Transformation of 3-(3-arylalkylcarbamoyl-4-hydroxy-2-oxo-1,2- dihydroquinolin-1-yl)propanenitriles into amides and acids

Article abstract of DOI:10.1134/S1070428013060122

A mixture of hydrochloric and acetic acids depleted in water was proposed to effect stepwise transformation of 3-(3-arylalkylcarbamoyl-4-hydroxy-2-oxo-1, 2-dihydroquinolin-1-yl)propanenitriles into the corresponding amides and then into the acids. The procedure turned out to be efficient with 3-[(2-phenylethyl)-carbamoyl] derivatives, whereas the reactions with benzylcarbamoyl analogs were accompanied by partial or complete debenzylation.

Full text of DOI:10.1134/S1070428013060122

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 6, pp. 867–871. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © I.V. Ukrainets, O.V. Gorokhova, K.V. Andreeva, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 6,
pp. 883–887.
Transformation of 3-(3-Arylalkylcarbamoyl-4-hydroxy-2-oxo-
1,2-dihydroquinolin-1-yl)propanenitriles into Amides and Acids
I. V. Ukrainets, O. V. Gorokhova, and K. V. Andreeva
National University of Pharmacy, ul. Pushkinskaya 53, Kharkiv, 61002 Ukraine
e-mail: uiv-2@mail.ru
Received October 18, 2012
Abstract—A mixture of hydrochloric and acetic acids depleted in water was proposed to effect stepwise
transformation of 3-(3-arylalkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)propanenitriles into the
corresponding amides and then into the acids. The procedure turned out to be efficient with 3-[(2-phenylethyl)-
carbamoyl] derivatives, whereas the reactions with benzylcarbamoyl analogs were accompanied by partial or
complete debenzylation.
DOI: 10.1134/S1070428013060122
We previously showed that 3-(3-benzylcarbamoyl-
4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)propanoic
acids, as well as their synthetic precursors, the corre-
sponding 3-(quinolin-1-yl)propanenitriles, attract inter-
est as base structures for the design of new potential
analgesics [1]. However, intermediate 3-(quinolin-1-
yl)propanamides that are unavoidably formed in the
course of the transformation of nitriles into acids have
received almost no attention. Taking into account that
metabolism of nitriles in vivo can take different path-
ways, including primary hydration to amides [2],
interest in such intermediates exceedingly increases.
2-phenylethanamine, respectively, in boiling ethanol
(Scheme 1).
The hydrolysis of nitriles can by no means always
be stopped at the stage of formation of the corre-
sponding amide. In fact, this was the case when
3-(quinolin-1-yl)propanenitriles I and II were treated
with aqueous alkali. Up to now, numerous procedures,
both chemical [4] and biochemical [5], have been
proposed for the transformation of nitriles to amides
with fairly high selectivity.
We made an attempt to convert 3-(quinolin-1-yl)-
propanenitriles I and II into amides IV and V using
a solution of hydrogen chloride in acetic acid with low
water content. High dissolving ability of this system
makes it applicable to various nitriles. The procedure
was initially proposed for the hydrolysis of alkyl
4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates
[6] and is now among the most appropriate methods
Initial 3-(3-arylalkylcarbamoyl-4-hydroxy-2-oxo-
1,2-dihydroquinolin-1-yl)propanenitriles I and II were
synthesized in two steps, via condensation of
3-anilinopropanenitrile with triethyl methanetricarbox-
ylate [3], followed by aminolysis of heterocyclic ester
III thus obtained with phenylmethanamine and
Scheme 1.
R
R
NH2
NH2
OH
N
O
OH
O
OH
N
O
N
OEt
N
R
R
H
H
O
N
O
O
CN
CN
CN
Ia, Ib
III
IIa, IIb
R = 4-MeO (a), 3,4-(MeO)2 (b).
867

UKRAINETS et al.
868
Scheme 2.
