878 Russian Chemical Bulletin, International Edition, Vol. 67, No. 5, pp.

878—883, May, 2018

Synthesis of new acridine-9-carboxylic acid derivatives

V. V. Melyshenkova, D. N. Kuznetsov, A. G. Ruchkina, and K. I. Kobrakov

А. N. Kosygin Russian State University

"Technologies. Design. Art", Chair of Organic Chemistry,
1 ul. Malaya Kaluzhskaya, 119991 Moscow, Russian Federation.
E-mail: occd@mail.ru

New 1,3-dihydroxyacridine-9-carboxylic acids were obtained by Pfitzinger reaction from

2,4,6-trihydroxytoluene (methylphloroglucinol). Their bromination and azo-coupling reactions
were studied. Computer simulation was used to determine potential pharmacokinetic and
toxic properties of the synthesized compounds.

Key words: methylphloroglucinol, Pfitzinger reaction, isatin, 1,3-dihydroxy-2-methyla-

cridine-9-carboxylic acids, bromination, azo-coupling.

Acridine derivatives are widely used in science and Scheme 1

technology, for example, as dyes and biologically active
compounds. In particular, alkaloids isolated from plants
of the family Rutaceae and possessing pronounced anti-
malarial activity include a fragment of the acridine struc-
ture.1 Taking into account the above, the interest of re-
searchers in the acridine-derived compounds remained
high for many years.2
Earlier, we have shown that 2,4,6-trihydroxytoluene
(a product of chemical transformation of demilitarized
2,4,6-trinitrotoluene) is a highly active, promising sub-
strate in the synthesis of dihydroxy-2H-1-benzopyran-2-
ones, synthetic analogs of natural compounds.3,4
In the work,5 it was shown that the reaction of isatin
derivatives with resorcinol and phloroglucinol at 80  °С
leads to functionally substituted 1,3-dihydroxyacridine-9-
carboxylic acids, which exist in the form of a zwitterion, 2, 3: R = H (a), Me (b), Br (c), Cl (d), I (e), F (f)
which causes poor solubility in water and, as a conse-
Reagents and conditions: NaOH, H2O, reflux, aqueous HCl.
quence, complicates their identification. The use of
2,4,6-trihydroxytoluene (methylphloroglucinol) in the
reaction with isatins following Pfitzinger method has not by their existence in the form of zwitterions,5 which com-
been yet studied. plicates their identification. In this connection, to establish
In the present work, we for the first time carried out the structure of the synthesized compounds 3а—f we re-
Pfitzinger reaction based on the presently available, but corded their NMR spectra (including 2D heteronu-
still poorly studied, methylphloroglucinol 1 and function- clear procedures {1Н—13С} HMBC) in the mixture of
ally substituted isatins 2а—f to synthesize functionalized D2O—NaOD. The 1Н NMR spectrum of product 3а
1,3-dihydroxyacridine-9-carboxylic acids 3a—f (Scheme exhibits six signals. The singlets at δ 2.02 and 7.18 were
1), as well as studied some of their physicochemical and assigned to the СН3 group and the atom Н(4). Two triplets
biological properties. at δ 7.45 (J = 6.7 Hz) and 7.52 (J = 7.1 Hz) and two dou-
The reaction of methylphloroglucinol 1 with function- blets at δ 7.76 (J = 7.7 Hz) and 7.86 (J = 8.4 Hz) were
ally substituted isatins 2а—f was carried out upon reflux assigned to the protons of the benzene fragment.
in aqueous solution of NaOH during 4 h. The yields of the The 13С NMR spectrum of compound 3а exhibits
target products 3a—f were within 25—97%. 15 signals. A signal at δ 9.72 was assigned to the carbon
Compounds 3а—f are very poorly soluble in water and atom of the methyl group. The {1H-13C}—HMBC ex-
common organic solvents. Most likely, it can be explained periment showed three correlations for the CH3 protons

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 0878—0883, May, 2018.
1066-5285/18/6705-0878 © 2018 Springer Science+Business Media, Inc.
New derivatives of acridine-9-carboxylic acids Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018 879

