrous methanol 2.75 (2H, br, 6-CH2 of piperidine ring), 2.84 (3H, d, Jϭ5 Hz, NCH3), 2.89
and the mixture was kept at room temperature for 24 h, then evaporated to [1H, dd, Jϭ13, 5 Hz, –NHCH(CONϭ)CHHNϭ], 4.51 [1H, dt, Jϭ10, 5 Hz,
dryness in vacuo. After a few such treatments with methanolic HCl, the m, –NHCH(CONϭ)CH2Nϭ], 7.40—7.44 (2H, m, 3,5H-aromatic), 7.47—
residue finally crystallized completely. The yield was quantitative. Recrys- 7.50 (2H, m, 4H-aromatic, Ar-CONH), 7.82— 7.84 (2H, m, 2,6H-aromatic),
tallization from methanol gave an analytical sample of 7. This compound
8.25 (1H, br d, Jϭ5 Hz, NHCOCH3). 13C-NMR (CDCl3) d: 23.9 (C4 of
was colorless prisms and quite hygroscopic, mp 178 °C (dec.). IR (KBr): piperidine ring), 25.9 (NCH3), 26.2 (C3, C5 of piperidine ring), 49.5
1759 cmϪ1. Negative FAB-MS m/z: 257 (Mϩ2HClϪH)Ϫ. 1H-NMR (DMSO- [–NHCH(CONϭ)CH2–], 54.3 (C2, C6 of piperidine ring), 59.6
d6) d: 1.55 (2H, br s, 4-CH2 of piperidine ring), 1.81—1.86 (4H, m, 3,5-CH2 [–NHCH(CONϭ)CH2–], 127.0 (C2, C6-aromatic), 128.4 (C3, C5-aromatic),
of piperidine ring), 3.17—3.51 [3H, m, 2-CH2 of piperidine ring and 131.5 (C4-aromatic), 139.9 (C1-aromatic), 167.1 (Ar-CO), 171.9 (CON-
NH2CH(CONϭ)CHHNϭ], 3.64—3.70 [3H, m, 6-CH2 of piperidine ring HCH3).
and NH2CH(CONϭ)CHHNϭ], 3.79 (3H, s, CH3), 4.90 [1H, q, Jϭ4 Hz,
Compounds 4b—d and 5a—d were also obtained according to the above
NH2CH(CONϭ)CH2Nϭ], 9.64 (2H, br, NH2). 13C-NMR (DMSO-d6) d: procedure.
20.9 (C4 of piperidine ring), 22.3 (C3, C5 of piperidine ring), 47.8
[NH2CH(CONϭ)CH2–], 53.2 (C2 of piperidine ring), 53.4 (CH3), 55.6
4-Amino-3-chloro-6-methoxy-N-[1-(methylaminocarbonyl)-2-(1-
piperidinyl)ethyl]benzamide (4b): The yield was 35%. Treatment of 4b with
(NH2CH(CONϭ)CH2–), 56.0 (C6 of piperidine ring), 166.6 (CO). Anal. 20% HCl/EtOH gave the hydrochloride of 4b. IR (KBr): 3465, 1684, 1622,
Calcd for C9H18N2O2·2HCl·0.1H2O: C, 41.42; H, 7.80; N, 10.73. Found: C,
41.20; H, 7.66; N, 10.77.
1606 cmϪ1
.
