Synthesis and regioselective hydrolysis of novel dialkyl 4-imidazolyl-1,4-dihydropyridine-3,5-dicaroxlates as potential dual acting angiotensin II inhibitors and calcium channel blockers

Article abstract of DOI:10.1007/bf03245875

Most of the known effects of angiotensin II are mediated via AT₁ receptor by increasing intracellular Ca²⁺ by influx of extracellular Ca²⁺. Combination therapies of angiotensin receptor blocker (ARB) with calcium channel blocker (CCB) which act through L-type calcium channel have beneficial therapeutic and protective effects on cardiovascular system. Thus, it was hypothesized that merging the key structural elements present in an AT₁ receptor antagonist (telmisartan) with key structural elements in 1,4-dihydropyridine calcium channel blockers (nifedipine) would yield a compound with dual activity for both receptors. This strategy led to the design and synthesis of dialkyl 1,4-dihydro-2,6-dimethyl-4-[2-n-alkyl-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-4(or 5)-yl]-3,5-pyridinedicarboxylates (4 and 6). The synthesis of compounds 4 and 6 was accomplished through the reaction of 2-n-alkyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]imidazole-4(or 5)-carboxaldehydes with alkyl acetoacetate followed by regioselctive hydrolysis of carboethoxybiopheny to carboxybiphenyl that are essential for ARB activity. It is suggested that existence of hindrance by substituted groups prevent hydrolysis of esteric groups on dihydropyridine ring. The structures of the compounds were characterized by ¹H-nuclear magnetic resonance, infrared and mass spectroscopy.

Full text of DOI:10.1007/bf03245875

J. Iran. Chem. Soc., Vol. 7, No. 1, March 2010, pp. 171-179.
JOURNAL OF THE
Iranian
Chemical Society
Synthesis and Regioselective Hydrolysis of Novel Dialkyl 4-Imidazolyl-1,4-
Dihydropyridine-3,5-dicaroxlates as Potential Dual Acting Angiotensin II Inhibitors
and Calcium Channel Blockers
J. Shahbazi Mojarrada,*, H. Nazemiyehb and F. Kaviania
aDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
bDepartment of Pharmacognosy and Food Science, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
(Received 7 December 2008, Accepted 28 February 2009)
Most of the known effects of angiotensin II are mediated via AT1 receptor by increasing intracellular Ca2+ by influx of
extracellular Ca2+. Combination therapies of angiotensin receptor blocker (ARB) with calcium channel blocker (CCB) which act
through L-type calcium channel have beneficial therapeutic and protective effects on cardiovascular system. Thus, it was
hypothesized that merging the key structural elements present in an AT1 receptor antagonist (telmisartan) with key structural
elements in 1,4-dihydropyridine calcium channel blockers (nifedipine) would yield a compound with dual activity for both
receptors. This strategy led to the design and synthesis of dialkyl 1,4-dihydro-2,6-dimethyl-4-[2-n-alkyl-1-[(2ꢀ-carboxybiphenyl-
4-yl)methyl]imidazole-4(or 5)-yl]-3,5-pyridinedicarboxylates (4 and 6). The synthesis of compounds 4 and 6 was accomplished
through the reaction of 2-n-alkyl-1-[(2ꢀ-carbomethoxybiphenyl-4-yl)methyl]imidazole-4(or 5)-carboxaldehydes with alkyl
acetoacetate followed by regioselctive hydrolysis of carboethoxybiopheny to carboxybiphenyl that are essential for ARB activity.
It is suggested that existence of hindrance by substituted groups prevent hydrolysis of esteric groups on dihydropyridine ring. The
structures of the compounds were characterized by 1H-nuclear magnetic resonance, infrared and mass spectroscopy.
Keywords: Dual mechanism, Angiotensin II antagonist, Calcium channel blocker, 1,4-Dihydropyridine
Angiotensin receptor blockers (ARBs), such as Losartan,
Telmisartan (Fig. 1), antagonize Ang II effects on vascular
smooth muscle and are used for controlling hypertension.
Their vasodilatation actions are due to reduction of
intracellular Ca2+ [5].
Structure activity relationships (SAR) of 1,4-
dihydropyridines (1,4-DHP) indicate that substituted
heterocycles on the C4 position of 1,4-DHP ring can be CCB
[6-12]. It has been reported that the compounds, dialkyl 1,4-
dihydro-2-[2-(dimethylamino)ethyl]-6-methyl-4-(1-benzyl-2-
alkylthio-5-imidazolyl)-3,5-pyrdinedicarboxylates [13] and
dialkyl 1,4-dihydro-2,6-dimethyl-4-[2-methylthio-1-(phenyl-
amino)-1H-imidazole-5-yl]-3,5-pyridinedicarboxylates A, are
CCB (see Fig. 1) [14].
