Aminolysis of 6-[1-(2,6-difluorophenyl)cyclopropyl]-5-methyl-2-(nitroamino)pyrimidin-4(3H)-one

Article abstract of DOI:10.1134/S1070428017120107

The aminolysis of 6-[1-(2,6-difluorophenyl)cyclopropyl]-5-methyl-2-(nitroamino)pyrimidin-4(3H)-one with various amines in butan-1-ol and under solvent-free conditions is successful when the amino group in the reagent is sterically unshielded and the reaction medium is characterized by a high dielectric permittivity. Reactions of the title compound with sterically shielded amines are accompanied by alcoholysis where the amine acts as a base catalyst.

Full text of DOI:10.1134/S1070428017120107

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 12, pp. 1844–1850. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © I.A. Novakov, L.L. Brunilina, A.A. Vernigora, I.A. Kirillov, A.S. Mkrtchyan, M.B. Navrotskii, D.S. Sheikin, A.S. Yablokov,
E.A. Ruchko, V.V. Kachala, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 12, pp. 1808–1815.
Aminolysis of 6-[1-(2,6-Difluorophenyl)cyclopropyl]-5-methyl-
2
-(nitroamino)pyrimidin-4(3H)-one
a
a
a
a
a
I. A. Novakov , L. L. Brunilina ,* A. A. Vernigora , I. A. Kirillov , A. S. Mkrtchyan ,
a
a
a
b
c
M. B. Navrotskii , D. S. Sheikin , A. S. Yablokov , E. A. Ruchko , and V. V. Kachala
a
Volgograd State Technical University, pr. imeni Lenina 28, Volgograd, 400005 Russia
*
e-mail: leila_1974@mail.ru
b
”
Pharm-Sintez” Closed Corporation, 2-ya Kabel’naya ul. 2 bld. 46, Moscow, 111024 Russia
c
Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences,
Leninskii pr. 47, Moscow, 119991 Russia
Received August 30, 2017
Abstract—The aminolysis of 6-[1-(2,6-difluorophenyl)cyclopropyl]-5-methyl-2-(nitroamino)pyrimidin-4(3H)-
one with various amines in butan-1-ol and under solvent-free conditions is successful when the amino group in
the reagent is sterically unshielded and the reaction medium is characterized by a high dielectric permittivity.
Reactions of the title compound with sterically shielded amines are accompanied by alcoholysis where the
amine acts as a base catalyst.
DOI: 10.1134/S1070428017120107
In continuation of our studies on the synthesis of
functional non-nucleoside pyrimidine derivatives and
their antiviral activity [1], we have found that 2-(alkyl-
sulfanyl)-6-[1-(2,6-difluorophenyl)cyclopropyl]-
pyrimidin-4(3H)-ones A at a nanomolar concentration
exhibit a pronounced inhibitory effect on the replica-
tion of wild-type HIV-1 [2]. In this respect,
to ambiguous results [5] due to considerable sensitivity
of compound 1 to steric factor related to the structure
and orientation of the 6-substituent, which affected
2
nucleophilic attack of C . We have studied the aminol-
ysis of 1 with various amines such as piperidine,
morpholine, 4-methoxybenzylamine, 3-phenylpropan-
1-amine, adamantan-2-amine, and (adamantan-1-yl)-
methanamine and obtained isocytosine derivatives 2a–
2c, 2e, and 2f.
6
-[1-(2,6-difluorophenyl)cyclopropyl]-5-methyl-2-
(
nitroamino)pyrimidin-4-(3H)-one (1) turned out to be
less active than the experimental drug MC1501 which
is an isocytosine derivative [3, 4].
The choice of these amines was not accidental.
As we showed previously, pyrimidine 1 reacted with
cyclopentanamine in butan-1-ol to give the corre-
sponding aminolysis products and that alcoholysis
product was obtained in the reactions of 1 with
Attempted syntheses of direct analogs of MC1501
containing a 1-(2,6-difluorophenyl)cyclopropyl substit-
uent in the 6-position of the pyrimidine ring have led
F
O
F
Me
HN
Me
Me
F
S
Me
O
N
N
F
F
Me
O
N
N
Me
F
R
R
N
N
N
H
H
R'
A
MC1501
2a–2f
A, R = MeSCH
2
CH
2
5 9 2 2 6 4 2 2 3
, i-Pr, Pr, EtCH(Me), cyclo-C H , Me CHCH , Bu; 2, R = H, R′ = 4-MeOC H CH (a), Ph(CH ) (b),
1
-AdCH (c), 2-Ad (d); RR′N = piperidin-1-yl (e), morpholin-4-yl (f).
