Synthesis of novel 3-substituted benzamides related to imatinib

Article abstract of DOI:10.3184/174751916X14576998046299

Twelve new 3-substituted benzamide derivatives structurally related to tyrosine kinase inhibitor imatinib have been synthesised by a Cu(I)-catalysed coupling of three previously synthesised (5-iodo-2-methylphenyl)-[4-(pyridin-3-yl)-6-perfluoroalkylpyrimidin-2-yl]amines with four synthesised 3-substituted 4-(4-methylpiperazin-1-ylmethyl)benzamides.

Full text of DOI:10.3184/174751916X14576998046299

224 RESEARCH PAPER
VOL. 40 APRIL, 224–227
JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis of novel 3-substituted benzamides related to imatinib
Svetlana Terentjeva*, Dzintra Muceniece, Jekaterina Petushkova and Viesturs Lūsis
Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia
Twelve new 3-substituted benzamide derivatives structurally related to tyrosine kinase inhibitor imatinib have been synthesised by a
Cu(I)-catalysed coupling of three previously synthesised (5-iodo-2-methylphenyl)-[4-(pyridin-3-yl)-6-perfluoroalkylpyrimidin-2-yl]amines
with four synthesised 3-substituted 4-(4-methylpiperazin-1-ylmethyl)benzamides.
Keywords: (6-perfluoroalkylpyrimidin-2-yl)amines, 3,4-substituted benzamides, Cu(I) catalysed coupling
N-Arylamides are prevalent in numerous compounds that are
of pharmaceutical interest. Imatinib – 4-(4-methylpiperazin-
1-ylmethyl)-N-{4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2-
ylamino]phenyl} benzamide (3, R = R1 = H) mesylate – a
selective tyrosine kinase inhibitor belongs to this class of
compounds. The imatinib success story has stimulated the
discovery of many novel inhibitors of protein kinases and
further studies of imatinib derivatives promise to enhance
understanding of how changes in drug structure affect biological
activity.1,2 A series of 3-substituted benzamide derivatives
structurally related to imatinib was prepared and found3 to be
much more potent than the parent compound. In continuation
of our research4,5 on the synthesis of perfluoroalkyl imatinib
analogous, 12 new derivatives have been prepared for biological
testing by coupling three (5-iodo-2-methylphenyl)-[4-(pyridin-
3-yl)-6-perfluoroalkylpyrimidin-2-yl]amines 1a–c obtained
previously5 with four 3-substituted-4-(4-methylpiperazin-1-
ylmethyl)benzamides 2a–d.
Scheme 2. Esterification6 of the carboxylic acids gave methyl or
ethyl esters, a-bromination7 of which with N-bromosuccinimide
and coupling3,8 of the products with 1-methylpiperazine
afforded the corresponding 3-substituted 4-(4-methylpiperazin-
1-yl)benzoates which were further converted into benzamides
2a–d. These compounds were coupled with iodo compounds
1a–c in the presence of Cu(I), K3PO4 and DMEDA in solvent
t-BuOH under an argon atmosphere to give the 3-substituted
4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-
3-yl-6-polyfluoromethyl-pyrimidin-2-yl-amino)phenyl]
benzamides 3a–l as imatinib (3, R = R1 = H) analogues in
moderate to good yields.
In some cases (synthesis of 3a, 3i), the iodide was consumed
completely after 18–24 h and good yields were obtained, but
for others mainly starting material (revealed by LC/MS) was
present even after 48 h. For example, the coupling of iodide 1c
with benzamides 2b and 2d gave low yields, which could not be
improved even by a prolonged reaction time, and unconsumed
iodide was recovered in 43% yield. Even when the amount of
Cu(I) iodide was increased up to 100 mol%, the coupling reaction
could not be effected efficiently. During the coupling of iodides
1 with bromo benzamide 2b, minor amounts of iodo derivatives
4 originated from halogen exchange could be detected. This
is in agreement with the disclosure9 of a so called aromatic
Finkelstein reaction, i.e. copper-catalysed halogen exchange in
aryl halides. In the case of coupling iodide 1a with amide 2b, we
Results and discussion
The synthetic route designed for obtaining the target compounds
3a–l is shown in Scheme 1 and employs the same Cu(I)-
catalysed coupling method described by us5 for synthesising the
parent analogues 3 (R = CF3, C2F5, C3F7, R1 = H). The starting
amides 2a–d were prepared from commercially available
disubstituted benzoic acids by standard methods as shown in
N
N
N
N
N
O
N
N
O
R1
R1
N
I
I
HN
HN
+
i
H2N
N
N
N
N
R
N
N
R
N
N
F
N
N
3C
H
H
H
O
1a-c
2a-d
3a-l
1
a
R
4
2
a
R1
Cl
CF3
C2F5
F7
3
a
R
R1
b
c
CF3 Cl
CF3 Br
b
c
Br
C3
b
c
F
F
CF3
CF3 CF3
F5
d
CF3
d
e
C2
Cl
f
C2F5 Br
F5
F5
F
C2
C2
g
h
i
CF3
Cl
F7
C3
C3
C3
C3
F7 Br
j
k
F7
F7
F
l
CF3
Scheme 1 (i) Cu(I), DMEDA, K3PO4, t-BuOH, reflux.
