Reaction of 6-chloropyrimidine-2,4(1H,3H)-dione with 2-(chloromethoxy)ethyl benzoate. Synthesis of new acyclic nucleosides

Article abstract of DOI:10.1134/S1070428015030124

New acyclic pyrimidine nucleosides, analogs of the antiviral drug acyclovir, were synthesized starting from 6-chloropyrimidine-2,4(1H,3H)-dione. The addition of side carbohydrate chain to the N¹ or N³ atoms of the heterocyclic base w

Full text of DOI:10.1134/S1070428015030124

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 3, pp. 361–367. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © R.G. Melik-Ohanjanyan, T.R. Hovsepyan, S.G. Israelyan, M.S. Ghukasyan, G.S. Karakhanyan, H.A. Panosyan, R.A. Tamazyan,
A.G. Ayvazyan, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 3, pp. 377–383.
Reaction of 6-Chloropyrimidine-2,4(1H,3H)-dione
with 2-(Chloromethoxy)ethyl Benzoate. Synthesis
of New Acyclic Nucleosides
a
a
a
a
R. G. Melik-Ohanjanyan , T. R. Hovsepyan , S. G. Israelyan , M. S. Ghukasyan ,
a
b
b
b
G. S. Karakhanyan , H. A. Panosyan , R. A. Tamazyan , and A. G. Ayvazyan
Scientific–Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of Armenia,
pr. Azatutyan 26, Yerevan, 0014 Armenia
a
Mndzhoyan Institute of Fine Organic Chemistry
e-mail: melik@raen.am
b
Molecular Structure Research Center
Received July 31, 2014
Abstract—New acyclic pyrimidine nucleosides, analogs of the antiviral drug acyclovir, were synthesized
1
3
starting from 6-chloropyrimidine-2,4(1H,3H)-dione. The addition of side carbohydrate chain to the N or N
1
3
atoms of the heterocyclic base with formation of N - and N -substituted isomers, respectively, was confirmed
1
1
3
by H NMR and X-ray analysis. N - and N -Substituted 6-chloropyrimidine-2,4(1H,3H)-diones were subjected
1
to amination with secondary amines, and cyclocondensation of 6-allylamino derivative afforded N -substituted
pyrido[2,3-d]pyrimidine.
DOI: 10.1134/S1070428015030124
The discovery of potent antiviral properties of
acyclic nucleosides such as acyclovir {9-[(2-hydroxy-
ethoxy)methyl]-9H-guanine} [1, 2] and ganciclovir
ciency. In the present article we describe the synthesis
and X-ray diffraction study of some acyclic pyrimidine
nucleosides.
{
9-[(1,3-dihydroxypropan-2-yloxy)methyl]guanine}
As starting compound for the synthesis of targeted
acyclic nucleosides we selected 6-chloropyrimidine-
2,4(1H,3H)-dione (1) which was prepared according to
the procedure reported in [5]. To append a side acyclic
component we used 2-(chloromethoxy)ethyl benzoate
[
3, 4] has stimulated search for new acyclic nucleo-
sides in the pyrimidine and fused pyrimidine series.
However, compounds synthesized as a result of these
studies did not exceed acyclovir in therapeutic effi-
Scheme 1.
O
OSiMe3
(
Me Si) NH, MeCN
3 2
HN
N
O
N
H
Cl
Me SiO
N
Cl
3
1
A
O
N
O
BzO
+
HN
O
N
ClCH OCH CH OBz (2)
2
2
2
O
Cl
O
N
H
Cl
OBz
O
3
4
3
61

3
62
MELIK-OHANJANYAN et al.
2
. It was synthesized in two steps including the reac-
Scheme 2.
tion of sodium benzoate with ethylene chlorohydrin to
obtain 2-hydroxyethyl benzoate which was subjected
to chloromethylation by treatment with paraformal-
dehyde in dichloroethane while passing dry gaseous
hydrogen chloride [6, 7].
O
HN
HNRR'
3
O
N
NRR'
OBz
O
Freshly distilled chloride 2 was brought into reac-
tion with intermediate bis(trimethylsilyl) derivative A
5
a–5e
in acetonitrile in the presence of SnCl [8]. From the
O
4
1
reaction mixture we isolated two isomeric N - and
BzO
3
O
N
O
N -substituted compounds 3 and 4 melting at 123–124
4
+
and 169–170°C, respectively (51 and 10%; Scheme 1).