1H-NMR (D2O) d: 1.67 (2H, br s, 4-CH2 of piperidine ring),
1.87—1.88 (4H, m, 3,5-CH2 of piperidine ring), 2.82 (3H, s, NCH3), 3.30—
a-Amino-N-methyl-1-piperidinepropionamide (8) Methyl a-amino- 3.38 (4H, m, 2,6-CH2 of piperidine ring), 3.45 [1H, dd, Jϭ14,
1-piperidinepropanoate dihydrochloride 7 (2 g, 7.7 mmol) was added to a 9 Hz, –NHCH(CONϭ)CHHNϭ], 3.68 [1H, dd, Jϭ14, 5 Hz, –NHCH
40% solution of methylamine in methanol (6 ml) and the reaction mixture (CONϭ)CHHNϭ], 3.95 (3H, s, OCH3), 5.07 [1H, dd, Jϭ9, 5 Hz,
was allowed to stand at room temperature for 3 h, then the solvent was evap- –NHCH(CONϭ)CH2Nϭ], 6.57 (1H, s, 3H-aromatic), 7.76 (1H, s, 6H-aro-
orated to dryness. After addition of Et2O to the residue, the separated precip- matic). 13C-NMR (D2O) d: 23.8 (C4 of piperidine ring), 25.6 (C3, C5 of
itate was isolated by filtration. The filtrate was concentrated to dryness to piperidine ring), 29.0 (NCH3), 52.0 [–NHCH(CONϭ)CH2–], 57.0 (C2, C6
give 8 (1.06 g, 74%). The precipitate was made basic with small amount of of piperidine ring), 59.1 (OCH3), 60.7 [–NHCH(CONϭ)CH2–], 101.5 (C3-
aqueous NaOH (ca. 2%), extracted with AcOEt, and the extract was concen- aromatic), 112.4 (C1-aromatic), 114.0 (C5-aromatic), 134.6 (C6-aromatic),
trated to dryness to give 8 (0.18 g, 13%). The total yield was 87%. An ana-
151.9 (C4-aromatic), 161.2 (C2-aromatic), 170.1 (CONHCH3), 173.2 (Ar-
lytical sample was obtained by recrystallization from diisopropylether, CO).
prisms, mp 99—100 °C. IR (KBr): 3376, 3325, 1651 cmϪ1. FAB-MS m/z:
3,4-Dimethoxy-N-[1-(methylaminocarbonyl)-2-(1-piperidinyl)ethyl]-
1
1
186 (MϩH)ϩ. H-NMR (CDCl3) d: 1.46 (2H, q, Jϭ6 Hz, 4-CH2 of piperi- benzamide (4c): The yield was 26%. IR (KBr): 3260, 1620 cmϪ1. H-NMR
dine ring), 1.58 (4H, q, Jϭ6 Hz, 3,5-CH2 of piperidine ring), 1.95 (2H, br s, (CDCl3) d: 1.48—1.52 (2H, m, 4-CH2 of piperidine ring), 1.59—1.64 (4H,
NH2), 2.36—2.42 (2H, m, 2-CH2 of piperidine ring), 2.39 [1H, dd, Jϭ13, 8 m, 3,5-CH2 of piperidine ring), 2.44—2.48 [3H, m, 2-CH2 of piperidine
Hz, NH2CH(CONϭ)CHHNϭ], 248—2.49 (2H, m, 6-CH2 of piperidine ring, –NHCH(CONϭ)CHHNϭ], 2.77 (2H, br, 6-CH2 of piperidine ring),
ring), 2.60 [1H, dd, Jϭ13, 6 Hz, NH2CH(CONϭ)CHHNϭ], 2.80 (3H, d,
Jϭ5 Hz, CH3), 3.50 [1H, dd, Jϭ8, 6 Hz, NH2CH(CONϭ)CH2Nϭ], 7.88
(1H, br s, CONH). 13C-NMR (CDCl3) d: 24.2 (C4 of piperidine ring), 25.7
2.86 (3H, d, Jϭ5 Hz, NCH3), 2.91 [1H, dd, Jϭ13, 4 Hz,
–NHCH(CONϭ)CHHNϭ], 3.921, 3.922 (each 3H, s, OCH3), 4.46—4.49
[1H, m, –NHCH(CONϭ)CH2Nϭ], 6.88 (1H, d, Jϭ8 Hz, 5H-aromatic),
(NCH3), 26.1 (C3, C5 of piperidine ring), 51.6 [NH2CH(CONϭ)CH2–], 54.4 7.35—7.45 (1H, br, Ar-CONH), 7.39 (1H, dd, Jϭ8, 2 Hz, 6H-aromatic),
(C2, C6 of piperidine ring), 62.2 [NH2CH(CONϭ)CH2–], 175.1 (CO). Anal. 7.45 (1H, d, Jϭ2 Hz, 2H-aromatic), 8.26 (1H, br s, CONHCH3). 13C-NMR
Calcd for C9H19N3O: C, 58.35; H, 10.34; N, 22.68. Found: C, 58.32; H,
10.32; N, 22.46.
2-Amino-3-(1-piperidinyl)-1-(1-pyrrolidinyl)-1-propanone (9) Methyl
a-amino-1-piperidinepropanoate dihydrochloride 7 (2 g, 7.7 mmol) was
added to pyrrolidine (5.5 ml) and stirred for 4 h. Et2O was added to the reac- matic), 149.0 (C3-aromatic), 152.0 (C4-aromatic), 166.8 (Ar-CO), 172.2
tion mixture and the precipitate was filtered off. The ethereal solution was (CONHCH3).