* Correspondent. E-mail: terentjeva@osi.lv

JOURNAL OF CHEMICAL RESEARCH 2016 225
The same synthesis protocol was used to obtain the other amides
2a,b,d.
COOH
COOAlk
COOAlk
iv
3-Chloro-4-(4-methylpiperazin-1-ylmethyl)benzamide (2a): Yield
2.07 g (87%); white solid; m.p. 88–91 °C (toluene); 1H NMR (400 MHz):
d 2.27 (3H, s, CH3), 2.42–2.53 (4H, br s, CH2 piperazine), 2.52–2.63
(4H, br s, CH2 piperazine), 3.67 (2H, s, CH2), 4.83 (2H, s, NH2), 7.58
(1H, d, J = 8.0 Hz, H-5 Ar), 7.76 (1H, dd, J = 8.0, 1.8 Hz, H-6 Ar), 7.89
(1H, d, J = 1.8 Hz, H-2 Ar); 13C NMR (100 MHz): d 46.0 (CH3), 53.6
(C piperazine), 55.8 (C piperazine), 59.7 (CH2), 127.0 (C-6), 129.8 (C-2),
132.1 (C-5), 135.4 and 135.6 (C-1 and C–Cl), 140.5 (C-4), 170.4 (C=O);
HRMS (ESI) for C13H19ClN3O [M + 1]+: calcd 268.1217, found: 268.1217.
3-Bromo-4-(4-methylpiperazin-1-ylmethyl)benzamide (2b): Yield
i, ii
iii
2 a-d
R1
R1
R1
Br
Alk=Me, Et
N
R1=Cl, Br, F, CF3
N
Scheme 2 (i) MeOH or EtOH, H2SO4, 60 °C, 18 h; (ii) NBS, (PhCOO)2,
benzene, 250W, reflux, 4 h; (iii) N-methylpiperazine, K2CO3, THF, 18 h, rt;
(iv) NH3, 150 °C, 50 atm, 18 h.
1
2.23 g (80%); white solid; m.p. 163–165 °C; H NMR (400 MHz): d
2.26 (3H, s, N–CH3), 2.35–2.50 (4H, br s, CH2 piperazine), 2.50–2.65
(4H, br s, CH2 piperazine), 3.63 (2H, s, CH2), 4.84 (2H, s, NH2), 7.55
(1H, d, J = 7.8 Hz, H-5 Ar), 7.80 (1H, d, J = 7.8 Hz, H-6 Ar), 8.07 (1H,
s, H-2 Ar); 13C NMR (100 MHz): d 46.0 (CH3), 53.6 (C piperazine),
55.9 (C piperazine), 62.3 (CH2), 125.5 (C–Br), 127.6 (C-6), 131.9 (C-5),
133.1 (C-2), 135.5 (C-1), 142.3(C-4), 170.3 (C=O). MS m/z (%): 312,
314 [M + 1]+ (100); Anal. calcd for C13H18BrN3O: C, 50.01; H, 5.81; N,
13.46; found: C, 49.99; H, 5.76; N, 13.40%.
managed to characterise compound 4 as a reaction by-product.
Minor iodo products of type 4 are easily distinguishable from
major bromo derivatives by MS and NMR methods. Halogen
exchange causes dramatic changes in the 13C spectra and in the
chemical shifts of protons (H and CH2) next to halogen.
1
All the compounds were characterised by their H and 13C
NMR spectra. 2D COSY spectroscopy was applied for correct
chemical shift attributions in N-aryl amide and benzoic acid
subunits.
4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzamide
1
(2d): Yield 2.2 g (81%), white solid; m.p. 83–86 °C; H NMR (400
MHz): d 2.29 (3H, s, N–CH3), 2.48 (8H, br s, CH2 piperazine), 3.68
(2H, s, CH2), 5.91 (1H, br s, NH2), 6.19 (1H, br s, NH2), 7.90 (1H, d,
J = 8.1 Hz, H-5 Ar), 7.93 (1H, dd, J = 8.1, 1.6 Hz, H-6 Ar), 8.06 (1H,
br s, H-2 Ar). 13C NMR (100 MHz): d 45.9 (CH3), 53.1 (C piperazine),
55.1 (C piperazine), 57.9 (d, J = 1.9 Hz, CH2), 124.0 (q, J = 274.2 Hz,
CF3), 125.0 (q, J = 5.7 Hz, C-2), 129.0 (q, J = 30.9 Hz, C-3), 130.4 (q,
J = 0.9 Hz, C-5), 130.7 (C-6); 132.0 (C-1); 142.2 (q, J = 1.3 Hz, C-4),
168.0 (C=O); HRMS (ESI) for C14H19F3N3O·[M + 1]+: calcd 302.1480,
found: 302.1484.
