Synthesis of N-[2(3,4)-aminophenyl]-4-({4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2-ylamino]phenyl}aminomethyl)benzamides

Article abstract of DOI:10.1134/S1070428015100164

New N-[2(3,4)-aminophenyl]benzamides containing a pharmacophoric 2-(arylamino)pyrimidine fragment have been synthesized from the corresponding substituted benzoic acid.

Full text of DOI:10.1134/S1070428015100164

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 10, pp. 1449–1452. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © Zh.V. Ignatovich, Yu.V. Sinyutich, K.N. Gusak, E.V. Koroleva, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51,
No. 10, pp. 1479–1482.
Synthesis of N-[2(3,4)-Aminophenyl]-4-({4-methyl-3-[4-(pyridin-
3-yl)pyrimidin-2-ylamino]phenyl}aminomethyl)benzamides
Zh. V. Ignatovich, Yu. V. Sinyutich, K. N. Gusak, and E. V. Koroleva
Institute of New Materials Chemistry, National Academy of Sciences of Belarus,
ul. F. Skoriny 36, Minsk, 220141 Belarus
e-mail: evk@ichnm.basnet.by
Received March 30, 2015
Abstract—New N-[2(3,4)-aminophenyl]benzamides containing a pharmacophoric 2-(arylamino)pyrimidine
fragment have been synthesized from the corresponding substituted benzoic acid.
DOI: 10.1134/S1070428015100164
Advances of molecular biology in the determina-
tion of mechanisms of inhibition of tumor growth by
small molecules gave rise to a radically new approach
to the design of drugs for targeted antitumor therapy.
A relevant synthetic strategy implies combination in
a single molecule of pharmacophoric fragments of
known compounds inhibiting different stages of tumor
genesis and growth. A number of biologically active
compounds were synthesized by combining structural
fragments of tyrosine kinase and histone deacetylase
inhibitors in a single relatively small molecule. The
resulting structures showed additive and synergistic
effects compared to the precursors. They displayed
a broader spectrum of tyrosine kinase inhibition while
remaining histone deacetylase inhibitors; in particular,
they inhibited AblT315I Imatinib-resistant mutant [1, 2].
N-(2-Aminophenyl)-4-{[4-(pyridin-3-yl)-3-(pyrimidin-
2-ylamino)phenyl]aminomethyl}benzamide is a struc-
tural analog (with respect to the arylaminopyrimidine
fragment) of Imatinib, which is the known tyrosine
kinase inhibitor and antileukemic drug [3]. It has
recently been shown that this compound also inhibits
hystone deacetylase in vitro [1].
8, following a procedure developed previously. Acid 5
was used as hydrochloride without purification at the
step of synthesis of its benzotriazolyl ester [4, 5].
Amides 1–4 were synthesized in 54–75% yield by
aminolysis of activated benzotriazolyl ester derived
from acid 5 with benzenediamines 6a–6d (Scheme 1).
Amides 1–4 are structural analogs of compounds
acting as specific histone deacetylase inhibitors. In all
cases, the aminolysis selectively afforded the corre-
sponding monoamide. In the reaction with 4-methyl-
benzene-1,3-diamine (6d), only the more sterically
accessible amino group in the para position with
respect to the methyl group was involved. The
aminolysis of acid 5 benzotriazolyl ester with nitro-
anilines was characterized by a lower yield, whereas
no desired amide was obtained from o-nitroaniline,
presumably due to electron-withdrawing effect of the
nitro group [6].