INTRODUCTION
The rennin-angiotensin system (RAS) is a master regulator
of blood pressure and fluid homeostasis. Angiotensin II (Ang
II) acts on a wide spectrum of target tissues including the
adrenals, vascular smooth muscle, endothelium, kidney and so
on. It is not only a steroidogenic and vasoactive peptide but
also a growth factor-like agent able to induce hypertrophy and
hyperplasia via AT1 [1-3]. Most of the known effects of Ang II
in adult tissues are attributable to AT1 which increases
intracellular Ca2+ by influx of extracellular Ca2+ to induce
vasoconstriction and immediately elevates blood pressure [4].
*Corresponding author. E-mail: shahbazi_j@tbzmed.ac.ir

Shahbazi Mojarrad et al.
SCH3
N
n-Pr
N
CO2H
N
N
N
NO2
H
H3CO2C
CO2CH3
R1O2C
H3C
CO2R1
CH3
H3C
N
CH3
N
H
CH3
CH3
N
N
H
Nifedipine
A
Telmisartan
R
N
HO2C
R
N
CO2H
N
N
CO2R1
CH3
R1O2C
H3C
CO2R1
CH3
R1O2C
H3C
N
H
4
N
H
6
R= n-Pr or n-Bu , R1=CH3 or C2H5
Fig. 1. Chemical structure of some CCB (compound A and nifedipine), ARB (telmisartan) and designed
dual CCB-ARB (compound 4 and 6).
On the basis of SAR of ARBs, the C4 and C5 position of
imidazole ring can be substituted with other lipophilic and
hydrogen acceptor groups [6]. Telmisartan as a potent ARB,
has a bulky group (benzoimidazole) in the C6 position of
benzoimidazole ring.
For the following reasons: 1) the existence of correlation
between L-type calcium channel and AT1 receptor [15], 2) low
dose and low side effect of combination therapy of a CCB and
ARB [16], 3) beneficial effect of monotherapy alone or
combination therapy of a CCB and ARB in controlling blood
pressure [17,18], 4) cardioprotection, renoprotection and anti-
atherosclerosis activity of CCB and ARB [19-21], 5) dual
antagonists such as monatepil [22] and alatriopril [23,24] and
2'-substituted N-3-isoxazolyl biphenylsulfonamide derivatives
[25] having potent antihypertensive effect, 6) bulky groups in
C4 and C5 position of imidazole ring and substituted
heterocycles on the C4 position of 1,4-DHP ring retained
biological activity, we hypothesized that merging the key
structural elements present in AT1 receptor antagonists (2ꢀ-
carboxybiphenyl-4-yl)methylimidazole with key structural
elements in 1,4-dihydropyridine calcium channel blockers
(dialkyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate)
would yield a compound with dual activity for both receptors.
This strategy led to the design and synthesis of dialkyl 1,4-
dihydro-2,6-dimethyl-4-[2-n-alkyl-1-[(2ꢀ-carboxybiphenyl-4-
yl)methyl]imidazole-4(or 5)-yl]-3,5-pyridinedicarboxylates (4
and 6) (see Fig. 1).
CHEMISTRY
Scheme 1 shows synthesis of 1,4-dihydropyridines with 2'-
carboxybiphenyl moiety (4a-d and 6a-d). 2-Alkyl-imidazole-
4(5)-carboxaldehyde [26,27] was reacted with methyl 4´-
(bromomethyl)biphenyl-2-carboxylate in the presence of
172

Synthesis and Regioselective Hydrolysis
O
O
N
N
i
H
H
R
R
N
N
H
BPM
R = n-Pr or n-Bu
1 = 4-yl 2 = 5-yl
BPM
N
R
BPC
N
R
R1
O
R1
O
N
N
O
O
O
O
R1
R1
O
O
ii
iii
1
CH3
N
H
CH3
CH3
N
H
CH3
3a-d
4a-d
R
R
BPM
N
BPC
O
N
O
N
R1
N
R1
O
O
O
R1
R1
O
O
ii
O
iii
2
CH3
N
CH3
CH3
N
CH3
H
H
5a-d
H3CO2C
HO2C
6a-d
a: R= n-Pr, R1= CH3
b: R= n-Pr, R1= C2H5
c: R= n-Bu, R1= CH3
CH2
CH2
BPM =
BPC =
d: R= n-Bu, R1= C2H5
Scheme 1. Synthesis of 1,4-dihydropyrides with 2'-carboybiphenyl moiety, reagents and conditions: i) K2CO3,
