Synthesis of 2-hydroxyethyl and 2-chloroethyl esters of 1-alkyl (1,2-dialkyl)-4-Aminoimidazolyl-5-carboxylic acids

Full text of DOI:10.1023/A:1005269424291

Pharmaceutical Chemistry Journal
Vol. 34, No. 7, 2000
DRUG SYNTHESIS METHODS
AND MANUFACTURING TECHNOLOGY
SYNTHESIS OF 2-HYDROXYETHYL AND
2-CHLOROETHYL ESTERS OF 1-ALKYL(1,2-DIALKYL)-
4-AMINOIMIDAZOLYL-5-CARBOXYLIC ACIDS
L. A. Reznichenko,1 E. V. Aleksandrova,2 and P. M. Kochergin 3
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 34, No. 7, pp. 31 – 33, July, 2000.
Original article submitted November 22, 1999.
The esters of 1-alkyl(1,2-dialkyl)-4-aminoimidazolyl-5-car-
boxylic acids belong to the group of insufficiently studied com-
pounds [1, 2]. In the search for new biologically active sub-
stances, it was of interest to synthesize and characterize some of
the 4-aminoimidazolyl-5-carboxylic acid esters containing
2-hydroxyethyl and 2-chloroethyl groups in the ester chains.
The initial (1-methyl)- and (1-isobutyl-2-isopropyl)-4-
nitroimidazolyl-5-carboxylic acids (I, II) were obtained us-
ing well-known methods [1, 3, 4] and converted into the cor-
responding chloroanhydrides (III, IV) as described in [4],
which were used without additional purification in the
esterification reactions with ethylene glycol and ethylene
chlorohydrin.
It was established that the reaction pathways of
chloroanhydrides III and IV with ethylene glycol are rather
ambiguous, leading to mixtures of 1-alkyl(1,2-dialkyl)-4-nit-
roimidazolyl-5-carboxylic acid 2-hydroxyethyl esters (V, VI)
with the corresponding diimidazolyl glycol esters (VII, VIII).
We succeeded in separating these products by means of frac-
tional crystallization from lower alcohols. The maximum
yields of esters V and VI (60 and 90%, respectively) were
obtained using 5 mole of ethylene glycol per mole of chloro-
anhydride III or IV.
The reactions of chloroanhydrides III and IV with ethyl-
ene chlorohydrin proceed by a unique pathway, leading to
the corresponding chloroethyl esters of (1-methyl)- and
(1-isobutyl-2-isopropyl)-4-nitroimidazolyl-5-carboxylic ac-
ids (IX, X) with a yield of 85%. Alternatively, the same
2-chloroethyl esters IX and X (yield of 77 and 57%) were
obtained by reactions of 2-hydroxyethyl esters V, VI with
thionyl chloride.
R
R
COCl
COOH
N
N
HOCH2CH2OH
SOCl2
R'
R'
N
N
NO2
NO2
III, IV
I, II
R
COOCH2CH2OH
N
N
R
COOCH2CH2Cl
+
N
N
R'
HOCH2CH2Cl
III, IV
R'
NO2
V, VI
NO2
IX, X
R
R
COOCH2CH2OOC
SOCl2
N
N
N
V, VI
R'
R'
+
N
The hydrogenation of methyl and ethyl esters of
(1-methyl)- and (1-isobutyl-2-isopropyl)-4-nitroimidazolyl-
5-carboxylic acids in the presence of various catalysts (car-
bon-supported palladium chloride, Raney nickel, etc.) was
originally described by Mann and Porter [1]. We established
that hydrogenation of 4-nitroimidazolyl-5-carboxylic acid
esters (VI, IX, X) to the corresponding amines (XI – XIII) is
most readily performed with hydrogen at atmospheric pres-
sure and room temperature in a lower alcohol medium in the
NO2
O2N
VII, VIII
I, III, V, VII: R = Me, R¢ = H;
II, IV, VI, VIII: R = Me2CHCH2, R¢ = Me2CH.
1
Pharmaceutical Chemistry Research Institute, Novokuznetsk, Russia.
State Medical University, Zaporozh’e, Ukraine.
2
3
Center for Drug Chemistry–All-Russia Research Institute of Pharmaceuti-
cal Chemistry, Moscow, Russia.
368
0091-150X/00/3407-0368$25.00 © 2000 Kluwer Academic/Plenum Publishers

Synthesis of 2-Hydroxyethyl and 2-Chloroethyl Esters
369
presence of a catalyst (5% palladium oxide supported on car-
bon). The yield of 1-alkyl(1,2-dialkyl)-4-nitroimidazolyl-5-
carboxylic acid esters was 50 – 90%; compound XIII was
also obtained at a 80% yield using a reaction of ester XI with
thionyl chloride in benzene.
chloride in anhydrous benzene [4]. Upon evaporation of the
residual benzene and excess thionyl chloride in vacuum, the
technical-purity chloroanhydrides III and IV were used in
esterification reactions with ethylene glycol and ethylene
chlorohydrin. The yields of compounds V – X were calcu-
lated with respect to the initial acids I and II.