2
1
844

AMINOLYSIS OF 6-[1-(2,6-DIFLUOROPHENYL)CYCLOPROPYL]-5-METHYL-...
1845
Scheme 1.
F
F
F
RR'NH, BuOH
+
F
Me
O
F
Me
O
F
Me
O
N
N
N
O N
R
2
N
H
N
H
N
N
H
Me
O
N
H
R'
1
2a–2c, 2e, 2f
3
N-methylpropan-1-amine and N-methylpropan-2-
amine [5]. In order to elucidate the predominant
reaction pathway (alcoholysis or aminolysis), we used
both primary but sterically hindered amines of the
adamantane series and secondary cyclic amines (piper-
idine and morpholine) characterized by lower con-
formational flexibility of hydrocarbon fragments on
the nitrogen atom than in N-methylpropan-1-amine.
Taking into account fairly high dielectric permittivity
of morpholine (ε = 7.3), the reaction of 1 with that
amine was carried out without a solvent. The reactions
of 1 with 4-methoxybenzylamine and 3-phenylpropan-
The subsequent heating of the reaction mixtures ob-
tained with morpholine, 3-phenylpropan-1-amine, and
(adamantan-1-yl)methanamine resulted in the forma-
tion of only aminolysis products. The reactions with
4-methoxybenzylamine and piperidine were not selec-
tive. In the reaction with 4-methoxybenzylamine, the
mixture contained the corresponding aminolysis prod-
uct and a by-product (t = 3.65 min) which was
R
isolated with a purity of 84.9% by column chromatog-
raphy and additionally purified by preparative TLC. It
was identified as 4-methoxybenzaldehyde; obviously,
it was formed by hydrolysis of the corresponding
aldimine during the isolation procedure or during
HPLC analysis of a sample of the reaction mixture
(Scheme 2).
1
-amine could give compounds exhibiting a high
antiviral activity, as might be expected on the basis of
our previous results [6].
In all cases (except for the reaction with adaman-
tan-2-amine), the reaction mixtures were kept for
The reaction of 1 with piperidine in butan-1-ol
under reflux involved concurrent aminolysis and
alcoholysis of the initial compound. After a time, the
concentration ratio of compounds 1 and 3 indicated
that both of them underwent aminolysis (see table;
Scheme 3). The reaction mixture was heated until
initial compound was no longer detected by HPLC and
only traces of butoxy derivative 3 were detected (the
concentration of 3 no longer decreased). These find-
ings were somewhat surprising. As shown in [7],
2-ethoxypirimidin-4(3H)-one can be converted to iso-
cytosine by the action of alcoholic ammonia under
pressure at elevated temperature. Analogous trans-
60 days at room temperature and analyzed by HPLC
using initial compound 1 and 2-butoxy derivative 3
(
(
prepared as described in [5]) as external standards
retention times t = 4.79 and 19.36 min for com-
R
pounds 1 and 3, respectively; Scheme 1). The results
are collected in the table.
Compound 1 reacted with piperidine in butan-1-ol
at room temperature to give exclusively the alcoholysis
product which is likely to be kinetically controlled.
The reactions with other amines, including morpho-
line, followed the aminolysis pathway.
Fractions (%) of compounds 1‒3 in the aminolysis of 6-[1-(2,6-difluorophenyl)cyclopropyl]-5-methyl-2-(nitroamino)pyrimi-
din-4-(3H)-one (1) under different conditions
4
8 h, ~115°C
60 h, ~115°C
72 h, ~115°C
90 h, ~115°C
1440 h, 25–30°C
Comp.
no.