Experimental
1H, 19F and 13C NMR spectra were obtained on a Varian 300-MR,
400-MR or a 600-MR spectrometer in DMSO-d6, except 2a–c (in
CD3OD), 2d (in CDCl3) and 3e (19F NMR spectrum obtained in
CDCl3). The residual solvent protons served as internal standard
in DMSO-d6 (2.50 ppm for H nuclei and 39.5 ppm for 13C nuclei), in
CHCl3 (7.26 ppm for H nuclei and 77.16 ppm for 13C nuclei) and in
CD3OD (3.31 ppm for 1H nuclei). Chemical shifts (d) are given in ppm
and coupling constants (J) in Hz. The assignment of resonance signals
to individual protons of compounds 3 was based on COSY spectra.
The COSY spectra recorded for compounds 3e–h served as a basis for
analysis of related compounds 3a–d and 3i–l spectra.
The high resolution mass spectra were done on an Agilent UPLC
(Agilent 6230 TOF LC/MS) instrument. The mass spectra were
obtained with an Acquity UPLC liquid chromato-mass spectrometer
of the Waters-Q-TOF (Micromass) system. Elemental analyses were
determined on a Carlo Erba Instrument (EA-1106). The melting points
of derivatives were determined on a Boetius apparatus. Unless noted
below, starting compounds were supplied by Alfa Aesar or Acros, and
used without purification. The assay of the DMEDA used was 85%.
1
1
2-Arylamino-4-(pyridin-3-yl)-6-perfluoroalkylpyrimidines (3); general
procedure
To a suspension of (5-iodo-2-methylphenyl)pyrimidin-2-ylamine 1
(0.80 mmol), the corresponding amide 2 (0.80 mmol), Cu(I) iodide
(0.1 g, 0.56 mmol) and finely powdered K3PO4 (0.34 g, 1.60 mmol)
in t-BuOH (10 mL), DMEDA (71 μl, 0.56 mmol, 85%) was added
by syringe under an argon atmosphere. The heterogenous mixture
was refluxed for 18–72 h (conversion monitoring by LC/MS),
cooled and diluted with 5% aqueous solution of NH4OH (10 mL)
and dichloromethane (20 mL). The layers were separated, and the
aqueous layer was extracted with dichloromethane (2 × 10 mL). The
combined organic extracts were washed sequentially once with
NH4OH (8 mL) and water (8 mL), and dried (Na2SO4). The extract
was evaporated under reduced pressure. The residue was purified by
silica gel column chromatography using CH2Cl2–MeOH as eluent (6:1
for 3a,c,d,g–l and 10:1 for 3b,e,f). From the first fraction unreacted
(5-iodo-2-methylphenyl)pyrimidin-2-ylamine 1 could be recovered.
From the second fraction 2-arylamino-4-(pyridin-3-yl)-6-perfluoro-
alkylpyrimidine 3 was isolated and crystallised from an appropriate
solvent.
3-Chloro-4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-
(4-pyridin-3-yl-6-trifluoromethyl-pyrimidin-2-ylamino)phenyl]
benzamide (3a): Yellow solid, 0.32 g (67%); m.p. 234–236 °C
(toluene); 1H NMR (400 MHz): d 2.17 (3H, s, N–CH3), 2.21 (3H, s, C–
CH3), 2.35 (4H, br s, H piperazine), 2.40–2.50 (4H, br s, H piperazine,
overlap with DMSO), 3.61 (2H, s, CH2), 7.26 (1H, d, J = 8.4 Hz, H-5
Ar), 7.51 (1H, dd, J = 8.4, 1.8 Hz, H-6 Ar), 7.54 (1H, ddd, J = 8.1, 4.9,
0.6 Hz, H-5 Py), 7.62 (1H, d, J = 8.0 Hz, H-5), 7.86 (1H, s, H Pm), 7.89
(1H, dd, J = 8.0, 1.9 Hz, H-6), 7.98–8.03 (2H, m, H-2 Ar and H-2),
8.54 (1H, ddd, J = 8.1, 1.9, 1.6 Hz, H-4 Py), 8.72 (1H, dd, J = 4.9, 1.6
Hz, H-6 Py), 9.33 (1H, dd, J = 1.9, 0.6 Hz, H-2 Py), 9.70 (1H, s, NH),
10.29 (1H, s, NH); 13C NMR (100 MHz): 17.6 (C–CH3), 45.6 (N–CH3),
52.6 (C piperazine), 54.6 (C piperazine), 58.4 (CH2), 102.7 (C-5 Pm),
117.6, 117.7, 120.7 (q, J = 277 Hz, CF3), 123.8, 126.3, 128.2, 128.7,
130.3, 130.6, 131.2, 133.2, 134.9, 135.2, 136.9, 137.0, 139.2, 148.6,
3-Fluoro-4-(4-methylpiperazin-1-ylmethyl)benzamide
(2c).
Methyl 3-fluoro-4-(4-methyl-piperazin-1-ylmethyl)benzoate6 (2.37 g,
8.9 mmol) and ~5 mL of liquid ammonia (acetone/CO2) in a stainless
steel reactor were stirred and heated for 15 h at 150 °C and 50 bar
pressure. Then the reactor was cooled to –50 °C and kept for 15 min at
this temperature. After release of pressure the autoclave was opened
and the remaining ammonia was volatilised warming by allowing
the mass to warm slowly to room temperature. The yellowish residue
was taken up in methanol (10–15 mL), with addition of 2.5 g of silica
gel. The solvent was distilled off on a rotary evaporator to give the
crude product absorbed on silica gel which was purified by column
chromatography using EtOAc–MeOH–NH4OH (3:1:0.1) as eluent.