DMF, methyl 4´-(bromomethyl)biphenyl-2-carboxylate, 24 h, room temperature , ii) NH3 25%,
methyl or ethyl acetoacetate, alcohol, reflux, iii) KOH, H2O/alcohol (1:1), reflux
China). 2-Alkyl-imidazole-4(5)-carboxaldehyde was prepared
according to the literature [28,29]. Other chemicals were
purchased from Merck Chemical Company (Darmstadt,
Germany). Melting points were determined by a Gallenkamp
capillary apparatus and are uncorrected. 1H NMR spectra were
obtained with a Bruker-Spectrospin 200 MHz spectrometer
(Bruker, Germany). Tetramethylsilane was used as an internal
standard. Mass spectra were obtained using a Finnigan Mat
TSQ-70 spectrometer at 70 eV (Finnigan Mat, Bremen,
Germany). The FT-IR spectrum was recorded on a Shimadzu
FTIR 4300 spectrometer (KBr disks) (Shimadzu, Kyoto,
Japan). The purity of compounds was confirmed by TLC using
K2CO3 to give 1a-b and 2a-b. The two isomers were separated
by chromatography [28,29]. Dihydropyridine compounds (3a-
d and 5a-d) were prepared by the classic Hantzsch reaction of
methyl or ethyl acetoacetate and ammonium hydroxide with
1a-b and 2a-b respectively [30]. Finally mild hydrolysis of 3a-
d and 5a-d in alkaline solution provided compounds 4a-d and
6a-d, respectively [28].
EXPERIMENTAL
Methyl 4´-(bromomethyl) biphenyl-2-carboxylate was
obtained from Sinosource Pharma Ltd. (Hengsha Guangzhou,
173

Shahbazi Mojarrad et al.
different mobile phases. Elemental analyses were carried out
carbomethoxybiphenyl-4-yl)methyl]imidazole-4-yl]-3,5-
pyridinedicarboxylate (3b). Yield: 58%; m.p.: 180-182 °C;
FT-IR (KBr): ꢁ 3500 (N-H), 1714 (C=O, ester), 1693 cm-1
(C=O, ester DHP); MS: m/z (%) 585 [M+] (6), 570 (10), 512
(16), 315 (14), 252 (13), 226 (100), 192 (53),225 (76), 165
(10); Anal. Calcd. for C34H39N3O6: C, 69.72; H, 6.71; N, 7.17.
Found: C, 69.85; H, 6.86; N, 7.02.
Dimethyl 1,4-dihydro-2,6-dimethyl-4-[2-n-butyl-1-[(2ꢀ-
carbomethoxybiphenyl-4-yl)methyl]imidazole-4-yl]-3,5-
pyridinedicarboxylate (3c). Yield: 37%; mp: 199-201 °C;
FT-IR (KBr): ꢁ 3425 (N-H), 1737 (C=O, ester), 1693 cm-1
(C=O, ester DHP); MS: m/z (%) 572 [M++1] (43), 557 (17),
513 (23), 347 (17), 346 (11), 225 (92), 224 (100), 165 (24);
Anal. Calcd. for C33H37N3O6: C, 69.33; H, 6.52; N, 7.35.
Found: C, 69.40; H, 6.64; N, 7.29.
on a Heraeus CHN-O rapid elemental analyzer (Heraeus
GmbH, Germany) for C, H and N and the results were within
0.4% of the theoretical values.
Preparation
of
2-n-Alkyl-1-[(2ꢀ-carbomethoxy-
biphenyl-4-yl)methyl]imidazole-4-carboxaldehyde
(1a,b) and its Regioisomer 2-n-Alkyl-1-[(2ꢀ-
carbomethoxybiphenyl-4-yl)methyl]imidazole-5-
carboxaldehyde (2a,b)
A solution of 2-n-propyl-imidazole-4(5)-carboxaldehyde
(30 mmol) in anhydrous dimethylformamide (90 ml) and
anhydrous K2CO3 (8.3 g, 60 mmol) were stirred at room
temperature
for
30
min.
Then
methyl
4´-
(bromomethyl)biphenyl-2-carboxylate (10.4 g, 33 mmol) was
added to the reaction mixture and stirring was continued for 24
h. The reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was diluted
with 30 ml of water and extracted with ethyl acetate (3 × 30
ml). The combined organic phases were dried over anhydrous
sodium sulfate and the solvent was removed to give a viscous
liquid. Column chromatography using toluene-ethyl acetate
(70:30) as eluent afforded 14% of 2a,b (regioisomer of higher
Rf value) and 3.21 g (29%) of 1a,b.