R
COOCH2CH2OH
N
N
1-Methyl-4-nitroimidazolyl-5-carboxylic acid 2-hyd-
roxyethyl ester (V). To unpurified chloroanhydride III, ob-
tained from 3.4 g (0.02 mole) of acid I, was added 6.3 g
(0.1 mole) of ethylene glycol. The mixture was heated to
80 – 90°C, kept until obtaining a transparent solution,
cooled, and diluted with 30 ml of water. The precipitated vis-
cous deposit exhibited slow crystallization in the course of
trituration. The deposit was separated by filtration, washed
with water, and dried to obtain 4.0 g of a substance melting at
56 – 69°C. TLC in system 1 showed this substance to be a
mixture of two compounds. Double (the first stage with char-
coal) crystallization from a 60% aqueous isopropanol solu-
tion yielded 2.6 g (60%) of pure ester V; m.p., 60 – 62°C; Rf,
0.47. Upon evaporating isopropanol from the mother liquor,
the residue was washed with ether and recrystallized from a
60% aqueous isoropanol solution to obtain 0.4 g (10%) of a
product melting at 75 – 78°C, identified as compound VII;
Rf, 0.75.
H2
R'
VI
PdO/C
NH2
XI
R
COOCH2CH2Cl
N
N
H2
R'
IX, X
PdO/C
NH2
XII, XIII
XI, XIII: R = Me2CHCH2, R¢ = Me2CH;
XII: R = Me, R¢ = H.
The purity of the previously unreported compounds
(V – XIII) was checked by TLC. The proposed structures
and compositions were confirmed by the results of elemental
1
analyses, by the data of IR, H NMR, and mass-spectromet-
ric measurements, and by the counter synthesis of com-
pounds IX, X, and XIII.
1-Isobutyl-2-isopropyl-4-nitroimidazolyl-5-carboxylic
acid 2-hydroxyethyl ester (VI). Compound VI was ob-
tained by a method analogous to that employed for the syn-
thesis of compound V, proceeding from chloroanhydride IV,
prepared using 2.5 g (0.01 mole) of acid II, and 3 ml
(0.05 mole) of ethylene glycol. The yield of technical-purity
compound VI is 2.78 g (by TLC data, the product contains a
certain amount of compound VIII). Recrystallization from an
aqueous methanol solution yields pure compound VI; m.p.,
103 – 104°C; Rf, 0.75 (system 2).
1,2-Di(1-methyl-4-nitroimidazolyl-5-carboxy)ethylene
glycol (VII). Compound VII was obtained by a method anal-
ogous to that employed for the synthesis of compound V,
proceeding from equimolar amounts (0.01 mole) of chloro-
anhydride III and ethylene glycol; yield, 0.65 g (20%); m.p.,
75 – 78°C (60% aqueous isopropanol); Rf, 0.75 (system 1). A
mixture of this product with compound VI obtained as de-
scribed above shows no evidence of depression in the melt-
ing temperature; the IR spectra of compounds VI and VII are
identical.
The IR spectrum of 1,2-diimidazolyl glycol VIII (in con-
trast to the spectrum of ester VI) contains no absorption
bands due to OH groups in the region of 3450 cm – 1, while
the mass spectrum of the former compound displays a peak
due to the molecular ion with m/z = 536.
EXPERIMENTAL PART
The IR spectra were recorded on a UR-20 spectrophoto-
meter (Germany) using samples pelletized with KBr. The
mass spectra were obtained with a Varian MAT-112 spec-
trometer with direct sample injection into the ion source, op-
erated at an ionization chamber temperature of 180°C and an
ionizing electron beam energy of 70 eV. The melting temper-
atures were determined using a heating table of the Boetius
type.
The course of the reactions was monitored and the reac-
tion product purity was checked by TLC on Silufol UV-254
plates eluted in the benzene – dioxane mixtures 1 : 1 (system 1)
and 1 : 10 (system 2). The spots were visualized by exposure
to iodine vapor or under UV illumination.
1,2-Di(1-isobutyl-2-isopropyl-4-nitroimidazolyl-5-car
boxylic acid 2-hydroxyethyl ester (VIII). Compound VIII
was obtained by a method analogous to that employed for the
synthesis of compound VII, proceeding from chloroanhydri-
de IV, prepared using 1.0 g (4 mmole) of acid II, and 0.25 g
(4 mmole) of ethylene glycol. TLC of the technical-purity
compound VIII shows that the product represents a mixture
of compounds VI and VIII in approximately equal amounts.
The mixture was separated by means of fractional crystalli-
zation from isopropanol. The yield of pure compound VIII,
0.5 g (24%); Rf, 0.89 (system 2).
The results of elemental analyses for the previously unre-
ported compounds V – VIII, XI (C, H, N) and IX, X, XII,
XIII (C, H, N, Cl) agree with the data calculated using their
empirical formulas. The yields and physicochemical charac-
teristics of compounds V – XIII are presented in Table 1.