R
t , min
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
2
2
2
2
2
a
b
c
e
f
3.08
3.41
6.54
3.92
3.22
28.5 42.9 0.0
–
–
–
–
–
–
0.7 65.5 00.0
–
–
–
28.7 42.30 00.0
–
–
–
–
–
–
–
–
–
0.7 98.4 00.7 61.9 03.63 00.0
51.0 49.00 00.0
08.1 91.9 0.0
0.5 98.2 00.0
–
–
–
13.1 72.0 14.2 0.3 44.3 53.3 0.3 84.7 12.1 0.5 85.1 10.0 44.9 0.0 49.2
01.9 98.1 0.0 1.2 98.3 00.5 48.1 51.90 00.0
–
–
–
–
–
–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 12 2017

1
846
NOVAKOV et al.
Scheme 2.
O
Me
NH
o'
NH2
BuOH
1
+
N
F
N
m'
–
H O, –N O
H
2
2
MeO
F
o'
OMe
m'
m
m
p
2
a
CHO
NH2
NO
2
NH
HCl–H
2
O
–
H O, –N
2
–NH Cl
4
2
MeO
MeO
MeO
Scheme 3.
m
F
p
NH
NH
, BuOH, 115°C
m
NH
,
BuOH, 25°C
, BuOH, 115°C
F
Me
1
3
1
N
2
5
2
'
3
3
'
N
N
O
H
4
'
6
'
5
'
2
e
Scheme 4.
O
O
O
N
O
O N
O N
NH , EtOH, ∆
2
NH , EtOH, ∆
2
3
3
NH
NH
NH
NH
8
5%
50%
N
OEt
N
NH2
NO2
OEt
O
N
NH2
NO2
HO
HO
O
O
O
NH , EtOH, ∆
3
6
1%
N
NH
OPr-i
N
NH
HO
NH
HO
NH2
Scheme 5.
O
O
O
3
R NH , NaH
R1
R2
2
R1
R2
+
R1
decalin
N– Na+
NHR3
H /H O
2
NH
N
OMe
N
R2
N
NHR3
5
0–87%
3
1
2
1
2
1
2
3
1
2
R = Bu: R = H, R = Me (77%); R = R = Me (52%); R R = (CH
2
)
4
(66%); R = cyclo-C
6
H
11: R = H, R = Me (65%);
1
2
1
2
3
1
2
1
2
1
2
2 4 2 4
R = R = Me (50%); R R = (CH ) (87%); R = Ph: R = H, R = Me (70%); R = R = Me (65%); R R = (CH ) (50%).
formation, but under milder conditions, was reported
for 5-nitropyrimidin-4(3H)-one derivatives [8, 9] in
which the nitro group favors the reaction due to its
electron-withdrawing effect in combination with the
hyperconjugation effect (Scheme 4).
um alkyl- or arylamide generated in situ in tetralin or
decalin [10] (Scheme 5).
Our results indicated that not only the conditions
given in [10] are unreasonably harsh but they also do
not favor formation of the aminolysis products. First,
both tetralin (ε = 2.773) and decalin (ε = 2.20) are less
polar than butanol (ε = 17.8), which negatively affects
Unlike ethoxy derivatives, the aminolysis of 2-me-
thoxypirimidin-4(3H)-one required heating with sodi-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 12 2017

AMINOLYSIS OF 6-[1-(2,6-DIFLUOROPHENYL)CYCLOPROPYL]-5-METHYL-...
1847
2
ionic reactions. Second, the reactions in tetralin or
decalin are heterogeneous, and the solvent, unlike
butan-1-ol, is hardly capable of effectively solvating
transition state of the reaction because of its chemical
nature.
cleophilic attack of amine on the electron-deficient C
atom of the pyrimidine ring is possible. The direction
of nucleophilic attack conforms well to the hard and
soft acids and bases principle, according to which just
2
the C atom rather than nitrogen atom of the nitro
4
group or C becomes the reaction center (Scheme 7).
Finally, the crucial factors are acid–base equilib-
rium and concentration of the molecular form of initial
compound 1 in the system. Due to relatively high NH
Deprotonation of NH-acidic pyrimidin-4(3H)-one
derivative with sodium alkyl- or arylamide is almost
irreversible, and the initial 2-alkoxypyrimidin-4(3H)-
one is completely converted to the anion which is inert
toward nucleophiles. Moderate yield of the aminolysis
products is determined by extremely harsh reaction
conditions which make the process thermodynamically
controlled.
acidity (pK 7.72) [11], compound 1 can be completely
a
or partially deprotonated with the amine to give a salt-
like coordination complex (Scheme 6). The presence
of a negative charge on the pyrimidine fragment of this
complex makes it resistant to attack of amine as
neutral nucleophile.