The structure of amides 1–4 was confirmed by
elemental analyses and 1H and 13C NMR, IR, and mass
spectra. The IR spectra of 1–4 contained absorption
bands due to stretching vibrations of the N–H (3450–
3280 cm–1) and carbonyl groups (1630–1620 cm–1) and
N–H bending vibrations (1580–1570 cm–1). In the
1H NMR spectra of these compounds we observed
signals from protons in the benzene, pyrimidine, and
pyridine rings (δ 6.0–10.0 ppm), methyl groups
(δ 2.05–3.00 ppm), primary amino group (δ 3.40–
4.80 ppm), and NH groups [δ 6.10–8.80 and 8.03–
10.10 ppm (NHCO), depending on the solvent]. The
NH proton in the CH2NH fragment resonated as
We have developed a rational synthesis of
N-[2(3,4)-aminophenyl]-4-({3-[4-(pyridin-3-yl)pyrimi-
din-2-ylamino]phenyl}aminomethyl)benzamides 1–4
according to a convergent scheme. The amide bond
was built up in the final step from acid 5 and isomeric
phenylenediamines 6a–6d. Substituted benzoic acid 5
was synthesized in 85% yield by direct reductive
amination of methyl 4-formylbenzoate (7) with amine
1449

IGNATOVICH et al.
1450
Scheme 1.
NH2
HN
(1) NaBH(OAc)3
CHCl3, 0–5°C
CHO
(2) H+/H2O, 100°C
N
N
COOH
+
MeO
N
N
N
N
H
H
O
Me
Me
N
N
7
8
5
HN
ArNH2 (6a–6d), DCC, HOBt
Et3N, DMF, 0–5°C
NHAr
N
53–75%
O
N
N
H
Me
1–4
N
Ar = 2-H2NC6H4 (a), R = 4-H2NC6H4 (b), R = 3-H2NC6H4 (c), R = 2-Me-5-H2NC6H3 (d).
a triplet at δ 5.8–6.9 ppm, and the CH2 signal was
a doublet at δ 3.6–4.4 ppm (3J = 5.5–6.8 Hz). The
latter signal was not split when no NH signal was
observed (as a result of fast H–D exchange with the
solvent).
The carbonyl carbon signal appeared in the 13C
NMR spectra at δC 165.00–185.00 ppm, and it was not
observed in the DEPT spectrum. Carbon signals be-
longing to methyl (δC 16.0–21.0 ppm) and methylene
groups (δC 46–63 ppm) were distinguished by the
DEPT spectrum.
hydrazine hydrate over a skeletal catalyst [7] and were
used as hydrochlorides. The synthesis of diamine 8
was described in [8].
4-({4-Methyl-3-[4-(pyridin-3-yl)pyrimidin-2-yl-
amino]phenyl}aminomethyl)benzoic acid dihydro-
chloride (5). A suspension of 2.0 g (0.053 mol) of
sodium tetrahydridoborate in 16 mL of chloroform was
cooled to 0–5°C, 14 mL (0.23 mol, 9 equiv) of acetic
acid was slowly added over a period of 1 h, and the
mixture was stirred for 1.5 h on cooling. A mixture of
7.2 g (0.026 mol, 1 equiv) of 4-methyl-N3-[4-(pyridin-
3-yl)pyrimidin-2-yl]benzene-1,3-diamine (8) and 4.3 g
(0.26 mol, 1 equiv) of methyl 4-formylbenzoate (7) in
30 mL of chloroform was then added, maintaining the
temperature at 0–5°C. The mixture was stirred for
1.5 h on cooling and for 12 h at room temperature,
treated with 20 mL of water, and neutralized with
a saturated aqueous solution of sodium carbonate. The
organic layer was separated, the aqueous phase was
extracted with chloroform and ethyl acetate, and the
extracts were combined with the organic phase,
washed with one portion of water, dried over Na2SO4,
and evaporated. The residue was 4-substituted methyl
benzoate which was subjected (without purification) to
hydrolysis with dilute aqueous HCl (60 mL of water
and 120 mL of concentrated aqueous HCl per mole of
ester). The mixture was heated to the boiling point,
diluted with a double volume of hot water, and heated
for 4–6 h under reflux. When the reaction was com-
plete, 2 g of charcoal was added to the hot solution,
the mixture was heated for 30 min under reflux and
filtered, and the filtrate was evaporated. Benzene,
EXPERIMENTAL
The IR spectra were recorded in the range 400–
4000 cm–1 on a Bruker Tensor 27 spectrometer with
1
13
Fourier transform. The H and C NMR spectra were
measured on a Bruker Avance-500 spectrometer at 500
and 125 MHz, respectively, using tetramethylsilane as
internal standard. Gas chromatographic and mass spec-
trometric analyses were obtained on Accela-LCQ Fleet
(APCI or ESI), Hewlett Packard HP 6850/5973, and
Thermo Scientific Trace GC Ultra/DSQ II (direct inlet
probe) instruments. The progress of reactions was
monitored, and the purity of products was checked,
by TLC on Merk DC-Plasticfolien Kieselgel 60 F254
plates using butan-1-ol–ethanol–aqueous ammonia
(8:1:1) and chloroform–methanol (95:5) as eluents.
