4-Hydroxyquinol-2-ones. 85*. Synthesis of 2-chloro-4- hydroxyquinoline-3-carboxylic acid ethyl ester

Article abstract of DOI:10.1007/s10593-005-0271-8

The behavior of 2-chloro-4-hydroxy- and 4-chloro-2-oxoquinoline-3- carboxylic acids under acid catalyzed esterification conditions with methanol has been studied. A method is proposed for obtaining 2-chloro-4- hydroxyquinoline-3-carboxylic acid ethyl ester.

Full text of DOI:10.1007/s10593-005-0271-8

Chemistry of Heterocyclic Compounds, Vol. 41, No. 8, 2005
4-HYDROXYQUINOL-2-ONES. 85*. SYNTHESIS
OF 2-CHLORO-4-HYDROXYQUINOLINE-
3-CARBOXYLIC ACID ETHYL ESTER
I. V. Ukrainets, O. V. Gorokhova, and L. V. Sidorenko
The behavior of 2-chloro-4-hydroxy- and 4-chloro-2-oxoquinoline-3-carboxylic acids under acid
catalyzed esterification conditions with methanol has been studied. A method is proposed for obtaining
2
-chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester.
Keywords: quinoline-3-carboxylic acid, chloroquinoline, esterification.
While developing methods for obtaining thio analogs of 1H-3-(2-benzimidazolyl)-4-hydroxy-2-
oxoquinoline as one of the possible variants of the synthesis of a 4-hydroxy-2-thio-substituted derivative we
suggested the use of 2-chloro-4-hydroxyquinoline-3-carboxylic acid (1) [2], readily obtained by alkaline
hydrolysis of 2,4-dichloro-3-ethoxycarbonylquinoline (2) [3]. The need to esterify acid 1 was noted due to the
inclination of such compounds to decarboxylate.
However, our attempts to effect this reaction were not crowned with success. As it turned out
esterification of acid 1 with an excess of absolute methyl alcohol in the presence of catalytic amounts of conc.
H SO leads to the formation of the methyl ester of 1H-4-hydroxy-2-oxoquinoline-3-carboxylic acid (3).
2
4
Probably the total amount of water (separated on esterification of the carboxyl group and the residual moisture in
the alcohol) proved to be sufficient to hydrolyze the 2-chloroquinoline to a quinol-2-one, which in general is
characteristic for compounds of this class [4]. At the same time, 4-chloro-2-oxoquinoline-3-carboxylic acid (4)
forms the corresponding 4-chloro-substituted ester 5 under analogous conditions without any difficulty.
Participation of the 4-OH group in the formation of stable intramolecular hydrogen bonds (IMHB)
enabled the synthesis of 3-(2-benzimidazolyl)-2-chloro-4-hydroxyquinoline to be effected by direct treatment of
the 4-hydroxy-2-oxo derivative with phosphorous oxychloride [2]. It is evident that this principle may also be
used to obtain 2-chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester (6), all the more so, since, according to
X-ray structural analysis data, the 4-OH group in 1-R-3-ethoxycarbonyl-4-hydroxy-2-oxoquinolines forms stable
IMHB with the carbonyl oxygen atoms of the ester groupings, while the C=O group in position 2 of the
quinoline ring participates only in the formation of significantly less stable intermolecular hydrogen bonds [5, 6]
(
Scheme 1).
As was shown by the results of our experiments, the 2-chloro-substituted ester 6 is actually formed in
satisfactory yield on short term (no more than 5 min) treatment of 4-hydroxy-2-oxoquinoline 7 with phosphorus
oxychloride. It is interesting to note that after such short interaction the initial ester 7 was not detected in the
reaction mixture, i.e. the exchange of the 2-hydroxy group by halogen takes place unusually readily.
_
*
_
______
For Part 84 see [1].
_________________________________________________________________________________________
National Pharmaceutical University, Kharkov 61002, Ukraine; e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1195-1197, August, 2005. Original article submitted
March 9, 2004.
0
009-3122/05/4108-1019©2005 Springer Science+Business Media, Inc.
1019