If neutral molecules of amine and compound 1
That is why the alcoholysis of 2-methoxypyrimi-
form a contact pair surrounded by a solvate shell, nu-
din-4(3H)-ones was successful only under very severe
Scheme 6.
H
N
H
N
H
N
H
N
O
O
N
O
N
F
NO2
NO2
NO2
N
N
N
Me
F
+ RNH
2
Me
F
Me
F
RNH3
RNH3
F
F
H
N
H
N
O
N
F
O
N
F
NO2
NO2
N
N
Me
F
Me
F
RNH3
RNH3
Scheme 7.
R
H
H
H H
N
2
N
H
O
N
N
O
NHNO2
O
N
NH R···NHNO2
2
NO2
AN
E1cb
N
N
N
+
RNH2
Me
F
Me
F
Me
F
F
F
F
H
O
N
NHR
F
H O
2
N
Me
+
[H NNO ]
2 2
N O
2
F
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 12 2017

1
848
NOVAKOV et al.
Scheme 8.
O
N
R
R
O
N
OMe
R
NaOBu, BuOH, ∆
MeO
HN
N– Na+
O
MeO
R
Me
R
O
N
+
H /H O
MeO
2
NH
R
O
Me
R = H (74%), MeO (70%).
conditions, on treatment with 10 equiv of the corre-
sponding potassium or sodium alkoxide [1, 12]
is determined by spatial accessibility of the nitro group
and considerable shielding of the amino group in ada-
mantan-2-amine (Scheme 9).
(
Scheme 8); i.e., the situation is almost the same as
in the aminolysis of 2-methoxypyrimidin-4(3H)-ones
with sodium amides.
Analogous pattern was observed in the aminolysis
of (4-methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-2-
yl)pentylcyanamide with pyrrolidine [13]. Nucleo-
philic attack of pyrrolidine is directed at the electron-
deficient carbon atom of the cyano group, and the
latter is removed.
We succeeded in developing a milder and more
efficient procedure for the synthesis of compounds of
this series from 2-(nitroamino)pyrimidin-4(3H)-ones
and alcohols in the presence of an aliphatic amine as
base catalyst.
Thus, we have developed efficient procedures for
the synthesis of isocytosine derivatives by aminolysis
of 6-[1-(2,6-difluorophenyl)cyclopropyl]-5-methyl-2-
(nitroamino)pyrimidin-4-(3H)-one (1) with primary
amines in butan-1-ol and alcoholysis of the same sub-
strate in the presence of secondary and tertiary amines
as catalysts.
The reaction of 1 with adamantan-2-amine in
butan-1-ol at room temperature was very slow, and it
followed exclusively the alcoholysis pathway (accord-
ing to the HPLC data). The alcoholysis remained the
predominant reaction pathway under reflux conditions;
however, as the ratio 3 :1 reached 34.7:55.1, the
alcoholysis almost stopped, and another product began
to appear; the fraction of the latter gradually attained
EXPERIMENTAL
1
0.2%. Judging by the HPLC data (t = 3.4 min), this
R
1
compound may be the product of elimination of the
nitro group from 1 by the action of adamantan-2-
amine. In this case, the direction of nucleophilic attack
The H NMR spectra were recorded on a Varian
Mercury 300 BB spectrometer at 300 MHz using hexa-
methyldisiloxane as internal standard. The H NMR
1
Scheme 9.
F
Me
F
Me
NH2
NHNO2
O
O
BuOH, ∆
1
+
+
+
N
NH
NH2
N
NH
OBu
F
F
–
N O
2
tR = 3.4 min
OH
O
N
O
N
NO2
Me
NO2
Me
, EtOH, ∆
NH
HN
HN
Me
79%
Me
N
N
H
CN
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 12 2017

AMINOLYSIS OF 6-[1-(2,6-DIFLUOROPHENYL)CYCLOPROPYL]-5-METHYL-...
1849
spectrum of 2a was measured on a Bruker 360 instru-
cyclopropyl), 1.53–1.65 m (3H, CH ), 3.41–3.53 m
3
ment at 360 MHz.
