Derivatives of hydroxybenzoic acids and their salts: Synthesis and pharmacological activity

Article abstract of DOI:10.1134/S1070363215020073

Preparation of salicylic and acetylsalicylic acid esters via esterification and alkylation of the salts with alkyl halides has been examined. The effect of the alkylating agent nature and the reaction conditions (catalyst and solvent) on yield of the target products has been elucidated. The biological properties of the resulting compounds can be modified by varying the nature of the alkali metal cation (K⁺, Na⁺, or Li⁺) of the salt form of hydroxybenzamides.

Full text of DOI:10.1134/S1070363215020073

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 2, pp. 387–391. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © A.K. Brel’, S.V. Lisina, Yu.N. Budaeva, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 2, pp. 213–218.
To the 80th Anniversary of B.I. Ionin
Derivatives of Hydroxybenzoic Acids and Their Salts:
Synthesis and Pharmacological Activity
A. K. Brel’, S. V. Lisina, and Yu. N. Budaeva
Volgograd State Medical University, pl. Pavshikh Bortsov 1, Volgograd, 1400131 Russia
e-mail: svlisina@gmail.com
Received December 8, 2014
Abstract—Preparation of salicylic and acetylsalicylic acid esters via esterification and alkylation of the salts
with alkyl halides has been examined. The effect of the alkylating agent nature and the reaction conditions
(
catalyst and solvent) on yield of the target products has been elucidated. The biological properties of the
+
+
+
resulting compounds can be modified by varying the nature of the alkali metal cation (K , Na , or Li ) of the
salt form of hydroxybenzamides.
Keywords: hydroxybenzoic acid, esterification, alkylation, Schotten–Baumann reaction, pharmacological
activity, toxicity
DOI: 10.1134/S1070363215020073
The key strategy in synthesis of novel drugs
involve modification and utilization of molecular
moieties capable of interacting with several receptors
and, therefore, exhibiting a complex of pharma-
cological properties. Nowadays a popular approach to
develop new biologically active compounds consists in
preparation of structures containing pharmacophore
groups [1] and using as simple equipment as possible.
and examine their biological activity. Considering the
low water solubility and consequent poor bio-
availability of those compounds, we prepared their
water-soluble salts and demonstrated the possibility of
changing their biological properties by varying the
+
+
+
nature of the alkali metal cation (K , Na , or Li ).
The new derivatives of hydroxybenzoic acids were
synthesized according to the Scheme 1.
Such
promising
structures
may
contain
1
hydroxybenzoic acid [2–5], amino acids [6–8], and
organophosphorus [9] fragments. Since recently,
pharmaceutical companies have been particularly
focused on development of drugs based on derivatives
of hydroxybenzoic acids [10, 11].
The products structures were confirmed by
NMR spectroscopy data.
H
In the course of the study we elaborated the optimal
conditions for preparation of esters of salicylic and
acetylsalicylic acids via esterification with aliphatic
alcohols and their derivatives. The conventional
method of esterification in the presence of acid
In view of the above, the aim of this study was to
synthesize new derivatives of hydroxybenzoic acids
Scheme 1.
O
X
1
O
X2
C
COOH
OH
C
(
1) SOCl2
ROH
(2) NH R, NaOH
2
X
X
p-TsOH
Х = ОН, OC(O)CH
3
; X
1 2
= OR, X = NHR.
3
87

3
88
BREL’ et al.
Scheme 2.
OH
OH
COOR
+
ROH
+
H O
2
OH
COOH
p-TsOH
COOCH CH P(O)(OR)
2
2
2
+
HOCH CH P(O)(OR)
2 2
2
+
H O
2
Scheme 3.
