Synthesis of 4-hydroxybenzamides and their salts

Full text of DOI:10.1134/S1070363215090261

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 9, pp. 2200–2202. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © A.K. Brel, S.V. Lisina, Yu.N. Budaeva, S.S. Popov, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 9, pp. 1561–
1563.
LETTERS
TO THE EDITOR
To the 85th Anniversary of birthday of late Yu.G. Gololobov
Synthesis of 4-Hydroxybenzamides and Their Salts
A. K. Brel, S. V. Lisina, Yu. N. Budaeva, and S. S. Popov
Volgograd State Medical University, Ministry of Health of the Russian Federation,
pl. Pavshikh Bortsov 1, Volgograd, 400131 Russia
e-mail: svlisina@gmail.com
Received July 9, 2015
Keywords: hydroxybenzamide, Schotten–Baumann reaction, pharmacological activity
DOI: 10.1134/S1070363215090261
Hydroxybenzamides are important and well known
nitrogen-containing compounds. Their derivatives
attract considerable interest owing to the wide range of
their biological activity [1–7].
biologically active compounds and drugs is concerned
[7]; moreover, it significantly reduces the yield of the
target product in the case of multi-stage synthesis. The
mentioned drawbacks could be overcome by using
oxalyl chloride [10] instead of thionyl chloride. The
latter method has afforded hydroxybenzoyl chloride in
high yields (up to 91%) and free of the sulfur-con-
taining admixtures.
Certain derivatives of 4-hydroxybenzamide exhibit
cerebroprotective activity; however, the low solubility
in water limits their bioavailability. In view of the
above, in this work we prepared the water-soluble salt
forms of 4-hydroxybenzamides and studied their
cerebroprotective activity in vivо.
The target 4-hydroxybenzamides, 4-hydroxyhippuric
acid 3 and 4-[(4-hydroxybenzoyl)amino]butanoic acid
4, were prepared via the Schotten–Baumann reaction
of compound 2 with glycine or γ-aminobutyric acid,
respectively, in aqueous alkali solution [7]. Compound
3: yield 85%, white crystals, mp 220–223°C; com-
pound 4: yield 73%, white crystals, mp 170–173°C.
First, we prepared 4-hydroxybenzoyl chloride 2
from 4-hydroxybenzoic acid 1. Carboxylic acid
chlorides are generally prepared via the reaction of
thionyl chloride with the corresponding carboxylic
acid. A serious drawback of this method is the
requirement of high purity of thionyl chloride: it
should always be additionally purified prior to use.
Furthermore, the reaction should be carried out upon
slight boiling at 30°C; overheating or cooling would
reduce the product yield and purity. In the case of
hydroxybenzoic acid, the excess of thionyl chloride is
usually distilled off to afford the crude hydroxy-
benzoyl chloride that is introduced in further reactions
without purification [8] to avoid the product decom-
position. Isolation of pure hydroxybenzoyl chloride
requires multiple purification stages, since the product
as-prepared via the thionyl chloride method contains
1–2% of organosulfur compounds formed via the side
reaction of thionyl chloride with phenolic hydroxy
group of hydroxybenzoic acid [9]. Such product cont-
amination is a serious problem as far as preparation of
Acetylation [11] of 4-hydroxybenzamides 3 and 4
gave derivatives 5 (yield 78%) and 6 (yield 76%),
respectively; the latter products were further converted
into the water-soluble potassium, sodium, and lithium
salts 7–12. The potassium and sodium salts were
prepared via the interaction of potassium (or sodium)
methylate with 4-hydroxybenzamides at room tem-
perature. The lithium salts were synthesized via the
interaction with anhydrous lithium hydroxide in
benzene [12, 13].
The high solubility of compounds 7–12 allowed
determination of their cerebroprotective (anti-ischemic)
activity in vivo. The cerebrovascular insufficiency was
simulated via a single-step irreversible bilateral
occlusion of common carotid arteries under the chloral
hydrate anesthesia (intraperitoneal introduction,
2200