The initial (1-methyl)- and (1-isobutyl-2-isopropyl)-4-ni-
troimidazolyl-5-carboxylic acids (I, II) were obtained as de-
scribed in [3, 4]. The acids were converted into the corre-
sponding chloroanhydrides (III, IV) by treating with thionyl

370
L. A. Reznichenko et al.
TABLE 1. Yields and Physicochemical Characteristics of Compounds V – XIII
IR spectrum: n, cm – 1
Com-
pound
Empirical
formula
R
R¢
M.p., °C
M+
Yield, %
C–O–C
NO2
CO
OH
NH2
V
C7H9N3O5
CH3
H
60 – 62
…
1120
1080
1140
1105
1010
1105
1110
–
1330, 1520
1350, 1520
1740
1740
3400
3450
–
–
60
93
VI
C13H21N3O5
i-C4H9
i-C3H7
103 – 104
299
VII
VIII
IX
C12H12N6O8
C24H36N6O8
C7H8ClN3O4
C13H20ClN3O4
C13H23N3O3
C7H10ClN3O2
CH3
i-C4H9
CH3
H
i-C3H7
H
75 – 78
175 – 177
76 – 78
…
1340, 1500
1310, 1510
1320, 1510
1330, 1510
–
1740
1790
1750
1750
1680
1690
–
–
10 – 20
24
536
233
…
–
–
–
–
77 – 85
57 – 86
50
X
i-C4H9
i-C4H9
CH3
i-C3H7
i-C3H7
H
55 – 57
–
–
XI
103 – 104
109 – 111
269
203
3430
–
3320
3310,
3380
3160,
3280,
3460
XII
–
–
87
XIII
C13H22ClN3O2
i-C4H9
i-C3H7
153 – 154
287
–
–
1680
–
80 – 90
1-Alkyl(1,2-dialkyl)-4-aminoimidazolyl-5-carboxylic
mixture was hydrogenated with hydrogen at atmospheric
pressure and room temperature until gas absorption ceased.
Then the catalyst was separated by filtration and washed on
acid 2-chloroethyl esters (IX, X).
M e t h o d A . To technical-purity chloroanhydride III,
prepared using 2.0 g (0.012 mole) of acid I, was added
1.5 ml (0.02 mole) of ethylene chlorohydrin. The mixture
was heated for 5 min at 90 – 100°C, cooled, and diluted with
20 ml of water. The precipitate was separated by filtration,
washed with water, and dried to obtain 2.3 g (85%) of com-
pound IX. An analogous procedure (proceeding from acid II
via chloroanhydride IV) was used to obtain ester X at an
86% yield.
the filter with methanol (2 ´ 8 ml). The filtrate was evapo-
rated in vacuum. The residue was washed with water and
dried to obtain amino compounds XI – XIII.
M e t h o d B . A mixture of 2.7 g (0.01 mole) of amino
compound XI and 5 ml (0.07 mole of thionyl chloride was
boiled for 10 min, cooled, and poured into 50 ml of water
with stirring. The residue was separated by filtration, washed
with water, and dried to obtain 2.3 g (80%) of compound
XIII. A mixture of this product with the sample obtained by
method A shows no evidence of depression in the melting
temperature; the IR spectra of the two samples of compound
XIII are identical.
M e t h o d B . A mixture of 2.15 g (0.01 mole) of ester V
and 5 ml of thionyl chloride was heated for 30 min at
50 – 60°C. Upon evaporation of the residual benzene and ex-
cess thionyl chloride, the residue was washed with water and
dried to obtain 1.8 g (77%) of ester IX; m.p., 76 – 78°C
(aqueous methanol). A mixture of this product with the sam-
ple obtained by method A shows no evidence of depression
in the melting temperature; the IR spectra of the two samples
of compound IX are identical. An analogous procedure (pro-
ceeding from ester VI and thionyl chloride) was used to ob-
tain ester X at a 57% yield (the reaction is conducted at room
temperature).
The amino compounds XI – XIII appear as colorless
crystalline substances insoluble in water and soluble in or-
ganic solvents and in mineral acid solutions. For analytical
purposes, the products were purified by recrystallization
from aqueous methanol (compound XI), methanol (XII), and
aqueous 2-propanol (XIII).
4-Nitroimidazolyl-5-carboxylic acid esters V – X appear
as pale-yellow crystalline substances insoluble in water and
soluble in most organic solvents. Esters V – X are uncapable
of forming hydrochlorides and picrates.
REFERENCES
1. F. G. Mann and J. V. G. Porter, J. Chem. Soc., 751 – 760 (1945).
2. R. N. Gireva,
P. M. Kochergin, Khim.-Farm. Zh., 8(11), 25 – 29 (1974).
G. A. Aleshina, L.
A. Reznichenko,
and
1-Alkyl(1,2-dialkyl)-4-aminoimidazolyl-5-carboxylic
acid esters (XI – XIII).
3. J. Sarasin and E. Wegmann, Helv. Chim. Acta, 7, 713 – 719
(1924).
M e t h o d A . To a solution of 0.01 mole of initial nitro
compound VI, IX, or X in 50 ml of methanol was added
1.0 g of 5% palladium oxide supported on carbon and the
4. R. N. Gireva, G. A. Aleshina, L. A. Reznichenko, and
P. M. Kochergin, Khim.-Farm. Zh., 8(10), 24 – 29 (1974).