(CDCl3) d: 24.0 (C4 of piperidine ring), 26.0 (NCH3), 26.3 (C3, C5 of
piperidine ring), 49.6 [–NHCH(CONϭ)CH2–], 54.4 (C2, C6 of piperidine
ring), 56.0 (OCH3ϫ2), 59.7 [–NHCH(CONϭ)CH2–], 110.4 (C2 or C5-aro-
matic), 110.5 (C5 or C2-aromatic), 119.8 (C6-aromatic), 126.6 (C1-aro-
concentrated, and the excess pyrrolidine was removed under reduced pres-
3,4,5-Trimethoxy-N-[1-(methylaminocarbonyl)-2-(1-piperidinyl)ethyl]-
sure to give 9 (1.31 g, 75%). An analytical sample was obtained by recrystal- benzamide (4d): The yield was 33%. IR (KBr): 3281, 1662, 1622 cmϪ1
.
lization from acetone/Et2O. mp 42—46 °C. IR (KBr): 1638 cmϪ1. FAB-MS 1H-NMR (CDCl3) d: 1.49—1.50 (2H, m, 4-CH2 of piperidine ring), 1.51—
1
m/z: 226 (MϩH)ϩ. H-NMR (CDCl3) d: 1.44 (2H, quintet, Jϭ6 Hz, 4-CH2 1.52 (4H, m, 3,5-CH2 of piperidine ring), 2.45—2.49 [3H, m, 2-CH2 of
of piperidine ring), 1.51—1.62 (4H, m, 3,5-CH2 of piperidine ring), 1.86 piperidine ring, –NHCH(CONϭ)CHHNϭ], 2.79 (2H, m, 6-CH2 of piperi-
(2H, quintet, Jϭ7 Hz, 3-CH2 of pyrrolidine ring), 1.92—1.99 (2H, m, 4-CH2 dine ring), 2.86 (3H, d, Jϭ4.5 Hz, NCH3), 2.91—2.93 [1H, m,
of pyrrolidine ring), 2.39 [1H, dd, Jϭ13, 9 Hz, NH2CH(CONϭ)CHHNϭ], –NHCH(CONϭ)CHHNϭ], 3.88 (3H, s, 4Ј-OCH3), 3.90 (6H, s, 3Ј,5Ј-
2.43 (2H, m, 2-CH2 of piperidine ring), 2.47 (1H, dd, Jϭ13, 5 Hz,
OCH3), 4.46—4.49 [1H, m, –NHCH(CONϭ)CH2Nϭ], 7.09 (2H, s, 2,6H-
NH2CH(CONϭ)CHHNϭ), 2.52—2.57 (2H, m, 6-CH2 of piperidine ring), aromatic), 7.27 (1H, br, Ar-CONH), 8.30 (1H, br , CONHCH3). 13C-NMR
2.87 (2H, br s, NH2), 3.41—3.46 (2H, m, 2-CH2 of pyrrolidine ring), 3.50— (CDCl3) d: 24.0 (C4 of piperidine ring), 26.0 (NCH3), 26.3 (C3, C5 of
3.58 (2H, m, 5-CH2 of pyrrolidine ring), 3.77 (1H, dd, Jϭ9, 5 Hz, piperidine ring), 50.0 [–NHCH(CONϭ)CH2–], 54.4 (C2, C6 of piperidine
NH2CH(CONϭ)CH2Nϭ). 13C-NMR (CDCl3) d: 24.1 (C4 of piperidine ring,
C3 of pyrrolidine ring), 25.9 (C3, C5 of piperidine ring), 26.0 (C4 of pyrro- 104.5, (C2, C6-aromatic), 129.2 (C1-aromatic), 141.3 (C4-aromatic), 153.2
lidine ring), 45.9 (C2 of pyrrolidine ring), 46.2 (C5 of pyrrolidine ring), 51.0 (C3, C5-aromatic), 166.8 (Ar-CO), 172.1 (CONHCH3).
ring), 56.3 (3Ј,5Ј-OCH3), 59.6 [–NHCH(CONϭ)CH2–], 60.9 ( 4Ј-OCH3),
[NH2CH(CONϭ)CH2–], 55.1 (C2, C6 of piperidine ring), 63.7
[NH2CH(CONϭ)CH2–], 172.3 (CO). Anal. Calcd for C12H23N3O·0.5H2O: The yield was 74%. Treatment of 5a with 20% HCl/EtOH gave the hy-
C, 61.51; H, 10.32; N, 17.93. Found: C, 61.42; H, 10.14; N, 17.72.
