Catalytic effect of nanosized metal oxides on the Hantzsch reaction

Article abstract of DOI:10.1134/S0023158410040166

The effect of nanosized copper and aluminum oxides, which have a higher sorption capacity than that of bulk samples, on the Hantzsch reaction was studied. The adsorption of starting benzaldehydes and ethyl acetoacetate on the surface of copper and aluminum nanooxides resulted in the activation of these molecules and accelerated the Hantzsch reaction. In addition, considerable activation of ammonia and intermediates (chalcone and enamine) on the surface of aluminum nanooxide facilitated an increase in the rate and selectivity of the process. The experimental results were used to develop a one-pot method for the preparation of nifedipine and nitrendipine.

Full text of DOI:10.1134/S0023158410040166

ISSN 0023ꢀ1584, Kinetics and Catalysis, 2010, Vol. 51, No. 4, pp. 566–572. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © O.V. Fedorova, O.V. Koryakova, M.S. Valova, I.G. Ovchinnikova, Yu.A. Titova, G.L. Rusinov, V.N. Charushin, 2010, published in Kinetika i Kataliz,
2010, Vol. 51, No. 4, pp. 590–596.
Catalytic Effect of Nanosized Metal Oxides
on the Hantzsch Reaction
O. V. Fedorova, O. V. Koryakova, M. S. Valova, I. G. Ovchinnikova,
Yu. A. Titova, G. L. Rusinov, and V. N. Charushin
Postovsky Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, 620219 Russia
eꢀmail: fedorova@ios.uran.ru
Received August 4, 2009
Abstract—The effect of nanosized copper and aluminum oxides, which have a higher sorption capacity than
that of bulk samples, on the Hantzsch reaction was studied. The adsorption of starting benzaldehydes and
ethyl acetoacetate on the surface of copper and aluminum nanooxides resulted in the activation of these molꢀ
ecules and accelerated the Hantzsch reaction. In addition, considerable activation of ammonia and intermeꢀ
diates (chalcone and enamine) on the surface of aluminum nanooxide facilitated an increase in the rate and
selectivity of the process. The experimental results were used to develop a oneꢀpot method for the preparation
of nifedipine and nitrendipine.
DOI: 10.1134/S0023158410040166
INTRODUCTION
a search for conditions and catalysts that make it posꢀ
sible to perform this reaction in a single step is promꢀ
ising.
The threeꢀstep Hantzsch reaction (see the scheme)
is widely used in organic synthesis for the preparation
In this work, we used nanosized metal oxides
(nanooxides), which possess a highly developed surꢀ
face and contained active sites of different nature, as
catalysts for the threeꢀcomponent Hantzsch reaction
[3]. We studied the sorption of reagents and Hantzsch
reaction intermediates on the surface of copper and
aluminum nanooxides. The experiments were perꢀ
formed with bulk and nanosized copper and alumiꢀ
num oxides using an analysis of the diffuse reflectance
of substituted dihydropyridines (1a, 1b) from the series
of nifedipine, which is a wellꢀknown drug used in the
treatment of cardiovascular diseases [1]. However, the
commonly used synthetic procedure is characterized
by low selectivity, especially, with the use of nitroꢀsubꢀ
stituted aromatic aldehydes. The reaction is perꢀ
formed stepwise with the isolation of intermediate
enamine
3 and chalcone 2a or 2b (scheme, reaction
path II); this considerably complicates the process and
increases the consumption of solvents [2]. Therefore, IR spectra. The composition of crude Hantzsch reacꢀ
NO2
O
O
NO2
R2O
OR2
NO2
O
H+
+
NO2
O
O
O
O
O
H
O
I
II
2a R2 = Me,
o
ꢀNO2
O
H
R1O
OR2
R1O
OR2
2b
R2 = Et
mꢀNO2
+
O
O
O O
NH3
N
H
MeO
NH3 +
1a R1, R2 = Me,
1b R1 = Me, R2 = Et,
o
ꢀNO2
mꢀNO2
MeO
O
NH2
3
Scheme. Reaction scheme of the preparation of nifedipine (1a) and nitrendipine (2b) (I) with the use of the threeꢀ
component Hantzsch reaction and (II) the conventional threeꢀstep procedure
566

CATALYTIC EFFECT OF NANOSIZED METAL OXIDES
567
1
tion products was studied using H NMR spectrosꢀ
copy and HPLC.
