4-arylamino-2-(2-acetoxyethyl)amino-6-methylpyrimidines: Synthesis, deacetylation, and biological activity

Article abstract of DOI:10.1134/S1070363207110163

The reaction of 2-(2-acetoxyethyl)amino-4-chloro-6-methylpyrimidine with aromatic amines leads to a series of 4-arylamino-2-(2-acetoxyethyl)amino-6- methylpyrimidines. Deacetylation of these compounds proceeds in both acidic and basic media. Most of the a

Full text of DOI:10.1134/S1070363207110163

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 11, pp. 1939 1943.
Pleiades Publishing, Ltd., 2007.
Original Russian Text A.V. Erkin, V.I. Krutikov, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 11, pp. 1887 1892.
4-Arylamino-2-(2-acetoxyethyl)amino-6-methylpyrimidines:
Synthesis, Deacetylation, and Biological Activity
A. V. Erkin and V. I. Krutikov
St.-Petersburg State Technological Institute,
Moskovskii pr. 26, St.-Petersburg, 190013 Russia
Received May 10, 2007
Abstract The reaction of 2-(2-acetoxyethyl)amino-4-chloro-6-methylpyrimidine with aromatic amines
leads to a series of 4-arylamino-2-(2-acetoxyethyl)amino-6-methylpyrimidines. Deacetylation of these com-
pounds proceeds in both acidic and basic media. Most of the arylaminopyrimides obtained exhibit a pro-
nounced antituberculous effect.
DOI: 10.1134/S1070363207110163
A convenient synthetic approach to new biologically
active compounds of the pyrimidine series is provided
by nucleophilic substitution of halogen atoms or
other easily leaving groups in even positions of the
ring by pharmacophoric groups. The aim of this work
was to synthesize 4-arylamino-2-(2-acetoxyethyl)-
amino-6-methylpyrimidines Ia Ij by amination of
2-(2-acetoxyethyl)amino-6-methylpyrimidin-4(3H)-
one (III) with aromatic amines, to study deacetylation
of the target compounds under various conditions, and
to assess their biological activity. According to pub-
lished data [1], the target compounds would be ex-
pected to exhibit antibacterial properties.
We compared exchange chlorination of 2-(2-acet-
oxyethyl)amino-6-methyl-pyrimidin-4(3H)-one (III)
with phosphorus oxytrichloride [2] and pentachloride
[3] and gave preference to latter method as providing
stable yields of 60 70% and high purity of chloride
II. Heating of an equimolar mixture of acetate III and
phosphorus pentachloride at 100 110 C for no longer
than 15 min and subsequent decomposition of the re-
action mixture with ice and its neutralization with
aqueous ammonium hydroxide at 0 C (external cool-
ing) should be considered close to optimal conditions.
When no cooling is applied, strong heat release takes
place, which reduces the yield of chloride II to 35%.
Cl
O
NHAr
N
PCl5
HN
ArNH2
N
AcO
AcO
AcO
Me
Me
Me
N
N
N
N
N
N
H
H
H
III
II
Ia Ij
C6H11NH2
HN
N
AcO
Me
N
N
VIII
The decreased reactivity of the halogen atom in
2-amino-4-chloropyrimidines [4] prompted us to carry
out amination of compound II with aromatic amines
under rigid conditions at a 1:2 substrate:reagent
ratio (method a). However, under such conditions
arylaminopyrimidines Ia Id could not be isolated in
reasonable yields and chromatographic purity due to
significant tarring of the reaction mixture. To go
1939

1940
ERKIN, KRUTIKOV
Table 1. Yields, melting points, and TLC and elemental analysis data of 4-arylamino-2-(2-acetoxyethyl)amino-6-methyl-
pyrimidines Ia Ij
Found, %
H
Calculated, %
Method
of
synthesis
Comp.
no.