Diethyl
1,4-dihydro-2,6-dimethyl-4-[2-n-butyl-1-[(2ꢀ-
carbomethoxybiphenyl-4-yl)methyl]imidazole-4-yl]-3,5-
pyridinedicarboxylate (3d). Yield: 60%; m.p.: 184-186 °C;
FT-IR (KBr): ꢁ 3500 (N-H), 1722 (C=O, ester), 1691 cm-1
(C=O, ester DHP); MS: m/z (%) 599 [M+] (4), 526 (21), 373
(19), 314 (33), 252 (10), 225 (81), 223 (45), 132 (100); Anal.
Calcd. for C35H41N3O6: C, 70.09; H, 6.89; N, 7.01. Found: C,
70.21; H, 7.05; N, 6.86.
Dimethyl
1,4-dihydro-2,6-dimethyl-4-[2-n-propyl-1-
[(2ꢀ-carbomethoxybiphenyl-4-yl)methyl]imidazole-5-yl]-
3,5-pyridinedicarboxylate (5a). Yield: 39%; m.p.: 189-190
°C; FT-IR (KBr): ꢁ 3357 (N-H), 1730 (C=O, ester), 1699 cm-1
(C=O, ester DHP); MS: m/z (%) 558 [M++1] (8), 499 (12),
333 (11), 278 (22), 225 (100), 206 (91), 195 (43), 179 (28);
Anal. Calcd. for C32H35N3O6: C, 68.92; H, 6.33; N, 7.53.
Found: C, 69.11; H, 6.47; N, 7.43.
Diethyl 1,4-dihydro-2,6-dimethyl-4-[2-n-propyl-1-[(2ꢀ-
carbomethoxybiphenyl-4-yl)methyl]imidazole-5-yl]-3,5-
pyridinedicarboxylate (5b). Yield: 61%; m.p.: 176-178 °C;
FT-IR (KBr): ꢁ 3400 (N-H), 1728 (C=O, ester), 1693 cm-1
(C=O, ester DHP); MS: m/z (%) 586 [M++1] (14), 571 (5),
513 (19), 360 (8), 251 (8), 225 (100), 166 (10); Anal. Calcd.
for C34H39N3O6: C, 69.72; H, 6.71; N, 7.17. Found: C, 69.90;
H, 6.87; N, 7.32.
General Procedure for the Preparation of Dialkyl 1,4-
Dihydro-2,6-dimethyl-4-[2-alkyl-1-[(2ꢁ-carbo-
methoxybiphenyl-4-yl)methyl] Imidazole-4(5)-yl]-3,5-
pyridinedicarboxylate
A solution of aldehyde (1a-b or 2a-b) ((1.5 mmol), methyl
or ethyl acetoacetate (3 mmol) and ammonium hydroxide (0.5
ml) in 5 ml of methanol was protected from light and stirred at
25 °C for 30 min and then refluxed over night. The solvents
removed under vacuum and purification with column
chromatography provided 3a-d or 5a-d.
Dimethyl
1,4-dihydro-2,6-dimethyl-4-[2-n-propyl-1-
[(2ꢀ-carbomethoxybiphenyl-4-yl)methyl]imidazole-4-yl]-
3,5-pyridinedicarboxylate (3a). Yield: 45%; m.p.: 208-210
°C; FT-IR (KBr): ꢁ 3400 (N-H), 1695 cm-1 (C=O, ester); MS:
m/z (%) 513 (15), 300 (30), 251 (15), 225 (100), 177 (32), 150
(14); Anal. Calcd. for C32H35N3O6: C, 68.92; H, 6.33; N, 7.53.
Found: C, 69.01; H, 6.52; N, 7.41.
Dimethyl 1,4-dihydro-2,6-dimethyl-4-[2-n-butyl-1-[(2ꢀ-
carbomethoxybiphenyl-4-yl)methyl]imidazole-5-yl]-3,5-
pyridinedicarboxylate (5c). Yield: 43%; m.p.: 170-172 °C;
FT-IR (KBr): ꢁ 3448 (N-H), 1730 cm-1 (C=O, ester); MS: m/z
Diethyl 1,4-dihydro-2,6-dimethyl-4-[2-n-propyl-1-[(2ꢀ-
174

Synthesis and Regioselective Hydrolysis
(%) 571 [M+] (46), 556 (21), 512 (54), 346 (18), 225 (100),
223 (59), 165 (23); Anal. Calcd. for C33H37N3O6: C, 69.33; H,
6.52; N, 7.35. Found: C, 69.48; H, 6.61; N, 7.46.
FT-IR (KBr): ꢁ 3480 [(N-H), (O-H, acid)], 1693 cm-1 (C=O,
acid and ester DHP); MS: m/z (%) 558 [M++1] (9), 499 (11),
333 (5), 225 (100), 165 (14); Anal. Calcd. for C32H35N3O6: C,
68.92; H, 6.33; N, 7.53. Found: C, 68.99; H, 6.41; N, 7.44.