(4H, 2′-H, 6′-H), 6.94–6.99 m (2H, m-H), 7.26–7.31 m
3
(
1H, p-H), 11.00 s (1H, N H). Found, %: C 65.81;
HPLC analysis was performed with a chromato-
graphic system consisting of a Jasco PU-980 pump,
Jasco UV-975 UV/Vis detector, and Rheodyne injector
H 5.89; N 11.94. C H F N O. Calculated, %:
1
9
21
2
3
C 66.07; H 6.13; N 12.17.
Compounds 2a–2c were synthesized in a similar
way.
-[1-(2,6-Difluorophenyl)cyclopropyl]-5-methyl-
-[(4-methoxybenzyl)amino]pyrimidin-4(3H)-one
(
3
Reprosil C18 AQ column, 150×4.6 mm, grain size
μm; eluent H O–MeCN–85% H PO , 200:200:1 by
2
3
4
volume, flow rate 0.8 mL/min; λ 220 nm, 25°C). The
elemental analyses were obtained on a Vario EL Cube
analyzer. Polygram Sil G UV254 plates were used for
TLC; spots were visualized under UV light, λ 254 nm.
The products were isolated by column chromatography
on silica gel L14002 (Alfa Aesar, 0.06–0.20 mm or
6
2
(
2a) was obtained in the reaction of 1 with 2 mL
(
2.1 g, 15.3 mmol) of 4-methoxybenzylamine. The
major and minor products were isolated by column
chromatography. The major product was additionally
purified by preparative HPLC. Yield 160 mg (26%),
7
0–230 mesh). The reaction mixtures and extracts
were concentrated using a Heidolph Hei-VAP Preci-
sion rotary evaporator.
1
purity 98.2%, R 0.35 (EtOAc–C H , 3:1). H NMR
f
6
14
spectrum (DMSO-d ), δ, ppm: 1.13–1.16 m (2H, H ,
6
ax
Commercial reagents from Alfa Aesar and solvents
from Komponent-Reaktiv were used. Acetonitrile
cyclopropyl), 1.55–1.58 m (2H, H , cyclopropyl), 3.73 s
eq
(
3H, CH O), 4.37 d (2H, CH , J = 5.8 Hz), 6.49 t (1H,
3 2
(
Panreac 221074, HPLC-gradient grade) and phos-
2
-NH, J = 5.8 Hz), 6.87 d (2H, o′-H, J = 8.6 Hz), 7.01 t
phoric acid (Komponent-Reaktiv, ultrapure grade 17-4)
were used for HPLC. The solvents were dried and
purified by standard procedures [14]. The study was
performed using the equipment of the “Physico-
chemical Methods of Study” Joint Center and
(
8
2H, m′-H, J = 8.6 Hz), 7.27 d (2H, m-H, J =
.6 Hz), 7.28–7.36 m (1H, p-H), 10.64 s (1H, N H).
3
Found, %: C 66.21; H 4.98; N 10.94. C H F N O .
Calculated, %: C 66.49; H 5.33; N 10.57.
2
2
21
2
3
2
The minor product contained 84.9% of the main
“Polymeric Composite Materials and Technologies”
substance (HPLC, t = 3.65 min).
R
Engineering Center of the Volgograd State Technical
University.
6-[1-(2,6-Difluorophenyl)cyclopropyl]-5-methyl-
2
-[(3-phenylpropan-1-yl)amino]pyrimidin-4(3H)-
one (2b) was obtained in the reaction with 2 mL (1.9 g,
4.1 mmol) of 3-phenylpropan-1-amine. The residue
6
-[1-(2,6-Difluorophenyl)cyclopropyl]-5-methyl-
2
-(piperidin-1-yl)pyrimidin-4(3H)-one (2e). A mix-
1
ture of 0.5 g (1.55 mmol) of compound 1, 10 mL of
butan-1-ol, and 2 mL (1.7 g, 20 mmol) of piperidine
was shaken until a transparent solution was obtained.
The solution was refluxed with stirring until compound
was dissolved in ethyl acetate, the solution was washed
with 1 M aqueous HCl and brine, dried over anhydrous
Na SO , and filtered, and the solvent was distilled off.
