Synthesis and antiviral activity of new substituted pyrimidine glycosides

Article abstract of DOI:10.1002/jhet.686

A number of N-substituted pyrimidine glycosides were synthesized by coupling reaction of the pyrimidine base with acetobromosugars followed by deprotection. The synthesized compounds were tested for their antiviral activity against Hepatitis B Virus (HBV). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with tested compounds which showed moderate to high anti viral activities.

Full text of DOI:10.1002/jhet.686

1028
Synthesis and Antiviral Activity of New Substituted Pyrimidine
Glycosides
Vol 48
Mahmoud M. M. Ramiz,a Wael A. El-Sayed,b* Ezzat Hagag,c
and Adel A.-H. Abdel-Rahmanc*
aDepartment of Physics and Mathematical Engineering, Faculty of Electronic Engineering,
Menoufia University, Menouf, Egypt
bPhotochemistry Department, National Research Center, El Dokki, Cairo, Egypt
cChemistry Department, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
*E-mail: adelnassar63@hotmail.com or waelshendy@gmail.com
Received December 1, 2009
DOI 10.1002/jhet.686
Published online 11 May 2011 in Wiley Online Library (wileyonlinelibrary.com).
A number of N-substituted pyrimidine glycosides were synthesized by coupling reaction of the pyrim-
idine base with acetobromosugars followed by deprotection. The synthesized compounds were tested for
their antiviral activity against Hepatitis B Virus (HBV). Plaque reduction infectivity assay was used to
determine virus count reduction as a result of treatment with tested compounds which showed moderate
to high anti viral activities.
J. Heterocyclic Chem., 48, 1028 (2011).
INTRODUCTION
found that 3,4-dihydropyrimidin-2(1H)-ones (DHPMs)
have interesting multifaceted pharmacological profile as
hepatitis B virus (HBV) replication inhibitors [10–12].
Moreover, the pyrimidine ring in an organic molecule
also shows prominent activity as antagonist of both a1-
adrenergic and serotonin-S2 receptors [13]. A number of
synthetic pharmacophores with antibacterial [14], anti-
fungal [15], and antimycotic activities [16] are based on
the pyrimidyl motif. Also, pyrimidines are present in
Pyrimidines are an important class of compounds and
have widespread applications from pharmaceuticals to
materials [1]. They have been recognized as important
heterocyclic compounds due to their diverse biological
activities such as Tie-2 kinase inhibitors [2], HIV-1 in-
hibitor [3], antimalarial [4] secretive adenosine A1 re-
ceptor antagonist [5], anticancer [6,7], analgesic [8], and
cardiovascular [9] activities. Furthermore, it has been
C
V
2011 HeteroCorporation