HN
O
N
N
1
H
The H NMR spectra of 3 and 4 were almost identical,
O
1
and it was difficult to distinguish them as N - or
6
3
N -isomer. Unfortunately, we failed to obtain single
R = H, R′ = Me (a); R = R′ = Et (b); RR′ = (CH
2
)
5
(c),
crystals of 3 and 4 suitable for X-ray analysis.
(
CH O(CH (d); R = H, R′ = CH =CHCH (e).
2
)
2
2
)
2
2
2
On the other hand, by treatment of 3 and 4 with
primary and secondary amines we synthesized the
corresponding 6-amino derivatives 5a–5e and 6
ethylamine, piperidine, morpholine, and allylamine.
The latter was used taking into account that 6-(allyl-
amino)pyrimidines are convenient intermediate prod-
ucts for the preparation of pyrido[2,3-d]pyrimidines
[9]. The reaction of isomer 4 (mp 169–170°C) with
morpholine was carried out with the goal of comparing
physical constants and fine structure of the isomeric
amination products. The amination was performed in
chloroform, and the reaction time depended on the
amine nature.
(
Scheme 2) which gave high-quality single crystals.
Major isomer 3 was reacted with methylamine, di-
2
6
C
27
7
C
3
O
2
5
N
18
C
22
12
C
N
2
C
1
3
C
17
C
10
C
O
19
1
C
N
14
C
6
2
4
C
C
9
2
3
16
C
11
C
4
15
C
5
C
C
O
C
20
8
2
1
C
C
O
The structure of 6-amino derivatives 5a, 5d, and 6
was unambiguously determined by X-ray analysis of
their single crystals. The morpholine ring in molecule
6 (Fig. 1) adopts a chair conformation: deviations of
the N , C , C , O , C , and C atoms from the
mean-square plane were –0.1734(12), 0.1899(14),
–0.2375(15), 0.2684(14), –0.2370(15), and
Fig. 1. Structure of the molecule of 2-{[6-(morpholin-4-yl)-
,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl]methoxy}ethyl
benzoate (6) according to the X-ray diffraction data
arbitrary atom numbering); non-hydrogen atoms are shown
as thermal vibration ellipsoids with a probability of 50%.
2
(
2
2
23
24
25
26
27
8
ii
c
O
b
0
0
.1896(14) Å, respectively. Molecules 6 in crystal are
a
linked through intermolecular hydrogen bonds
1
ii
N
1
1
8
1
ii
N –H ···O [2.803(2) Å] to form infinite chains along
the [1 0 0] axis (Fig. 2). In the three-dimensional
crystal packing the chains are held together via van der
Waals interactions. The structure of compound 6 was
also confirmed by the 2D NOESY experiment which
H
8
O
1
N
1
H
8
i
displayed coupling between the NH proton and NCH2
O
protons of the morpholine ring.
1
i
Molecule 5d (Fig. 3) is structurally related to 6. In
both molecules, the morpholine ring is attached to C .
N
1
i
6
H
The difference is the position of the alkyl benzoate
3
1
substituent which is linked to N in 6 and to N in 5d.
As in molecule 6, the morpholine ring in 5d has
a chair conformation with the following deviations of
atoms from the mean-square plane: 0.2440(15),
Fig. 2. One-dimensional infinite chain formed by molecules
6
in crystal along the [1 0 0] plane. Symmetry operations: i =
+ x, y, z; ii = –1 + x, y, z.
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

REACTION OF 6-CHLOROPYRIMIDINE-2,4(1H,3H)-DIONE
363
1
2
11
7
–
–
0.2379(19), 0.2336(21), –0.2340(19), 0.2295(20), and
0.2352(19) Å for N , C , C , O , C , and C ,
C
C
O
2
2
23
24
25
26
27
9
C
2
C
respectively. Unlike compound 6, molecules 5d in
crystal are linked to dimers by intermolecular hydro-
gen bond N –H ···O 2.851(3) Å (Fig. 4).