OH
OH
O
COOK
DMF
O
CH CH CH2
2
+
H C CH CH2
+ KBr
2
Br
catalysts possesses a number of drawbacks and
limitations, including formation of side products (via
alcohol dehydration or resin formation) and low
reaction rate [12]. Other attractive reaction routes may
either use alternative catalysts for esterification, or be
based on alkylation of salicylic and acetylsalicylic acid
salts. Studies on preparation of salicylic acid esters via
esterification or alkylation of salicylic and acetyl-
salicylic acid salts [13–15] revealed that using p-
toluenesulfonic acid (p-TsOH) as catalyst significantly
accelerated the process and enhanced the yield of
target product (Scheme 2).
elucidate the optimal conditions of alkylation. As
expected, the yield of target ester was higher in the
case of potassium salicylate as compared to sodium
salicylate; bromides were more reactive in nucleophilic
substitution reactions as compared with chlorides.
Alkylation was favored by polar aprotic solvents
efficiently solvating the metal cations. We elucidated
the solvent nature effect on the yield of the target
product using alkylation of potassium salicylate with
allyl bromide as model reaction [16] (Scheme 3).
Table 1 summarizes the results of alkylation at 65°C
in four different aprotic solvents. Dielectric constant
An alternative method of the esters synthesis
consists in alkylation of the corresponding acid salts
with alkyl halides. Herein, we report the first
experimental study of the pseudo-first-order kinetics of
the reaction (salt : allyl bromide = 1 : 60) in order to
(ε) and donor number (DN) of the solvent were clearly
correlated with the yield of the target product.
Based on those data, N,N-dimethylformamide was
chosen as the best solvent to determine the kinetic and
Table 1. Influence of the solvent nature on yield of the
Table 2. Kinetic and activation parameters of the reaction
target allyl salicylate (65°C)
Temperature,
Rate constant,
Mean-square
deviation
–1
°
C
min
Donor
Dielectric constant
Yield of allyl
salicylate, %
Solvent
number
DN)
(
ε)
15
0.0007
0.0022
0.0060
0.0086
0.0126
0.0205
0.0001
0.0001
0.0004
0.0004
0.0009
0.0014
(
2
3
4
5
5
5
5
5
DMF
36.7
2.1
26.6
14.8
17.0
–
84
52
65
19
Dioxane
Acetone
Toluene
20.8
2.4
65
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 2 2015

DERIVATIVES OF HYDROXYBENZOIC ACIDS AND THEIR SALTS
389
–3
activation parameters of the reaction from temperature
dependence of the rate constant; alkylation of potas-
sium salicylate with allyl bromide was again used as
model reaction.
1
/T, 10
ln k
The least-squares estimation of the kinetic and
activation parameters gave Е = 51.52 kJ/mol, ln А =
6
–1
1
4.51, and А = 2.0 × 10 s (see figure and Table 2).
Density functional theory method at the B3LYP/
LanL2DZ level was applied to examine the S 1 and
N
SN2 mechanisms of t potassium salicylate reaction with
allyl bromide taken in a 1 : 1 ratio, as well as to
elucidate the influence of the solvent nature on spatial
and energetic characteristics of the reaction. The
results of simulation of the possible S 1 and S 2
Determination of the activation parameters of the studied
reaction.
N
N
reaction pathways have been presented in [11, 18]. The
SN1 pathway involves formation of the allyl cation via
heterolytic cleavage of the C–Br bond, followed by the
interaction with potassium salicylate. On the contrary,
various methods are available to do so [13, 19]. In this
work, we employed the Schotten–Baumann reaction,
the interaction of hydroxybenzoic acid chloro-
anhydride with amino acids (glycine, γ-aminobutyric
acid, or taurine) and morpholine. Sodium hydroxide or
carbonate served as base binding the evolving
hydrogen chloride. The reactions were carried out in
water or in a water–DMF mixture (1 : 3). It was found
that the yield of the target reaction products in a
strongly alkaline aqueous medium was slightly higher
than that achieved using of a water–DMF mixture in
the presence of sodium carbonate [12] (Scheme 4).
in the course of the S 2 reaction allyl bromide is
N
attacked by desolvated carboxylate anion to form a
transition state. The simulation has shown that, for the
studied reaction the S 2 mechanism is energetically
N
more favorable both in the gas phase and considering
the solvent effect. Furthermore, with DMF and acetone
as solvents, the activation barriers are lower, which is
supported by the experimental data.
