Effect of halogen atom localization on the level of antimycobacterial activity of 2-amino-4-arylamino-6-methylpyrimidines

Article abstract of DOI:10.1134/S1070363210040237

Several hydrochlorides of 2-alkyl(cycloalkyl, aralkyl)-5-bromo-6-methyl-4- phenylaminopyrimidines have been synthesized as isosteric analogs of the corresponding 2-alkyl(cycloalkyl, aralkyl)-4-(3-bromophenyl)amino-6- methylpyrimidine hydrochlorides. Moving the bromine atom from the benzene ring into the heterocycle is accompanied by a significant decrease in the level of antimycobacterial activity. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070363210040237

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 4, pp. 818–824. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.V. Erkin, V.I. Krutikov, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 4, pp. 657–663.
Effect of Halogen Atom Localization
on the Level of Antimycobacterial Activity
of 2-Amino-4-arylamino-6-methylpyrimidines
A. V. Erkin and V. I. Krutikov
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: kruerk@yandex.ru
Received November 11, 2009
Abstract―Several hydrochlorides of 2-alkyl(cycloalkyl, aralkyl)-5-bromo-6-methyl-4-phenylaminopyrimi-
dines have been synthesized as isosteric analogs of the corresponding 2-alkyl(cycloalkyl, aralkyl)-4-(3-
bromophenyl)amino-6-methylpyrimidine hydrochlorides. Moving the bromine atom from the benzene ring into
the heterocycle is accompanied by a significant decrease in the level of antimycobacterial activity.
DOI: 10.1134/S1070363210040237
groups of compounds by the efficiency of the in-
hibition of the cell growth of the strain.
Discovery of strong cell growth inhibitors of a
Mycobacterium smegmatis strain among hydro-
chlorides of 2-(2-acetoxyethyl)amino-4-haloaryl-amino-
6-methylpyrimidones [1] and their analogs [2] points
to the obvious prospects of further search for new
antibacterial agents among similar compounds.
2-(2-Acetoxyethyl)amino-5-bromo-6-methyl-4-
phenylaminopyrimidine hydrochloride (IIa) was ob-
tained by amination of 2-(2-acetoxyethyl)amino-5-
bromo-6-methyl-4-chloropyrimidine (III) with an equi-
molar amount of phenylamine without solvent at 100–
110°C. The key product III was prepared starting from
5-bromo-2-(2-hydroxyethyl)amino-6-methylpyrimidin-
4(3H)-one (IV), by acetylation in pyridine at 100°C
followed by the exchange chlorination of 2-(2-
acetoxyethyl)amino-5-bromo-6-methylpyrimidin-4(3H)-
one (V), or alternatively by bromination of 2-(2-
acetoxyethyl)amino-6-methyl-4-chloropyrimidine (VI)
in accordance with the following scheme.
In order to establish the impact of displacement of
the halogen atom from the benzene ring of 2-amino-4-
(3-bromophenyl)amino-6-methylpyrimidines hydro-
chlorides (Ia–Ic) into the heterocyclic frame on the
level of their inhibitory action, we have synthesized
hydrochlorides of 2-amino-5-bromo-6-methyl-4-phenyl-
aminopyrimidines (IIa–IIc) and, having evaluated
their antimycobacterial activity, compared these
O
O
N
Br
Br
HN
HN
Ac2O
HO
AcO
N
N
N
Me
Me
H
H
IV
V
a, b
NHPh
N
Cl
Cl
Br
Br
N
N
N
c, d
PhNH2
HCl
Me
AcO
AcO
AcO
N
H
N
N
H
N
Me
N
Me
H
IIа
VI
III
818

EFFECT OF HALOGEN ATOM LOCALIZATION
819
It should be noted that the exchange chlorination of
bromopyrimidinone V allows the preparation of di-
halopyrimidine III only in low yields, regardless of the
type of chlorinating agent. On treating V with
phosphorus oxychloride (method a), along with the
target dihalopyrimidine III a significant amount of tars
formed, and the yield after double crystallization was
only 3–4%. The yield somewhat increases (up to 10%)
when phosphorus pentachloride is used (method b), but
this version of the reaction is also accompanied with a
considerable tarring.