The crude product was crystallised from toluene and dried in a
vacuum (70 °C, 1–10 mbar, 18 h) to obtain 1.73 g (77%) of amide 2c
1
as a white solid; m.p. 145–148 °C; H NMR (400 MHz): d 2.24 (3H,
s, CH3), 2.35–2.65 (8H, br s, CH2 piperazine), 3.61 (1H, d, J = 1.2 Hz,
CH2), 4.84 (2H, s, NH2), 7.49 (1H, t, J = 7.8 Hz, H-5 Ar), 7.58 (1H,
dd, J = 10.6, 1.8 Hz, H-2 Ar), 7.66 (1H, dd, J = 7.8, 1.8 Hz, H-6 Ar);
13C NMR (100 MHz): d 44.9 (CH3), 53.3 (C piperazine), 55.5 (d,
J = 1.9 Hz, CH2), 55.6 (C piperazine), 114.2 (d, J = 24.5 Hz, C-2), 122.9
(d, J = 3.4, C-6), 127.8 (d, J = 15.0, C-4), 131.7 (d, J = 4.4, C-5), 135.0
(d, J = 7.3, C-1), 161.1 (d, J = 246.4 Hz, C–F), 169.1 (C=O); Mass m/z
(%): 252 [M + 1]+ (100); Anal. calcd for C13H18FN3O: C, 62.13; H, 7.22;
N, 16.72; found: C, 62.12; H, 7.23; N, 16.60%.

226 JOURNAL OF CHEMICAL RESEARCH 2016
152.0, 156.3 (q, J = 34 Hz, C–CF3), 161.2, 163.8, 165.1. Anal. calcd for
C30H29ClF3N7O: C, 60.45; H, 4.90; N, 16.45; found: C, 60.11; H, 4.89;
N, 16.13%.
piperazine), 3.68 (1H, s, CH2), 7.27 (1H, d, J = 8.3 Hz, H-5 Ar), 7.51
(1H, dd, J = 8.3, 1.8 Hz, H-6 Ar), 7.54 (1H, dd, J = 8.0, 4.8 Hz, H-5
Py), 7.86 (1H, s, H Pm), 7.91 (1H, d, J = 8.1 Hz, H-5), 7.97 (1H, d,
J = 1.8 Hz, H-2 Ar), 8.20 (1H, d, J = 8.1 Hz, H-6), 8.22 (1H, s, H-2),
8.55 (1H, ddd, J = 8.0, 2.3, 1.6 Hz, H-4 Py), 8.73 (1H, dd, J = 4.8, 1.6
Hz, H-6 Py), 9.34 (1H, d, J = 2.3 Hz, H-2 Py), 9.72 (1H, s, NH), 10.4
(1H, s, NH); 13C NMR (100 MHz): d 17.6 (C–CH3), 45.6 (N–CH3),
52.7 (C piperazine), 54.6 (C piperazine), 57.5 (CH2), 102.7 (C-5 Pm),
117.8 (2C), 120.6 (q, J = 275 Hz, CF3), 121.4 (q, J = 275 Hz, CF3),
123.8 (C-5 Py), 125.0, 127.2 (q, J = 30 Hz, C–CF3), 128.8, 130.3, 130.7,
131.2, 131.5, 133.9, 134.9, 136.90, 136.95, 141.0, 148.6, 152.2, 156.5 (q,
J = 34 Hz, C–CF3), 161.2, 163.9, 165.1; HRMS (ESI) for C31H30F6N7O
[M + 1]+: calcd 630.2411, found: 630.2387.
3-Bromo-4- (4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-
(4-pyridin-3-yl-6-trifluoromethyl-pyrimidin-2-ylamino)phenyl]
benzamide (3b) was purified by preparative TLC (PLC plates, 20
× 20 cm, silica gel 60 F254, 2 mm, Merck) using CH2Cl2–MeOH–
NH3 (10:20:0.1) as eluent to give a yellow solid, 0.30 g (59%); m.p.