2201
SYNTHESIS OF 4-HYDROXYBENZAMIDES AND THEIR SALTS
Scheme 1.
O
O
OH
O
NH(CH2)nCOOH
Cl
(COCl)2
H2N(CH2)nCOOH
n = 1, 3
OH
OH
OH
1
3, 4
2
O
NH(CH2)nCOOH
O
NH(CH2)nCOOM
CH3OM
M = K, Na
(CH3CO)2O
O
O
O
O
CH3
CH3
5, 6
7, 9
LiOH
O
NH(CH2)nCOOLi
O
O
CH3
11, 12
n = 1, M = K (7); n = 3, M = K (8); n = 1, M = Na (9); n = 3, M = Na (10); n = 1 (11), 3 (12).
40 mg/kg). Introduction of compounds 7, 8, 9, and 12
resulted in a significant cerebroprotective effect. The
LD50 value (reflecting the acute toxicity) was above
2000 mg/kg for compounds 7, 8, 9, and 12 (2543 mg/kg
for compound 7), allowing for classifying the prepared
salts of 4-hydroxybenzamides as low-toxic compounds
(Scheme 1). The best results were obtained in the case
of potassium N-(4-acetoxybenzoyl)glycinate [14]; that
compound is recommended for further pharmacological
studies.
Preparation of compounds 3–5 has been
described elsewhere [15].
4-[(4-Acetoxybenzoyl)amino]butanoic acid (6).
0.2 mol of acetic anhydride and 0.2 mL of conc.
sulfuric acid were sequentially added to
0.1 mol of
compound 4; the reaction mixture was spontaneously
heated up to 75°C, and the solution became
transparent. The reaction mixture was stirred at that
temperature during 20 min, and then cooled down to
ambient, poured in cold water, and left standing for 2 h.
The formed crystals were filtered off, washed with
water, and dried. Yield 76%, white crystals, mp 195–
In summary, in this work we prepared and studied
new water-soluble salts of 4-hydroxybenzoic acid
amides with amino acids, combining the low toxicity
with significant anti-ischemic activity. Those com-
pounds are interesting in view of possible application
as efficient cerebroprotective drugs.
1
197°C. H NMR spectrum (DMSO-d6, 500 MHz), δ,
ppm: 8.35 s (1Н, NH), 7.18–7.79 m (4Н, Ph), 2.28 s
[3Н, C(O)СН3], 1.59–3.16 m (6Н,С3Н6). Mass
spectrum (ESI-MS), m/z: 265 [M]+. Found, %: C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 9 2015

2202
BREL et al.
4. Deason, M.E. and Whitten, K.R., US Patent 6407285,
58.78; H 4.69; N 5.27. C13H15NO5. Calculated, %: C
58.86; H 5.70; N 5.28.
2002; С. А., 1993, 2075666а.
5. Abdellah, M.A., Hadjikakou, S.K., Hadjiliadis, N.,
Kubicki, M., Bakas, T., Kourkoumelis, N., Simos, Y.V.,
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Bioinorg. Chem. Appl., 2009. DOI: 10.1155/2009/542979.
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Matsumoto, K., Taniguchi, T., Iwanaga, T., and Nagata, O.,
US Patent 8367843, 2013.
1Н NMR spectrum was recorded using a Bruker
DRX500 spectrometer with HMDS as internal
reference. Mass spectrum (ESI-TOF) was recorded
using a Hewlett Packard GC 5890 Series II/MSD 5972
spectrometer. The metal content was measured using a
Shimadzu AA-670 spectrophotometer (Li 670.8 nm,
K 766.5 nm, and Na 589.0 nm).
7. Brel, A.K., Lisina, S.V., Salomatina, J.N., and Kova-
lev, D.G., Pharm. Chem. J., 2014, vol. 47, no. 10, p. 521.
ACKNOWLEDGMENTS
8. Nguien, Т.Т., RF Patent 2174985, 2001.
9. Bissinger, W.E. and Kung, F.E., J. Am. Chem. Soc.,
This work was financially supported by the Russian
Foundation for Basic Research (project 15-43-
02445/15) and Administration of Volgograd region
(resolution 77/3323).
1948, vol. 70, no. 8, p. 2664.
10. Tietze, L. and Eicher, T., Preparative Organic
Chemistry, Moscow: Mir, 2013.
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