We performed the synthesis of 5-bromo-6-methyl-
4-phenylamino-2-cyclohexylaminopyrimidine hydro-
chloride (IIb), as well as previously unknown 4-(3-
bromophenyl)amino-6-methyl-2-cyclohexylaminopyr-
imidine hydrochloride (Ib), using a multistage scheme,
based on 6-methyl-2-cyclohexylaminopyrimidin-4(3H)-
one hydrochloride (VII). Compound VII was sub-
jected to exchange chlorination with phosphorus
oxychloride to form 6-methyl-4-chloro-2-cyclohexyl-
aminopyrimidine (VIII) followed by amination with
equimolar amounts of phenyl- and 3-bromophenyl-
amine in the absence of solvent at 100–110°C. The
resulting 6-methyl-4-phenylamino-2-cyclohexylamino-
pyrimidine hydrochloride (IX) was reacted with an
excess of aqueous sodium hydroxide to afford the free
base X, which by treating with bromine (method a) or
with N-bromosuccinimide (method b) in carbon
tetrachloride was transformed into 5-bromo-6-methyl-
4-phenylamino-2-cyclohexylaminopyrimidine (XI).
Finally, hydrochloride IIb was prepared from the free
base XI by the action of hydrochloric acid.
Higher yields of dihalopyrimidine III can be ob-
tained by the direct bromination of amino-
chloropyrimidine VI with bromine in the presence of
HBr acceptor, like triethylamine (method c), and
especially by using N-bromosuccinimide (NBS)
(method d) in carbon tetrachloride. Bonding the
liberated hydrogen bromide and thereby shifting the
reaction equilibrium toward formation of III is
particularly important in view of reduced nucleophility
of C5 atom of the ring because of the influence of
electron-withdrawing effect of a halogen atom.
Br
HN
N
HCl
N
N
Me
H
Ib
3-BrC6H4NH2
O
N
Cl
N
NHPh
N
POCl3
PhNH2
HN
N
N
HCl
Me
Me
Me
N
N
H
N
H
H
VII
VIII
IX
NaOH
NHPh
N
NHPh
N
NHPh
Br
Br
a, b
HCl
N
N
N
HCl
N
Me
N
H
Me
Me
N
N
H
H
IIb
X
XI
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

820
ERKIN, KRUTIKOV
aminopyrimidinone hydrochloride VII in 26% yield,
calculated on the free base content.
The exchange chlorination of quaternized substrate
VII was not accompanied by any difficulty, but
because of the complexity of the vacuum distillation of
small quantities of chloropyrimidine VIII we used this
compound in the amination stage without purification.
The main disadvantage of bromination of the free
base X is the low yield of the product XI obtained with
the reaction both by way of a, and by the method b.
This may be due primarily to the possibility of
aromatic ring bromination [3] and to a lesser extent, to
sterically hindrance to the attack of the bromine atom
on the position 5 of the heterocycle. Indeed, the results
of quantum-chemical geometry optimization of X
indicated a significant distance between phenyl and
pyrimidine nuclei and their noncoplanar location in
space (see the figure).
Quantum-chemical optimization of the geometry of the
molecule of 6-methyl-4phenylamino-2-cyclohexylamino-
pyrimidine (X).
Unlike the 2-benzylamine-6-methylpyrimidin-4(3H)-
one [2] we could not isolate aminopyrimidinone VII in
the form of a free base with acceptable yield by the
interaction of 6-methyl-2-methylthiopyrimidin-4(3H)-
one (XII) with cyclohexylamine. After removal of
excess amine from the reaction mixture and crys-
tallization of the residue from ethanol, we have ob-
tained dequaternized compound VII in 23% yield. To
isolate the remaining product we saturated the ethanol
filtrate with dry hydrogen chloride and isolated
For the preparation of 2-benzylamine-5-bromo-6-
methyl-4-phenylamino-pyrimidine hydrochloride (IIc)
we chose similar sequence of transformations to the
above mentioned for 2-benzylamine-6-methyl-4-
chloropyrimidine (XIII) presented in the scheme
below.