R
OH
O
O
OH
N
O
O
AcOH, HCl, H2O
80°C, 3 h
AcOH, HCl, H2O
80°C, 12 h
NH2
NH2
OH
N
O
O
+
N
N
H
CONH2
COOH
CONH2
IVa, IVb
Ia, Ib
VI
VII
OH
O
KOH, H2O
100°C, 4 h
N
R
H
N
O
COOH
VIIIa, VIIIb
OH
N
O
O
OH
N
O
O
R
R
AcOH, HCl, H2O
80°C, 3 h
AcOH, HCl, H2O
80°C, 15 h
N
N
H
IIa, IIb
H
CONH2
COOH
Va, Vb
IXa, IXb
R = 4-MeO (a), 3,4-(MeO)2 (b).
for the preparation of extremely unstable 4-hydroxy-
2-oxo-1,2-dihydroquinoline-3-carboxylic acids, in
particular of 4-hydroxy-1-(2-carbamoylethyl)-2-oxo-
1,2-dihydroquinoline-3-carboxylic acid possessing
strong analgesic properties [7].
after the reaction started, whereas in the reaction with
3,4-dimethoxybenzyl derivative Ib, diamide VI was
detected even in 45 min. Chromatographic study also
revealed one more important feature, namely target
propanamides IV were detected almost immediately
after dissolution of initial compounds I in HCl–
AcOH–H2O. This means that the rate of hydration of
the cyano group in I is considerably higher than the
rate of debenzylation. Taking advantage of the differ-
ent rates of the main and side reactions we were able to
optimize the conditions for the hydrolysis of nitriles I
to amides IV so as to at least minimize the debenzyla-
tion process unless avoid it. We succeeded in doing so
by shortening the reaction time with 4-methoxybenzyl
derivative Ia to 2 h. By this time, only traces of Ia
remained in the reaction mixture.
Our experiments showed that compounds I and II
readily undergo hydrolysis to amides IV and V,
respectively, on heating for 3 h at 80°C in the system
HCl–AcOH–H2O. However, the reaction smoothly
occurred only with phenethylcarbamoyl derivatives II.
Their benzylcarbamoyl analogs Ia and Ib turned out to
be less stable, and their hydrolysis under similar con-
ditions was accompanied by partial (by 12 and 26%,
1
respectively, according to the H NMR spectra of the
crude products) debenzylation with formation of
1-(2-carbamoylethyl)-4-hydroxy-2-oxo-1,2-dihydro-
quinoline-3-carboxamide (VI) as an undesirable im-
purity (Scheme 2).
According to the data of chromatographic monitor-
ing, the rate of elimination of the N-benzyl group is
determined by substituents present in its benzene ring.
In the reaction with 4-methoxybenzyl derivative Ia,
diamide VI appeared in the reaction mixture in ~2 h
Selective hydrolysis of benzylcarbamoyl nitriles I
to carboxylic acids under the same conditions seems to
be apparently unfeasible, and increase of the reaction
time to 15 h leads to hydrolysis of the aliphatic car-
bamoyl group with simultaneous complete debenzyla-
tion. As a result, 3-(3-carbamoyl-4-hydroxy-2-oxo-1,2-
dihydroquinolin-1-yl)propanoic acid (VII) was isolat-
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TRANSFORMATION OF 3-(3-ARYLALKYLCARBAMOYL-4-HYDROXY-2-OXO-...
869
1
ed in a good yield. Therefore, benzylcarbamoyl deriv-
atives I were hydrolyzed to acids VIII with aqueous
potassium hydroxide. Unlike compounds I, phenethyl-
carbamoyl nitriles II can be converted into the corre-
sponding propanoic acids IX in the system HCl–
AcOH–H2O without appreciable decomposition of the
N-arylalkylamide fragment.
Rf 0.68. H NMR spectrum, δ, ppm: 2.88 t (2H,
CH2CN, J = 7.0 Hz), 3.78 s (3H, OCH3), 4.52 d (2H,
NHCH2, J = 5.6 Hz), 4.56 t (2H, 1-CH2, J = 7.0 Hz),
6.89 d (2H, 2′-H, 6′-H, J = 8.8 Hz), 7.30 d (2H, 3′-H,
5′-H, J = 8.8 Hz), 7.36 t (1H, 6-H, J = 6.5 Hz), 7.79–
7.75 m (2H, 7-H, 8-H), 8.15 d (1H, 5-H, J = 8.0 Hz),
10.47 t (1H, 3-CONH, J = 5.5 Hz), 17.38 s (1H,
4-OH). Found, %: C 66.74; H 4.96; N 11.05.