Scheme 2

at δН 2.02 with the carbon atoms at δС 111.66, 165.45, and In the course of the study, it was shown that reflux of
176.72, which belong to the atoms С(2), С(1), and С(3), 5-nitroisatin 2g and methylphloroglucinol 1 in aqueous
respectively. The peaks at δС 115.25 and 178.58 have no solution of NaOH for 4 h leads to the product identified
correlations with protons, therefore, they belong to the as 1,3,7-trihydroxy-2-methylacridine-9-carboxylic acid
atoms С(4) and СООН. The signals at δС 131.04 and 3g (Scheme 3).
145.53 were assigned to the atoms С(9а) and С(4а) based
on the cross-peaks with the atom Н(4) at δН 7.18. The Scheme 3
signal at δС 130.10 based on the cross-peak was as-
signed to the proton at δН 7.86, which identifies the at-
oms С(9) and Н(8). Using the signal for the atom Н(8),
the signals at δН 7.45, 7.52, and 7.76 were assigned to
the atoms Н(7), Н(6), and Н(5), respectively, while the
signals at δС 126.45, 123.27, 121.17, and 126.85 to the atoms
С(5), С(6), С(7), and С(8), respectively. The signal at
δС 146.37 was attributed to the atom С(10а) based on the
correlations with the atoms Н(8), Н(5), and Н(6), while
the signal at δ С 118.42 was assigned to the atom
С(8а) based on the correlations with the atoms Н(8), Н(7),
and Н(5).
Based on the above spectral data, it can be confidently
concluded that the condensation of methylphloroglucinol 1
with isatin derivatives 2а—f leads to the formation of one Reagents and conditions: NaOH, H2O, reflux, aq. HCl.
product with the methyl group at position 2.
The synthesized compounds 3а—f were also character- Several data speak in favor of this fact. In the mass
ized by mass spectrometry, IR spectroscopy, elemental spectrum of compound 3g, there is a peak m/z 269
analysis, and electronic absorption spectra (EAS). ([М – Н2О]+), which corresponds to the molecular weight
The mass spectra of compounds 3а—f give no mo- of the 7-hydroxy derivative, rather than the 7-nitro de-
lecular ion peak, exhibiting instead a strong peak of the rivative characterized by a peak m/z 296. This assumption
[М – Н2О]+ ion, as well as the peaks of the [М – СО]+, was additionally confirmed by the absence in the IR spec-
[М – 2 СО]+, [М – 3 СО]+ fragment ions, which cor- trum of compound 3g of asymmetric and symmetric
responds to the fragmentation process given in Scheme 2. stretching vibrations of the nitro group in the region of
In the IR spectra of compounds 3а—f, the absorption 1560—1490 cm–1 and 1360—1310 cm–1, respectively. This
bands of the stretching asymmetric and symmetric vibra- circumstance can be explained by the proceeding of the
tions of the carboxylate anion group are observed in the side nucleophilic substitution reaction.
region of 1590—1571 cm–1 and 1423—1413 cm–1, while We studied a bromination reaction for some earlier
the absorption bands corresponding to the C—OH bond unknown 1,3-dihydroxy-2-methylacridine-9-carboxylic
are found in the region of 1250—1216 cm–1. acids 3а—c and characterized its products.
880 Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018 Melyshenkova et al.

Bromine was added portionwise to a suspension of Scheme 5

compounds 3а—c in chloroform and the reaction mixture
was refluxed until the HBr gas ceased to evolve. The yields
of bromination products 4а—c were within 64—84%
(Scheme 4).

Scheme 4

3, 4: R = H (a), Me (b), Br (c) 3, 5: R = H (a), Me (b), Br (c)

Reagents and conditions: CHCl3, reflux.