Diethyl
1,4-dihydro-2,6-dimethyl-4-[2-n-butyl-1-[(2ꢀ-
carbomethoxybiphenyl-4-yl)methyl]imidazole-5-yl]-3,5-
pyridinedicarboxylate (5d). Yield: 43%; m.p.: 128-130 °C;
FT-IR (KBr): ꢁ 3400 (N-H), 1730 (C=O, ester), 1697 cm-1
(C=O, ester DHP); MS: m/z (%) 600 [M++1] (3), 527 (7), 251
(8), 225 (26), 207 (100), 178 (13); Anal. Calcd. for
C35H41N3O6: C, 70.09; H, 6.89; N, 7.01. Found: C, 70.28; H,
7.05; N, 6.88.
Diethyl
1,4-dihydro-2,6-dimethyl-4-[2-n-butyl-1-[(2ꢀ-
carboxybiphenyl-4-yl)methyl]imidazole-4-yl]-3,5-
pyridinedicarboxylate (4d). Yield: 62.5%; m.p.: 123-125 °C;
FT-IR (KBr): ꢁ 3500 [(N-H), (O-H, acid)], 1687 cm-1 (C=O,
acid and ester DHP); MS: m/z (%) 586 [M++1] (8), 513 (14),
360 (6), 314 (8), 251 (19), 225 (100), 205 (73), 166 (38); Anal.
Calcd. for C34H39N3O6: C, 69.72; H, 6.71; N, 7.17. Found: C,
69.87; H, 6.84; N, 7.35.
General Method for the Hydrolysis of Esteric Group
on Biphenyl Moiety of Compounds 3a-d and 5a-d
Compound (3a-d or 5a-d) (0.9 m mol) was dissolved in
4.5 ml of methanol and then 0.25 ml of water and 2.7 ml of
methanol solution of potassium hydroxide (0.5 N) were added.
The reaction mixture was refluxed for 30 h. The progress of
the reaction was monitored with TLC. After completion of the
reaction, the solvent was removed under vacuum and to the
residue was added water. The solution was adjusted to pH 4
with dilute hydrochloric acid. The precipitated solid was
collected by filtration. Column chromatography (elution: 10-
20% methanol/chloroform) afforded compounds 4a-d or 6a-d.
Dimethyl
1,4-dihydro-2,6-dimethyl-4-[2-n-propyl-1-
[(2ꢀ-carboxybiphenyl-4-yl)methyl]imidazole-5-yl]-3,5-
pyridinedicarboxylate (6a). Yield: 74%; m.p.: 148-150 °C;
FT-IR (KBr): ꢁ 3490 [(N-H), (O-H, acid)], 1690 cm-1 (C=O,
acid and ester DHP); MS: m/z (%) 543 [M+] (13), 484 (19),
332 (18), 300 (24), 225 (69), 211 (100), 166 (30), 165 (60);
Anal. Calcd. for C31H33N3O6: C, 68.49; H, 6.12; N, 7.73.
Found: C, 68.60; H, 6.23; N, 7.65.
Diethyl 1,4-dihydro-2,6-dimethyl-4-[2-n-propyl-1-[(2ꢀ-
carboxybiphenyl-4-yl)methyl]imidazole-5-yl]-3,5-
pyridinedicarboxylate (6b). Yield: 56%; m.p.: 153-155 °C;
FT-IR (KBr): ꢁ 3500 [(N-H), (O-H, acid)], 1690 cm-1 (C=O,
acid and ester DHP); MS: m/z (%) 572 [M++1] (8.5), 512 (16),
247 (13), 226 (100), 225 (51), 165 (19); Anal. Calcd. for
C33H37N3O6: C, 69.33; H, 6.52; N, 7.35. Found: C, 69.53; H,
6.69; N, 7.30.
Dimethyl 1,4-dihydro-2,6-dimethyl-4-[2-n-butyl-1-[(2ꢀ-
carboxybiphenyl-4-yl)methyl]imidazole-5-yl]-3,5-
pyridinedicarboxylate (6c). Yield: 62%; m.p.: 149-150 °C;
FT-IR (KBr): ꢁ 3465 [(N-H), (O-H, acid)+], 1701 cm-1 (C=O,
acid and ester DHP); MS: m/z (%) 557 [M ] (4), 513 (10), 345
(14), 225 (100), 164 (64), 152 (15); Anal. Calcd. for
C32H35N3O6: C, 68.92; H, 6.33; N, 7.53. Found: C, 69.01; H,
6.48; N, 7.59.