2
4
The residue was treated three times with toluene,
followed by evaporation under reduced pressure, and
purified by column chromatography. The product was
recrystallized from C H –EtOAc until constant
1
disappeared (HPLC), and only traces of 2-butoxy-
pirimidin-4(3H)-one 3 were detected. The solvent was
distilled off under reduced pressure, the residue was
treated with toluene, and the solvent was distilled off.
This operation was repeated three times. The residue
was dissolved in a minimum amount of 2-methyltetra-
hydrofuran, the solution was applied onto silica gel,
and the product was isolated by column chromatog-
raphy using ethyl acetate–cyclohexane (3:1 by
volume) as eluent. Fractions containing the aminolysis
product were evaporated to dryness, and the residue
was recrystallized from hexane until constant melting
point. Yield 300 mg (56%), purity 98.7% (HPLC),
colorless needles, mp 164.5–165.5°C (from hexane),
6
14
melting point. Yield 250 mg (41%), purity 99.2%
HPLC), off-white finely crystalline powder,
mp 199.5–200.5°C (decomp.). R 0.38 (EtOAc–C H ,
(
f
6
14
1
4
1
:1). H NMR spectrum (DMSO-d ), δ, ppm: 1.29–
6
.41 m (2H, H , cyclopropyl), 1.50–1.62 m (2H, H ,
ax
eq
cyclopropyl), 1.80–1.90 m (5H, PhCH CH , CH ),
2
2
3
2
7
9
.60–2.68 m (2H, CH ), 3.23–3.35 m (2H, CH ), 7.04–
2
2
.24 m (7H, Ph, m-H), 7.35–7.37 m (1H, p-H),
3
.51 br.s (1H, 2-NH), 11.77 br.s (1H, N H). Found, %:
C 70.10; H 6.00; N 11.02. C H F N O. Calculated,
23
23
2
3
1
%: C 69.86; H 5.86; N 10.63.
R 0.48 (EtOAc–C H , 3:1). H NMR spectrum
f
6
14
(
DMSO-d ), δ, ppm: 1.05–1.16 m (2H, H , cyclo-
2-{[(Adamantan-1-yl)methyl]amino}-6-[1-(2,6-di-
fluorophenyl)cyclopropyl]-5-methylpyrimidin-
6
ax
propyl), 1.43–1.51 m (8H, CH , 3′-H, 4′-H, 5′-H, H ,
2
eq
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 12 2017

1
850
NOVAKOV et al.
4
(3H)-one (2c) was obtained in the reaction with 2 mL
REFERENCES
(
2.2 g, 13.3 mmol) of (adamantan-1-yl)methanamine.
1
. Novakov, I.A., Navrotskii, M.B., Zakharova, E.K., and
Brunilina, L.L., Russ. Chem. Bull., Int. Ed., 2015,
vol. 64, no. 11, p. 2545.
The product crystallized from the reaction mixture.
The mixture was cooled and filtered, and the precip-
itate was washed on a filter with butan-1-ol and recrys-
tallized from ethanol until constant melting point.
Yield 500 mg (76%), purity 99.5% (HPLC), colorless
2
. Novakov, I.A., Yablokov, A.S., Orlinson, B.S., Nav-
rotskii, M.B., Kirillov, I.A., Vernigora, A.A., Babush-
kin, A.S., Kachala, V.V., and Schols, D., Russ. J. Org.
Chem., 2016, vol. 52, no. 8, p. 1188.
crystalline powder, decomposition point >282.5°C
1
(from EtOH), R 0.41 (EtOAc–C H , 4:1). H NMR
3. Mai, A., Artico, M., Rotili, D., Tarantino, D., Clotet-
Codina, I., Armand-Ugon, M., Ragno, R., Simeoni, S.,
Sbardella, G., Nawrozkij, M.B., Samuele, A., Maga, G.,
and Este, J.A., J. Med. Chem., 2007, vol. 50, p. 5412.
f
6
14
spectrum (DMSO-d ), δ, ppm: 1.03–1.15 m (2H, H ,
cyclopropyl), 1.32–1.44 m (6H, 2-H, 8-H, 9-H, Ad),
1
1
CH NH), 6.04 br.s (1H, 2-NH), 6.90–7.00 m (2H,
m-H), 7.21–7.33 m (1H, p-H), 10.36 br.s (1H, N H).