Yield, mp,
%
Ar
Rf
Formula
a
Cb
C
N
C
H
N
Ia Ph
Ib 3-MeC6H4
Ic 4-MeC6H4
Id 4-MeOC6H4
b
b
b
b
a
a
a
a
a
a
66
29
61
26
41
53
44
65
46
35
218 0.81 55.50 5.92 17.05 C15H18N4O2 HCl
202 0.80 57.19 6.34 16.57 C16H20N4O2 HCl
206 0.82 57.22 6.46 16.73 C16H20N4O2 HCl
193 0.75 55.03 6.43 15.87 C16H20N4O3 HCl
224 0.77 53.18 5.62 17.08 C15H17FN4O2 HCl
222 0.76 50.76 5.27 15.37 C15H17ClN4O2 HCl 50.39 5.04 15.68
226 0.82 50.32 5.31 15.51 C15H17ClN4O2 HCl 50.39 5.04 15.68
209 0.81 44.64 4.49 13.48 C15H17BrN4O2 HCl 44.81 4.48 13.95
222 0.82 44.72 4.32 13.78 C15H17BrN4O2 HCl 44.81 4.48 13.95
55.76 5.89 17.35
57.00 6.23 16.63
57.00 6.23 16.63
54.42 5.95 15.87
52.82 5.28 16.43
Ie
If
4-FC6H4
3-ClC6H4
Ig 4-ClC6H4
Ih 3-BrC6H4
Ii
Ij
4-BrC6H4
4-IC6H4
220 0.82 40.14 4.35 12.44 C15H17IN4O2 HCl
40.11 4.01 12.48
a
b
c
Yields of hydrochlorides are given. The products all, except for Id, melt with decomposition. Aqueous ethanol solutions of all
the compounds give positive tests for the chloride ion with aqueous solution of silver nitrate.
around these drawbacks, we treated chloride II with
equimolar amounts of phenyl-, 3- and 4-methylphenyl-,
and 4-methoxyphenylamines (method b). As a result,
the yields of arylaminopyrimidines Ia Id could be
improved by 10 30%, and the products were chro-
matographically pure after single crystallization.
Physicochemical characteristics of compounds Ia Ij
synthesized by methods a or b and isolated as hydro-
chlorides are listed in Table 1.
tion site. According to [5], 2,4-diaminopyrimidines
are quaternized by the most basic nitrogen atom in
the 1 position of the ring. To reveal the situation in
the target compounds, we compared the UV spectra
of 2-(2-acetoxyethyl)amino-6-methyl-4-(4-methyl-
phenyl)aminopyrimidine (Ic) and the neutral form of
the model compound, 6-methyl-4-(4-methylphenyl)-
aminopyrimidin-2(1H)-one (IV). The spectra proved
to be similar to each other in the long-wave range (see
figure), implying that compound Ic is protonated by
The structure of compounds Ia Ij was confirmed
1
N1 [6]. Substituted cytosine IV was synthesized by
stepwise modification of the structure of 6-methyl-
pyrimidine-2,4(1H, 3H)-dione (V). Sulfurization of
diketone V with phosphorus pentasulfide leads to
6-methyl-4-thioxo-3,4-dihydropyrimidin-2(1H)-one
(VI). Its S-methylation with methyl iodide gives
6-methyl-4-(methylsulfanyl)pyrimidin-2(1H)-one
(VII). Amination of thioether VII with (4-methyl-
phenyl)amine under rigid conditions gave model
compound IV.
by the H NMR spectra which contain characteristic
multiplets of aromatic ring protons at 6.8 8.00 ppm,
as well as broadened singlets of protons of the amino
group at the pyrimidine C4 atom near 10.5 ppm and
of the proton at the quaternary nitrogen atom of the
ring near
13 ppm. Spectral parameters of com-
pounds Ia Ij are listed in Table 2.
Arylaminopyrimidines Ia Ij were isolated as hyd-
rochlorides. It was important to find out their protona-
Me
S
SMe
HN
O
Me
NH2
MeI
P2S5
HN
N
N
HN
Me
Me
Me
Me
O
O
O
O
N
H
N
H
N
H
N
H
V
VI
VII
IV
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 11 2007

4-ARYLAMINO-2-(2-ACETOXYETHYL)AMINO-6-METHYLPYRIMIDINES
1941
Table 2. 1H NMR spectral parameters of 4-arylamino-2-(2-acetoxyethyl)amino-6-methylpyrimidines Ia Ij
Chemical shifts of protons, , ppma
Comp.
no.
Ac
Me
CH2
CH2
CH
N2H
N4H
Ar
N+H
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
Ii
1.99
1.98
2.00
2.00
1.98
1.99
1.99
2.02
1.99
2.01
2.32
2.31
2.31
2.31
2.31
2.33
2.33
2.35
2.32
2.33
3.65
3.65
3.64
3.64
3.63
3.66
3.64
3.67
3.64
3.66
4.18
4.18
4.18
4.17
4.16
4.18
4.17
4.20
4.18
4.18
6.25
6.23
6.22
6.17
6.23
6.27
6.23
6.29
6.27
6.26
8.14
8.11
8.16
8.12
8.11
8.14
8.11
8.25
8.15
8.21
10.80
10.71
10.73
10.67
10.93
11.05
10.90
11.05
11.03
10.93
7.12 7.69
6.94 7.55
7.11 7.56
6.86 7.58
7.13 7.71
7.13 7.92
7.35 7.71
7.26 7.63
7.48 7.68
7.55 7.64
13.28
13.21
13.29
13.18
13.22
13.32
13.23
13.46
13.28
13.42
Ij
a
The integral intensities of signals are consistent with the number of protons in the corresponding group.