The prepared salicylates included derivatives showing
a stronger prolonged antipyretic effect and tenfold
lower toxicity (Table 3) as compared to aspirin, acute
In order to prepare water-soluble biologically
accessible forms of the synthesized amides and to
elucidate the influence of the cation nature on the
pharmacological activity, we obtained potassium,
–1
toxicity of the latter being of ≈250 mg kg [14, 16, 17].
Another route we considered for modification of
hydroxybenzoic acids was synthesis of their amides,
Scheme 4.
O
O
NHCH CH SO H
O
Cl
O
O
N
2
2
3
C
HN
O
H NCH CH SO H
2
2
2
3
X
X
X
−
HCl
NH(CH ) COOH
2
n
H N(CH ) COOH
2
2 n
−
HCl
X
Х = 2-ОН, 3-ОН, 4-ОН, 4-ОС(О)СН
3
; n = 1, 3.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 2 2015

3
90
BREL’ et al.
Table 3. Pharmacological activity and acute toxicity of selected salicylates
Compound Pharmacological activity
Glycidyl salicylate
LD50, mg/kg
> 2500
Antipyretic, antibacterial (S. aureus)
Dimethyl-β-(O-salicyloyl)ethylphosphonate
Diethyl-β-(O-salicyloyl)ethylphosphonate
Antipyretic, antibacterial (S. Aureus, E. coli)
Antipyretic, antibacterial (S. Aureus, E. coli)
> 2000
> 2000
Diisopropyl-β-(O-salicyloyl)ethylphosphonate Antipyretic, antibacterial (S. Aureus, E. coli)
≈ 2000
Butyl salicylate
Antipyretic, antibacterial (S. aureus)
Antipyretic, antibacterial (S. aureus)
> 3500
Allyl acetylsalicylate
> 2500
Table 4. Pharmacological activity and acute toxicity of selected hydroxybenzamides
Compound
Cation
Pharmacological activity
LD50, mg/kg
+
N-(2-Hydroxybenzoyl)morpholine
Li
Psychotropic (antidepressant, nootropic)
1473 (i. p.)
+
Na
Psychotropic (anxiolytic, nootropic), analgesic,
2550 (i. p.)
antibacterial (S. aureus, E. coli)
>5000 (per oz.)
+
N-[(2-Hydroxybenzoyl)amino]ethanoic acid
Na
Cerebroprotective, psychotropic
Psychotropic (antidepressant, nootropic)
Psychotropic (anxiolytic, nootropic)
Cerebroprotective, psychotropic
Cerebroprotective, psychotropic
Psychotropic (anxiolytic, nootropic)
Cerebroprotective, psychotropic
1236 (i. p.)
2341 (i. p.)
1346 (i. p.)
2689 (i. p.)
2543 (i. p.)
3751 (i. p.)
2259 (i. p.)
+
Li
+
4
-[(2-Hydroxybenzoyl)amino]butanoic acid
Li
+
N-[(3-Hydroxybenzoyl)amino]ethanoic acid
N-[(4-Acetoxybenzoyl)amino]ethanoic acid
Na
+
Na
+
Li
+
4
-[(4-Acetoxybenzoyl)amino]butanoic acid
Н
lithium, and sodium salts of the amides [20–23]. The
salts of hydroxybenzoic acid amides with amino acids
have not been described so far. When performing the
reaction, we had to consider the salts possible
hydrolysis. We proposed the following technique in an
attempt to increase the salts yield: the reaction of
potassium ethylate, sodium ethylate, or lithium
hydroxide with N-hydroxybenzoyl derivatives of
amino acids was carried out in refluxing benzene with
removal of the resulting water. The technique allowed
significant acceleration of the reaction and increasing
the yields of the target salts. The content of the alkali
metal ions in the resulting salts was determined via
potentiometry with ion-selective electrodes.
and nootropic effects, as well as psychostimulating
effect combined with analgesic [20–24] and anti-
lysozyme activities [25]. Some of the tested com-
pounds showed enhanced cerebroprotective activity as
compared with the reference drugs (piracetam and
mexidol) while causing the less postischemic
neurological damage (as demonstrated with the animal
models study). The intraperitoneal injection of the salts
showed LD50 >1 g/kg, and the products could be
classified as moderately toxic compounds (Table 4).