The elemental compositions were determined using
a Vario MICRO CHNS analyzer. The melting points
were measured on a Kofler hot stage.
Phenylenediamines 6a–6d were synthesized by
reduction of the corresponding nitroanilines with
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 10 2015

SYNTHESIS OF N-[2(3,4)-AMINOPHENYL]-4-({4-METHYL-3-[4-(PYRIDIN-3-YL)...
1451
15 mL, was added to the residue, and the mixture was
heated under reflux in a flask equipped with a Dean–
Stark trap until water no longer separated. The precip-
itate of acid 5 dihydrochloride was filtered off and
washed with benzene (3×10 mL). Yield 81%, yellow
crystals, mp 185–186°C. IR spectrum (KBr), ν, cm–1:
3432 (N–H), 3169–2598 (C–H), 1699 (C=O), 1632,
7.14 d (1H, J = 7.7 Hz), 7.36 d (1H, J = 1.6 Hz), 7.46 d
(2H, J = 8.1 Hz), 7.53 d.d (1H, J = 7.9, 4.9 Hz), 7.90 d
(2H, J = 8.0 Hz), 8.40 d (1H, J = 8.0 Hz), 8.45 d (1H,
J = 5.1 Hz), 8.69 s (2H, NH, =CHN=), 9.25 d [1H,
HNC(N)N, J = 1.8 Hz], 9.61 s (1H, NHCO, J =
0.86 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm:
17.00, 46.31, 107.02, 108.92, 109.36, 115.94, 116.10,
119.30, 123.18, 123.65, 126.27, 126.48, 126.66,
127.60, 130.22, 132.10, 132.74, 134.09, 137.87,
142.92, 144.22, 146.68, 147.92, 151.17, 159.19, 160.99,
161.28, 165.04. Mass spectrum: m/z 501 (Irel 18%)
[M]+. Found, %: C 71.95; H 5.46; N 19.48. C30H27N7O.
Calculated, %: C 71.84; H 5.43; N 19.55.
1
1610, 1441. H NMR spectrum (DMSO-d6), δ, ppm:
2.24 s (3H, CH3), 4.57 s (2H, CH2), 7.14 d (1H, J =
7.2 Hz), 7.28 d (1H, J = 8.3 Hz), 7.67 d (2H, J =
7.9 Hz), 7.69 s (1H), 7.83 s (1H), 7.85 d (2H,
J = 7.9 Hz), 8.18 d.d (1H, J = 8.2, 5.6 Hz), 8.66 d (1H,
J = 5.2 Hz), 9.02 d (1H, J = 4.9 Hz), 9.21 d (1H, J =
8.2 Hz), 9.32 s (1H), 9.55 d (1H, J = 1.7 Hz), 10.09 s
N-(4-Aminophenyl)-4-({4-methyl-3-[4-(pyridin-
3-yl)pyrimidin-2-ylamino]phenyl}aminomethyl)-
benzamide (2). Yield 54%, light brown crystals,
mp 136–137°C. IR spectrum (KBr), ν, cm–1: 3406–
3054 (N–H), 3050–2928 (C–H), 1622 (C=O), 1576,
13
(1H). C NMR spectrum (DMSO-d6), δC, ppm: 17.43,
51.85, 108.46, 117.64, 117.73, 127.01, 128.96, 130.07,
130.53, 130.92, 134.81, 134.92, 137.39, 137.88,
141.10, 142.61, 142.66, 143.56, 158.71, 159.67,
160.10, 166.69. Mass spectrum: m/z 483 (Irel 100%)
[M]+. Found, %: C 59.63; H 4.75; N 14.49.