C21H19N3O4. Calculated, %: C 66.83; H 5.07; N 11.13.
All the synthesized compounds were colorless or
off-white crystalline substances which melted in
a fairly narrow temperature range. Their structure was
confirmed by the analytical data and 1H NMR spectra.
Compounds Ib, IIa, and IIb were synthesized in
a similar way.
1-(2-Cyanoethyl)-N-(3,4-dimethoxybenzyl)-4-hy-
droxy-2-oxo-1,2-dihydroquinoline-3-carboxamide
(Ib). Yield 95%, off-white crystals, mp 154–156°C
(from aqueous ethanol), Rf 0.65. 1H NMR spectrum, δ,
ppm: 2.88 t (2H, CH2CN, J = 7.0 Hz), 3.79 s and
3.81 s (3H each, OCH3), 4.53 d (2H, NHCH2, J =
5.7 Hz), 4.57 t (2H, 1-CH2, J = 7.0 Hz), 6.86 d (1H,
6′-H, J = 8.2 Hz), 6.91 d (1H, 5′-N, J = 8.2 Hz), 6.96 s
(1H, 2′-H), 7.37 t (1H, 6-H, J = 6.5 Hz), 7.79–7.76 m
(2H, 7-H, 8-H), 8.16 d (1H, 5-H, J = 8.0 Hz), 10.48 t
(1H, 3-CONH, J = 5.6 Hz), 17.37 s (1H, 4-OH).
Found, %: C 64.75; H 5.12; N 10.22. C22H21N3O5. Cal-
culated, %: C 64.86; H 5.20; N 10.31.
The analgesic activity of nitriles I and II, amides
IV and V, and acids VII–IX was studied in 18–23-g
white mice using standard acetic acid writhing model
[8]. The compounds were tested via peroral adminis-
tration at a dose of 5 mg/kg as a fine aqueous suspen-
sion stabilized by Tween 80. Diclofenac [9] was used
as reference at the same dose [10]. The results showed
that the acids were generally the least active in the
series nitrile > amide > acid. In some cases, amides
displayed higher analgesic effect as compared to their
synthetic precursors. Therefore, it is reasonable to
search for potential analgesics among 1-(2-cyanoethyl)
and 1-(2-carbamoylethyl) derivatives within the exam-
ined series of compounds. Lower acidity of amides and
nitriles as compared to the corresponding carboxylic
acids reduces the probability for their ulcerogenic
effect which is a serious drawback of many modern
analgesics [9].
1-(2-Cyanoethyl)-4-hydroxy-N-[2-(4-methoxy-
phenyl)ethyl]-2-oxo-1,2-dihydroquinoline-3-carbox-
amide (IIa). Yield 92%, off-white crystals, mp 133–
1
135°C (from aqueous ethanol). H NMR spectrum, δ,
ppm: 2.81 t (2H, CH2Ar, J = 7.2 Hz), 2.89 t (2H,
CH2CN, J = 7.0 Hz), 3.59 q (2H, NHCH2, J = 6.7 Hz),
3.75 s (3H, OCH3), 4.55 t (2H, 1-CH2, J = 7.0 Hz),
6.82 d (2H, 2′-H, 6′-H, J = 8.6 Hz), 7.16 d (2H, 3′-H,
5′-H, J = 8.6 Hz), 7.34 t (1H, 6-H, J = 6.4 Hz), 7.77–
7.73 m (2H, 7-H, 8-H), 8.13 d (1H, 5-H, J = 8.0 Hz),
10.21 t (1H, 3-CONH, J = 5.3 Hz), 17.46 s (1H,
4-OH). Found, %: C 67.43; H 5.34; N 10.85.