1
5
O
13
10
3
O
O
1
N
3
3
8
N
14
17
C
4
C
Molecule 5a differs from 5d and 6 by the presence
16
C
of a methylamino group instead of morpholine ring on
C . Its structure is closer to the structure of 5d rather
6
21
C
6
C
5
8
C
O
C
than 6 since the alkyl benzoate group in 5a is linked to
20
1
C
N (Fig. 5). Molecule 5a is characterized by intra-
18
C
2
2
22
10
molecular hydrogen bond N –H ···O [2.999(2) Å].
1
9
Like compound 5d, molecules 5a in crystal form
C
3
3
8
dimers via double hydrogen bonding N –H ···O
2.809(2) Å]. However, the dimers are not isolated but
Fig. 3. Structure of the molecule of 2-{[6-(morpholin-4-yl)-
,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl]methoxy}ethyl
benzoate (5d) according to the X-ray diffraction data
(arbitrary atom numbering); non-hydrogen atoms are shown
as thermal vibration ellipsoids with a probability of 50%.
[
2
are linked to infinite chains along the [1 1 –1] plane
through double intermolecular hydrogen bonds
2
2
22
15
N –H ···O [3.008(2) Å] (Fig. 6).
According to the 2D NOESY data, the structures of
5
b and 5e are similar to structure 5a, i.e., the alkyl
1
benzoate group is attached to N , and the amino group,
to C . Compound 5b displayed NOE between the
N CH and C N(CH ) protons, while correlation be-
tween the N CH protons and 6-NH was observed for
8i
O
6
3
H
1
6
3
3
i
N
2
2 2
N
1
2
3i
H
8
compound 5e.
O
Thus, the X-ray diffraction study showed that the
amination of 6-chloropyrimidine-2,4-dione 3 with
lower melting point (123–124°C) yields exclusively
N -substituted isomers 5a and 5d and that N -substi-
tuted analog 6 is formed from higher-melting isomer 4
Fig. 4. Dimer formed by 2-{[6-(morpholin-4-yl)-2,4-dioxo-
1,2,3,4-tetrahydropyrimidin-1-yl]methoxy}ethyl benzoate
1
3
(5d) in crystal; intermolecular hydrogen bonds are shown
with dashed lines. Symmetry operation: i = –x, –y, –z.
(
mp 169–170°C). These findings confirm the assign-
ment of structures 3 and 4 (Scheme 1).
7
O
1
1
The benzoyl protection was removed from com-
pounds 5a and 5e in two ways, by passing gaseous
methylamine through a solution of 5a in methanol or
by heating compound 5e in anhydrous methanol in the
presence of sodium methoxide. We thus obtained
C
1
2
C
2
3
9
C
10
15
N
C
O
O
1
1
3
N
O
14
C
4
C
1
-substituted 6-(methylamino)- and 6-(allylamino)-
pyrimidine-2,4-diones 7a and 7b, respectively
Scheme 3). 6-Allylamino derivative 5e was also
6
C
16
1
7
C
(
8
C
21
20
O
C
subjected to intramolecular cyclization with formation
5
C
1
8
C
Scheme 3.
C
O
MeNH , MeOH
19
2
C
5
5
a
e
HN
Fig. 5. Structure of the molecule of 2-{[6-(methylamino)-
,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl]methoxy}ethyl
benzoate (5a) according to the X-ray diffraction data
arbitrary atom numbering); non-hydrogen atoms are shown
as thermal vibration ellipsoids with a probability of 50%.
Intramolecular hydrogen bond is shown with a dashed line.
O
N
R
2
MeONa, MeOH
OH
O
(
7
a, 7b
2 2
R = MeNH (a), CH =CHCH NH (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

3
64
MELIK-OHANJANYAN et al.
1
5iii
0
O
a
b
c
2
2ii
8
ii
15i
1
0iii
O
N
22ii
O
H
O
3
iii
N
3
iii
H
2
2iii
3ii
N
3ii
N
H
2
2iii
10ii
H
8iii
O
O
8
22
1
0i
O
N
O
3
i
3
i
H
2
2
N
H
2
2i
3
N
3
N
H
1
0
1
5ii
22i
O
8
i
O
H
O
1
5
O
Fig. 6. Dimers of 2-{[6-(methylamino)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl]methoxy}ethyl benzoate (5a) molecules linked to
an infinite chain along the [1 1 –1] plane. Hydrogen bonds are shown with dashed lines. Symmetry operations: i = 1 – x, 1 – y, 1 – z;
ii = 1 + x, 1 + y, –1 + z; iii = 2 – x, 2 – y, –z.
of pyrido[2,3-d]pyrimidine 8 by heating in dioxane in
a stream of oxygen in the presence of palladium(II)
chloride (Scheme 4).