N-[2-(1-Piperidinyl)-1-(1-pyrrolidinylcarbonyl)ethyl]benzamide (5a):
drochloride of 5a, which was recrystallized from CH3CN to afford col-
1
N-[1-(Methylaminocarbonyl)-2-(1-piperidinyl)ethyl]benzamide (4a) orless needles. IR (KBr): 3218, 1666, 1645 cmϪ1. H-NMR (D2O) d: 1.68
A solution of DCC (1.34 g, 6.5 mmol) in CH2Cl2 was added to a stirred solu- (2H, br s, 4-CH2 of piperidine ring), 1.85—1.91 (4H, m, 3,5-CH2 of pi-
tion of 8 (1.0 g, 5.4 mmol) and benzoic acid (0.79 g, 6.5 mmol) in CH2Cl2 peridine ring), 1.93—2.01 (4H, m, 3,4-CH2 of pyrrolidine ring), 3.33—
and the mixture was stirred at room temperature for 1 d. The dicyclohexyl- 3.61 (4H, m, 2,6-CH2 of piperidine ring), 3.48—3.67 [6H, m, 2,5-CH2 of
urea (DCU) was removed by filtration and washed with a small amount of pyrrolidine ring, –NHCH(CONϭ)CH2Nϭ], 5.30—5.33 [1H, m,