xylic acids 3а—c leads to a small (by 9 nm) bathochromic
The structures of the synthesized compounds 4а—c shift of λmax relative to that of the starting compounds
were characterized by elemental analysis, EAS, 1H NMR 3а—c and a significant change in the shape of the absorp-
spectroscopy, mass spectrometry, and IR spectroscopy. tion curve.
The key point in establishing the structure of com- In the electronic absorption spectra of azo derivatives
pounds 4а—c is the absence in the 1H NMR spectra of 5а—c, a shift of λmax to the long-wavelength region of the
a signal for the proton of the aromatic ring of methyl- spectrum relative to that of the starting compounds 3а—c
phloroglucinol in the region of δ 7.18, which indicates that is observed on the average by 100 nm, which is due to the
the bromination occurred in the ring of acridine. insertion of the azo group in the conjugate system of the
The IR spectra of compounds 4а—c exhibit absorption acridine ring.
bands in the range 1045—1035 cm–1 corresponding to the Using the ChemoSoft software (Chemical Diversity
stretching vibrations of the С—Br bond. Labs, Inc.),6 we calculated molecular descriptors of the
We also investigated an azo-coupling reaction for some library of new polyfunctional 1,3-dihydroxy-2-methyl-
1,3-dihydroxy-2-methylacridine-9-carboxylic acid de- acridine-9-carboxylic acids 3а—f, 4а—с, 5а—c. From the
rivatives 3а—c with 4-nitrophenyldiazonium chloride 6 data obtained, it follows that the molecular weights of these
and characterized its products. compounds vary within 269—497. For all the compounds,
The azo-coupling reaction proceeds in an aqueous the sums of the hydrogen bond donors and acceptors (Hd
alkaline medium for 3 h with subsequent acidification of and Ha) meet the Lipinski criteria, as well as satisfy the
the reaction mixture with aqueous hydrochloric acid to "lead-like" concept in the number of nonterminal rotating
pH 6—7 (Scheme 5). bonds.7 However, the lipophilicity of azo derivatives 5а—c
The structures of the synthesized compounds 5а—c
were established based on elemental analysis, mass spec-
logε
trometry, IR and UV spectroscopy.
4.4
In the IR spectra of products 5а—c, the absorption
4.3
bands characteristic of the stretching vibrations of the 4.2
N=N bond (1438—1435 cm –1) and the NO 2 group 4.1
5a
(1504—1497 cm–1). 4.0
Analysis of EAS of the synthesized compounds 3а—f, 3.8
4a—c, and 5а—c allowed us to reveal the nature and level 3.6
3.4
of influence of substituents on the position and intensity 4a
3.2
of characteristic absorption bands (Fig. 1). The introduc- 3.0
tion of different substituents at position 7 of the conjugate 2.8 3a
system of 1,3-dihydroxyacridine-9-carboxylic acid 3a has 2.6
no noticeable effect on the absorption band maximum
position. 300 400 500 600 λ/nm
The introduction of a bromine atom at position 4 of Fig. 1. EAS of compounds 3а, 4а, and 5а recorded in aqueous
the conjugate system of 1,3-dihydroxyacridine-9-carbo- solution of KOH (С = 0.1%).
New derivatives of acridine-9-carboxylic acids Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018 881