1
203–205 °C (Et2O); H NMR (600 MHz): d 2.12 (3H, s, N–CH3),
2.17 (3H, s, C–CH3), 2.35 (4H, br s, H piperazine), 2.46 (4H, br s, H
piperazine), 3.55 (2H, s, CH2), 7.21 (1H, d, J = 8.3 Hz, H-5 Ar), 7.48
(1H, dd, J = 8.3, 1.7 Hz, H-6 Ar), 7.50 (1H, dd, J = 8.1, 4.8 Hz, H-5
Py), 7.57 (1H, d, J = 8.1 Hz, H-5), 7.80 (1H, s, H Pm), 7.90 (1H, dd,
J = 8.1, 1.7 Hz, H-6), 7.97 (1H, d, J = 1.7 Hz, H-2 Ar), 8.13 (1H, d,
J = 1.7 Hz, H-2), 8.50 (1H, ddd, J = 8.1, 2.0, 1.7 Hz, H-4 Py), 8.68 (1H,
dd, J = 4.8, 1.7 Hz, H-6 Py), 9.29 (1H, d, J = 2.0 Hz, H-2 Py), 9.68 (1H,
s, NH), 10.26 (1H, s, NH); 13C NMR (150 MHz): d 18.4 (C–CH3), 46.2
(N–CH3), 53.1 (C piperazine), 55.2 (C piperazine), 61.4 (CH2), 103.2
(C-5 Pm), 118.1 (C-6 Ar), 118.2 (C-2 Ar), 121.2 (q, J = 273 Hz, CF3),
124.1 (C–Br), 124.4 (C-5 Py), 127.4 (C-6), 129.2 (C-4 Ar), 130.8 (C-5
Ar), 131.1 (C-1), 131.7 (C-5), 131.9 (C-2), 135.5 (C-3 Py), 135.8 (C-4
Py), 137.4 (C-1 Ar), 137.5 (C-3 Ar), 141.4 (C-4), 149.1 (C-2 Py), 152.7
(C-6 Py), 156.9 (q, J = 34 Hz, C–CF3), 161.6 (C-2 Pm), 164.2 (C=O),
165.6 (C-4 Pm); HRMS (ESI) for C30H30BrF3N7O [M + 1]+: calcd
640.1642, found: 640.1641.
3-Iodo-4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-
pyridin-3-yl-6-trifluoromethyl-pyrimidin-2-ylamino)phenyl]
benzamide (4) was detected in mixture with 3b (ratio 3b:4 was 4:1).
1H NMR (600 MHz): d 2.12 (3H, s, N–CH3), 2.17 (3H, s, C–CH3),
2.35 (4H, br s, H piperazine), 2.46 (4H, br s, H piperazine), 3.47 (2H,
s, CH2), 7.21 (1H, d, J = 8.3 Hz, H-5 Ar), 7.48 (1H, dd, J = 8.3, 1.7 Hz,
H-6 Ar), 7.50 (1H, dd, J = 8.1, 4.8 Hz, H-5 Py), 7.47 (1H, d, J = 8.1 Hz,
H-5), 7.80 (1H, s, H Pm), 7.89 (1H, dd, J = 8.1, 1.7 Hz, H-6), 7.96 (1H, d,
J = 1.7 Hz, H-2 Ar), 8.35 (1H, d, J = 1.7 Hz, H-2), 8.50 (1H, ddd, J = 8.1,
2.0, 1.7 Hz, H-4 Py), 8.68 (1H, dd, J = 4.8, 1.7 Hz, H-6 Py), 9.29 (1H,
d, J = 2.0 Hz, H-2 Py), 9.68 (1H, s, NH), 10.26 (1H, s, NH); 13C NMR
(150 MHz): d 18.4 (C–CH3), 46.2 (N–CH3), 53.0 (C piperazine),
56.5 (C piperazine), 65.9 (CH2), 100.9 (C–I), 103.2 (C-5 Pm), 118.1
(C-6 Ar), 118.2 (C-2 Ar), 121.2 (q, J = 273 Hz, CF3), 124.4 (C-5 Py),
127.9 (C-6), 129.2 (C-4 Ar), 130.4 (C-5), 130.8 (C-5 Ar), 131.1 (C-1),
138.4 (C-2), 135.5 (C-3 Py), 135.8 (C-4 Py), 137.4 (C-1 Ar), 137.5 (C-3
Ar), 144.3 (C-4), 149.1 (C-2 Py), 152.7 (C-6 Py), 156.9 (q, J = 34 Hz,
C–CF3), 161.6 (C-2 Pm), 164.2 (C=O), 165.6 (C-4 Pm); HRMS (ESI)
for C30H30N7OF3I [M + 1]+: calcd 688.1509, found: 688.1487.
3-Chloro-N-[4-methyl-3- (4-pentafluoroethyl-6-pyridin-3-
ylpyrimidin-2-ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)
benzamide (3e): Yellow solid, 0.30 g (59%), m.p. 223–224 °C
1
(MeOH); H NMR (400 MHz): d 2.18 (3H, s, N–CH3), 2.20 (3H, s,
C–CH3), 2.37 (4H, br s, H piperazine), 2.46 (4H, br s, H piperazine),
3.62 (2H, s, CH2), 7.26 (1H, d, J = 8.2 Hz, H-5 Ar), 7.50 (1H, dd, J = 8.2,
2.1 Hz, H-6 Ar), 7.54 (1H, dd, J = 8.0, 4.9 Hz, H-5 Py), 7.62 (1H, d,
J = 8.0 Hz, H-5), 7.87 (1H, s, H Pm); 7.89 (1H, dd, J = 8.0, 1.7 Hz, H-6),
7.98 (1H, d, J = 2.1 Hz, H-2 Ar), 7.99 (1H, d, J = 1.7 Hz, H-2), 8.54 (1H,
ddd, J = 8.0, 2.0, 1.7 Hz, H-4 Py), 8.72 (1H, dd, J = 4.9, 1.7 Hz, H-6 Py),
9.33 (1H, d, J = 2.0 Hz, H-2 Py), 9.71 (1H, s, NH), 10.28 (1H, s, NH);
19F NMR (400 MHz): d −82.0 (CF3), −118.1 (CF2); Anal. calcd for
C31H29ClF5N7O: C, 57.63; H, 4.52; N, 15.18; found: C, 57.57; H, 4.46;
N, 14.96%.