132
Vol. 50, No. 1
a column packed with ion-exchange resin (AG 11A8®, Bio-Rad Lab-
oratories) to give crude product, which was recrystallized from H2O to
afford 10 (5.3 g, 67%), mp 139—141 °C (dec.). IR (KBr): 1647, 1605
cmϪ1. FAB-MS m/z: 277 (MϩH)ϩ. 1H-NMR (D2O) d: 1.55—2.10 (6H,
br, 3,4,5-CH2 of piperidine ring), 2.90—3.82 (4H, br, 2,6-CH2 of piperi-
dine ring), 3.47 [1H, dd, Jϭ13, 8 Hz, –NHCH(CONϭ)CHHNϭ], 3.61 [1H,
dd, Jϭ13, 6 Hz, –NHCH(CONϭ)CHHNϭ], 4.84 [1H, dd, Jϭ8, 6 Hz,
–NHCH(CONϭ)CH2Nϭ], 7.57 (2H, t, Jϭ8 Hz, 3,5H-aromatic), 7.67 (1H,
t, Jϭ8 Hz, 4H-aromatic), 7.86 (2H, d-like, Jϭ8 Hz, 2,6H-aromatic). 13C-
NMR (D2O) d: 23.9 (C4 of piperidine ring), 25.6 (C3, C5 of piperidine
ring), 52.8 [–NHCH(CONϭ)CH2–], 56.6 (C2, C6 of piperidine ring), 60.9
[–NHCH(CONϭ)CH2–], 130.2 (C2, C6-aromatic), 131.7 (C3, C5-aromatic),
135.5 (C1 or C4-aromatic), 135.6 (C4 or C1-aromatic), 173.4 (CONH),
176.8 (COOH). Anal. Calcd for C15H20N2O3·H2O: C, 61.21; H, 7.53; N,
9.52. Found: C, 61.08; H, 7.53; N, 9.51.
N-[2-(1-Piperidinyl)-1-(1-piperidinylcarbonyl)ethyl]benzamide (5e)
(Method via Mixed Anhydride) To a solution of compound 10 (1 g, 3.6
mmol) and N-methylmorpholine (0.56 g, 5.5 mmol) in anhydrous dimethyl-
formamide (DMF) (50 ml), pivaloyl chloride (0.67 g, 5.5 mmol)was added at
Ϫ15 °C with stirring. After 5 min, piperidine (0.47 g, 5.5 mmol) was added
and the reaction mixture was allowed to stand at 0 °C for 30 min and then
overnight at room temperature with stirring. The reaction mixture was con-
centrated in vacuo, the residue was extracted with 1 N HCl, and the aqueous
solution was washed with Et2O and basified with K2CO3. The resulting pre-
cipitate was collected by filtration, washed with water, and dried to give 5e
(0.62 g, 50%), which was recrystallized from CH3CN to afford colorless
needles. IR (KBr): 3300, 1653, 1619 cmϪ1. 1H-NMR (CDCl3) d: 1.39—1.43
(2H, m, 4-CH2 of piperidine ring), 1.51—1.59 (6H, m, 3,5-CH2 of piperidine
ring, 4-CH2 of 1-acylpiperidine ring), 1.67 (4H, br s, 3,5-CH2 of 1-
acylpiperidine ring), 2.44—2.56 (4H, m, 2,6-CH2 of piperidine ring), 2.64—
2.69 [2H, m, –NHCH(CONϭ)CH2Nϭ], 3.53—3.58 (2H, m, 2,6-CHA of 1-
acylpiperidine ring), 3.62—3.67 (2H, m, 2,6-CHB of 1-acylpiperidine ring),
5.21 [1H, q, Jϭ7 Hz, –NHCH(CONϭ)CH2Nϭ], 7.20 (1H, br d, Jϭ7 Hz,
NH), 7.40—7.43 (2H, m, 3,5H-aromatic), 7.46—7.49 (1H, m, 4H-aromatic),
7.80—7.82 (2H, m, 2,6H-aromatic). 13C-NMR (CDCl3) d: 24.2 (C4 of
piperidine ring), 24.5 (C3 of 1-acylpiperidine ring), 25.6 (C4 of 1-
acylpiperidine ring), 26.1 (C3, C5 of piperidine ring), 26.6 (C5 of 1-
acylpiperidine ring), 43.4 (C2 of 1-acylpiperidine ring), 47.0 (C6 of 1-
acylpiperidine ring), 47.6 [–NHCH(CONϭ)CH2–], 55.1 (C2, C6 of piperi-
dine ring), 61.8 [–NHCH(CONϭ)CH2–], 127.1 (C2, C6-aromatic), 128.4
(C3, C5-aromatic), 131.4 (C4-aromatic), 134.3 (C1-aromatic), 166.5 (Ar-
CO), 170.1 (ϭCHCONϭ).
–NHCH(CONϭ)CH2Nϭ], 7.56—7.60 (2H, m, 3,5H-aromatic), 7.67—7.71
(1H, m, 4H-aromatic), 7.85—7.88 (2H, m, 2,6H-aromatic). 13C-NMR (D2O)
d: 23.8 (C4 of piperidine ring), 25.4 (C3, C5 of piperidine ring), 26.4 (C3 of
pyrrolidine ring), 28.3 (C4 of pyrrolidine ring), 49.7 (C2 of pyrrolidine
ring), 50.0 (C5 of pyrrolidine ring), 50.6 [–NHCH(CONϭ)CH2–], 57.1 (C2,
C6 of piperidine ring), 59.6 [–NHCH(CONϭ)CH2–], 130.2 (C2, C6-aro-
matic), 131.8 (C3, C5-aromatic), 134.8 (C1-aromatic), 135.8 (C4-aromatic),
169.9 (ϭCHCONϭ), 173.3 (Ar-CO). This compound 5a could also be pre-
pared in a similar manner described for the preparation of 5e in 63% yield.
4-Amino-3-chloro-6-methoxy-N-[2-(1-piperidinyl)-1-(1-pyrrolidinylcar-
bonyl)ethyl]benzamide (5b): The yield was 35%. IR (KBr): 3368,
1638 cmϪ1 1H-NMR (CDCl3) d: 1.40—1.42 (2H, m, 4-CH2 of piperi-
.