Cl
NHPh
NHPh
N
N
NaOH
PhNH2
N
HCl
Me
Ph
N
N
Me
Ph
N
N
Ph
N
H
N
Me
H
H
XIII
XIV
XV
NBS
NHPh
N
NHPh
N
Br
HCl
Me
Br
N
N
HCl
Ph
N
Ph
N
H
Me
H
IIc
XVI
The amination of compound XIII with equimolar
amount of phenylamine in the absence of solvent at
100–110°C led to the hydrochloride of 2-benzylamino-
6-methyl-4-phenylaminopyrimidine (XIV), the neutra-
lization by an excess of aqueous sodium hydroxide
gave free base XV. The latter by treating with N-
bromosuccinimide was converted into 2-benzylamino-
5-bromo-6-methyl-4-phenylaminopyrimidine (XVI)
that was suspended in hydrochloric acid to give
benzylaminobromopyrimidine hydrochloride IIc.
Since the bromination of the free base X with
bromine has no obvious advantages over the use of N-
bromosuccinimide and, moreover, can provide the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

EFFECT OF HALOGEN ATOM LOCALIZATION
821
The values of IC100, providing 100% inhibition of cell
growth of a Mycobacterium smegmatis strain
product IIb of reduced, according to its mp, purity, we
have performed bromination of diaminopyrimidine XV
exclusively with N-bromosuccinimide.
Comp. no.
IC100, g l–1
References
0.0125
0.010
> 0.100а
≥ 0.100
0.100
[1]
–
Iа
Structures of compounds IIa–IIc were confirmed
by their H NMR spectra containing signals of the
1
Ib
[2]
–
Ic
protons of aliphatic and aromatic groups with
characteristic chemical shifts. In the spectrum of
acetoxyethylaminobromopyrimidine IIa there are
unresolved signals of the protons of methylene groups
at 3.45 and 4.0 ppm, and a multiplet of aromatic
protons in the region of 7.2–7.5 ppm. The spectrum of
IIb is characterized by the presence of multiplets of
cyclohexane protons and phenyl rings in the regions of
0.9–1.9 and 7.2–7.5 ppm respectively. The spectrum of
benzylaminobromopyrimidine IIc contains a multiplet
in the region of 7.1–7.4 ppm with integral intensity
corresponding to ten aromatic protons.
IIа
IIb
IIc
–
≥ 0.100
–
a
The quantitative value of the concentration is given in addition
to the cited paper’s data.
Compound IV was synthesized by the method
described in [4], compound VI, in accordance with [5],
and compound XIII, according to [2]. Free bases X
and XV were obtained by suspending the cor-
responding hydrochlorides IX and XIV in water
containing a double molar excess of sodium hydroxide.
The precipitated solid was filtered off, washed with
water until the filtrate pH reached ~7, dried in a
vacuum over phosphorus pentoxide to constant weight,
and was used in the bromination stage without re-
crystallization.
Moving the halogen atom from the aromatic ring of
2-(2-acetoxyethyl)amino-4-(3-bromophenyl)amino-6-
methylpyrimidine hydrochloride (Ia) and bromophenyl-
aminopyrimidine Ib into the heterocyclic nucleus
causes a sharp decrease in antimycobacterial activity
of 5-bromo-2,4-diaminopyrimidine hydrochlorides IIa,
IIb (see the table). Benzylaminobromopyrimidine
hydrochloride IIc, as well as hydrochloride of its
isosteric analogue, 2-benzylamine-4-(3-bromophenyl)
amino-6-methylpyrimidine (Ic) do not inhibit cell
growth of the strain of Mycobacterium smegmatis in
the concentration range of 0–100 mg ml–1. The data
obtained demonstrated the importance of maintaining
the original configuration of Ia, Ib providing pharma-
cophore properties towards the given biological object.