exceeds the allowable criteria, which to some extent can dium hydroxide (0.68 g, 0.017 mol in water (5.5 mL)) was refluxed
reduce their effect. for 4 h, using a reflux condenser. The resulting mixture was cooled
Preliminary assessment of the biological activity of the to room temperature, acidified with a 10% solution of hydrochlo-
ric acid to рН ≈ 6—7. A precipitate formed was collected by filtra-
synthesized compounds was carried out by computer
tion on a Buchner funnel, washed with water and acetone on the
simulations using the PASS (Prediction of Activity Spectra
filter, and dried in air to obtain the product (1.21 g, 97%) as a light
for Substances) system.8 The evaluation of the pharma- orange powder, m.p. 270 °C. 1H NMR (D2O—NaOD), δ: 2.02
cological activity of the compounds synthesized in this (s, 3 H, Me(2)); 7.18 (s, 1 Н, Н(4)); 7.45 (t, 1 Н, Н(7),
work showed that the following types of activities are J = 6.7 Hz); 7.52 (t, 1 Н, Н(6), J = 7.1 Hz); 7.76 (d, 1 Н, Н(5),
predicted for all the compounds with a probability of more J = 7.7 Hz); 7.86 (d, 1 Н, Н(8), J = 8.4 Hz). 13C NMR (D2O—
than 60—70%: inhibition of certain enzymes, antiseptic, NaOD), δ: 9.72 (Ме); 111.66 (С(2)); 115.25 (C(4)); 118.42
antiarrhythmic, antituberculosis, antiseborrheic, stimula- (C(8a)); 121.17 (С(7)); 123.27 (C(6)); 126.45 (C(5)); 126.85
tion of kidney function, etc. (С(8)); 130.10 (С(9)); 131.04 (С(9а)); 145.53 (C(4a)); 146.37
(С(10a)); 165.45 (C(1)); 176.72 (С(3)); 178.58(C(COOH)). IR,
The development of any new potential biologically
ν/cm–1: 3252 (ν, O—H); 1583 (νas, CО2); 1423 (νs, CО2); 1216
active substance includes a stage of evaluation of its toxic (ν, Carom—OH); 1990 (ν, C—CH3). MS (EI, 10 eV), m/z
effect on human organism. (Irel (%)): 251 [М – Н2О]+ (100); 223 [М – Н2О – СО]+ (35);
To determine the toxic effects on the human organism 195 [М – Н2О – 2 СО]+ (30); 167 [М – Н2О – 3 СО]+ (20);
of compounds synthesized in the present study, a progno- 140 [М – Н2О – 4 СО]+ (20). UV (0.1% aq. KOH), λmax/nm
sis of the acute toxicity was made for all the new polyfunc- (lgε): 239.74 (4.41); 357.77 (3.97). Found (%): C, 66.86; H, 4.21;
tional 9-acridinecarboxylic acid dihydroxy derivatives N, 5.16. C15H11NO4. Calculated (%): C, 66.91; H, 4.12; N, 5.20.
using the Acute rat toxicity prediction software.9 Based on 1,3-Dihydroxy-2,7-dimethylacridine-9-carboxylic acid (3b).
the computer prediction on lethal toxicity, all the com- The synthesis was carried out similarly to the synthesis of com-
pound 3а, using MPHG 1 (0.5 g, 0.0036 mol), 5-methylisatin
pounds studied in this work can be classified as a group of
2b (0.53 g, 0.0033 mol), and sodium hydroxide (0.48 g, 0.012
nontoxic or weakly toxic compounds. mol). The product (0.69 g, 73%) was obtained as a red powder,
In conclusion, using modern physicochemical methods m.p. 271 °C. 1H NMR (D2O—NaOD), δ: 2.02 (s, 3 H, Me(2));
of analysis, it was confirmed for the first time that the 2.45 (s, 3 Н, Ме(7)); 7.18 (s, 1 Н, Н(4)); 7.48 (d, 1 Н, Н(6),
reaction between methylphloroglucinol and functionally J = 7.4 Hz); 7.64 (s, 1 Н, Н(8)); 7.72 (d, 1 Н, Н(5), J = 7.9 Hz).
substituted isatins leads to earlier unknown 1,3-dihydroxy- IR, ν/cm–1: 1993 (ν, C—CH3); 1571 (νas, CО2); 1420 (νs, CО2);
2-methylacridine-9-carboxylic acids. These compounds 1246 (ν, Carom—OH). MS (EI, 10 eV), m/z (Irel (%)): 265