Selected hydroxybenzamides were also tested for
antiviral activity. The antiviral properties were
examined in vitro using the standard protocol [19] at
Rega Institute for Medical Research (Belgium) over
the 0.01–250 μmol/L concentration range. The com-
pounds were characterized by effective concentration
(EC ) at which they provide 50% protection of the
The prepared compounds were tested for
psychotropic activity. The sodium salts formed by the
amides of salicylic acid with amino acids produced
negligible psychotropic action, and the sodium salts of
other nitrogen-containing derivatives showed only a
general psychostimulating effect. Some of the lithium
salts revealed antidepressant (anxiolytic), anti-amnesic,
5
0
infected cells against virus-induced cytopathic effect,
the inhibitory (cytotoxic) concentration for uninfected
cells (IC ), and the selectivity index (IC /EC ). Our
5
0
50
50
data indicated the lack of pronounced antiviral activity
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 2 2015

DERIVATIVES OF HYDROXYBENZOIC ACIDS AND THEIR SALTS
391
for the tested compounds. Lithium salt of N-
salicyloylglycine exhibited antiviral activity against
herpes simplex virus via inhibiting the virus-induced
cytopathic effect by 50% when in the 50 μmol/L
concentration. Sodium salts of N-salicyloylglycine,
salicyloylmorpholide, and 4-(N-salicyloylamino)-
butanoic acid inhibited cancer cells proliferation.
5. Brel’, A.K., Lisina, S.V., Spasov, A.A., and Mazanova, L.S.,
Butlerov. Soobshch., 2009, vol. 15, no. 1, p. 50.
6. Huth, A., Seidelmann, D., and Thierauch, K.-H., RF
Patent 2353618, Byull. Izobret., 2009, no. 12.
7
8
9
. Duncan, S.M., Osuma, A.T., Daigneault, S., and
Bernatchez, M., US Patent 7294740, 2007.
. Deason, M.E. and Whitten, K.R., US Patent 6407285,
2
002.
To conclude, kinetic features of potassium
salicylate alkylation with allyl bromide in aprotic polar
solvents were examined, and the kinetic parameters
corresponding to the pseudo-first-order reaction rate
order in the presence of a large excess of allyl bromide
were determined. Quantum-chemical simulation of the
energy parameters showed that the reaction followed
. Yudelevich, V.A. and Ionin, B.I., Fosfororganicheskie
lekarstvennye preparaty (Organophosphorus Drugs), St.
Petersburg: Theza, 1995.
1
0. Yudelevich, V.A., Shneider, M.A., Belakhov, V.V.,
Komarov, E.V., Ionin, B.I., Antonova, T.I., Brel’, A.K.,
and Lebedev, V.B., Pharm. Chem. J., 1985, vol. 19,
no. 11, p. 780.
the S 2 mechanism at the 1 : 1 reactant ratio. The
11. Lisina, S.V., Cand. Sci. (Chem.) Dissertation, Volgograd,
N
simulation data showed that using DMF as the solvent
led to increased reactivity of carboxylate anion in the
studied reaction, coinciding with the experimental data.
2009.
12. Budaeva, Yu.N., Cand. Sci. (Chem.) Dissertation,
Volgograd, 2013.
1
3. Tietze, L.F. and Eicher, T., Reaktionen und Synthesen im
organisch-chemischen Praktikum und Forschun-
gslaboratorium, Stuttgart: Georg Thieme, 1991.
4. Lisina, S.V., Brel’, A.K., Spasov, A.A., and Mazanova, L.S.,
Pharm. Chem. J., 2008, vol. 42, no. 10, p. 574.
5. Brel, A.K. and Lisina, S.V., Malays. J. Sci., 2014,
vol. 33, no. 1, p. 106.