Quantum-chemical optimization of the geometry of
6-methyl-4-phenylamino-2-cyclohexylaminopyrimidine
(X) molecule was performed by Fletcher-Reeves
method, using “HyperChem™ Release 6.03 for
Windows Molecular Modeling System” software
package.
4-(3-Bromophenyl)amino-6-methyl-2-cyclohexyl-
aminopyrimidine (Ib). A mixture of 0.24 g of VIII
and 0.19 g of 3-bromoaniline was heated at 100–110°C
until solidification. The solid reaction product was
mechanically crushed and crystallized from aceto-
nitrile–ethanol (15:2) mixture. After drying in a
vacuum over phosphorus pentoxide 71 mg (16%) of
bromophenylaminopyrimidine Ib was obtained, mp
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker WM-
400 spectrometer (operating frequency 400.13 MHz)
in DMSO-d6, with residual solvent protons as internal
reference. TLC was carried out on Silufol UV-254
plates in the following systems: 1-butanol-acetic acid–
water, 2:2:1 (A), 1-butanol-acetic acid–water, 1:1:1
(B), chloroform–methanol, 7:1 (C), chloroform–
methanol, 9:1 (D), acetone-hexane, 2:1 (E), acetone–
hexane plus 2 drops of pyridine (F), acetone–heptane,
1:1 (G), and 1-butanol-acetic acid–water, 2:1:1 (H).
Elemental analysis was performed on a Hewlett-
Packard B-185 CHN-analyzer. Water–ethanol solu-
tions of hydrochlorides Ib and IIa–IIc gave a positive
test when treated with aqueous silver nitrate.
1
258°C (decomp.), Rf 0.72 (A). H NMR spectrum, δ,
ppm: 0.84–1.95 m (10H, cyclo-C6H11), 2.31 s (3H,
Me), 3.81 s (1H, CH), 6.18 s (1H, CHpyr), 7.27–8.25 m
(4H, Ar), 7.47 s (1H, N2H), 10.84 s (1H, N4H). Found,
%: С 50.94; Н 5.43; N 13.89. C17H21BrN4·HCl.
Calculated, %: C 51.34; H 5.58; N 14.09. Isolated as
hydrochloride.
2-(2-Acetoxyethyl)amino-5-bromo-6-methyl-4-
phenylaminopyrimidine (IIa). A mixture of 0.17 g of
III and 0.05 g of phenylamine was heated at 100–110°C
until solidification. The solid reaction product was
mechanically crushed and crystallized from
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

822
ERKIN, KRUTIKOV
acetonitrile. After drying in a vacuum over phosphorus
pentoxide 99 mg (45%) of acetoxyethylaminobromo-
pyrimidine IIa was obtained, mp 164 0C, Rf 0.78 (B).
1H NMR spectrum, δ, ppm: 1.97 s (3H, Me), 2.48 s
(3H, Me), 3.45 s (2H, CH2), 4.04 s (2H, CH2), 7.20–
7.51 m (5H, Ph), 7.98 s (1H, N2H), 9.71 s (1H, N4H).
Found, %: C 44.15; H 4.21; N 13.67. C15H17BrN4O2·
HCl. Calculated, %: C 44.85; H 4.52; N 13.95. Isolated
as hydrochloride.
over phosphorus pentoxide 0.34 g (29%) of benzyl-
aminobromopyrimidine IIc was obtained, mp 202°C,
1
Rf 0.80 (B). H NMR spectrum, δ, ppm: 2.49 s (3H,
Me), 4.39 s (2H, CH2), 7.11–7.38 m (10H, Ph), 8.56 s
(1H, N2H), 9.69 s (1H, N4H). Found, %: C 52.81; H
4.34; N 13.65. C18H17BrN4·HCl. Calculated, %: C
53.29; H 4.47; N 13.81. Isolated as hydrochloride.