were studied in electrophilic substitution reactions (bro- [М – Н2О]+ (100); 237 [М – Н2О – СО]+ (55); 209 [М – Н2О –
– 2 СО]+ (41); 181 [М – Н2О – 3 СО]+ (35). UV (0.1% aq. KOH),
mination and azo coupling). The results of computer
λmax/nm (lgε): 242.54 (4.51); 359.35 (4.09). Found (%): C, 67.79;
screening of biophysical characteristics, biological activity, H, 4.69; N, 4.93. C16H13NO4. Calculated (%): C, 67.84; H, 4.63;
and acute toxicity of the compounds obtained allow us to N, 4.94.
conclude that they are promising as the objects for study 7-Bromo-1,3-dihydroxy-2-methylacridine-9-carboxylic acid
as chemicopharmaceutical agents or in the schemes for (3c). The synthesis was carried out similarly to the synthesis of
fragmentary-oriented design of drugs. compound 3а, using MPHG 1 (0.5 g, 0.0036 mol), 5-bromoisa-
tin 2c (0.75 g, 0.0033 mol), and sodium hydroxide (0.48 g,
0.012 mol). The product (0.94 g, 82%) was obtained as a red
Experimental
powder, m.p. 247 °C. 1H NMR (D2O—NaOD), δ: 2.01 (s, 3 H,
Me(2)); 7.18 (s, 1 Н, Н(4)); 7.70 (d, 1 Н, Н(6), J = 7.5 Hz); 7.81
Electronic absorption spectra of samples prepared in an (d, 1 Н, Н(5), J = 7.8 Hz); 7.89 (s, 1 Н, Н(8)). IR, ν/cm–1: 1580
aqueous solution of sodium hydroxide with a concentration of (νas, CО2); 1419 (νs, CО2); 1239 (ν, Carom—OH); 1027 (ν, C—Br).
1•10–4 mol L –1 were obtained on a Uvidec-610 instrument with MS (EI, 10 eV), m/z (Irel (%)): 331 [М – Н2О]+ (100); 303
a pathlength of 0.5 cm. IR spectra of compounds under study [М – Н2О – СО]+ (35); 273 [М – Н2О – 2 СО]+ (15); 245
were recorded on a Spectrum Two PERKIN ELMER Fourier- [М – Н2О – 3 СО]+ (20). UV (0.1% aq. KOH), λmax/nm (lgε):
transform spectrometer with a universal diamond ATR sampling 243.96 (4.49); 365.08 (3.97). Found (%): C, 51.80; H, 2.83;
accessory (ATR stands for attenuated total reflection) in the N, 4.04 C15H10BrNO4. Calculated (%): C, 51.75; H, 2.90; N, 4.02.
550—4000 cm–1 frequency range. 1Н and 13C NMR spectra of 7-Chloro-1,3-dihydroxy-2-methylacridine-9-carboxylic acid
compounds were recorded on a Bruker DRX-500 spectrometer (3d). The synthesis was carried out similarly to the synthesis of
(500.13 and 125.76 МHz) in DMSO-d6 and D2O—NaOD at compound 3а, using MPHG 1 (0.2 g, 0.0014 mol), 5-chlorois-
22—24  °C, using SiMe4 as an internal standard (DMSO-d6 atin 2d (0.24 g, 0.0013 mol), and sodium hydroxide (0.2 g,
(1H: 2.50, 13C: 39.5)). Mass spectra were obtained on a INCOS50 0.005 mol). The product (0.37 g, 92.5%) was obtained as a brown
instrument (EI, 10 eV). Elemental analysis was carried out using powder, m.p. 249 °C. 1H NMR (D2O—NaOD), δ: 2.02 (s, 3 H,
a Carlo Erba-110 analyser. Melting points of the synthesized Me(2)); 7.19 (s, 1 Н, Н(4)); 7.71 (d, 1 Н, Н(6), J = 7.5 Hz); 7.79
compounds were determined on a Boetius microblock. (d, 1 Н, Н(5), J = 7.8 Hz); 7.87 (s, 1 Н, Н(8)). IR, ν/cm–1: 1582
1,3-Dihydroxy-2-methylacridine-9-carboxylic acid (3а). A mix- (νas, CО2); 1417 (νs, CО2); 1237 (ν, Carom—OH); 1027 (ν, C—Cl).
ture of methylphloroglucinol (MPHG) 1 (0.7 g, 0.005 mol), MS (EI, 10 eV), m/z (Irel (%)): 285 [М – Н2О]+ (100); 257
isatin 2а (0.68 g, 0.0046 mol), and an aqueous solution of so- [М – Н2О – СО]+ (30); 229 [М – Н2О – 2 СО]+ (30); 200
882 Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018 Melyshenkova et al.