TLC on Silufol UV-254 plates; spots were visualized
by UV irradiation.
The X-ray diffraction data for single crystals of 5a,
5
d, and 6 were obtained at room temperature on
Scheme 4.
an Enraf–Nonius CAD-4 automated diffractometer. All
calculations were performed using SHELXTL software
package [10]. The structures were solved by the direct
method. The positions of hydrogen atoms were deter-
mined from the Fourier difference maps. The struc-
tures were refined by the full-matrix least-squares
procedure in anisotropic approximation for non-hydro-
gen atoms and isotropic approximation for hydrogen
atoms. The sets of crystallographic data for compounds
O
HN
O , PdCl2
2
5
e
O
N
N
OBz
O
8
In summary, we have developed procedures for the
synthesis of new 1- and 3-substituted acyclic pyrimi-
dine nucleosides on the basis of 6-chloropyrimidine-
5
a, 5d, and 6 were deposited as CIF files to the
Cambridge Crystallographic Data Centre (see table).
-Chloropyrimidine-2,4(1H,3H)-diones 3 and 4.
6
2
,4(1H,3H)-dione. The synthesized compounds attract
Hexamethyldisilazane, 15 mL, was added to a solution
of 6 g (40 mmol) of chloropyrimidine 1 in 20 mL of
anhydrous acetonitrile, and the mixture was heated
under reflux until it became homogeneous (~1 h). The
solution was evaporated to dryness, 100 mL of anhy-
drous acetonitrile and 8.6 g (40 mmol) of chloride 2
were added to the oily residue (bis-silyl derivative A),
the resulting solution was cooled to –3 to –4°C, and
a solution of 10.4 g (40 mmol) of tin(IV) chloride in
50 mL of anhydrous acetonitrile was added dropwise
over a period of 1 h. The mixture was stirred for 2–3 h
more at –3 to –4°C and left overnight. It was then
interest as both potential biologically active substances
and substrates for further transformations into fused
pyrido[2,3-d]pyrimidines.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Mercury-300 spectrometer (300 MHz) from solutions
in DMSO-d –CCl (1:3) using tetramethylsilane as
6
4
internal reference. The melting points were determined
on a Boetius 72/2064 micro hot stage. The progress of
reactions and the purity of products were monitored by
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

REACTION OF 6-CHLOROPYRIMIDINE-2,4(1H,3H)-DIONE
365
a
Crystallographic data and parameters of X-ray diffraction experiments for compounds 5a, 5d, and 6
Parameter
CCDC entry no.
5a
5d
6
945514
945511
945513
Formula
C
15
H
17
N
3
O
5
C
18
H
21
N
3
O
6
18 21 3 6
C H N O
Molecular weight
319.32
375.38
375.38
a, Å
b, Å
c, Å
9.1336(18)
9.1637(18)
9.891(2)00
0005.9770(12)
12.411(3)
13.355(3)
0006.6382(13)
11.344(2)
12.512(3)
α, deg
β, deg
γ, deg
81.39(3)
74.57(3)
73.92(3)
71.73(3)
77.94(3)
77.27(3)
74.44(3)
81.86(3)
75.18(3)
3
V, Å
764.2(3)
1.388
907.1(4)
1.374
874.8(4)
1.425
3
d
calc, g/cm
–
1
μ(MoK
F(000)
α
), mm
0.106
0.104
0.108
336
396
396
Crystal dimensions, mm
0.35×0.40×0.42
2.1, 30.0
0–0 ≤ h ≤ 12
0.25×0.32×0.38
1.6, 30.0
0.32×0.38×0.40
1.7, 30.0
θ
min., θmax, deg
Scan range
0–0 ≤ h ≤ 8
–17 ≤ k ≤ 17
–18 ≤ l ≤ 18
0–0 ≤ h ≤ 9
–15 ≤ k ≤ 15
–17 ≤ l ≤ 17
–
–
12 ≤ k ≤ 12
13 ≤ l ≤ 13
Total number of reflections
Number of independent reflections
Number of reflections with I > 2σ(I)
Number of variables
4703
4442
5748
5279
5501
5091
3211
0328
0.0497
0.1372
1.0200
2
2758
2850
0276
0328
R
0.0496
0.1308
1.0200
0.0557
0.1452
1.0000
2
wR
Goodness of fit S
a
2
MoK
α
radiation, λ 0.71073 Å; temperature 293 K; triclinic crystal system, space group P-1, Z = 2; weight scheme w = 1/[σ (Fo ) +
2
2
2
(
0.0620P) + 0.1380P], where P = (Fo + 2Fc )/3.