dine ring), 1.50—1.55 (4H, m, 3,5-CH2 of piperidine ring), 1.86—1.90
(2H, m, 3-CH2 of pyrrolidine ring), 1.95—2.00 (2H, m, 4-CH2 of pyrro-
lidine ring), 2.47 (4H, d, Jϭ5 Hz, 2,6-CH2 of piperidine ring), 2.62 [1H,
dd, Jϭ13, 7 Hz, –NHCH(CONϭ)CHHNϭ], 2.70 [1H, dd, Jϭ13,7 Hz,
–NHCH(CONϭ)CHHNϭ], 3.43—3.47 (1H, m, 2-CHA of pyrrolidine ring),
3.54—3.57 (1H, m, 2-CHB of pyrrolidine ring), 3.72—3.76 (2H, m, 5-CH2
of pyrrolidine ring), 3.84 (3H, s, OCH3), 4.57 (2H, s, Ar-NH2), 4.93—4.94
[1H, q, Jϭ7 Hz, –NHCH(CONϭ)CH2Nϭ], 6.23 (1H, s, 3H-aromatic), 8.03
(1H, s, 6H-aromatic), 8.48 (1H, br d, Jϭ7 Hz, CONH). 13C-NMR (CDCl3) d:
24.2 (C4 of piperidine ring), 26.0 (C3, C4 of pyrrolidine ring), 26.2 (C3, C5
of piperidine ring), 46.0 (C2 of pyrrolidine ring), 46.7 (C5 of pyrrolidine
ring), 49.9 [–NHCH(CONϭ)CH2–], 55.0 (C2, C6 of piperidine ring), 56.0
(OCH3), 61.0 [–NHCH(CONϭ)CH2–], 97.8 (C3-aromatic), 111.3 (C1-
aromatic), 112.1 (C5-aromatic), 132.8 (C6-aromatic), 147.0 (C4-aromatic),
157.8 (C2-aromatic), 164.0 (Ar-CO), 170.6 (ϭCHCONϭ).
3,4-Dimethoxy-N-[2-(1-piperidinyl)-1-(1-pyrrolidinylcarbonyl)ethyl]-
1
benzamide (5c): The yield was 45%. IR (KBr): 3245, 1628 cmϪ1. H-NMR
(CDCl3) d: 1.40—1.43 (2H, m, 4-CH2 of piperidine ring), 1.51—1.55 (4H, m,
3,5-CH2 of piperidine ring), 1.88—1.92 (2H, m, 3-CH2 of pyrrolidine ring),
1.96—2.04 (2H, m, 4-CH2 of pyrrolidine ring), 2.46—2.51 (4H, m, 2,6-CH2
of piperidine ring), 2.66 [1H, dd, Jϭ13, 7 Hz, –NHCH(CONϭ)CHHNϭ],
2.73 [1H, dd, Jϭ13, 7 Hz, –NHCH(CONϭ)CHHNϭ], 3.45—3.49 (1H, m,
2-CHA of pyrrolidine ring), 3.53—3.58 (1H, m, 2-CHB of pyrrolidine ring),
3.75—3.78 (2H, m, 5-CH2 of pyrrolidine ring), 3.91, 3.92 (each 3H, s,
OCH3), 4.97 [1H, q, Jϭ7 Hz, –NHCH(CONϭ)CH2Nϭ], 6.86 (1H, d, Jϭ8
Hz, 5H-aromatic), 7.08 (1H, br d, Jϭ7 Hz, CONH), 7.36 (1H, dd, Jϭ8, 2 Hz,
6H-aromatic), 7.43 (1H, d, Jϭ2 Hz, 2H-aromatic). 13C-NMR (CDCl3) d:
24.2 (C4 of piperidine ring), 26.0 (C3, C4 of pyrrolidine ring), 26.2 (C3, C5
of piperidine ring), 46.0 (C2 of pyrrolidine ring), 46.7 (C5 of pyrrolidine
ring), 49.6 [–NHCH(CONϭ)CH2–], 55.0 (C2, C6 of piperidine ring), 56.0
(OCH3ϫ2), 61.0 [–NHCH(CONϭ)CH2–], 110.3 (C2 or C5-aromatic), 110.6
(C5 or C2-aromatic), 120.0 (C6-aromatic) , 126.7 (C1-aromatic), 148.9 (C3-
aromatic), 151.8 (C4-aromatic), 166.3 (Ar-CO), 170.3 (ϭCHCONϭ).
3,4,5-Trimethoxy-N-[2-(1-piperidinyl)-1-(1-pyrrolidinylcarbonyl)ethyl]-
Acknowledgments We thank Dr. M. Fujiwara, Dr. K. Mishima, and Ms.
Y. Iwase for their encouragement throughout this work.
benzamide (5d): The yield was 50%. IR (KBr): 3318, 1664, 1633 cmϪ1
.