Product yield, %
90
1
80
70
60
50
40
30
20
10
EXPERIMENTAL
Methanol (98%), an aqueous ammonia solution
(30%), 2ꢀnitrobenzaldehyde (99%), 3ꢀnitrobenzaldeꢀ
hyde (99%), and methyl 3ꢀaminocrotonate (enamine)
(97%) from Lancaster and ethyl acetoacetate (99%)
and methyl acetoacetate (99%) from Acros Organics
were used in this study. Nanosized copper oxide (parꢀ
ticle size of 50–80 nm) and nanosized aluminum
oxide (particle size of 20–50 nm), which were preꢀ
pared using a gasꢀphase procedure at the Institute of
Metal Physics, Ural Division, Russian Academy of
Sciences (Laboratory of Prof. A.E. Ermakov), were
used as catalysts [4].
2
0
0.5
1.0
1.5
2.0
2.5
3.0
Reaction time, h
Fig. 1. Yields of nifedipine (according to HPLC data) (1)
The melting points measured on combined Boetius
plates were uncorrected. The diffuse reflectance specꢀ
tra were measured on a Spectrum One FTIR specꢀ
trometer (Perkin Elmer) using an automated diffuse
in the presence and (
nanooxide.
2) in the absence of aluminum
1
Ethyl 2ꢀAcetylꢀ3ꢀ(3ꢀNitrophenyl)ꢀAcrylate
(Chalcone) (2b
reflectance attachment. The H NMR spectra were
)
obtained on an AVANCE DRXꢀ400 spectrometer
(Bruker) with an operating frequency of 400 MHz.
3ꢀNitrobenzaldehyde (3.3 mmol, 0.5 g), ethyl aceꢀ
toacetate (9.9 mmol, 1.15 g), nanosized Al2O3
(1.1 mmol), morpholine (3.3 mmol), and acetonitrile
(5 ml) were mixed. The reaction mass was kept with
stirring at 60°С for 6 h with a reflux condenser; thereꢀ
after, crystallization from ethanol was performed. The
yield of the product with mp 109°С was 74%.
The Hantzsch reaction was performed by heating a
reaction mixture with an aldehyde : methyl acetoaceꢀ
tate : ammonia : metal nanooxide ratio of 1 : 2 : 1 : 0.1
(in the preparation of nifedipine) or an aldehyde :
ethyl acetoacetate : methyl acetoacetate : ammonia :
metal nanooxide ratio of 1 : 1 : 1 : 1 : 0.1 (in the prepꢀ
aration of nitrendipine) in methanol. Then, the reacꢀ
tion mixture was evaporated, and the resulting crude
For С13Н13О5N
anal. calcd. (%):
C 59.32;
C 59.11;
H 4.94;
H 4.97;
N 5.32.
N 5.29.
1
product was analyzed by H NMR spectroscopy and
Found (%)
:
HPLC (a normalꢀphase LiChrosorb Si 60 column;
mobile phase, a mixture of hexane with isopropanol in
a ratio of 9 : 1). The retention times (min) were the folꢀ
lowing: 18.70, nifedipine; 42.70, nitrendipine; 25.24, 7.16 Hz, С(О)CH2СН3); 2.45 (s, 3H, СН3); 4.38 (kv,
chalcone; and 16.12, enamine.
1H NMR spectrum (
, ppm): 1.31 (t, 3H, J =
δ
2H,
7.60 (t, H,
C(6)Ar); 8.26 (dd, H,
C(2)Ar).
J
= 7.16 Hz, С(О)CH2СН3); 7.59 (s, H, –СН=);
= 7.8 Hz, C(5)Ar); 7.76 (d, H, = 7.8 Hz,
= 7.8 Hz, C(4)Ar); 8.34 (s, H,
J
J
J
Dimethyl 2,6ꢀDimethylꢀ4ꢀ(2ꢀNitrophenyl)ꢀ1,4ꢀ
Dihydropyridineꢀ3,5ꢀDicarboxylate (Nifedipine) (1a
)
Methyl 3ꢀAminocrotonate (Enamine) (
3)
After recrystallization from ethanol, the yield of the
product with mp 165°С was 67%. 1H NMR spectrum
1H NMR spectrum (
δ
, ppm): 1.90 (s, 3H, ОСН3);
( , ppm): 2.25 (s, 6H, CH3); 3.51 (s, 6H, OCH3); 5.49
(s, H); 7.34–7.59 (m, 4H, Ar); 9.00 (s, H, NH).
δ
3.64 (s, 3H, СН3); 4.52 (s, H, CH=); 4.8 (br s, H, NH2);
7.9 (br s, H, NH2).