2-(2-Acetoxyethyl)amino-5-bromo-6-methyl-4-
chloropyrimidine (III). a. A mixture of 0.7 g of V
and 5 ml of freshly distilled phosphorus oxychloride
was boiled for 3 h. After distilling off the excess of
phosphorus oxychloride in a vacuum to the residue
finely crushed ice was added and to thus formed
suspension 25% aqueous ammonia solution was added
until stable weakly basic reaction. The precipitate
formed was filtered off and crystallized from ethanol.
The purified product was dissolved in 10 ml of diethyl
ether, insoluble substance was filtered off, and the
filtrate was concentrated in vacuo to 1/2 of its initial
volume and cooled to –25°C. The precipitate formed
was filtered off and washed with a minimal amount of
diethyl ether cooled to the same temperature. After
drying in a vacuum 26 mg (3.4%) of dihalopyrimidine
5-Bromo-6-methyl-4-phenylamino-2-cyclohexyl-
aminopyrimidine (IIb). a. To a solution of 0.4 g of X
in 5 ml of carbon tetrachloride 0.22 g of bromine in
2 ml of carbon tetrachloride was added dropwise with
stirring. After the addition of bromine the reaction
mixture was stirred at room temperature for 30 min
and then evaporated in a vacuum to dryness. To the
residue 5% aqueous sodium hydroxide solution was
added, thoroughly mixed, the precipitate formed was
filtered off, washed with water and was ground with
5 ml of concentrated hydrochloric acid to form a
suspension. Water was partly removed in a vacuum to
3/4 of the initial volume, the precipitate was filtered
off, dried at 60°C for 10 h, and crystallized from
anhydrous 2-propanol to give after drying in vacuo
over phosphorus pentoxide 46 mg (9%) of cyclo-
hexylaminobromopyrimidine IIb, mp 214°C (decomp.),
1
III was obtained, mp 144 0C, Rf 0.67 (B). H NMR
spectrum, δ, ppm: 2.00 s (3H, Ac), 2.45 s (3H, Me),
3.47, 3.50 (2H, CH2), 4.09 m (2H, CH2), 7.69 br.s (1H,
NH). Found, %: C 34.88; H 3.47; N 13.46.
C9H11BrClN3O2. Calculated, %: C 35.03; H 3.59; N
13.62.
1
Rf 0.79 (A). H NMR spectrum, δ, ppm: 0.88–1.87 m
(10H, cyclo-C6H11), 2.45 s (3H, Me), 3.51 s (1H, CH),
7.19–7.53 m (5H, Ph), 7.99 s (1H, N2H), 9.68 s (1H,
N4H). Found, %: C 50.55; H 5.23; N 13.71.
C17H21BrN4·HCl. Calculated, %: C 51.34; H 5.58; N
14.09. Isolated as hydrochloride.
b. A mixture of 1.6 g of V and 1.2 g of phosphorus
pentachloride was heated at 130°C to homogenisation.
To the cooled reaction mixture finely crushed ice was
added, the mixture was treated with 25% aqueous
ammonia solution till stable basic pH, and was ground
to form precipitate that was filtered off, washed with
cold water, and dried in vacuo over phosphorus
pentoxide. The dry product was dissolved in 20 ml of
boiling benzene, treated with activated alumina, and
filtered. The filtrate was evaporated in a vacuum to
dryness, and the resulting crystalline residue was
recrystallized from 80% aqueous ethanol. After drying
in a vacuum 0.25 mg (15%) of dihalopyrimidine III
was obtained, mp 141°C, Rf 0.67 (B). Mp of the mixed
sample of the product obtained by methods of a and b:
144°C.