Dimethyl
1,4-dihydro-2,6-dimethyl-4-[2-n-propyl-1-
[(2ꢀ-carboxybiphenyl-4-yl)methyl]imidazole-4-yl]-3,5-
pyridinedicarboxylate (4a). Yield: 65%; m.p.: 140-142 °C;
FT-IR (KBr): ꢁ 3431 [(N-H), (OH, acid)], 1691 cm-1 (C=O,
acid and ester DHP); MS: m/z (%) 499 (7), 346 (6), 286 (31),
225 (47), 211 (50), 192 (53), 165 (100); Anal. Calcd. for
C31H33N3O6: C, 68.49; H, 6.12; N, 7.73. Found: C, 68.54; H,
6.22; N, 7.85.
Diethyl 1,4-dihydro-2,6-dimethyl--4-[2-n-propyl-1-[(2ꢀ-
carboxybiphenyl-4-yl)methyl]imidazole-4-yl]-3,5-
pyridinedicarboxylate (4b). Yield: 71%; m.p.: 135-136 °C;
FT-IR (KBr): ꢁ 3450 [(N-H), (O-H, acid)], 1689 cm-1 (C=O,
acid and ester DHP); MS: m/z (%) 572 [M++1] (5), 498 (14),
360 (10), 319 (33), 300 (50), 251 (19), 211 (100), 165 (63);
Anal. calcd. for C33H37N3O6: C, 69.33; H, 6.52; N, 7.35.
Found: C, 69.49; H, 6.71; N, 7.51.
Diethyl
1,4-dihydro-2,6-dimethyl-4-[2-n-butyl-1-[(2ꢀ-
carboxybiphenyl-4-yl)methyl]imidazole-5-yl]-3,5-
pyridinedicarboxylate (6d). Yield: 68%; m.p.: 161-163 °C;
FT-IR (KBr): ꢁ 3444 [(N-H), (OH, acid)], 1690 cm-1 (C=O,
acid and ester DHP); MS: m/z (%) 586 [M++1] (10), 513 (11),
360 (5), 225 (100), 165 (9); Anal. Calcd. for C34H39N3O6: C,
69.72; H, 6.71; N, 7.17. Found: C, 69.83; H, 6.90; N, 7.01.
Dimethyl 1,4-dihydro-2,6-dimethyl-4-[2-n-butyl-1-[(2ꢀ-
carboxybiphenyl-4-yl)methyl]imidazole-4-yl]-3,5-
pyridinedicarboxylate (4c). Yield: 65%; m.p.: 150-152 °C;
175

Shahbazi Mojarrad et al.
RESULTS AND DISCUSSION
hydrolyzed to carboxylic acid without hydrolysis of esters on
DHP ring.
The direct alkylation
carboxaldehyde was performed
of 2-alkylimidazole-4(5)-
with methyl 4´-
To confirm the hydrolysis of carbomethoxy group on
biphenyl, we investigated the H NMR spectra of compounds
1
(bromomethyl)biphenyl-2-carboxylate (Scheme 1). A 2:1
mixture of regioisomers was obtained using column
chromatography [31], resulting from nonselective alkylation at
4 and 6. The peak of OCH3 on biophenyl of compounds 3b,
3d, 5b and 5d appeared at 3.5-3.7 ppm while in compounds
4b, 4d, 6b and 6d disappeared. In addition, peaks related to
OCH2CH3 group on 3 and 5 position of DHP ring did not
change. The OCH2 was observed at 3.9-4.1 ppm for 4H as
multiplet. The chemical shift of OCH3 on biphenyl and
dihydropyridine were at 3.7 and 3.5 ppm (CDCl3) for
compounds 3a and 5a or 3.5 and 3.4 ppm (DMSO-d6) for
compounds 3c, 5c, respectively. In addition after hydrolysis,
the 1H NMR spectra data showed the chemical shift for OCH3
on dihydropyridine at 3.38 (6a), 3.42 (6c), 3.57 (4a) and 3.56
ppm (4c) (see Table 1). In addition MS of the compounds
showed molecular weight, expectable fragmentation and
established the existence of carboxylic acid group on biphenyl
ring and dialkyl ester on dihydropyridine. The Mass spectrum
fragmentation pattern of compounds 3d and 4a is shown in
Fig. 2 and is in agreement with the suggested structure.
Comparable fragmentations were previously reported for some
dihydropyridine derivatives [34,35].
1
the 1 or 3 positions. H NMR spectra of compounds 1 and 2
show that the benzylic hydrogen (N-CH2) of compound 2 was
more deshielded than that of compound 1 which appeared at
5.63 and 5.17 ppm respectively [29,31]. Dihydropyridines
have been classically synthesized using the “Hantzsch
dihydropyridine synthesis” described in 1882. Variations of
the conditions of the reaction using acidic medium or catalytic
reagents are described [32].