Scheme 1
Cl
O
O
Cl
O
O
OMe
OH
MeOH, H+
N
H
N
H
1
. AcONa, AcOH
. KOH, H O
5
4
2
2
OH
O
O
OH
O
Cl
N
O
POCl3,
OEt
OEt
OEt
o
1
00 C
+
N
H
7
N
Cl
Cl
6
2
KOH, H O
2
OH
O
O
OH
O
MeOH, H+
OMe
OH
N
H
N
1
Cl
3
EXPERIMENTAL
1
The H NMR spectra of the synthesized compounds were recorded on a Varian Mercury VX-200
(
200 MHz) instrument, solvent was DMSO-d , internal standard was TMS. The mass spectrum of ester 6 was
6
recorded on a Finnigan MAT Incos 50 quadrupole spectrometer in the complete scanning mode in the range
3-700 m/z, ionization for electron impact was 70 eV, with direct insertion of sample, heating rate was ~5°C/sec.
H-4-Hydroxy-2-oxoquinoline-3-carboxylic Acid Methyl Ester (3). Conc. H SO (3-4 drops) was
3
1
2
4
added to a mixture of 2-chloro-4-hydroxyquinoline-3-carboxylic acid (2.23 g, 0.01 mol) and absolute methyl
alcohol (30 ml), and the mixture was boiled with protection from air moisture until complete solution (10 h). The
mixture was cooled, and diluted with water. The precipitated solid ester 3 was filtered off, washed with water,
1
and dried. Yield 2.08 g (95%); mp 222-224°C (methanol). H NMR spectrum, δ, ppm (J, Hz): 13.41 (1H, s,
OH); 11.58 (1H, s, NH); 7.93 (1H, d, J = 7.8, H-5); 7.64 (1H, t d, J = 7.0 and J = 1.5, H-7); 7.12-7.38 (2H, m, H-
8
, 6); 3.90 (3H, s, CH ). Found, %: C 60.37; H 4.25; N 6.31. C H NO . Calculated, %: C 60.28; H 4.14; N 6.39.
3 11 9 4
1
H-4-Chloro-2-oxoquinoline-3-carboxylic Acid Methyl Ester (5) was obtained from acid 4 by the
1
procedure of the previous experiment. Yield 97%; mp 187-189°C (methanol). H NMR spectrum, δ, ppm
J, Hz); 12.48 (1H, s, NH); 7.92 (1H, d, J = 8.0, H-5); 7.70 (1H, td, J = 8.0 and J = 1.8, H-7), 7.27-7.48 (2H, m,
H-8, 6); 3.83 (3H, s, CH ). Found, %: C 55.52; H 3.51; N 5.97. C H ClNO . Calculated, %: C 55.60; H 3.39;
(
3
11
8
3
N 5.88.
2
-Chloro-4-hydroxyquinoline-3-carboxylic Acid Ethyl Ester (6). A mixture of ester 7 (2.33 g,
0
.01 mol) and POCl (10 ml) was maintained at 100°C for 5 min, after which the mixture was poured directly
3
onto finely powdered ice. After decomposition of the excess of POCl , Na CO was added with thorough mixing
3
2
3
to the reaction mixture to pH 8, and the mixture was filtered. The solid on the filter was washed with water, and
dried. The 2,4-dichloro-substituted ester 2 was obtained (0.32 g, 12%), the properties of which were identical to
1
020

those described previously in [3]. Acetic acid was added to the filtrate to pH 4.5-5.0. The precipitated solid ester
1
6
was filtered off, washed with water, and dried. Yield 1.69 g (67%); mp 171-173°C (ethanol). H NMR
spectrum, δ, ppm (J, Hz): 12.98 (1H, s, OH); 8.12 (1H, dd, J = 8.0 and J = 1.8, H-5); 7.78 (1H, td, J = 8.1 and
J = 1.8, H-7); 7.62 (1H, dd, J = 8.5 and J = 2.0, H-8); 7.46 (1H, td, J = 7.0 and J = 2.0, H-6); 4 29 (2H, q,
+
J = 7.0, CH CH ); 1.30 (3H, t, J = 7.0, CH CH ). Mass spectrum, m/z (I , %): 251 (28) [M] , 205 (100)
[
2
3
2
3
rel
+
35
M-EtOH] , 170 (84), 114 (33). Values of m/z are given for the Cl isotope. Found, %: C 57.18; H 3.91; N 5.50.
C H ClNO . Calculated, %: C 57.27; H 4.00; N 5.58.
1
2
10
3
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1
2
.
.
I. V. Ukrainets, L. V. Sidorenko, and O. V. Gorokhova, Khim. Geterotsikl. Soedin., 1060 (2004).
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3
4
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.
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1
021