[М – Н2О – 3 СО]+ (30). UV (0.1% aq. KOH), λmax/nm (lgε): – СО]+ (35); 275 [М – Н2О – 2 СО]+ (5). UV (0.1% aq. KOH),
242.17 (4.46); 366.38 (3.95). Found (%): C, 59.37; H, 3.25; λmax/nm (lgε): 240.30 (4.25); 366.37 (3.85). Found (%): C, 51.80;
N, 4.63. C15H10ClNO4. Calculated (%): C, 59.32; H, 3.32; N, 4.61. H, 2.82; N, 4.05. C15H10BrNO4. Calculated (%): C, 51.75;
1,3-Dihydroxy-7-iodo-2-methylacridine-9-carboxylic acid H, 2.90; N, 4.02.
(3e). The synthesis was carried out similarly to the synthesis of 4-Bromo-1,3-dihydroxy-2,7-dimethylacridine-9-carboxylic
compound 3а, using MPHG 1 (0.1 g, 0.0007 mol), 5-iodoisatin 2e acid (4b). The product (0.09 g, 70%) was obtained as a red pow-
(0.18 g, 0.0006 mol), and sodium hydroxide (0.1 g, 0.0025 mol). der, m.p. 223—224 °C. 1H NMR (DMSO-d6), δ: 2.20 (s, 3 Н,
The product (0.06 g, 25%) was obtained as a violet powder, Ме(2)); 2.44 (s, 3 Н, Ме(7)); 7.79 (d, 1 Н, H(5), J = 7.8); 7.87
m.p. 214 °C. 1H NMR (D2O—NaOD), δ: 2.02 (s, 3 H, Me(2)); (d, 1 Н, H(6), J = 7.6); 8.25 (s, 1 Н, H(8)). IR, ν/cm–1: 3129
7.19 (s, 1 Н, Н(4)); 7.70 (d, 1 Н, Н(6), J = 7.5 Hz); 7.80 (d, 1 Н, (ν, CОO—H), 1716 (ν, C=О); 1626 (νas, CО2); 1447 (νs, CО2);
Н(5), J = 7.8 Hz); 7.87 (s, 1 Н, Н(8)). IR, ν/cm–1: 1581 1220 (ν, Carom—OH); 1045 (ν, C—Br). MS (EI, 10 eV), m/z
(νas, CО2); 1413 (νs, CО2); 1239 (ν, Carom—OH); 616 (ν, C—I). (Irel (%)): 344 [М – Н2О]+ (100); 316 [М – Н2О – СО]+ (35);
MS (EI, 10 eV), m/z (I rel (%)): 377 [М – Н 2О] + (100); 288 [М – Н2О – 2 СО]+ (7). UV (0.1% aq. KOH), λmax/nm
351 [М – Н2О – СО]+ (30); 321 [М – Н2О – 2 СО]+ (20); 293 (lg ε): 242.17 (4.34); 368.54 (3.87). Found (%): C, 53.11; H, 3.32;
[М – Н2О – 3 СО]+ (10). UV (0.1% aq. KOH), λmax/nm (lgε): N, 3.84. C16H12BrNO4. Calculated (%): C, 53.06; H, 3.34;
246.46 (4.41); 363.19 (3.98). Found (%): C, 45.54; H, 2.48; N, 3.87.
N, 3.66. C15H10INO4. Calculated (%): C, 45.59; H, 2.55; 4,7-Dibromo-1,3-dihydroxy-2-methylacridine-9-carboxylic
N, 3.54.aaa acid (4c). The product (0.13 g, 84%) was obtained as a red pow-
7-Fluoro-1,3-dihydroxy-2-methylacridine-9-carboxylic acid der, m.p. 225 °C. 1H NMR (DMSO-d6), δ: 2.19 (s, 3 Н, Ме(2));
(3f). The synthesis was carried out similarly to the synthesis of 7.80 (d, 1 Н, H(5), J = 7.9 Hz); 7.97 (d, 1 Н, H(6), J = 7.4 Hz);
compound 3а, using MPHG 1 (0.2 g, 0.0014 mol), 5-fluorois- 8.48 (s, 1 Н, H(8)). IR, ν/cm–1: 3084 (ν, CОO—H), 1716
atin 2f (0.22 g, 0.0013 mol), and sodium hydroxide (0.2 g, (ν, C=О); 1616 (νas, CО2); 1441 (νs, CО2); 1224 (ν, Carom—OH);
0.005 mol). The product (0.33 g, 88%) was obtained as a dark 1035 (ν, C—Br). MS (EI, 10 eV), m/z (Irel (%)): 409 [М – Н2О]+
orange powder, m.p. 265 °C. 1H NMR (D2O—NaOD), δ: 2.02 (100); 381 [М – Н2О – СО]+ (40); 353 [М – Н2О – 2 СО]+
(s, 3 H, Me(2)); 7.19 (s, 1 Н, Н(4)); 7.60 (d, 1 Н, Н(6), J = 7.5 Hz); (10). UV (0.1% aq. KOH), λmax/nm (lgε): 240.77 (4.30); 374.54
7.80 (d, 1 Н, Н(5), J = 7.8 Hz); 7.85 (s, 1 Н, Н(8)). IR, ν/cm–1: (3.84). Found (%): C, 42.12; H, 2.17; N, 3.30. C15H9Br2NO4.
1980 (ν, C—CH3); 1590 (νas, CО2); 1414 (νs, CО2); 1250 (ν, Calculated (%): C, 42.19; H, 2.12; N, 3.28.
Carom—OH); 1213, 1147 (ν, C—F). MS (EI, 10 eV), m/z (Irel (%)): 4-Nitrophenyldiazonium chloride 6 was synthesized accord-
269 [М – Н2О]+ (100); 243 [М – Н2О – СО]+ (45); 213 ing to the known procedure.10
[М – Н2О – 2 СО]+ (42); 185 [М – Н2О – 3 СО]+ (65); 158 Synthesis of azo compounds 5a—c (general procedure). A corr-
[М – Н2О – 4 СО]+ (50). UV (0.1% aq. KOH), λmax/nm (lgε): esponding acridine-9-carboxylic acid 3a—c (0.0007 mol) was
237.11 (4.47); 362.14 (4.03). Found (%): C, 62.67; H, 3.49; dissolved in water (3 mL) and 10% aqueous solution of sodium