C22H21N3O4. Calculated, %: C 67.51; H 5.41; N 10.74.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Mercury-400 spectrometer at 400 MHz from solutions
in DMSO-d6 with tetramethylsilane as internal refer-
ence. Ethyl 1-(2-cyanoethyl)-4-hydroxy-2-oxo-1,2-di-
hydroquinoline-3-carboxylate (III) was synthesized
according to the procedure described in [3]. The prog-
ress of reactions was monitored by TLC using Sorbfil
plates (eluent acetic acid–hexane–diethyl ether, 5:5:7);
spots were visualized by treatment with iodine vapor.
1-(2-Cyanoethyl)-N-[2-(3,4-dimethoxyphenyl)-
ethyl]-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-car-
boxamide (IIb). Yield 90%, off-white crystals,
mp 157–159°C (from aqueous ethanol). 1H NMR spec-
trum, δ, ppm: 2.89 t (2H, CH2CN, J = 6.9 Hz), 2.92 t
(2H, CH2Ar, J = 7.1 Hz), 3.63 q (2H, NHCH2, J =
6.4 Hz), 3.77 s and 3.82 s (3H each, OCH3), 4.57 t
(2H, 1-CH2, J = 6.9 Hz), 6.78 d.d (1H, 6′-H, J = 8.2,
1.7 Hz), 6.82 d (1H, 5′-H, J = 8.2 Hz), 6.85 d (1H,
2′-H, J = 1.7 Hz), 7.36 t (1H, 6-H, J = 6.3 Hz), 7.79–
7.76 m (2H, 7-H, 8-H), 8.15 d (1H, 5-H, J = 8.0 Hz),
10.25 t (1H, 3-CONH, J = 5.3 Hz), 17.50 s (1H,
4-OH). Found, %: C 65.65; H 5.59; N 10.06.
C23H23N3O5. Calculated, %: C 65.55; H 5.50; N 9.97.
1-(2-Cyanoethyl)-4-hydroxy-N-(4-methoxyben-
zyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide
(Ia). 4-Methoxybenzylamine, 1.51 g (0.011 mol), was
added to a solution of 2.86 g (0.01 mol) of compound
III in 20 ml of ethanol, and the mixture was heated for
3 h under reflux. The mixture was cooled, diluted with
100 ml of cold water, and acidified with aqueous HCl
to pH 4. The precipitate was filtered off, washed with
cold water, and dried. Yield 3.62 g (96%), off-white
crystals, mp 149–151°C (from aqueous ethanol),
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UKRAINETS et al.
870
1-(2-Carbamoylethyl)-4-hydroxy-N-(4-methoxy-
7.3 Hz), 6.84 d (2H, 2′-H, 6′-H, J = 8.5 Hz), 7.18 d
(2H, 3′-H, 5′-H, J = 8.5 Hz), 6.95 s (1H, CONH2),
7.34 t (1H, 6-H, J = 7.4 Hz), 7.45 s (1H, CONH2),
7.64 d (1H, 8-H, J = 8.5 Hz), 7.78 t (1H, 7-H, J =
7.6 Hz), 8.08 d (1H, 5-H, J = 8.0 Hz), 10.34 t (1H,
3-CONH, J = 5.2 Hz), 17.42 s (1H, 4-OH). Found, %:
C 64.45; H 5.59; N 10.35. C22H23N3O5. Calculated, %:
C 64.54; H 5.66; N 10.26.
benzyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide
(IVa). A mixture of 3.77 g (0.01 mol) of nitrile Ia and
20 ml of a ~2.8 M solution of HCl in acetic acid with
a low water content (prepared by mixing required
amounts of acetic anhydride and concentrated aqueous
HCl according to the procedure described in [6]) was
heated for 2 h at 80°C. The mixture was cooled and
diluted with 50 ml of cold water, and the precipitate
was filtered off and washed with water. The crude
product was thoroughly ground with 10 ml of ethanol,
and the precipitate was filtered off, washed with
a small amount of cold ethanol, and dried. Yield 2.81 g
(71%), colorless crystals, mp 176–178°C (from
ethanol), Rf 0.13 (cf. Rf 0.88 for diamide VI in the
1-(2-Carbamoylethyl)-N-[2-(3,4-dimethoxyphe-
nyl)ethyl]-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-
carboxamide (Vb). Reaction time 3 h. No diamide VI
was formed, and there was no need of grinding the
crude product with ethanol. Yield 86%, colorless crys-
1
tals, mp 145–147°C (from ethanol). H NMR spec-
trum, δ, ppm: 2.40 t (2H, CH2CO, J = 7.3 Hz), 2.80 t
(2H, CH2Ar, J = 7.0 Hz), 3.58 q (2H, NHCH2, J =
6.2 Hz), 3.69 s and 3.73 s (3H each, OCH3), 4.39 t
(2H, 1-CH2, J = 7.3 Hz), 6.76 d (1H, 6′-H, J = 8.2 Hz),
6.84 d (1H, 5′-H, J = 8.2 Hz), 6.88 s (1H, 2′-H), 6.96 s
(1H, CONH2), 7.34 t (1H, 6-H, J = 7.3 Hz), 7.44 s (1H,
CONH2), 7.65 d (1H, 8-H, J = 8.4 Hz), 7.78 t (1H,
7-H, J = 7.6 Hz), 8.08 d (1H, 5-H, J = 8.1 Hz), 10.36 t
(1H, 3-CONH, J = 5.3 Hz), 17.43 s (1H, 4-OH).
Found, %: C 62.74; H 5.63; N 9.47. C23H25N3O6. Cal-
culated, %: C 62.86; H 5.73; N 9.56.
1
same solvent system). H NMR spectrum, δ, ppm:
2.39 t (2H, CH2CO, J = 7.4 Hz), 3.72 s (3H, OCH3),
4.40 t (2H, 1-CH2, J = 7.4 Hz), 4.50 d (2H, NHCH2,
J = 5.9 Hz), 6.91 d (2H, 2′-H, 6′-H, J = 8.8 Hz), 7.05 s
(1H, CONH2), 7.27 d (2H, 3′-H, 5′-H, J = 8.8 Hz), 7.36 t
(1H, 6-H, J = 7.3 Hz), 7.40 s (1H, CONH2), 7.64 d
(1H, 8-H, J = 8.4 Hz), 7.79 t (1H, 7-H, J = 7.6 Hz),
8.09 d (1H, 5-H, J = 8.0 Hz), 10.60 t (1H, 3-CONH,
J = 5.7 Hz), 17.29 s (1H, 4-OH). Found, %: C 63.87;
H 5.42; N 10.52. C21H21N3O5. Calculated, %: C 63.79;
H 5.35; N 10.63.
3-(3-Carbamoyl-4-hydroxy-2-oxo-1,2-dihydro-
quinolin-1-yl)propanoic acid (VII) was synthesized
from compound Ib as described above for amides V,
the reaction time being 15 h. Yield 91%, colorless
crystals, mp 230–232°C (from ethanol), Rf 0.60.
1H NMR spectrum, δ, ppm: 2.56 t (2H, CH2CO, J =
7.6 Hz), 4.43 t (2H, 1-CH2, J = 7.6 Hz), 7.34 t (1H,
6-H, J = 7.4 Hz), 7.64 d (1H, 8-H, J = 8.6 Hz), 7.78 t
(1H, 7-H, J = 7.7 Hz), 8.08 d (1H, 5-H, J = 8.0 Hz),
8.60 s and 9.59 s (1H each, 3-CONH2), 12.45 br.s (1H,
COOH), 17.86 s (1H, 4-OH). Found, %: C 56.60;
H 4.43; N 10.08. C13H12N2O5. Calculated, %: C 56.52;
H 4.38; N 10.14.
Compounds IVb, Va, and Vb were synthesized in
a similar way.