The sorption of starting compounds and Hantzsch
reaction intermediates on metal nanooxides was perꢀ
formed in methanol solutions at a sorbate : sorbent
molar ratio of 1 : 3 followed by the removal of the solꢀ
vent.
Methyl Ethyl 2,6ꢀDimethylꢀ4ꢀ(2ꢀNitrophenyl)ꢀ1,4ꢀ
Dihydropyridineꢀ3,5ꢀDicarboxylate (Nitrendipine) (1b
)
After extraction with chloroform and precipitation
with methanol, the yield of the product with mp 130–
132°С was 50%. 1H NMR spectrum (
δ
, ppm): 1.16 (t,
= 7.0 Hz); 2.25 (s, 6H, CH3); 3.51 (s,
3H, –OCH3); 3.98 (t, 2H, СН3СН2, = 7.0 Hz); 4.99
(s, H); 7.52–8.01 (m, 4H, Ar); 9.07 (s, H, NH).
RESULTS AND DISCUSSION
3H, СН3СН2,
J
J
The use of aluminum nanooxide allowed us to perꢀ
form a threeꢀcomponent version of the synthesis of
KINETICS AND CATALYSIS Vol. 51
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2010

568
FEDOROVA et al.
nifedipine (scheme, reaction path I); in this case, the
The aluminum nanooxides prepared by a gasꢀ
yield of the target product was increased by a factor of phase procedure can occur in various structural modꢀ
ifications [3]. In this work, we used a material whose
more than 2 (Fig. 1). The use of aluminum nanooxide
in the synthesis of nifedipine made it possible to obtain
this compound in 60% yield (according to HPLC
data) from four components in a single step. In the
presence of copper nanooxide, catalytic effects of this
kind were not observed.
structure was close to Al2O3, as judged from the
α
ꢀ
character of its spectrum. According to published data
[5], both AlO6 octahedrons and Al atoms with a lower
coordination number occur in its structure. In the
spectrum of nanodispersed powder, the absorption
bands of both of the polyhedrons are shifted by 30–
50 cm–1 to the region of smaller wavenumbers, as
compared with published data [5]. The surface of aluꢀ
minum nanooxide is a set of Al3+ central atoms in an
environment of oxygen atoms (νAl–O = 960, 710, and
Moreover, aluminum nanooxide optimizes the step
of chalcone formation (scheme, reaction path II); the
yield of chalcone increases from 48 to 74%. Thus, the
use of aluminum nanooxide has a favorable effect on
the commonly used procedure for the synthesis of
nitrendipine.
685 cm–1) and coordinated water molecules (νOH
3472–3515 cm–1 = 1620–1640 cm–1).
=
,
δН О
2
A comparison of diffuse reflectance IR spectra
indicated that the absorbance of copper nanooxide
decreased, as compared with that of a bulk sample,
and the absorption bands of Cu–O shifted by 10–
15 cm–1 to the highꢀfrequency region. Previously, in a
study of copper nanooxide with the use of probe molꢀ
ecules [4], we found that Cu+ and Cu2+ Lewis acid
sites are the active sites of the surface. The Lewis base
To study the Hantzsch reaction mechanism in the
presence of nanosized metal oxides by diffuse reflecꢀ
tance IR spectroscopy, we examined the sorption of
reactants and reaction intermediates on the surfaces of
copper and aluminum oxides. The IR spectra of benꢀ
zaldehydes sorbed on the surface of metal nanooxides
exhibited a change in the spectroscopic characteristics
corresponding to the vibrations of both the carbonyl
fragment of the aldehyde group (see the table) and the
M–O bonds of oxides. The νC=O bands of benzaldeꢀ
hyde sorbed on copper and aluminum oxides shifted
sites are the oxygen atoms of the oxide and hydroxyl
+
groups and ion pairs like Mn –O–. The Br
ø
nsted acid
sites are the protons of the hydroxyl groups of copper
hydroxy carbonate, which is formed upon the sorption
of carbon dioxide on the nanooxide surface. The
occurrence of an unresolved absorption band with
maximums at 601 and 547 cm–1 in the spectrum of a
sample used as a catalyst for the Hantzsch reaction
suggests the presence of a considerable amount of copꢀ
per(II) oxide along with copper(I) oxide in this samꢀ
1
by 156 and 150 cm⎯ , respectively. In this case, νCuO
and νAlO band maximums also shifted differently (by
47 and 43 cm–1, respectively). These changes can be a
consequence of the coordination of the oxygen atom
of the carbonyl group of benzaldehyde to the Lewis
site of the sorbent (metal oxide cation); in turn, this
ple. Other spectroscopic characteristics are also conꢀ increases a positive charge at the carbon atom of the
sistent with the results reported previously [4]. carbonyl group.