C24H25Cl2N5O2 (C24H23N5O2 ·2HCl). Calculated, %:
C 59.51; H 4.79; N 14.46.
1
1450, 1419. H NMR spectrum (acetone-d6), δ, ppm:
2.97 s (3H, Me), 3.66 s (2H, CH2), 5.22 br.s (2H,
NH2), 7.17 d.d (1H, J = 8.1, 1.5 Hz), 7.40 d (1H, J =
8.6 Hz), 7.43 d (1H, J = 8.6 Hz), 7.72 d (1H, J =
8.2 Hz), 8.11 d.d (1H, J = 5.1, 1.7 Hz), 8.14 t (1H, J =
3.0 Hz), 8.28–8.24 m (4H), 8.51 d.t (1H, J = 8.6,
2.2 Hz), 8.56 s (1H), 8.64 d (1H, J = 8.4 Hz), 8.66 d
(1H, J = 8.3 Hz), 9.21 d (1H, J = 8.0 Hz), 9.24 d.d
(1H, J = 5.1, 1.6 Hz), 9.45 d.t (1H, J = 4.8, 1.7 Hz),
9.93 s (1H, NH, J = 0.31 Hz), 10.07 s (1H), 10.18 s
(1H, NHCO, J = 0.4 Hz). 13C NMR spectrum (ace-
tone-d6), δC, ppm: 18.21, 48.99, 109.61, 110.63,
115.88, 119.79, 121.28, 122.41, 122.51, 123.48,
125.29, 128.82, 129.16, 131.13, 132.27, 135.74,
136.00, 136.45, 140.11, 146.26, 146.61, 149.02,
149.56, 150.15, 153.11, 161.01, 163.06, 163.84,
166.83. Found, %: C 71.90; H 5.41; N 19.62.
C30H27N7O. Calculated, %: C 71.84; H 5.43; N 19.55.
Amides 1–4 (general procedure). Triethylamine,
5.7 ml (40.1 mmol, 10 equiv), was added to a solution
of 2.0 g (4.1 mmol, 1 equiv) of acid 5 dihydrochloride
in 10 mL of dimethylformamide, and the mixture was
stirred for 1 h at room temperature. Diamine 6a–6d,
4.1 mmol (1 equiv) and 2.0 mL (14.4 mmol, 3.5 equiv)
of triethylamine were then added, and the mixture was
stirred for 0.5 h at room temperature. The mixture was
cooled to 0°C, 0.6 g (4.5 mmol, 1.1 equiv) of 1-hy-
droxybenzotriazole and 0.9 g (4.5 mmol, 1.1 equiv) of
N,N′-dicyclohexylcarbodiimide were added, and the
mixture was stirred for 1.5 h on cooling and for 20 h at
50°C. The precipitate of N,N′-dicyclohexylurea was
filtered off, the filtrate was evaporated to dryness, the
residue was treated with 20% aqueous sodium hydrox-
ide to pH 10–11 and extracted with chloroform. The
extract was evaporated, and the residue was recrys-
tallized from methylene chloride–diethyl ether.