Method b. A mixture of 0.5 g of X and 0.32 g of N-
bromosuccinimide in 10 ml of carbon tetrachloride
was boiled for 1 h, then evaporated in a vacuum to
dryness. The residue was ground with 5 ml of diluted
(1:1) hydrochloric acid, the suspension formed was
concentrated in vacuo to 1/4 of the initial volume,
filtered, and crystallized from ethanol. After drying in
a vacuum over phosphorus pentoxide 84 mg (12%) of
IIb were obtained, mp 217°C (decomp.), mp of the
mixed sample, obtained by methods a and b: 216°C.
2-Benzylamine-5-bromo-6-methyl-4-phenylamino-
pyrimidine (IIc). A mixture of 0.83 g of XV and
0.51 g of N-bromosuccinimide in 20 ml of carbon
tetrachloride was boiled for 1 h, then evaporated in a
vacuum to dryness. The crystalline residue was ground
with 10 ml of diluted (1:1) hydrochloric acid, filtered
off, washed with a small amount of cold water, and
crystallized twice from ethanol. After drying in vacuo
c. To a solution of 0.5 g of VI in 10 ml of carbon
tetrachloride heated to 60°C 0.12 g of bromine in 5 ml
of carbon tetrachloride was added dropwise under
stirring. The mixture was kept at the same temperature
for further 30 min, then decanted from the precipitated
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

EFFECT OF HALOGEN ATOM LOCALIZATION
823
tars, and cooled. The precipitate was filtered off and
crystallized from 80% aqueous ethanol. After drying in
vacuum 0.19 mg (27%) of dihalopyrimidine III was
obtained, mp 143°C, Rf 0.67 (B).
initial volume, cooled to –25°C, the precipitate was
filtered off and recrystallized from anhydrous ethanol.
After drying in a vacuum over phosphorus pentoxide
1.27 g (26%) of aminopyrimidinone hydrochloride VII
was obtained, mp 200°C ([7]: mp 200ºC), Rf 0.25 (E).
d. A mixture of 0.5 g of VI and 0.39 g of N-bromo-
succinimide in 15 ml of carbon tetrachloride was
boiled for 1 h. On cooling to room temperature the
suspension formed was kept at 5°C for 1 h, filtered off,
and crystallized from 80% aqueous ethanol. After
drying in a vacuum 0.29 mg (43%) of dihalo-
pyrimidine III were obtained, mp 145°C, Rf 0.67 (B).
Mp of the mixed sample of the product obtained by
methods of c and d: 144 0C.
6-Methyl-4-chloro-2-cyclohexylaminopyrimidine
(VIII). A mixture of 1.6 g of hydrochloride salt of VII
and 20 ml of freshly distilled phosphorus oxychloride
was boiled for 1 h. After that, the excess of phosphorus
oxychloride was distilled off in a vacuum, the residue
was treated with finely crushed ice, the precipitated
oily suspension was alkalinized with 25% aqueous
ammonia solution and extracted with dichloromethane
(2×20 ml). The extract was dried over anhydrous
sodium sulfate overnight, filtered, and evaporated to
dryness at atmospheric pressure to give 1.3 g (87%) of
chromatographically pure [Rf 0.54 (F)] chloropyr-
imidine VIII that was used in the next stage without
additional purification.
2-(2-Acetoxyethyl)amino-5-bromo-6-methylpyr-
imidine-4(3H)-one (V). To a suspension of 2.9 g of
IV in 10 ml of anhydrous pyridine heated to 85°C
1.84 g of acetic anhydride was added dropwise with
vigorous stirring. The reaction mixture was kept at
100°C for 1 h, cooled, the precipitate was filtered off,
washed with water, and crystallized from water. After
drying in vacuo over phosphorus pentoxide 1.79 g
(52%) of bromopyrimidinone V were obtained, mp
6-Methyl-4-phenylamino-2-cyclohexylaminopyr-
imidine (IX). A mixture of 1.3 g of VIII and 0.54 g of
phenylamine was heated at 100–110°C until solidifica-
tion. The residue was mechanically ground and
crystallized from acetonitrile. After drying in a vacuum
0.65 g (35%) of phenylaminopyrimidine IX was
1
184°C, Rf 0.43 (D). H NMR spectrum, δ, ppm: 1.92 s
(3H, Ac), 2.24 s (3H, Me), 3.47, 3.49, 3.52, 3.55 (2H
CH2), 4.07, 4.09, 4.12 (2H, CH2), 6.49 br.s (1H,
NHCH2CH2), 11.09 s (1H, NH). Found, %: C 33.78; H
3.92; N 14.27. C9H12BrN3O3. Calculated, %: C 37.26;
H 4.17; N 14.48.