Main absorption bands (cm–1) in the IR spectra of free and sorbed aldehydes
Benzaldehyde orthoꢀNitrobenzaldehyde
а (NO2),
metaꢀNitrobenzaldehyde
а (NO2),
C=O
Sorbent
ν
ν
ν
ν
ν
ν
ν
ν
skeleton
С=О
skeleton
C=O
skeleton
(С=С)
(НС=О)
(С=С)
ν
s (NO2) (HC=O)
(С=С)
ν
s (NO2) (НС=О)
Without a sorbent
1597
1584
1455
1593
1543
1448
1602
1703
1547
1553
1549
1607
1573
1448
1595
1569
1448
1605
1573
1480
1605
1573
1480
1514
1359
1687
1395
1701
1702
1615
1583
1471
1615
1583
1478
1479
1531
1347
1691
1703
NanoꢀCuO
NanoꢀAl2O3
Bulk Al2O3
1529
1395
1532
1353
1704
1707
1703
1535
1348
1539
1358
1600
1526
1346
1582
1477
1582
1477
Note: ν and ν refer to antisymmetrical and symmetrical stretching vibrations, respectively.
a
s
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CATALYTIC EFFECT OF NANOSIZED METAL OXIDES
Kubelka–Munk units
1717
569
+
+
O
δ
δ
O
1743
1367
1412
1152
1177
1041
1318
e
e
H
O
1266
e
e
O
O
O
H
O
O
Cu
O
Cu
O
Cu
Cu
Cu
1
1286
1605
1620
1528
1368
1416
499
580
778
1067
1021
1177
2
1470
547
1358
601
3
1808.1 1700 1600 1500 1400 1300 1200 1100 1000 900 800 700 600 500 382.2
, cm–1
ν
Fig. 2. Scheme of the interaction of ethyl acetoacetate with copper nanooxide and the IR spectra of (
1) ethyl acetoacetate, (2)
ethyl acetoacetate sorbed on copper oxide, and ( ) copper oxide.
3
A comparison between bulk and nanosized alumiꢀ resulted in the appearance of absorption bands due to
num oxides indicates that, in the IR spectrum of benꢀ only sorbed aldehydes. At the same time, the complete
zaldehyde sorbed on a nanosized sample, the absorpꢀ sorption of the above aldehydes occurred on the surꢀ
tion band intensity ratio is νС=О
/νAl
= 0.081, face of aluminum nanooxide at a sorbent : sorbate
⎯
O
whereas it is 0.014 in the spectrum of bulk aluminum ratio of 3 : 1.
oxide. The experimental results can be explained by an
In any event, the sorption of benzaldehyde, as well
as orthoꢀ and metaꢀnitrobenzaldehydes, on the surface
of copper or aluminum nanooxides caused an increase
increase in the sorption capacity of nanosized metal
oxide, as compared with a standard sample.
The sorption of orthoꢀnitrobenzaldehyde on the in the positive charge on the carbon atom of the carboꢀ
surface of copper nanooxide was accompanied by the nyl group; this could increase the reactivity of benzalꢀ
disappearance of an absorption band due to the vibraꢀ dehyde in the Hantzsch reaction.
tions of the carbonyl group and a considerable
As can be seen in Fig. 2, the sorption of ethyl aceꢀ
increase in the intensity and a shift of absorption bands
toacetate was accompanied by a change in the freꢀ
due to nitro groups toward low frequencies. It is likely
quency characteristics of the vibrations of bonds in
that absorption bands due to the vibrations of the NO2
both of the carbonyl groups (νC=O) and the vibrations
group and the C=O group coordinated to the copper
of the C–O–C unit. In addition, a lowꢀfrequency shift
atom superimposed on each other (see the table). This
and an increase in the intensity of the νC=С band of the
enol form of the sorbate occurred, as well as a broadꢀ
ening and shift of the νCu–O band of the sorbent. Eviꢀ
dently, the donor–acceptor interactions of the C=O,
is supported by a shift of the absorption band due to
the Cu–O bond to a lowꢀfrequency region by more
than 30 cm–1. Evidently, a weaker interaction occurred
in the case of aluminum oxide.