The strong absorption band near 300 nm in the UV
spectra of arylaminopyrimidines Ia Ij arises mainly
from charge-transfer processes in the arylamidine
was found to proceed under the action of both acids
and bases. Treatment of arylaminopyrimidine Ic with
HCl yields 2-(2-hydroxyethyl)amino-6-methyl-4-(4-
methylphenyl)aminopyrimidine (IX) as hydrochloride.
fragment, and, to a lower extent, from n
* transi-
1
tions in the alkylamidine fragment. These assignments
follow from published data [7], as well as from the
low molar absorption coefficient of the long-wave
band in the spectrum of 2-(2-acetoxyethyl)amino-4-
cyclohexylamino-6-methylpyrimidine (VIII) (see
figure) we synthesized by the reaction of equimolar
amounts of chloride II and cyclohexylamine. The
absence in the UV spectra of compounds Ia Ij of ab-
sorption bands in the range 230 260 nm related to
* transitions in the pyrimidine and benzene rings
suggests that the chromophores are incorporated in a
common conjugation system.
The H NMR spectrum of aminoethanol IX contains
no acetyl proton signal at 1.9 ppm but contains a
broadened signal of the hydroxyl proton at 4.7 ppm.
In going from acidic to basic media, some interesting
aspects of the reaction pathway are observed. Treat-
ment of compound Ic with aqueous KOH results ex-
clusively in dehydrochlorination, while the acetoxy
1
group remains intact. In the H NMR spectrum of the
resulting free base 2-(2-acetoxyethyl)amino-6-methyl-
4-(4-methylphenyl)aminopyrimidine (X), no broade-
ned singlet of the proton at the quaternary nitrogen
atom at 13.3 ppm is observed, but a signal of acetyl
protons is present in the same region, like in the
Me
HN
HCl
20000
Ic
1
N
HO
15000
Me
2
N
N
H
10000
IX
3
Me
5000
KOH
0
HN
200 220 240 260 280 300 320 340 360 380
, nm
N
AcO
Me
N
N
UV spectra of (1) 2-(2-acetoxyethyl)amino-6-methyl-
4-(4-methylphenyl)aminopyrimidine (Ic), (2) 6-methyl-
4-(methylphenyl)aminopyrimidin-2-(1H)-one (IV), and
(3) 2-(2-acetoxyethyl)amino-4-cyclohexylamino-6-me-
thylpyrimidine (VIII).
H
X
Deacetylation of arylaminopyrimidines Ia Ij was
studied on an example of compound Ic. The reaction
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 11 2007

1942
ERKIN, KRUTIKOV
spectrum of compound Ic. The reason of such
behavior of arylaminopyrimidine Ic in aqueous al-
kaline solution lies in the poor solubility of its de-
hydrochlorination product, acetylaminoethanol X, in
water. To provide homogeneous reaction, we carried
out deacetylation of arylaminopyrimidine Ic with
KOH in aqueous ethanol. But it occured that target
aminoethanol IX is difficult to isolate as the free base.
Therefore, we treated of the reaction product with
conc. HCl was added dropwise with vigorous stirring
to pH 5. After heating for 1 h at 0 5 C, the precipitate
that formed was filtered off , washed with the smallest
possible amount of ice water, and dried in a vacuum
over P2O5. Compounds Ia, Ic Ii were purified by
crystallization from acetonitrile, and compound Ib
was crystallized from acetone. Product Ij was ex-
tracted with 1,2-dichloroethane and finally crystallized
from acetonitrile. Crystals of the compounds obtained
were dried in a vacuum.
1
picric acid to obtain compound IX picrate. The H
NMR spectrum of this compound shows a broadened
singlet of hydroxyl proton at 4.8 ppm, and the integral
intensity of aromatic proton signals is 6 units.
b. A mixture of 0.0022 mol of chloride II and
0.0022 mol of arylamine was heated at 120 C for
30 min. The solidified reaction mixture was crystal-
lized from acetonitrile and dried in a vacuum.