poured into 300 mL of water and extracted with
chloroform (3×100 mL), the combined extracts were
dried over sodium sulfate, the solvent was distilled off,
the residue was treated with 50 mL of diethyl ether,
and the crystalline product was filtered off, washed
with 50 mL of diethyl ether, and dried. Recrystalliza-
tion of the crude product from acetone gave crystals of
N -isomer 3, and N -isomer 4 was isolated from the
mother liquor. Both isomers were purified by recrys-
tallization from ethanol.
N 9.37. C H N O . Calculated, %: C 58.13; H 4.53;
14 13 2 5
N 9.68.
-[(6-Chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
din-3-yl)methoxy]ethyl benzoate (4). Yield 1.92 g
10%), mp 169–170°C, R 0.76 (benzene–acetone,
2
(
1
f
1
:1). H NMR spectrum, δ, ppm: 3.88–3.93 m (2H,
OCH CH OCO), 4.35–4.40 m (2H, OCH CH OCO),
2
2
2
2
3
1
5
.29 s (2H, NCH ), 5.66 s (1H, =CH), 7.42–7.48 m
2
(
(
2H, Harom), 7.53–7.60 m (1H, Harom), 7.96–8.01 m
2H, Harom), 12.34 br.s (1H, NH). Found, %: C 58.27;
H 4.63; N 9.42. C H N O . Calculated, %: C 58.13;
H 4.53; N 9.68.
2
-[(6-Chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
din-1-yl)methoxy]ethyl benzoate (3). Yield 6.6 g
51%), mp 123–124°C, R 0.74 (benzene–acetone,
14 13
2
5
(
2-[(6-Methylamino-2,4-dioxo-1,2,3,4-tetrahydro-
pyrimidin-1-yl)methoxy]ethyl benzoate (5a). Gase-
ous methylamine was passed over a period of 2 h
through a solution of 2.6 g (8 mmol) of compound 3 in
20 mL of chloroform. The solvent was distilled off
to dryness, and the residue was recrystallized from
f
1
1
:1). H NMR spectrum, δ, ppm: 3.90–3.94 m (2H,
OCH ), 4.38–4.42 m (2H, CH OCOPh), 5.44 s (2H,
NCH O), 5.70 s (1H, 5-H), 7.38–7.45 m (2H, Harom),
.50–7.56 m (1H, Harom), 7.94–7.99 m (2H, Harom),
1.54 br.s (1H, NH). Found, %: C 58.35; H 4.24;
2
2
2
7
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

3
66
MELIK-OHANJANYAN et al.
ethanol. Yield 1.95 g (77%), mp 169–170°C, R 0.57
off, 20 mL of methanol was added to the residue, and
the mixture was kept for 4–5 h at room temperature.
The precipitate was filtered off and washed with
10 mL of methanol.
f
1
(chloroform–ethanol, 10:1). H NMR spectrum, δ,
ppm: 2.61 d (3H, NHCH , J = 4.6 Hz), 3.81–3.86 m
3
(
2H, OCH ), 4.37–4.41 m (2H, OCH ), 4.42 d (1H,
2 2
=
CH, J = 2.1 Hz), 5.34 s (2H, NCH ), 6.69 br.q (1H,
2
2
-{[6-(Morpholin-4-yl)-2,4-dioxo-1,2,3,4-tetra-
NH, J = 4.6 Hz), 7.49–7.57 m (2H, Harom), 7.63–
hydropyrimidin-1-yl]methoxy}ethyl benzoate (5d).
Yield 0.54 g (72%), mp 162–163°C, R 0.62 (benzene–
acetone, 1:1). H NMR spectrum, δ, ppm: 2.94–3.00 m
4H, CH NCH ), 3.58–3.64 m (4H, CH OCH ), 3.92–
7
1
.70 m (1H, Harom), 7.92–7.97 m (2H, Harom),
f
0.54 br.d (1H, NH, J = 2.1 Hz). Found, %: C 56.27;
1
H 5.19; N 13.32. C H N O . Calculated, %: C 56.42;
H 5.37; N 13.16.