N-(3-Aminophenyl)-4-({4-methyl-3-[4-(pyridin-
3-yl)pyrimidin-2-ylamino]phenyl}aminomethyl)-
benzamide (3). Yield 75%, light brown crystals,
mp 132–134°C. IR spectrum (KBr), ν, cm–1: 3417–
3343 (N–H), 3033–2928 (C–H), 1623 (C=O), 1576,
1533, 1450, 1417. 1H NMR spectrum (CDCl3), δ, ppm:
2.23 s (3H, Me), 4.38 s (2H, CH2), 6.31 d.d (1H, J =
8.1, 2.6 Hz), 6.43 d.d (1H, J = 7.9, 1.7 Hz), 6.80 d (1H,
J = 7.9 Hz), 6.99–6.97 m (2H), 7.08 d (2H, J =
7.9 Hz), 7.40–7.35 m (4H), 7.52 d (1H, J = 2.1 Hz),
7.74 d (2H, J = 8.1 Hz), 8.13 s (1H, NH), 8.27 d.t (1H,
J = 7.9, 1.7 Hz), 8.41 d (1H, J = 5.2 Hz), 8.67 d.d (1H,
J = 4.7, 1.4 Hz), 9.21 d (1H, J = 1.9 Hz), 9.51 s (1H,
NH, J = 0.16 Hz). 13C NMR spectrum (CDCl3), δC,
N-(2-Aminophenyl)-4-({4-methyl-3-[4-(pyridin-
3-yl)pyrimidin-2-ylamino]phenyl}aminomethyl)-
benzamide (1). Yield 53%, light yellow crystals,
mp 145–147°C. IR spectrum (KBr), ν, cm–1: 3443–
3279 (N–H), 3060–2922 (C–H), 1626 (C=O), 1577,
1
1535, 1449. H NMR spectrum (DMSO-d6), δ, ppm:
2.06 s (3H, Me), 4.34 d (2H, CH2, J = 6.0 Hz), 4.87 s
(2H, NH2), 6.21 t (1H, NH, J = 6.2 Hz), 6.33 d.d (1H,
J = 8.2, 2.3 Hz), 6.59 t (1H, J = 7.1 Hz), 6.77 d (1H,
J = 8.0 Hz), 6.88 m (2H), 6.96 t (1H, J = 7.0 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 10 2015

IGNATOVICH et al.
1452
ppm: 17.13, 48.05, 106.36, 108.02, 108.09, 108.34,
108.49, 110.08, 111.19, 117.48, 123.56, 127.21,
127.35, 127.48, 129.65, 130.99, 132.79, 133.82,
134.45, 137.94, 139.08, 143.88, 146.72, 147.26,
148.47, 151.28, 158.94, 160.66, 162.48, 165.65.
Found, %: C 71.98; H 5.47; N 19.60. C30H27N7O.
Calculated, %: C 71.84; H 5.43; N 19.55.
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(pyridin-3-yl)pyrimidin-2-ylamino]phenyl}amino-
methyl)benzamide (4). Yield 65%, light yellow crys-
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3332 (N–H), 3055–2927 (C–H), 1623 (C=O), 1577,
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1
1450, 1313. H NMR spectrum (CDCl3), δ, ppm: 2.12
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(3H, Me), 2.23 (3H, Me), 3.47 br.s (2H, NH2), 4.40 s
(2H, CH2), 6.32 d.d (1H, J = 8.2, 2.4 Hz), 6.74 d.d
(1H, J = 7.9, 1.8 Hz), 7.00–6.96 m (4H), 7.09 d (1H,
J = 5.1 Hz), 7.39 d.d (1H, J = 8.2, 2.3 Hz), 7.42 d (2H,
J = 7.9 Hz), 7.54 d (1H, J = 1.8 Hz), 7.76 d (2H, J =
7.9 Hz), 7.97 s (1H, NH), 8.29 d (1H, J = 7.9 Hz),
8.43 d (1H, J = 5.1 Hz), 8.68 d (1H, J = 3.8 Hz), 9.22 s
(1H, NHCO, J = 0.96 Hz). 13C NMR spectrum
(CDCl3), δC, ppm: 16.61, 16.89, 47.88, 106.12, 106.61,
107.85, 108.04, 109.90, 117.25, 117.30, 118.31,
123.31, 126.91, 127.14, 130.76, 132.55, 134.20,
137.71, 143.52, 144.80, 146.43, 148.25, 151.06,
158.69, 160.41, 162.27, 165.18, 179.76, 180.08,
181.39, 182.95. Found, %: C 72.55; H 5.66; N 19.10.
C31H29N7O. Calculated, %: C 72.21; H 5.67; N 19.02.
8. Koroleva, E.V., Ignatovich, Zh.V., Ermolinskaya, A.L.,
Sinyutich, Yu.V., Baranovskii, A.V., and Makhnach, S.A.,
Izv. Nats. Akad. Nauk Belarusi, Ser. Khim. Nauk, 2013,
no. 3, p. 79.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 10 2015