Biological screening of arylaminopyrimidines Ia Ij
in vitro showed that some of them exhibit a weak
antibacterial activity with respect to Staphylococcus
aureus, while most compounds exhibit a pronounced
antituberculous activity in the concentration range
6-Methyl-4-(4-methylphenyl)aminopyrimidin-
2(1H)-one (IV). A mixture of 0.5 g of thioether VII
and 0.34 g of 4-methylphenylamine was heated at
140 C until methanethiol no longer evolved. The re-
action mixture was cooled, mechanically ground,
crystallized from acetonitrile, and dried in a vacuum
to obtain 0.32 g (46%) of compound IV, mp 241 C
1
0.01 0.1 g l . Compounds Ih, Ij proved to be most
active. They inhibited the reproduction of Myco-
bactericum smegmatis by 100% in the concentration
1
0.0125 g l . Considering that chloride II and diamine
(decomp.), Rf 0.79. 1H NMR spectrum, , ppm:
VIII do not exhibit antituberculous properties, we can
suggest that the activity of arylaminopyrimidines Ia
Ij with respect to the above-mentioned strain is caused
by the presence of the pharmacophoric aryl fragment
in their structure.
2.11 s (3H, Me), 2.27 s (3H, Me), 5.59 s (1H, CH),
7.06, 7.07 d (2H, Ar); 7.46, 7.47 d (2H, Ar), 8.55 br.s
(1H, NH), 10.46 br.s (1H, NH). Found, %: C 65.73;
H 6.05; N 19.69. C12H13N3O. Calculated, %: C 66.96;
H 6.09; N 19.52.
EXPERIMENTAL
6-Methyl-4-(methylsulfanyl)pyrimidin-2(1H)-
one (VII). To a solution of 2 g of thioxoketone VI in
18 ml of water containing 2 g of NaOH, methyl
iodide, 2 g, was added with vigorous stirring. The re-
action mixture was heated for 1 h at 40 C and then
for 1 h at 70 C, after which it was cooled, filtered,
and acidified with conc. HCl. The precipitate that
formed was filtered off, washed with water, and dried
under a stream of warm air for 5 h. Crystallization
from acetonitrile and drying in a vacuum gave 1.05 g
1
The H NMR spectra were taken on a Bruker WM-
400 spectrometer (400.13 MHz) in DMSO-d6 against
residual DMSO protons. The UV spectra were re-
corded on an SF-26 spectrometer in ethanol (c
10 M). The purity of the compounds was controlled
by TLC on Silufol UV-254 plates, eluent n-butanol
acetic acid water (1:1:1), development under UV
light. Elemental analysis was carried out on a
Hewlett-Packard B-185 analyzer.
1
4
1
(48%) of compound VII, mp 229 C, Rf 0.82. H
2-(2-Acetoxyethyl)amino-4-chloro-6-methylpyrim- NMR spectrum, , ppm: 2.17 s (3H, Me), 2.42 s (3H,
idine (II) and 2-(2-acetoxyethyl)amino-6-methyl-
pyrimidin-4(3H)-one (III) were prepared by the pro-
cedures in [3] and [2], respectively. 6-Methylpyri-
midin-2,4-(1H, 3H)-dione V was synthesized by the
procedure in [8], and 6-methyl-4-thioxo-3,4-dihydro-
pyrimidin-2(1H)-one (VI) was obtained by the pro-
cedure in [9]. The solvents used were dried by con-
ventional procedures [10].
SMe), 5.87 s (1H, CH), 12.36 s (1H, NH). Found, %:
C 45.46; H 5.01; N 17.91. C6H8N2OS. Calculated,
%: C 46.14; H 5.16; N 17.93. Published data: mp
174 175 C [11] and 178 180 C [9]. According to our
observations, the published melting points relate to
only partial transfer of solid to liquid, while complete
melting takes place only at our specified temperature.