COO, and C=C fragments of ethyl acetoacetate with
Upon the coordination of metaꢀnitrobenzaldehyde the surface active sites of copper and aluminum
to the surface of nanooxides, absorption bands correꢀ nanooxides (Мn+, –OH) resulted in the formation of
sponding to the skeleton vibrations of the benzene ring polarized chelateꢀlike structures, including those with
changed, whereas the absorption bands of carbonyl a strained bond. However, note that the shift of sorbent
and nitro groups remained almost unchanged. This absorption bands in copper nanooxide was greater
fact suggest the interaction of the
π
ꢀelectron system of than that in aluminum nanooxide.
the ring with the Lewis base sites of the oxide surface.
Upon the sorption of ammonia on the surface of
Upon the sorption of orthoꢀ and metaꢀnitrobenzalꢀ copper nanooxide, almost no changes were detected in
dehydes on bulk aluminum oxide (a sorbent : sorbate the spectroscopic characteristics, whereas they were
ratio of 3 : 1), the IR spectra exhibited bands due to the considerable on the surface of aluminum nanooxide
vibrations of groups belonging to the initial aldehydes; (Fig. 3). In the IR spectrum of an aqueous solution of
however, a change in the sorbent : sorbate ratio to 9 : 1 ammonia, symmetrical deformation vibrations of the
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570
FEDOROVA et al.
Kubelka–Munk units
H
H
N
962
H
O
712
686
Al
Al
798
641
1094
960
1051
563
862
863
685
714
1386
913
1
1579
2
3
1737.4 1600 1500 1400 1300 1200 1100 1000 900 800 700 600 500460.7
ν
1
, cm−
Fig. 3. Scheme of the interaction of an aqueous solution of ammonia with aluminum nanooxide and the IR spectra of (
1) alumiꢀ
num oxide, ( ) ammonia sorbed on aluminum oxide, and ( ) ammonia solution.
2
3
distorted pyramidal NH3 molecule manifested themꢀ same time, the disappearance of absorption bands due
to free surface hydroxyl groups at 3693 cm–1 and
changes in the region of the vibrations of bridging
selves at 1160 cm–1, whereas the spectrum of the subꢀ
strate sorbed on the surface of aluminum nanooxide
exhibited bands at 1579 (δНNH), 1342, 913, and
C⎯
O–C groups (1000–1200 cm–1) suggest the occurꢀ
rence of a hydrogen bond between these groups.
740 cm–1 and a shoulder at 1070 cm–1
(
). This
ρ
NH2
suggests an elongation of the H–NH2 bond, probably,
due to the interaction of a hydrogen atom with strong
Lewis base sites of the surface; as a result of this, a
weakening of the H–N bond occurred to facilitate the
activation of ammonia in the Hantzsch reaction. The
appearance of additional absorption bands at 600–
800 cm–1 can be explained by the formation of addiꢀ
tional Al–OH groups. As for Al–O bonds, the intenꢀ
sity of an absorption band at 960 cm–1 increased with
reference to a doublet at 714 and 685 cm–1. This can be
a consequence of an increase in the number of coordiꢀ
natively unsaturated aluminum atoms—surface active
sites. Thus, the catalytic activity of aluminum nanooxꢀ
ide in the Hantzsch reaction in the absence of the
activity of copper nanooxide in this reaction can be
explained by differences in the sorption of ammonia
on their surfaces.