3-Bromo-N-[4-methyl-3- (4-pentafluoroethyl-6-pyridin-3-
ylpyrimidin-2-ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)
benzamide (3f): Yellow solid, 0.27 g (49%), m.p. 211.5–212.5 °C
(toluene); 1H NMR (300 MHz): d 2.16 (3H, s, N–CH3), 2.20 (3H,
s, C–CH3), 2.34 (4H, br s, H piperazine), 2.45–2.50 (4H, br s, H
piperazine, overlap with DMSO), 3.51 (2H, s, CH2), 7.25 (1H, d,
J = 8.2 Hz, H-5 Ar), 7.50 (1H, dd, J = 8.2, 2.2 Hz, H-6 Ar), 7.55 (1H,
dd, J = 8.0, 4.8 Hz, H-5 Py), 7.60 (1H, d, J = 8.0 Hz, H-5), 7.87 (1H, s,
H Pm), 7.92 (1H, dd, J = 8.0, 1.9 Hz, H-6), 7.97 (1H, d, J = 2.2 Hz, H-2
Ar), 8.15 (1H, d, J = 1.9 Hz, H-2), 8.54 (1H, ddd, J = 8.0, 2.0, 1.9 Hz,
H-4 Py), 8.73 (1H, dd, J = 4.8, 1.9 Hz, H-6 Py), 9.33 (1H, d, J = 2.0 Hz,
H-2 Py), 9.71 (1H, s, NH), 10.28 (1H, s, NH); 19F NMR (400 MHz): d
−82.0 (CF3), −118.1 (CF2); HRMS (ESI) for C31H30BrF5N7O [M + 1]+:
calcd 690.1610; found: 690.1587.
3-Fluoro-N-[4-methyl-3- (4-pentafluoroethyl-6-pyridin-3-
ylpyrimidin-2-ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)
1
benzamide (3g): 0.36 g (71%), m.p. 230–231 °C (toluene); H NMR
3-Fluoro-4- (4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-
(4-pyridin-3-yl-6-trifluoromethyl-pyrimidin-2-ylamino)phenyl]
benzamide (3c): Yellow solid, 0.27 g (59%); m.p. 239–241 °C
(400 MHz): d 2.15 (3H, s, N–CH3), 2.20 (3H, s, C–CH3), 2.33 (4H, br
s, H piperazine), 2.41 (4H, br s, H piperazine), 3.57 (2H, s, CH2), 7.25
(1H, d, J = 8.3 Hz, H-5 Ar), 7.50 (1H, dd, J = 8.3, 2.1 Hz, H-6 Ar), 7.51
(1H, ddd, J = 8.0, 4.8, 0.5 Hz H-5 Py), 7.54 (1H, dd, J = 7.9, 7.4 Hz,
H-5), 7.72 (1H, dd, J = 10.6, 1.5 Hz, H-2), 7.77 (1H, dd, J = 7.9, 1.5 Hz,
H-6), 7.86 (1H, s, H Pm), 7.99 (1H, d, J = 2.1 Hz, H-2 Ar), 8.53 (1H,
ddd, J = 8.0, J = 2.0, 1.6 Hz, H-4 Py), 8.72 (1H, dd, J = 4.8, 1.6 Hz,
H-6 Py), 9.33 (1H, dd, J = 2.0, 0.5, H-2 Py), 9.68 (1H, s, NH), 10.21
(1H, s, NH); 19F NMR (400 MHz): d −82.0 (CF3), −117.6 (F Ar), −118.1
(CF2); Anal. calcd for C31H29F6N7O: C, 59.14; H, 4.64; N, 15.57; found:
C, 59.41; H, 4.61; N, 15.46%.