1-(2-Carbamoylethyl)-4-hydroxy-N-(3,4-dime-
thoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carbox-
amide (IVb). Yield 58%, colorless crystals, mp 181–
1
183°C (from ethanol), Rf 0.16. H NMR spectrum, δ,
ppm: 2.41 t (2H, CH2CO, J = 7.5 Hz), 3.71 s and
3.73 s (3H each, OCH3), 4.40 t (2H, 1-CH2, J =
7.5 Hz), 4.49 d (2H, NHCH2, J = 5.7 Hz), 6.87 d (1H,
6′-H, J = 8.3 Hz), 6.91 d (1H, 5′-H, J = 8.3 Hz), 6.99 s
(1H, CONH2), 6.95 s (1H, 2′-H), 7.35 t (1H, 6-H, J =
7.4 Hz), 7.42 s (1H, CONH2), 7.65 d (1H, 8-H, J =
8.5 Hz), 7.78 t (1H, 7-H, J = 7.7 Hz), 8.08 d (1H, 5-H,
J = 8.0 Hz), 10.59 t (1H, 3-CONH, J = 5.7 Hz), 17.30 s
(1H, 4-OH). Found, %: C 62.18; H 5.36; N 9.74.
C22H23N3O6. Calculated, %: C 62.11; H 5.45; N 9.88.
3-[4-Hydroxy-3-(4-methoxybenzylcarbamoyl)-
2-oxo-1,2-dihydroquinolin-1-yl]propanoic acid
(VIIIa). A mixture of 3.77 g (0.01 mol) of nitrile Ia
and 20 ml of 20% aqueous potassium hydroxide was
heated at the boiling point until ammonia no longer
evolved (4 h). The mixture was cooled and filtered, the
filtrate was acidified with dilute aqueous HCl to pH 3,
and the precipitate was filtered off, washed with water,
dried, and recrystallized from ethanol. Yield 3.29 g
1-(2-Carbamoylethyl)-4-hydroxy-N-[2-(4-me-
thoxyphenyl)ethyl]-2-oxo-1,2-dihydroquinoline-3-
carboxamide (Va). Reaction time 3 h. No diamide VI
was formed, and there was no need of grinding the
crude product with ethanol. Yield 88%, colorless crys-
1
1
tals, mp 139–141°C (from ethanol). H NMR spec-
(83%), colorless crystals, mp 170–172°C. H NMR
trum, δ, ppm: 2.40 t (2H, CH2CO, J = 7.3 Hz), 2.80 t
(2H, CH2Ar, J = 7.1 Hz), 3.56 q (2H, NHCH2, J =
6.3 Hz), 3.70 s (3H, OCH3), 4.40 t (2H, 1-CH2, J =
spectrum, δ, ppm: 2.56 t (2H, CH2CO, J = 7.7 Hz),
3.72 s (3H, OCH3), 4.42 t (2H, 1-CH2, J = 7.7 Hz),
4.50 d (2H, NHCH2, J = 5.8 Hz), 6.91 d (2H, 2′-H,
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TRANSFORMATION OF 3-(3-ARYLALKYLCARBAMOYL-4-HYDROXY-2-OXO-...
871
6′-H, J = 8.5 Hz), 7.26 d (2H, 3′-H, 5′-H, J = 8.5 Hz),
7.34 t (1H, 6-H, J = 7.6 Hz), 7.64 d (1H, 8-H, J =
8.5 Hz), 7.77 t (1H, 7-H, J = 7.6 Hz), 8.07 d (1H, 5-H,
J = 8.0 Hz), 10.56 t (1H, 3-CONH, J = 5.7 Hz),
12.43 br.s (1H, COOH), 17.30 s (1H, 4-OH). Found,
%: C 63.71; H 4.98; N 7.16. C21H20N2O6. Calculated,
%: C 63.63; H 5.09; N 7.07.
J = 5.6 Hz), 12.43 br.s (1H, COOH), 17.44 s (1H,
4-OH). Found, %: C 62.63; H 5.54; N 6.25.
C23H24N2O7. Calculated, %: C 62.72; H 5.49; N 6.36.
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3-[3-(3,4-Dimethoxybenzylcarbamoyl)-4-hy-
droxy-2-oxo-1,2-dihydroquinolin-1-yl]propanoic
acid (VIIIb) was synthesized in a similar way. Yield
80%, colorless crystals, mp 164–166°C (from ethanol).