A considerable number of poorly resolved absorpꢀ
tion bands in the spectrum of intermediate
3 (Fig. 5)
suggests the presence of tautomeric forms in which
this compound occurs. In particular, in the range of
1800–1500 cm–1, both the vibrations of carbonyl
groups with various degrees of binding and the νС=С
and νC=N vibrations can manifest themselves. Upon
sorption on aluminum nanooxide, all of the bands in
this region shifted toward low frequencies, and a redisꢀ
tribution of their intensities occurred. In addition,
changes were observed in the region of the vibrations
of bridging C–O–C groups (1100–1250 cm–1), which
are indicative of changes in bond parameters and the
electronic state of the carbonyl group because of its
interaction with surface aluminum atoms. Simultaꢀ
neously, a shift in the absorption band maximums of
Al–O bonds and a redistribution of their intensity
occurred. This can be a consequence of a change in
the symmetry of the nearest environment of alumiꢀ
num atoms on the surface of nanopowder. A weak
absorption band due to free surface hydroxyl groups
disappeared from the highꢀfrequency region. Because
of the superposition of absorption bands due to the
The study of the sorption of enamine
3 and chalꢀ
cone 2b on aluminum nanooxide indicated that the
coordination of 2b was accompanied by a decrease in
the number of absorption bands, a shift in frequencies,
and a redistribution of intensities in the absorption
region of carbonyl groups (1730–1620 cm–1) and in stretching vibrations of water and –NH and NH2
the region of Al–O vibrations (Fig. 4). This allowed us groups, the shape of the overall band changed with the
to hypothesize that the aluminum atoms of the appearance of two absorption maximums of N–H
nanooxide participate in the formation of a chelateꢀ bonds shifted to the lowꢀfrequency region (at
like complex with carbonyl and ester groups. At the 3319 cm–1 and a shoulder at 3435 cm–1). The above
KINETICS AND CATALYSIS Vol. 51
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CATALYTIC EFFECT OF NANOSIZED METAL OXIDES
Kubelka–Munk units
NO
571
2
962
412
797
712
+
δ
1095
415
CH
O
673
3
C H
2
5
467
644
619
601
714
740
H
O
959
O
O
528
912
795
862
Al
Al
Al
1
O
O
1352
1351
1531
1620
1660
1722
1730
2
1247
1660
1628
1527
1046
1020
1299
1210
734
1384
1423
812
920
678
551
1104
3
1827.2 1700 1600 1500 1400 1300 1200 1100 1000 900 800 700 600 500
, cm−
1
ν
Fig. 4. Scheme of the interaction of intermediate 2b with aluminum nanooxide and the IR spectra of (
1) aluminum oxide, (2)
intermediate 2b on aluminum nanooxide, and (
3) intermediate 2b.
Kubelka–Munk units
O
O
H
H C
3
H C
3
C H
2
C H
2
5
5
H
HN
Al
O
H N
2
O
O
O
Al
Al
Al
Al
Al
689
O
O
O
O
721
1
3319
2980
1252
1218
1443
1369
1336
2933
1681
1294
1535
2
1092
1671
1296
1627
1568
1174
1695
1377
1097
1048
1224
1445
2982
2935
3333
3440
787
916
962
569
859
3
1
3826
3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600
ν
, cm−
Fig. 5. Scheme of the interaction of compound
3
with the surface of aluminum nanooxide and the IR spectra of (
) compound
1) aluminum
oxide, ( ) compound on aluminum oxide, and (
2
3
3
3.
changes in νС=С and νC=N are a consequence of the nanooxides allowed us to explain the reason for differꢀ
coordination of the nitrogen atom and the formation
of a hydrogen bond with the oxygen atoms of alumiꢀ
num oxide. Figure 5 shows a hypothetical scheme of
ent activities of copper and aluminum nanooxides in
this reaction. Aluminum nanooxide is a more efficient
catalyst because it activates initial reactants (nitroꢀ
substituted benzaldehyde, ethyl acetoacetate, and,
especially, ammonia) and increases the reactivity of
the interaction of Hantzsch reaction intermediate
with aluminum oxide.
3
intermediate enamine
this the rate of the Hantzsch reaction increases in the
3 and chalcone 2b; because of
Thus, an analysis of spectroscopic data concerning
the interaction of reagents participating in the Hantzsch
reaction and intermediates on the surface of metal presence of this oxide.
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FEDOROVA et al.
In addition, the analysis of the crude products of neous Catalysts with the Use of Nanosized Metals and
1
the synthesis of nifedipine and nitrendipine by H Metal Oxides”), the Russian Foundation for Basic
NMR spectroscopy and HPLC suggests a considerꢀ Research (project no. 07ꢀ03ꢀ96111ꢀr_ural_a), and the
able decrease in the amount of impurities in the target Korea Atomic Energy Research Institute (contract no.
products prepared under conditions of heterogeneous 01/06 “Development of New Chiral Catalytic Systems
catalysis; because of this, the additional purification of Based on Nanocrystalline Metals and Metal Oxides”).
the target compounds is not required.
The above experiments make it possible to use a
REFERENCES
singleꢀstep fourꢀcomponent procedure for the syntheꢀ
sis of nitrendipine or to optimize a commonly used
threeꢀstep procedure. We developed a oneꢀpot method
for the preparation of nifedipine in >60% yield. The
above experimental results show promise for the furꢀ
ther optimization of the method for the synthesis of
nifedipine and its analogs.
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ACKNOWLEDGMENTS
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This work was supported by the Presidium of the
Russian Academy of Sciences (project “Heterogeꢀ
KINETICS AND CATALYSIS Vol. 51
No. 4
2010