In the present work, we prepared 1,4-dihydropyridines by
reaction of regioisomers 2 or 1 with ethyl or methyl
acetoacetate in the presence of ammonia at reflux temperature.
On the basis of 1H NMR spectrums of compounds 3 and 5 H-
N, H-C4, OCH2CH3 and OCH3 of 1,4-dihydropyridines
appeared at 8.6-10.6 ppm as broad singlet, 4.8-5.1 ppm as
singlet, 3.9-4.1 as multiple and 3.4-3.6 ppm as singlet
respectively. The six hydrogens of 2,6-dimethyl-DHP
appeared as singlet at 2.2 ppm. Depending on type of
substituted imidazole (4-yl or 5-yl) and type of solvent (CDCl3
or DMSO-d6), the methoxy of biphenyl ring overlapped with
methoxy of DHP or appeared separately (see Table 1). The 1H
NMR spectrums corresponding to the methylene group on the
carboethoxy substituent shows a rather more complex splitting
pattern than a simple quartet. This behavior is due to a non-
equivalence of the two hydrogen of the methylene group. The
methylene hydrogen of the carboethoxy group in these
compounds is diasterotopic. This effect only has been
observed for ethyl ester but not for methyl ester. In CDCl3 the
carboethoxy group appeared as a simple quartet but in DMSO-
d6 complex splitting pattern was observed. DaSilva et al.
reported similar splitting pattern for diethyl 4-(nitroaryl)-1,4-
dihydropyridine-3,5-dicarboxylate derivatives [33].
CONCLUTIONS
Bulky substituent on C4 position of dihydropyridines
(compounds 3a-d and 5a-d) could be synthesized through
Hantzsch dihydropyridine synthesis. Their chemical structures
were confirmed with 1H NMR and mass spectroscopy studies.
The side ester on carbomethoxyphenyl is regioselectively
hydrolyzed to carboxylic acid in alkaline solution. Compounds
4 and 6 have key elemental structure for angiotensin II
receptor and calcium channel blockers activity. Therefore
compounds 4 and 6 could be candidates as dual angiotensin
receptor and calcium channel blockers.
ACKNOWLEDGMENTS
Compounds
3
and
5
having 4-[2-n-alky-1-[(2ꢂ-
We are grateful to the Vice-President for Research of
Tabriz University of Medical Sciences for financial support.
We also thank the Applied Drug Research Center of Tabriz
carbomethoxybiphenyl-4-yl)methyl]imidazole-4(or 5)-yl] as
bulky substituent and 2,6-dimethyl on DHP ring can induce
space hindrance on ester groups at 3 and 5 position of DHP.
Therefore, ester on biphenyl could be regioselectively
1
University of Medical Sciences for providing facilities for H
176

Synthesis and Regioselective Hydrolysis
1H NMR Spectroscopy Data for Synthesized Compounds in DMSO-d6
1,4-Dihydropyridine moiety
Table 1.
Imidazolyl biphenyl moiety
Compd.
N-H
C4H
2,6-DiCH3 3,5-Di-OCH3 or 3,5-DiOCH2CH3 HC5 imi or
CH2-N
OCH3
di-OCH2CH3
HC4 imi
7.55
1a,bi
2a,bii
3a
-
-
-
-
-
-
-
-
5.15
5.65
3.65
3.65
-
-
7.80
8.65 (brs) 4.87 (s)
8.84 (brs) 4.91 (s)
2.18 (s)
2.20 (s)
3.55(s)
3.92-4.13 (m)