6. Brel’, A.K., Lisina, S.V., Spasov, A.A., and Mazanova, L.S.,
RF Patent 2420532, Byull. Izobret., 2011, no. 16.
7. Brel’, A.K., Lisina, S.V., Spasov, A.A., and Mazanova, L.S.,
It was found that the yield of hydroxybenzoic acid
amides in a strongly alkaline aqueous medium ex-
ceeded that achieved when using DMF in the presence
of sodium carbonate. The alkali metal salts could be
prepared in up to 95% yield via the reaction of lithium
hydroxide (sodium ethylate or potassium ethylate) with
hydroxybenzamide in refluxing benzene.
1
1
1
1
1
The salicylates, both phosphorus-containing,
synthesized for the first time, as well as already known
butyl salicylate and allyl acetylsalicylate are highly
attractive candidates for antipyretics development. Due
to the pronounced psychotropic and cerebroprotective
activity, potassium, lithium, and sodium salts of 2-, 3-,
and 4-hydroxybenzamides are promising for pharma-
ceutical applications.
RF Patent 2382763, Byull. Izobret., 2010, no. 6.
8. Brel’, A.K., Lisina, S.V., Vasil'kova, E.A., Litinskii, A.O.,
and Kamnev, V.V., Butlerov. Soobshch., 2012, vol. 30,
no. 5, p. 60.
1
9. Brel’, A.K., Lisina, S.V., and Salomatina, Yu.N.,
Butlerov. Soobshch., 2012, vol. 32, no. 10, p. 81.
2
0. Brel’, A.K., Lisina, S.V., Kovalev, D.G., Salomatina, Yu.N.,
Bugaeva, L.I., and Myagkova, I.A., RF Patent 2495032,
Byull. Izobret., 2013, no. 28.
ACKNOWLEDGMENTS
This study was financially supported by the
Government of Volgograd Oblast (research project no.
2
2
1. Brel’, A.K., Lisina, S.V., Kovalev, D.G., Salomatina, Yu.N.,
Bugaeva, L.I., and Myagkova, I.A., RF Patent 2495867,
Byull. Izobret., 2013, no. 29.
7
7/3323).
REFERENCES
2. Brel’, A.K., Lisina, S.V., Kovalev, D.G., Salomatina, Yu.N.,
Bugaeva, L.I., and Myagkova, I.A., RF Patent.
1
. Balakin, K.V., Ivanenkov, Ya.A., Skorenko, A.V.,
Kovalenko, S.N., Zhuravel’, I.A., and Chernykh, V.P.,
Ukr. Zh. Org. Khim., 2004, vol. 2, no. 3, p. 48.
2
495866, Byull. Izobret., 2013, no. 29.
23. Brel’, A.K., Lisina, S.V., Kovalev, D.G., Salomatina, Yu.N.,
Bugaeva, L.I., and Myagkova, I.A., RF Patent 2505294,
2
. Mashkovskii, M.D., Lekarstvennye sredstva: posobie
dlya vrachei (Drugs: A Handbook for Physicians),
Moscow: Novaya Volna, 2014, p. 1216.
Byu
ll. Izobret., 2014, no. 3.
24. Brel, A.K., Lisina, S.V., Salomatina, J.N., and Kovalev, D.G.,
3
. Registr lekarstvennyh sredstv Rossii (Register of Drugs
Pharm. Chem. J., 2014, vol. 47, no. 10, p. 521.
of Russia), Moscow: RLS-MEDIA, 2009, p. 233.
. Korenyuk, I.I., Khusainov, D.R., and Shul’gin, V.F.,
Neurofiziologiya, 2005, vol. 37, no. 2, p. 142.
2
5. Brel’, A.K., Lisina, S.V., Kovalev, D.G., Salomatina, Yu.N.,
Bugaeva, L.I., Arzamaskova, E.A., and Chetvertnova, G.A.,
RF Patent 2504536, Byull. Izobret., 2014, no. 2.
4
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 2 2015