2-(2-Acetoxyethyl)amino-6-methyl-4-cyclohexyl-
aminopyrimidine (VIII). A mixture of 0.5 g of chlo-
ride II and 0.22 g of cyclohexylamine was heated for
1.5 h at 120 C. The reaction mixture was then crystal-
lized from acetonitrile and allowed to stand 25 C for
1 h for complete precipitation. The precipitate that
4-Arylamino-2-(2-acetoxyethyl)amino-6-methyl-
pyrimidines Ia-Ij. a. A mixture of 0.0022 mol of
chloride II and 0.0044 mol of arylamine was heated
for 1 2 h (TLC control) at 120 C. The reaction mix-
ture was cooled and suspended in 5 ml of water, and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 11 2007

4-ARYLAMINO-2-(2-ACETOXYETHYL)AMINO-6-METHYLPYRIMIDINES
1943
formed was filtered off and dried in a vacuum to ob-
The resulting mixture was kept at room temperature
for 3 h and then at 50 C for 1 h. A suspension formed
and was cooled and filtered. The crystals were washed
with water, crystallized from 40% aqueous ethanol,
and dried in a vacuum over P2O5 to obtain 0.2 g
tain 0.27 g (37%) of compound VIII hydrochloride,
1
mp 122 C, Rf 0.84. H NMR spectrum, , ppm: 1.12
2.91 m (17H, cyclo-C6H11, Ac, Me), 3.48 s (2H,
CH2), 4.09 t (2H, CH2), 6.49 s (1H, CH), 7.53 s (1H,
N2H), 8.01 br.s (1H, N4H). Found, %: C 52.44; H
6.86; N 17.00. C15H24N4O2 HCl. Calculated, %: C
54.74; H 7.60; N 17.03.
1
(45%) of compound X, mp 145 C, Rf 0.68 (A). H
NMR spectrum, , ppm: 2.00 s (6H, Ar, MeC6H4),
2.26 s (3H, Me), 3.48 and 3.49 d (2H, CH2), 4.11 and
4.13 d (2H, CH2), 5.82 s (1H, CH), 6.52 br.s (1H,
N2H), 7.01 and 7.03 d (2H, Ar), 7.48 and 7.50 d (2H,
Ar), 8.76 s (1H, N4H). Found, %: C 63.68; H 6.65;
N 18.41. C10H20N4O2. Calculated, %: C 63.98; H
6.71; N 18.65.
2-(2-Hydroxyethyl)amino-6-methyl-4-(4-methyl-
phenyl)aminopyrimidine (IX). A mixture of 0.25 g
of arylaminopyrimidine Ic and 10 ml of conc. HCl
was heated at 60 C for 3 h and then evaporated to
dryness. The dry residue was crystallized from pro-
pan-2-ol and dried in a vacuum over P2O5 to obtain
97 mg (44%) of compound IX hydrochloride, mp
217 C (decomp.). Rf 0.81. 1H NMR spectrum, , ppm:
2.30 s (6H, Me, MeC6H4), 3.46 s (2H, CH2), 3.56 and
3.57 d (2H, CH2), 4.72 br.s (1H, OH), 6.19 s (1H,
CH), 7.14 s (2H, Ar), 7.58 s (2H, Ar), 7.81 s (1H,
N2H), 10.72 br.s (2H, N4H), 12.97 br.s (N+H). Found,
%: C 56.34; H 5.95; N 18.72. C14H18N4O HCl.
Calculated, %: C 57.04; H 6.50; N 19.01.
ACKNOWLEDGMENTS
The authors express their gratitude to prof.
V.V. Tets and his coworkers (Pavlov St.-Petersburg
State Medical University) for performing microbio-
logical studies and to Yu.A. Efimova for participation
in this work.
REFERENCES
1. Ghoneim, K.M., El-Telbany, F., and Youssef, K.,
Arylaminopyrimidine Ic, 0.5 g, was added to a
solution of 0.16 g of KOH in 5 ml of 50% aqueous
ethanol. The reaction mixture was heated at 60 C for
3 h and then evaporated to dryness in a vacuum. The
residue was diluted with 5 ml of acetone, and the
precipitate that formed was filtered off. A solution of
0.33 g of picric acid in 5 ml of acetone was added to
the filtrate. The resulting mixture was refluxed for
15 min and then cooled to 0 C. The precipitate was
filtered off, crystallized from acetone, and dried in a
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1
picrate, mp 202 C, Rf 0.85. H NMR spectrum,
,
ppm: 2.28 s (3H, MeC6H4), 2.32 s (3H, Me), 3.44 d
(2H, CH2), 3.58 d (2H, CH2), 4.80 br.s (1H, OH),
6.07 s (1H, CH), 7.15 8.54 m (7H, Ar, N2H), 10.37
br.s (1H, N4H), 11.87 br.s (1H, HOC6H2). Found, %:
C 46.71; H 4.28; N 19.61. C14H18N4O C6H3N3O7.
Calculated, %: C 49.28; H 4.31; N 20.12.
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Ic, 0.5 g, was added in portions with vigorous stirring
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 11 2007