Found, %: C 70.22; H 7.02; N 10.04. C H F N O.
6
ax
.50–1.55 m (9H, 4-H, 6-H, 10-H, Ad; CH ), 1.81–
3
4
. Rotili, D., Samuele, A., Tarantino, D., Ragno, R.,
Musmuca, I., Ballante, F., Botta, G., Morera, L.,
Pierini, M., Cirilli, R., Nawrozkij, M.B., Gonzalez, E.,
Clotet, B., Artico, M., Este, J.A., Maga, G., and Mai, A.,
J. Med. Chem., 2012, vol. 55, p. 3558.
.93 m (3H, 3-H, 5-H, 7-H, Ad), 2.89–3.01 m (2H,
2
3
2
5
29
2
3
Calculated, %: C 70.57; H 6.87; N 9.88.
-[1-(2,6-Difluorophenyl)cyclopropyl]-5-methyl-
-(morpholin-4-yl)pyrimidin-4(3H)-one (2f). A solu-
tion of compound 1 in 10 mL (10.1 g, 116 mmol) of
anhydrous morpholine was refluxed with stirring until
the reaction was complete (HPLC). The mixture was
cooled, diluted with water, and neutralized with acetic
acid. The precipitate was filtered off, washed with
water, dried, and recrystallized from acetonitrile until
constant melting point. Yield 320 mg (60%), purity
5
6
7
. Novakov, I.A., Yablokov, A.S., Navrotskii, M.B.,
Mkrtchyan, A.S., Vernigora, A.A., Babushkin, A.S.,
Kachala, V.V., and Ruchko, E.A., Russ. J. Gen. Chem.,
6
2
2
017, vol. 87, no. 2, p. 224.
. Valuev-Elliston, V.T., Ivanov, A.V., Orlinson, B.S.,
Gerasimov, E.N., Brunilina, L.L., Kochetkov, S.N.,
Novakov, I.A., and Navrotskii, M.B., Pharm. Chem. J.,
2
012, vol. 46, no. 7, p. 397.
. Hilbert, G.E., Jansen, E.F., and Hendricks, S.B., J. Am.
Chem. Soc., 1935, vol. 57, p. 552.
8. Brown, D.J., J. Chem. Soc., 1959, p. 3647.
9
9.41% (HPLC), fine needles, mp 190–190.5°C (from
9. Delaney, M.O. and Greenberg, M.M., Chem. Res.
Toxicol., 2002, vol. 15, p. 1460.
1
MeCN), R 0.28 (EtOAc–C H , 3:1). H NMR spec-
f
6
14
trum (DMSO-d ), δ, ppm: 1.06–1.18 m (2H, H ,
10. Botta, M., De Angelis, F., Finizia, G., Gambacorta, A.,
6
ax
cyclopropyl), 1.46–1.58 m (2H, H , cyclopropyl),
and Nicoletti, R., Synth. Commun., 1985, vol. 15, p. 27.
eq
1
3
7
.58–1.64 m (3H, CH ), 3.40–3.52 m (4H, NCH ),
11. www.chemicalize.org
3
2
.52–3.60 m (2H, OCH ), 6.68–6.72 m (2H, m-H),
12. Botta, M., Artico, M., Massa, S., Gambacorta, A.,
Marongiu, M.E., Pani, A., and La Colla, P., Eur. J. Med.
Chem., 1992, vol. 27, p. 251.
2
3
.20–7.36 m (1H, p-H), 11.15 br.s (1H, N H). Found,
%
: C 61.88; H 5.50; N 12.20. C H F N O . Calculat-
18 19 2 3 2
1
3. Ulomsky, E.N., Voronin, V.V., Rusinov, V.L., and
Chupakhin, O.N., Russ. Chem. Bull., Int. Ed., 2001,
vol. 50, no. 4, p. 682.
ed, %: C 62.24; H 5.51; N 12.10.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 16-33-60003 mol_a_dk) and by the President of
the Russian Federation (project no. SP-496.2016.4).
1
4. Tietze, L.-F. and Eicher, T., Reaktionen und Synthesen
im organisch-chemischen Praktikum und Forschungs-
laboratorium, Stuttgart: Georg Thieme, 1991, 2nd ed.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 12 2017