1H NMR spectrum, δ, ppm: 2.57 t (2H, CH2CO, J =
7.6 Hz), 3.71 s and 3.76 s (3H each, OCH3), 4.44 t
(2H, 1-CH2, J = 7.6 Hz), 4.51 d (2H, NHCH2, J =
5.8 Hz), 6.85 d (1H, 6′-H, J = 8.1 Hz), 6.90 d (1H,
5′-H, J = 8.1 Hz), 6.97 s (1H, 2′-H), 7.33 t (1H, 6-H,
J = 7.5 Hz), 7.63 d (1H, 8-H, J = 8.5 Hz), 7.78 t (1H,
7-H, J = 7.7 Hz), 8.06 d (1H, 5-H, J = 8.0 Hz), 10.50 t
(1H, 3-CONH, J = 5.6 Hz), 12.44 br.s (1H, COOH),
17.36 s (1H, 4-OH). Found, %: C 62.08; H 5.30;
N 6.65. C22H22N2O7. Calculated, %: C 61.97; H 5.20;
N 6.57.
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3-{4-Hydroxy-3-[2-(4-methoxyphenyl)ethylcar-
bamoyl]-2-oxo-1,2-dihydroquinolin-1-yl}propanoic
acid (IXa) was synthesized from nitrile IIa as de-
scribed above for compound V, the reaction time being
15 h. Yield 87%, colorless crystals, mp 146–148°C
(from ethanol). 1H NMR spectrum, δ, ppm: 2.55 t (2H,
CH2CO, J = 7.5 Hz), 2.80 t (2H, CH2Ar, J = 7.0 Hz),
3.55 q (2H, NHCH2, J = 6.9 Hz), 3.70 s (3H, OCH3),
4.42 t (2H, 1-CH2, J = 7.5 Hz), 6.85 d (2H, 2′-H, 6′-H,
J = 8.6 Hz), 7.17 d (2H, 3′-H, 5′-H, J = 8.6 Hz), 7.33 t
(1H, 6-H, J = 7.4 Hz), 7.63 d (1H, 8-H, J = 8.5 Hz),
7.77 t (1H, 7-H, J = 7.7 Hz), 8.06 d (1H, 5-H, J =
7.9 Hz), 10.30 t (1H, 3-CONH, J = 5.6 Hz), 12.41 br.s
(1H, COOH), 17.42 s (1H, 4-OH). Found, %: C 64.47;
H 5.48; N 6.94. C22H22N2O6. Calculated, %: C 64.38;
H 5.40; N 6.83.
7. Ukrainets, I.V., Davidenko, A.A., Mospanova, E.V.,
Sidorenko, L.V., and Svechnikova, E.N., Khim. Getero-
tsikl. Soedin., 2010, p. 706.
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3-{3-[2-(3,4-Dimethoxyphenyl)ethylcarbamoyl]-
4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl}propa-
noic acid (IXb) was synthesized in a similar way.
Yield 84%, colorless crystals, mp 117–119°C (from
1
9. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
ethanol). H NMR spectrum, δ, ppm: 2.56 t (2H,
Moscow: Novaya Volna, 2009, p. 170.
CH2CO, J = 7.4 Hz), 2.80 t (2H, CH2Ar, J = 7.0 Hz),
3.58 q (2H, NHCH2, J = 6.1 Hz), 3.70 s and 3.73 s (3H
each, OCH3), 4.43 t (2H, 1-CH2, J = 7.4 Hz), 6.75 d
(1H, 6′-H, J = 8.1 Hz), 6.85 d (1H, 5′-H, J = 8.1 Hz),
6.88 s (1H, 2′-H), 7.34 t (1H, 6-H, J = 7.4 Hz), 7.65 d
(1H, 8-H, J = 8.5 Hz), 7.78 t (1H, 7-H, J = 7.7 Hz),
8.08 d (1H, 5-H, J = 8.0 Hz), 10.35 t (1H, 3-CONH,
10. Sigidin, Ya.A., Shvarts, G.Ya., Arzamastsev, A.P., and
Liberman, S.S., Lekarstvennaya terapiya vospalitel’-
nogo protsessa (eksperimental’naya i klinicheskaya
farmakologiya protivovospalitel’nykh preparatov) [Drug
Therapy of Inflammatory Process (Experimental and
Clinical Pharmacology of Anti-inflammatory Agents)],
Moscow: Meditsina, 1988, p. 62.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 6 2013