1
(toluene); H NMR (300 MHz): d 2.14 (3H, s, N–CH3), 2.21 (3H, s,
C–CH3), 2.31 (4H, br s, H piperazine), 2.41 (4H, br s, H piperazine),
3.57 (1.7H, s, CH2), 7.26 (1H, d, J = 8.0 Hz, H-5 Ar), 7.51 (1H, dd,
J = 8.0, 2.1 Hz, H-6 Ar), 7.53 (1H, t, J = 7.5 Hz, H-5), 7.55 (1H, ddd,
J = 8.0, 4.7, 0.6 Hz, H-5 Py), 7.73 (1H, dd, J = 11.0, 1.6 Hz, H-2),
7.77 (1H, dd, J = 7.5, 1.6 Hz, H-6), 7.86 (1H, s, H Pm), 8.01 (1H,
d, J = 2.1 Hz, H-2 Ar), 8.54 (1H, ddd, J = 8.0, 2.2, 1.6 Hz, H-4 Py),
8.72 (1H, dd, J = 4.7, 1.6 Hz, H-6 Py), 9.33 (1H, dd, J = 2.2, 0.6 Hz,
H-2 Py), 9.70 (1H, s, NH), 10.25 (1H, s, NH); 13C NMR (100 MHz):
d 17.8 (C–CH3), 46.1 (N–CH3), 52.9 (C piperazine), 55.0 (CH2), 55.2
(C piperazine), 103.6 (C-5 Pm), 113.9, 114.6 (d, J = 25 Hz, C-2), 116.2,
120.6 (q, J = 275 Hz, CF3), 122.3, 124.0, 125.2, 129.1 (d, J = 15 Hz,
C-4), 131.0, 131.6 (d, J = 7 Hz, C-5), 131.9, 135.3, 135.9 (d, J = 7 Hz,
C-1), 136.4, 137.2, 148.8, 152.3, 157.8 (q, J = 36 Hz, C–CF3), 160.7,
161.3 (d, J = 249 Hz, C-3), 164.4, 165.6; Anal. calcd for C30H29F4N7O:
C, 62.17; H, 5.04; N, 16.92; found: C, 61.97; H, 4.98; N, 16.69%.
N-[4-Methyl-3-(4-pentafluoroethyl-6-pyridin-3-yl-pyrimidin-
2-ylamino) phenyl]- 4- (4-methyl-piperazin-1-ylmethyl) -3-
trifluoromethylbenzamide (3h): 0.39 g (71%), m.p. 162–164 °C
1
(toluene); H NMR (300 MHz): d 2.16 (3H, s, N–CH3), 2.21 (3H, s,
C–CH3), 2.36 (4H, br s, H piperazine), 2.41 (4H, br s, H piperazine),
3.67 (2H, s, CH2), 7.26 (1H, d, J = 8.3 Hz, H-5 Ar), 7.51 (1H, dd, J = 8.3,
2.0 Hz, H-6 Ar), 7.54 (1H, dd, J = 8.0, 4.8 Hz, H-5 Py), 7.87 (1H, s, H
Pm), 7.91 (1H, d, J = 8.1 Hz, H-5), 7.97 (1H, d, J = 2.0 Hz, H-2 Ar), 8.20
(1H, dd, J = 8.1, 1.6 Hz, H-6), 8.22 (1H, d, J = 1.6 Hz, H-2), 8.55 (1H, dt,
J = 8.0, 1.6 Hz, H-4 Py), 8.72 (1H, dd, J = 4.8, 1.6 Hz, H-6 Py), 9.33 (1H,
d, J = 1.6 Hz, H-2 Py), 9.71 (1H, s, NH), 10.40 (1H, s, NH); 19F NMR (400
MHz): d −58.2 (CF3 Ar), −82.0 (CF3CF2), −118.1 (CF2); HRMS (ESI)
calcd for C32H30F8N7O [M + 1]+ 680.2379; found: 680.2351.
4 - (4 - Methylpiperazin-1-ylmethyl) -N- [4 -methyl-3- (4 -
pyridin-3-yl-6-trifluoromethylpyrimidin-2-ylamino)phenyl]-3-
trifluoromethylbenzamide (3d): Yellow solid, 0.40 g (80%); m.p.
1
211–213 °C (MeOH); H NMR (400 MHz): d 2.18 (3H, s, N–CH3),
2.21 (3H, s, C–CH3), 2.37 (4H, br s, H piperazine), 2.42 (4H, br s, H

JOURNAL OF CHEMICAL RESEARCH 2016 227
3-Chloro-N-[3-(4-heptafluoropropyl-6-pyridin-3-ylpyrimidin-
19F NMR (400 MHz): d −79.9 (CF3), −115.8 (CF3CF2CF2), −117.6 (F
Ar), −125.8 (CF3CF2CF2); Anal. calcd for C32H29F8N7O: C, 56.55; H,
4.30; N, 14.43; found: C, 56.75; H, 4.27; N, 14.16%.
2-ylamino)-4-methylphenyl]-4-(4-methylpiperazin-1-ylmethyl)
1
benzamide (3i): 0.41 g (74%), m.p. 215–216 °C (MeOH); H NMR
N- [3- (4-Heptaf luoropropyl- 6-pyridin-3-ylpyrimidin-2-
ylamino)-4-methylphenyl]-4-(4-methyl-piperazin-1-ylmethyl)-
3-trifluoromethylbenzamide (3l): 0.19 g (32%), m.p. 183–185 °C
(300 MHz, DMSO-d6): d 2.16 (3H, s, N–CH3), 2.20 (3H, s, C–CH3),
2.34 (4H, br s, H piperazine), 2.45–2.50 (4H, br s, H piperazine,
overlap with DMSO), 3.61 (2H, s, CH2), 7.26 (1H, d, J = 8.3 Hz, H-5
Ar), 7.51 (1H, dd, J = 8.3, 1.6 Hz, H-6 Ar), 7.54 (1H, dd, J = 7.6, 4.6
Hz, H-5 Py), 7.62 (1H, d, J = 8.0 Hz, H-5), 7.86 (1H, s, H Pm), 7.88 (1H,
dd, J = 8.0, 1.5 Hz, H-6), 7.97 (1H, d, J = 1.6 Hz, H-2 Ar), 7.99 (1H, d,
J = 1.5 Hz, H-2), 8.55 (1H, ddd, J = 7.6, 1.8, 1.6 Hz, H-4 Py), 8.73 (1H,
dd, J = 4.6, 1.6 Hz, H-6 Py), 9.33 (1H, d, J = 1.8 Hz, H-2 Py), 9.71 (1H,
s, NH), 10.28 (1H, s, NH); 19F NMR (400 MHz): d −79.8 (CF3), −115.9
(CF3CF2CF2), −125.8 (CF3CF2CF2). HRMS (ESI) for C32H30ClF7N7O
[M + 1]+: calcd 696.2083, found: 696.2078.