References and Notes
1H-NMR (CDCl3) d: 1.40—1.44 (2H, m, 4-CH2 of piperidine
ring), 1.51—1.55 (4H, m, 3,5-CH2 of piperidine ring), 1.88—1.92 (2H,
m, 3-CH2 of pyrrolidine ring), 1.98—2.02 (2H, m, 4-CH2 of pyrrolidine
ring), 2.46—2.52 (4H, m, 2,6-CH2 of piperidine ring), 2.66 [1H, dd,
Jϭ13, 7 Hz, –NHCH(CONϭ)CHHNϭ], 2.74 [1H, dd, Jϭ13, 7 Hz,
–NHCH(CONϭ)CHHNϭ], 3.45—3.49 (1H, m, 2-CHA of pyrrolidine ring),
3.53—3.56 (1H, m, 2-CHB of pyrrolidine ring), 3.76 (2H, t, Jϭ7 Hz, 5-CH2
of pyrrolidine ring), 3.87 (3H, s, 4Ј-OCH3), 3.89 (6H, s, 3Ј,5Ј-OCH3), 4.96
[1H, q, Jϭ7 Hz, –NHCH(CONϭ)CH2Nϭ], 7.06 (2H, s, 2,6H-aromatic),
7.15 (1H, d, Jϭ7 Hz, CONH). 13C-NMR (CDCl3) d: 24.2 (C4 of piperidine
ring), 26.0 (C3, C4 of pyrrolidine ring), 26.2 (C3, C5 of piperidine ring),
46.0 (C2 of pyrrolidine ring), 46.7 (C5 of pyrrolidine ring), 49.7
[–NHCH(CONϭ)CH2–], 54.9 (C2, C6 of piperidine ring), 56.3 (3Ј,5Ј-
OCH3), 60.8 [–NHCH(CONϭ)CH2–, 4Ј-OCH3], 104.6 (C2, C6-aromatic),
129.4 (C1-aromatic), 141.1 (C4-aromatic), 153.1 (C3, C5-aromatic),166.3
(Ar-CO), 170.2 (ϭCHCONϭ).
a-(Benzoylamino)-1-piperidinepropanoic Acid (10) Using a three-
neck round-bottomed flask, benzoyl chloride (8.03 g, 57 mmol) was
added dropwise to a vigorously stirred solution of 6 (7 g, 28.6 mmol) in
1 N NaOH (86 ml) and 2 N NaOH (43 ml) was added at the same time.
In this experiment, it is advantageous to terminate the addition of both
reagents together. The reaction mixture was stirred for 2 h at room tem-
perature and then acidified with 20% HCl. The resulting mixture was
washed with diethyl ether (Et2O) and the resulting aqueous layer was
evaporated to give residual oil. After the addition of ethanol to this resi-
due, the precipitated insoluble solid was removed by filtration. The mother
liquor was concentrated to dryness. The residue was passed through
1) For example, see Miyano S., Abe N., Takeda K., Fujisaki F., Sumoto
K., Synthesis, 1982, 852 and references cited therein.
2) Prepn.: Miyano S., Abe N., Ger. Offen. 2323301 [Chem. Abstr., 80,
70539h (1974)]; Pharmacology: Kase Y., Saita M., Takahama K.,
Masaki K., Miyata T., Jpn. J. Pharmacol., 24, 85—86 (1974).
3) Abe N., Fujisaki F., Sumoto K., Chem. Pharm. Bull., 46, 142—144
(1998).
4) Compound 7 is sparingly soluble in piperidine, and the reaction did
not give the desired product under the same reaction conditions. Use
of additional solvent resulted in the formation of unknown polymeric
products.
5) Introductions of other amino functionalities instead of a piperidine
ring substituent were also successful by the procedure via a mixed an-
hydride. These results together with pharmacological evaluation will
be described elsewhere.
6) a) Bishoff S., Bittiger H., Delini-Stula A., Ortmann R., Eur. J. Phar-
macol., 79, 225—232 (1982); b) Chivers J. K., Gommeron W., Leysen
J. E., Jenner P., Marsden C. D., J. Pharm. Pharmacol., 40, 415—421
(1988); c) Jenner P., Elliott P. N. C., Clow A., Reavill C., Marsden C.
D., ibid., 30, 46—48 (1978).
7) Dumuis A., Sebben M., Bockaert J., Naunyn-Schmideberg’s Arch.
Pharmacol., 340, 403—410 (1989).
8) The computational molecular model examinations were carried out by
“overlay” operation combined with MM2 calculation. Some of the
compounds in this series showed significant dopamine antagonist ac-
tivities. These results will be described elsewhere.