N, 4.95. C15H10FNO4. Calculated (%): C, 62.72; H, 3.51; N, 4.88. hydroxide (2 mL). The solution was cooled to 0—5  °C. Then,
1,3,7-Trihydroxy-2-methylacridine-9-carboxylic acid (3g). a solution of p-nitrophenyldiazonium chloride 6 (obtained by
The synthesis was carried out similarly to the synthesis of com- diazotization of p-nitroaniline (0.0007 mol)) was added to the
pound 3а. The product (0.5 g, 36%) was obtained as a dark reaction mixture over 20 min. The resulting mixture was stirred
brown powder, m.p. 422—423 °С. 1H NMR (D2O—NaOD), δ: for another 3 h at room temperature. The completion of the azo
2.02 (s, 3 H, Me(2)); 7.19 (s, 1 Н, Н(4)); 7.40 (d, 1 Н, Н(5), coupling reaction was monitored by testing for the diazonium
J = 7.8 Hz); 7.90 (d, 1 Н, Н(6), J = 7.5 Hz); 7.93 (s, 1 Н, Н(8)). salt with the R-salt. After the completion of the azo coupling
IR, ν/cm–1: 1704 (ν, C=О); 1583 (νas, CО2); 1388 (δ, O—H); reaction, the reaction mixture was acidified with a 10% aqueous
1229 (ν, Carom—OH). MS (EI, 10 eV), m/z (Irel (%)): 269 hydrochloric acid to рН ≈ 6—7. A precipitate formed was col-
[М – Н2О]+ (100); 244 [М – H2O – СО]+ (10). Found (%): lected by filtration on a Buchner funnel, washed with water and
C, 63.21; H, 3.92; N, 4.83. C15H11NO5. Calculated (%): C, 63.16; acetone on the filter, and dried in air.
H, 3.89; N, 4.91. 1,3-Dihydroxy-2-methyl-4-(4-nitrophenylazo)acridine-9-carb-
Bromination of compounds 3a—c (general procedure). A cor- oxylic acid (5a). The product (0.16 g, 52%) was obtained as
responding 9-acridinecarboxylic acid 3а—c (0.36 mmol) was a black powder, m.p. 180 °C (with decomp.). IR, ν/cm–1: 1590
suspended in chloroform (2 mL). A solution of Br2 (0.6 g, (νas, CО2); 1497 (νas, NO2); 1435 (ν, N=N); 1323 (νs, NO2);
0.36 mmol) in chloroform (1 mL) was added portionwise to the 1247 (ν, Carom—OH); 1102 (ν, C—O). MS (EI, 10 eV), m/z
resulting mixture. The reaction mixture was refluxed until the (Irel (%)): 400 [М – H2O]+ (100); 373 [М – NO2]+ (40); 329 (10);
HBr gas ceased to evolve and cooled. A precipitate formed was 138 [C6H4N2O2]+ (100). UV (0.1% aq. KOH), λmax/nm (lgε):
collected by filtration on a Buchner funnel, dissolved in ethanol, 230.89 (4.06); 469.24 (4.16). Found (%): C, 60.23; H, 3.51;
and filtered using a Buchner funnel to remove undissolved im- N, 13.31. C21H14N4O6. Calculated (%): C, 60.29; H, 3.37; N, 13.39.
purities. The solvent was evaporated on a rotary evaporator. 1,3-Dihydroxy-2,7-dimethyl-4-(4-nitrophenylazo)acridine-
4-Bromo-1,3-dihydroxy-2-methylacridine-9-carboxylic acid 9-carboxylic acid (5b). The product (0.21 g, 68%) was obtained
(4а). The product (0.08 g, 64%) was obtained as a red powder, as a black powder, m.p. 180 °C (with decomp.). IR, ν/cm–1: 1591
m.p. 220—222 °C. 1H NMR (DMSO-d6), δ: 2.20 (s, 3 Н, Ме(2)); (νas, CО2); 1502 (νas, NO2); 1438 (ν, N=N); 1316 (νs, NO2);
7.58 (t, 1 Н, H(7), J = 7.7 Hz); 7.83 (d, 1 Н, H(5), J = 8.4 Hz); 1238 (ν, Carom—OH); 1105 (ν, C—O). MS (EI, 10 eV), m/z
7.89 (t, 1 Н, H(6), J = 7.6 Hz); 8.31 (d, 1 Н, H(8), J = 8.6 Hz). (Irel (%)): 414 [М – H2O]+ (10); 138 [C6H4N2O2]+ (100). UV
IR, ν/cm–1: 2970 (ν, CОO—H), 1721 (ν, C=О); 1626 (νas, CО2); (0.1% aq. KOH), λmax/nm (lgε): 229.19 (4.38); 458.91 (4.5).
1442 (νs, CО2); 1227 (ν, Carom—OH); 1044 (ν, C—Br). MS (EI, Found (%): C, 61.09; H, 3.83; N, 12.88. C22H16N4O6. Calculat-
10 eV), m/z (Irel (%)): 331 [М – Н2О]+ (100); 303 [М – Н2О – ed (%): C, 61.11; H, 3.73; N, 12.96.
New derivatives of acridine-9-carboxylic acids Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018 883