1
obtained, mp 229°C (decomp.), Rf 0.73 (A). H NMR
spectrum, δ, ppm: 0.84–1.98 m (10H, cyclo-C6H11),
2.29 s (3H, Me), 3.78 s (1H, CH), 6.18 s (1H, CHpyr),
7.12–7.70 m (5H, Ar), 8.31 s (1H, N2H), 10.70 c (1H,
N4H). Found, %: C 63.51; H 6.92; N 17.33. C17H22N4·
HCl. Calculated, %: C 64.04; H 7.27; N 17.57. Isolated
as hydrochloride.
6-Methyl-2-cyclohexylaminopyrimidin-4(3H)-
one (VII). A mixture of 3.12 g of XII and 5.94 g of
cyclohexylamine was heated at 160°C for 5 h in an
autoclave. On cooling the mixture was diluted with 10
ml of anhydrous ethanol, and strong air stream was
passed through to remove methanethiol. After evapora-
tion in vacuo to dryness the residue was diluted with
10 ml of anhydrous ethanol, brought to boiling and
cooled to room temperature and then stored at –25°C
for 1 h. The precipitate formed was filtered off and
recrystallized from ethanol. After drying in vacuo over
phosphorus pentoxide 0.97 g (23%) of amino-
pyrimidinone VII was obtained, mp 110°C ([6]: mp 230–
2-Benzylamino-6-methyl-4-phenylaminopyr-
imidine (XIV). A mixture of 1 g of XIII and 0.4 g of
phenylamine was kept at 100–110°C until solidifica-
tion. The solid residue was mechanically ground and
crystallized from ethanol. After drying in a vacuum
0.96 g (68%) of phenylaminopyrimidine XIV was
1
obtained, mp 242°C (decomp.), Rf 0.69 (H). H NMR
spectrum, δ, ppm: 2.33 s (3H, Me), 4.60 s (2H, CH2),
6.23 s (1H, CH), 7.03–7.50 m (10H, Ph), 8.56 s ( 1H,
N2H), 10.77 s (1H, N4H). Found, %: C 65.91; H 5.69;
N 17.02. C18H18N4·HCl. Calculated, %: C 66.15; H
5.86; N 17.14. Isolated as hydrochloride.
1
232°C), Rf 0.32 (D). H NMR spectrum, δ, ppm: 1.20–
1.87 m (10H, cyclo-C6H11), 2.00 s (3H, Me), 3.69 s (1H,
CH), 5.37 s (1H, CHpyr), 6.34 br.s (1H, NH), 10.25 br.s
(1H, NHpyr). Found, %: C 63.47; H 8.02; N 20.17.
C11H17N3O. Calculated, %: C 63.74; H 8.27; N 20.27.
ACKNOWLEDGMENTS
The authors express their deep gratitude to Prof.
V.V. Tets with coworkers (Pavlov St. Petersburg State
Medical University) for microbiological assays, and to
O.V. Kozlova for participation in the work.
The ethanol filtrate after separation of compound
VII was saturated with dry hydrogen chloride to form
suspension that was concentrated in vacuo to 1/2 of the
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ERKIN, KRUTIKOV
4. Erkin, A.V., Krutikov, V.I., and Kosykh, A.V., Zh.
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