1
5
17
3
5
(
3
2 2 2 2
.96 m (2H, OCH ), 4.38–4.43 m (2H, OCH ), 5.08 s
2
2
2
-[(6-Dimethylamino-2,4-dioxo-1,2,3,4-tetrahy-
(1H, =CH), 5.23 s (2H, NCH
2
O), 7.50–7.56 m (2H,
dropyrimidin-1-yl)methoxy]ethyl benzoate (5b).
A mixture of 1.3 g (4 mmol) of compound 3 and 7.3 g
H
H
arom), 7.63–7.70 m (1H, Harom), 7.92–7.96 m (2H,
arom), 11.12 br.s (1H, NH). Found, %: C 57.41;
(
100 mmol) of diethylamine in 20 mL of chloroform
H 5.31; N 11.40. C18
H 5.64; N 11.19.
H N O . Calculated, %: C 57.59;
21 3 6
was heated for 7 h under reflux. The solvent was
distilled off, 30 mL of methanol was added to the
residue, and the mixture was kept for 7–8 h in a refrig-
erator. The precipitate was filtered off and washed with
methanol. Yield 0.8 g (55%), mp 126–128°C, R 0.46
(
2
-{[6-(Morpholin-4-yl)-2,4-dioxo-1,2,3,4-tetra-
hydropyrimidin-3-yl]methoxy}ethyl benzoate (6).
Yield 0.16 g (21%), mp 166–167°C, R 0.60 (benzene–
f
1
f
acetone, 1:1). H NMR spectrum, δ, ppm: 3.22–3.27 m
1
benzene–acetone, 1:1). H NMR spectrum, δ, ppm:
(
4H, CH NCH ), 3.63–3.68 m (4H, CH OCH ), 3.87–
2 2 2 2
1
.05 t [6H, N(CH CH ) , J = 7.0 Hz], 3.08 q [4H,
2 3 2
3.91 m (2H, OCH ), 4.35–4.39 m (2H, COOCH ),
2
2
N(CH CH ) , J = 7.0 Hz], 3.98–4.03 m (2H, OCH ),
4
1
Harom), 7.53–7.60 m (1H, Harom), 7.94–7.99 m (2H,
Harom), 10.90 br.s (1H, NH). Found, %: C 59.71;
H 6.41; N 11.38. C H N O . Calculated, %: C 59.82;
2
3 2
2
4.75 s (1H, =CH), 5.26 s (2H, OCH N), 7.42–7.48 m
2
.38–4.43 m (2H, OCH ), 5.01 d (1H, =CH, J =
2
(2H, Harom), 7.53–7.60 m (1H, Harom), 7.97–8.02 m
(2H, Harom), 10.64 s (1H, NH). Found, %: C 57.28;
H 5.42; N 11.37. C H N O . Calculated, %: C 57.59;
.8 Hz ), 5.23 s (2H, NCH O), 7.41–7.48 m (2H,
.
2
1
8
21
3
6
H 5.64; N 11.19.
1
8
23
3
5
2
-{[6-(Allylamino)-2,4-dioxo-1,2,3,4-tetrahydro-
H 6.41; N 11.63.
pyrimidin-1-yl]methoxy}ethyl benzoate (5e). A solu-
tion of 2.3 g (40.4 mmol) of allylamine in 20 mL of
chloroform was added to a solution of 1.0 g (3 mmol)
of compound 3 in 30 mL of chloroform, and the
mixture was heated for 3–4 h under reflux. The mix-
ture was evaporated, 20 mL of methanol was added to
the residue, and the precipitate was filtered off and
washed with 5 mL of methanol. Yield 0.7 g (67%),
2
-{[2,4-Dioxo-6-(piperidin-1-yl)-1,2,3,4-tetra-
hydropyrimidin-1-yl]methoxy}ethyl benzoate (5c).