1
(MeOH); H NMR (300 MHz): d 2.16 (3H, s, N–CH3), 2.20 (3H, s,
C–CH3), 2.35 (4H, br s, H piperazine), 2.42 (4H, br s, H piperazine),
3.67 (2H, s, CH2), 7.26 (1H, d, J = 8.3 Hz, H-5 Ar), 7.51 (1H, dd, J = 8.3,
1.6 Hz, H-6 Ar), 7.54 (1H, dd, J = 8.0, J = 4.8 Hz, H-5 Py), 7.86 (1H, s,
H Pm), 7.91 (1H, d, J = 8.0 Hz, H-5), 7.97 (1H, d, J = 1.6 Hz, H-2 Ar),
8.19 (1H, dd, J = 8.0, 1.4 Hz, H-6), 8.22 (1H, br s, H-2), 8.55 (1H, ddd,
J = 8.0, 2.1, 1.7 Hz, H-4 Py), 8.72 (1H, dd, J = 4.8, 1.7 Hz, H-6 Py),
9.34 (1H, d, J = 2.1 Hz, H-2 Py), 9.73 (1H, s, NH), 10.40 (1H, s, NH);
19F NMR (400 MHz): d −58.2 (CF3 Ar), −79.8 (CF3CF2CF2), −115.9
(CF3CF2CF2), −125.8 (CF3CF2CF2); HRMS (ESI) for C33H30F10N7O
[M + 1]+: calcd 730.2347, found: 730.2343.
3-Bromo-N-[3-(4-heptafluoropropyl-6-pyridin-3-ylpyrimidin-
2-ylamino)-4-methylphenyl]-4-(4-methylpiperazin-1-ylmethyl)
1
benzamide (3j): 0.18 g (32%), m.p. 186–188 °C (toluene); H NMR
(400 MHz): d 2.16 (3H, s, N–CH3), 2.20 (3H, s, C–CH3), 2.34 (4H, br s,
H piperazine), 2.45–2.50 (4H, br s, H piperazine overlap with DMSO),
3.58 (2H, s, CH2), 7.25 (1H, d, J = 8.2 Hz, H-5 Ar), 7.50 (1H, dd, J = 8.2,
2.0 Hz, H-6 Ar), 7.54 (1H, dd, J = 8.0, 4.8 Hz, H-5 Py), 7.60 (1H, d,
J = 8.0 Hz, H-5), 7.86 (1H, s, H Pm), 7.93 (1H, dd, J = 8.0, 1.7 Hz, H-6),
7.97 (1H, d, J = 2.0 Hz, H-2 Ar), 8.16 (1H, d, J = 1.7 Hz, H-2), 8.55
(1H, ddd, J = 8.0, 2.2, 1.7 Hz, H-4 Py), 8.72 (1H, dd, J = 4.8, 1.7 Hz,
H-6 Py), 9.33 (1H, d, J = 2.2 Hz, H-2 Py), 9.71 (1H, s, NH), 10.28 (1H,
s, NH); 19F NMR (400 MHz): d−79.8 (CF3), −115.9 (CF3CF2CF2),
−125.8 (CF3CF2CF2); HRMS (ESI) for C32H30BrF7 N7O [M + 1]+: calcd
740.1578, found: 740.1569.
This work was supported by a European Regional Development
Fund (ERDF) project No. 2DP/2.1.1.1.0/10/APIA/VIAA/065.
Received 19 January 2016; accepted 20 February 2016
Paper 1603855 doi: 10.3184/174751916X14576998046299
Published online: 18 March 2016
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1
benzamide (3k): 0.29 g (53%), m.p. 226–227 °C (toluene); H NMR
(300 MHz): d 2.14 (3H, s, N–CH3), 2.20 (3H, s, C–CH3), 2.32 (4H, br
s, H piperazine), 2.41 (4H, br s, H piperazine), 3.57 (2H, s, CH2), 7.25
(1H, d, J = 8.2 Hz, H-5 Ar), 7.48–7.58 (3H, m, H-5 Py, H-6 Ar, H-5),
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J = 8.0, 2.2, 1.7 Hz, H-4 Py), 8.72 (1H, dd, J = 4.8, 1.7 Hz, H-6 Py),
9.33 (1H, d, J = 2.2 Hz, H-2 Py), 9.72 (1H, s, NH), 10.24 (1H, s, NH);
4
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