-
6.49 (s)
6.51 (s)
5.04 (s)
5.06 (s)
3.55(s)
3.58 (s)
3b
1.16 (t, 6H,
J = 8 Hz)
-
3c CDCl3
3d CDCl3
10.60 (brs) 5.08 (s)
10.60 (brs) 5.07 (s)
2.27 (s)
2.28 (s)
3.65 (s)
6.69 (s)
6.68 (s)
5.08 (s)
5.09 (s)
3.70 (s)
3.69 (s)
4.12 (q, 4H, J =
8 Hz, J = 14 Hz)
3.57 (s)
1.20 (t, 6H,
J = 8 Hz)
-
4a
4b
8.80 (brs) 4.87 (s)
9.27 (brs) 4.94 (s)
2.21 (s)
2.27 (s)
6.56 (s)
7.31 (s)
5.07 (s)
5.36 (s)
-
-
3.95-4.13 (m)
1.11 (t, 6H,
J = 7 Hz)
-
4c
8.84 (brs) 4.88 (s)
8.94 (brs) 4.89 (s)
2.20 (s)
2.22 (s)
3.56 (s)
6.57 (s)
7.31 (s)
5.06 (s)
5.19 (s)
-
-
4d
3.92-4.12 (m)
1.12 (t, 6H,
J = 8 Hz)
-
5a
5b
9.13 (brs) 4.94 (s)
2.20 (s)
2.20 (s)
3.42 (s)
6.47 (s)
6.47 (s)
5.32 (s)
5.30 (s)
3.59 (s)
3.58 (s)
9.10 (s)
5.04 (s)
3.79-4.05 (m)
1.08 (t, 6H,
J = 8 Hz)
-
5c CDCl3
6.88 (brs) 5.10 (s)
9.06 (s) 5.04 (s)
2.31 (s)
2.17 (s)
3.51 (s)
6.78 (s)
6.46 (s)
5.43 (s)
5.29 (s)
3.69 (s)
3.58 (s)
5d
3.82-4.02 (m)
1.08 (t, 6H,
J = 8 Hz)
-
6a
6b
9.17 (brs) 4.92 (s)
9.09 (s) 5.00 (s)
2.18 (s)
2.17 (s)
3.38 (s)
6.44 (s)
6.42 (s)
5.30 (s)
5.26 (s)
-
-
3.80-4.00 (m)
1.04 (t, 6H,
J = 7 Hz)
-
6c
9.31 (brs) 5.03 (s)
9.14 (s) 5.04 (s)
2.21 (s)
2.18 (s)
3.42 (s)
6.87 (s)
6.51 (s)
5.47 (s)
5.32 (s)
-
-
6d
4.03-3.78 (m)
1.11-1.04 (m)
ii
ia: R = n-Pr, 4-yl substitution isomer; b: R = n-Bu, 4-yl substitution isomer; a: R = n-Pr, 5-yl substitution isomer; b: R =
n-Bu, 5-yl substitution isomer; hydrogen of carboxaldehyde in 1H NMR (CDCl ) appeared at 9.65 ppm as singlet for
compounds 1 and 2. n-Pr: 2.30 (t, 2H, J = 8 Hz, CH2-imidazole), 1.56- 1.41 (3m, 2H, CH2), 0.79 ppm (t, 3H, J = 8 Hz,
CH3). n-Bu: 2.51 (t, 2H, J = 8 Hz, CH2-imidazole), 1.45-1.24 (m, 4H, CH2), 0.80 ppm (t, 3H, J = 8 Hz, CH3). Biphenyl:
6.92 (d, 2H, J = 8 Hz, H-3, 5 phenyl), 7.31 (d, 2H, J = 8 Hz, H-2,6 phenyl), 7.59-7.34 (m, 3H, aromatic), 7.75 (dd, 1H,
J
3´,5´´ = 2 Hz, J3´,4´ = 8 Hz, H-3' phenyl), brs: broad singlet, d: doublet, m: multiple, q: quartet, s: singlet, t: triplet.
177

Shahbazi Mojarrad et al.
R
R2O
O
N
N
O
R2O
R1
+
O
O
O
O
R1
+
R1
H3C
N
H
CH3
O
O
R
N
N
R= n-Bu, R1= C2H5 , R2 =CH3 m/z 526
R= n-Pr, R1= CH3 , R2 = H m/z 484
H3C
N
H
CH3
+
RimiCH2biphCO2R2
R= n-Bu, R2 = CH3 m/z 347
R= n-Pr, R2 = H m/z 319
DHP
R1= C2H5 m/z 252
R1= CH3 m/z 224
-CO2R1
- CH2=CH2
O
R
R2O
O
N
O
R1
+
N
H
O
O
O
O
R1
R1
O
O
H3C
N
H
CH3
H3C
N
CH3
R1 = C2H5 m/z 224
H
+
R
3d, R= n-Bu, R1= C2H5,
N
N
R2 =CH3 m/z 599
O
O
R1
R1
O
O
4a, R= n-Pr, R1= CH3 ,
R2O
R2 = H m/z 543
O
H3C
N
H
CH3
CH2
RimiDHP
R= n-Bu, R1= C2H5 m/z 374
R= n-Pr, R1=CH3 m/z 332
CH2biphCO2R2
R2 = CH3 m/z 225
R2 = H m/z 211
Fig. 2. Proposed fragmentation pathways of compounds 3d and 4a in mass spectroscopy.
NMR spectroscopy. Thanks are also due to Dr. Mohsen
Amini, from Faculty Pharmacy, Tehran University of Medical
Sciences, for providing mass spectroscopy.
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