A mixture of 0.65 g (2 mmol) of compound 3 and 1.7 g
(
heated for 30 min under reflux. The solvent was
distilled off, 30 mL of aqueous methanol was added to
the residue, and the precipitate was filtered off, and
washed with water and diethyl ether. Yield 0.6 g
(
1
20 mmol) of piperidine in 30 mL of chloroform was
mp 131–132°C, R 0.41 (benzene–acetone, 1:1).
f
1
80%), mp 96–98°C, R 0.61 (benzene–ethyl acetate,
H NMR spectrum, δ, ppm: 3.64–3.69 m (2H, OCH2),
f
1
0:1). H NMR spectrum, δ, ppm: 1.42–1.58 m (6H,
3.90–3.94 m (2H, OCH ), 4.42–4.45 m (3H, NHCH ,
2
2
CH CH CH ), 2.87–2.95 m (4H, CH NCH ), 3.90–
=CH), 5.10 d.q (1H, =CH , J = 10.3, 1.6 Hz), 5.19 d.q
2
2
2
2
2
2
3
5
7
7
.95 m (2H, OCH ), 4.38–4.42 m (2H, OCH ),
(1H, =CH , J = 17.3, 1.6 Hz), 5.44 s (2H, NCH O),
2
2
2
2
.00 br.s (1H, =CH), 5.19 s (2H, NCH O), 7.49–
5.76 d.d.t (1H, =CH, J = 17.3, 10.3, 5.1 Hz), 6.49 br.t
(1H, NH, J = 5.5 Hz), 7.43–7.49 m (2H, Harom), 7.55–
7.61 m (1H, Harom), 7.96–8.00 m (2H, Harom), 10.34 br.s
(1H, NH). Found, %: C 59.43; H 5.27; N 12.31.
C H N O . Calculated, %: C 59.12; H 5.54; N 12.17.
2
.56 m (2H, Harom), 7.63–7.69 m (1H, Harom), 7.92–
.96 m (2H, Harom), 11.04 br.s (1H, NH). Found, %:
C 61.23; H 6.47; N 11.34. C H N O . Calculated, %:
1
9
23
3
5
C 61.11; H 6.21; N 11.25.
-(Morpholin-4-yl)pyrimidine-2,4(1H,3H)-di-
ones 5d and 6 (general procedure). A mixture of
.65 g (2 mmol) of compound 3 or 4 and 2 g
20 mmol) of morpholine in 20 mL of chloroform was
heated for 3 h under reflux. The solvent was distilled
1
7
19
3
5
6
1-[(2-Hydroxyethoxy)methyl]-6-(methylamino)-
pyrimidine-2,4(1H,3H)-dione (7a). Gaseous methyl-
amine was passed at 0 to –1°C through a solution of
3.2 g (0.01 mol) of compound 5a in 50 mL of metha-
nol until the initial compound disappeared (TLC). The
0
(
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

REACTION OF 6-CHLOROPYRIMIDINE-2,4(1H,3H)-DIONE
367
precipitate was filtered off and recrystallized from
20 mL, was added to the solid residue, and the precip-
itate was filtered off and washed with cold methanol.
water. Yield 1.45 g (66%), mp 209–210°C, R 0.58
f
1
(
chloroform–methanol, 1:1). H NMR spectrum, δ,
Yield 0.15 g (44%), mp 164–166°C, R 0.60 (benzene–
f
1
ppm: 2.74 d (3H, NCH , J = 4.6 Hz), 3.51–3.60 m (4H,
acetone, 1:1). H NMR spectrum, δ, ppm: 3.97–4.01 m
3
OCH CH O), 4.43 d (1H, =CH, J = 1.6 Hz), 4.47 br.t
(2 H , O C H C H O C O ) , 4 . 3 6 – 4 . 4 1 m ( 2 H,
2
2
2
2
(
1H, OH, J = 4.7 Hz), 5.30 s (2H, NCH ), 6.50 q (1H,
OCH CH OCO), 5.76 s (2H, NCH ), 7.26 d.d (1H,
2
2 2 2
NHCH , J = 4.6 Hz), 10.26 br.s (1H, NHCO). Found,
Py, J = 7.7, 4.8 Hz), 7.38–7.45 m (2H, Harom), 7.52–
7.58 m (1H, Harom), 7.90–7.94 m (2H, Harom), 8.32 d.d
(1H, Py, J = 7.7, 1.9 Hz), 8.62 d.d (1H, Py, J = 4.8,
3
%
: C 44.37; H 6.42; N 19.53. C H N O . Calculated,
8 13 3 4
%
: C 44.64; H 6.09; N 19.52.