7-Bromo-1,3-dihydroxy-2-methyl-4-(4-nitrophenylazo)acri- 5. M.-G. A. Shvekhgeymer, O. A. Moreva, Dokl. Akad. Nauk,

dine-9-carboxylic acid (5c). The product (0.22 g, 62%) was ob- 2000, 372, 778 [Dokl. Chem. (Engl. Transl.), 2000, 382].
tained as a black powder, m.p. 180 °C (with decomp.). IR, ν/cm–1: 6. Molinspiration Cheminformatics Slovak Republic, URL:
1592 (νas, CО2); 1504 (νas, NO2); 1437 (ν, N=N); 1327 (νs, NO2); http://www.molinspiration.com/cgi-bin/properties (date of
1238 (νCarom—OH); 1106 (ν, C—O); 1068 (ν, C—Br). MS (EI, application 19.05.2017).
10 eV), m/z (Irel (%)): 480 [М – H2O]+ (2); 138 [C6H4N2O2]+ 7. C. A. Lipinski, F. Lombardo, B. W. Dominy, P. Feeney, Adv.
(100). UV (0.1 % KOH), λmax/nm (lg ε): 233.47 (4.42); 461.86 Drug. Deliv. Rev., 1997, 23, 3.
(4.01). Found (%): C, 50.64; H, 2.80; N, 11.19. C21H13BrN4O6. 8. Institute of Biomedical Chemistry, URL: http://www.
Calculated (%): C, 50.72; H, 2.64; N, 11.27. pharmaexpert.ru/PASSOnline/ (date of application 21.02.2015).
9. Institute of Biomedical Chemistry. – URL: http://www.
way2drug.com/gusar/acutoxpredict.html (date of application
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