-(Allylamino)-1-[(2-hydroxyethoxy)methyl]-
1
.9 Hz), 11.72 br.s (1H, NH). Found, %: C 59.67;
6
H 4.31; N 12.17. C H N O . Calculated, %: C 59.82;
1
7
15
3
5
pyrimidine-2,4(1H,3H)-dione (7b). A 1 N solution of
sodium methoxide, 0.3 mL, was added to a solution of
H 4.43; N 12.31.
0
.35 g (1 mmol) of compound 5e in 10 mL of anhy-
REFERENCES
. Elion, G.B., Furman, P.A., Fyfe, J.A., de Miranda, P.,
Beauchamp, L., and Schaeffer, H.J., Proc. Natl. Acad.
Sci. USA, 1977, vol. 74, p. 5716.
. Schaeffer, H.J., Beauchamp, L., de Miranda, P.,
Elion, G.B., Bauer, D.J., and Collins, P., Nature
(London), 1978, vol. 272, p. 583.
drous methanol, and the mixture was heated under
reflux until the initial compound disappeared (TLC).
The solvent was distilled off, the residue was treated
with 10 mL of water, and the mixture was washed with
1
2
2
0 mL of chloroform. The aqueous phase was acidified
with aqueous HCl, and the precipitate was filtered off
and recrystallized from water. Yield 0.23 g (95%),
mp 179–180°C, R 0.65 (benzene–acetone, 1:1).
H NMR spectrum, δ, ppm: 3.53–3.60 m (4H,
3. Martin, J.C., Dvorak, C.A., Smee, D.F., Mattews, T.R.,
and Verheyden, J.P.H., J. Med. Chem., 1983, vol. 26,
p. 759.
f
1
OCH CH O), 3.74 t.t (2H, CH NH, J = 5.4, 1.6 Hz),
2
2
2
4
. Ogilvie, K.K., Cheriyan, U.O., Radatus, B.K.,
Smieth, K.C., Galloway, K.S., and Kennell, W.L., Can.
J. Chem., 1982, vol. 60, p. 3005.
4
5
.46 d (1H, =CH, J = 1.6 Hz ), 4.47 br.s (1H, OH),
.
.17 d.q (1H, =CH , J = 10.3, 1.6 Hz), 5.26 d.q (1H,
2
=
CH , J = 17.2, 1.6 Hz ), 5.35 s (2H, NCH O),
2 . 2
5
. Davoll, J. and Evans, B.B., J. Chem. Soc., 1960,
5
.83 d.d.t (1H, =CH, J = 17.2, 10.3, 5.4 Hz), 6.61 t
p. 5041.
(
1H, NHCH , J = 5.4 Hz), 10.30 br.s (1H, NHCO).
2
6. Robinson, B., J. Chem. Soc., 1963, p. 2417.
Found, %: C 49.91; H 6.47; N 17.53. C H N O .
1
0
15
3
4
7
. Beauchamp, L.M., Dolmach, B.L., Schaeffer, H.J.,
Collins, P., Bauer, D.J., Keller, P.M., and Fyfe, J.A.,
J. Med. Chem., 1985, vol. 28, p. 982.
Calculated, %: C 49.78; H 6.27; N 17.42.
2
-[(2,4-Dioxo-1,2,3,4-tetrahydropyrido[2,3-d]-
pyrimidin-1-yl)methoxy]ethyl benzoate (8). A mix-
ture of 0.35 g (1 mmol) of compound 5e, 0.18 g
8
. Niedballa, U. and Vorbrugen, H., J. Org. Chem., 1976,
vol. 41, p. 2084.
(
1 mmol) of PdCl , and 2 mL of water in 20 mL of
2
9. Itoh, T., Melik-Ohanjanyan, R.G., Ishikawa, I., Kawa-
hara, N., Mizuno, Y., Honma, Y., Hozumi, M., and
Ogura, H., Chem. Pharm. Bull., 1989, vol. 37, p. 3184.
dioxane was stirred for 8 h at 60–70°C under a stream
of oxygen. The mixture was filtered and evaporated to
dryness, 20 mL of chloroform was added to the resi-
due, and the mixture was evaporated again. Methanol,
10. Sheldrick, G.M., SHELXS97, SHELXL97, Göttingen,
Germany: Univ. of Göttingen, 1997.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015