September 2011
Synthesis and Antiviral Activity of New Substituted Pyrimidine Glycosides
1029
numerous natural products and, significantly, in the py-
rimidine and purineucleosides [17–20]. On the other
hand, nucleoside analogs are structurally, metabolically,
and pharmaco-dynamically related agents that have
diverse biological actions and therapeutic effects includ-
ing antiviral [21,22], and antitumor [23,24] activities.
Furthermore, the acyclic nucleoside [25–28], analogues
including modifications of both the acyclic glycon and
aglycon parts have stimulated extensive research as bio-
logical inhibitors [29,30]. The importance of substituted
hydroxyl alkyl chain conformation in the interaction of
acyclic nucleosides with enzymes has been demonstrated
[31]. Moreover, the 5-substituted derivatives of pyrimi-
dine acyclonucleoside analogs have exhibited pro-
nounced inhibitory properties with respect to uridine
phosphorylase and have enhanced antitumor action [24].
Owing to the above significance and our interest in the
synthesis of new and potent antiviral nucleoside analogs
[32–34], herein we report the synthesis and anti HBV
activity of new substituted pyrimidine acyclic
nucleosides.
tons which are indicative of the b-configuration. Deace-
tylation of 5a–c in a mixture of methanol and ammo-
nium hydroxide (25%) (1:1) at room temperature
afforded the free nucleosides 6a–c in 85–88% yields.
Similarly, the free nucleosides 6a–c showed, in their H
NMR spectra, the signals corresponding to the anomeric
1
protons as doublets at d 5.38, 5.39, and 5.35 with large
0
0
J1 ,2 coupling constants (9.5, 9.6, and 9.5 Hz, respec-
tively) clearly indicating that these compounds have
also the b-configuration.
Condensation of the sodium salt of 3a–c with 2,3,4,6-
tetra-O-acetyl-a-D-glucopyranosyl bromide (7) in dry
DMF at 90ꢀC afforded 1-(2,3,4,6-tetra-O-acetyl-b-D-glu-
copyranosyl)-6-aryl-5-cyano-2-(methylthio)-pyrimidin-
4(1H)-ones (8a–c) in 78–83% yields. Their IR spectra
showed characteristic absorption bands corresponding to
O-acetyl groups at 1736–1742 cmꢁ1, the N-acetyl and
N-CO groups at 1666–1670 cmꢁ1 and the CN groups at
1
2204–2206 cmꢁ1. The H NMR spectra of 8a–c showed
the anomeric protons as doublets at d 6.42, 6.44, and
6.43 with J coupling of 8.2, 8.1, and 8.3 Hz, respec-
tively, corresponding to a diaxial orientation of H-10 and
H-20 protons which are indicative of the b-configuration.
Deacetylation of 8a–c in a mixture of methanol and am-
monium hydroxide (25%) (1:1) at room temperature
gave the free nucleosides 9a–c in 88–92% yields. The
free nucleosides 9a–c showed, in their IR spectra
absorption bands corresponding to the hydroxyl groups
RESULTS AND DISCUSSION
Chemistry. 6-Aryl-5-cyanouracils (1a–c) were syn-
thesized by base-catalyzed condensation followed by
cyclization of ethyl cyanoacetate, urea, and aromatic
aldehydes in 40–45% yields. By the same way, 6-aryl-5-
cyano-2-thiouracils (2a–c) were synthesized by base-cat-
alyzed condensation followed by cyclization of ethyl
cyanoacetate, thiourea, and aromatic aldehydes in 45–
52% yields. Treatment of 2a–c with methyl iodide and
sodium hydroxide in water and ethanol at 60ꢀC afforded
6-aryl-5-cyano-2-(methylthio)uracils (3a–c) in 88–92%
yields.
1
at 3386–3435 cmꢁ1. Their H NMR spectra showed the
signals corresponding to the anomeric protons as dou-
blets at d 5.74, 5.75, and 5.77 with J coupling of 7.8,
7.5, and 7.7 Hz, respectively clearly indicating that
these compounds have also the b-configuration.
By the same way condensation of the sodium salt of
3a–c with 2,3,4,6-tetra-O-acetyl-a-D-galactopyranosyl
bromide (10) in dry DMF at 90ꢀC afforded 1-(2,3,4,6-
tetra-O-acetyl-b-D-galactopyranosyl)-6-aryl-5-cyano-2-
(methylthio)-pyrimidin-4(1H)-ones (11a–c) in 66–71%
yields. The 1H NMR spectra of 11a–c showed the
anomeric protons as doublets at d 4.70, 4.74, and 4.73
with J coupling of 7.4, 7.5, and 7.4 Hz, respectively,
corresponding to a diaxial orientation of H-10 and H-20
protons which are indicative of the b-configuration. The
axial protons (H-40) of the galactose moieties as dou-
The sodium salts of 3a–c were condensed with 2-
acetamido-1-chloro-3,4,6-tri-O-acetyl-2-deoxy-D-glucose
(4) in dry DMF. The reaction was proceeded at 90ꢀC to
give the desired 1-(2-acetamido-3,4,6-tri-O-acetyl-2-
deoxy-b-D-glucopyranosyl)-6-aryl-5-cyano-2-(methyl-
thio)pyrimidin-4(1H)-ones (5a–c) in 76–81% yields. The
structures of the nucleosides 5a–c were determined on
1
the basis of their respective IR, H NMR, mass spectra,
0
0
and microanalyses which were found to be consistent
with the assigned structures by comparison with the
structures of glycopyranoside analogues. Their IR spec-
tra showed the O-acetyl groups at 1738–1742 cmꢁ1, the
N-acetyl and N-CO at 1666–1672 cmꢁ1 in addition to
the bands corresponding to CN groups at 2205–2207
blets of doublets at d 5.36, 5.33, and 5.37 with J3 ,4
0
0
coupling of 3.4, 3.3, and 3.5 Hz, and J4 ,5 coupling of
1.1, 1.0, and 1.2 Hz, respectively. Deacetylation of 11a–
c in a mixture of methanol and ammonium hydroxide
(25%) (1:1) at room temperature gave the free nucleo-
1
sides 12a–c in 78–80% yields. The H NMR spectra of
1
cmꢁ1. The H NMR spectra of 5a–c showed the anome-
the free nucleosides 12a–c showed the anomeric protons
as multiplets at d 4.48, 4.54, and 4.50. The axial protons
(H-40) of the galactose moieties showed as multiplets at
d 3.88, 3.90, and 3.93, respectively (Figs. 1–3).
ric protons as doublets at d 5.70, 5.74, and 5.72 with J
coupling of 9.5, 9.6, and 9.4 Hz, respectively, corre-
sponding to a diaxial orientation of H-10 and H-20 pro-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1030
M. M. M. Ramiz, W. A. El-Sayed, E. Hagag, and A. A. Abdel-Rahman
Vol 48
Figure 1. Synthesis rout of compounds 3–6.
Glucosylation of the sodium salt of the 6-aryl-5-cya-
nouracils (1a–c) with 4 in dry DMF at 90ꢀC gave the
desired 1-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl)-6-aryl-5-cyanopyrimidin-4(1H)-ones
(13a–c) in 75–80% yields. The glucosides 13a–c showed,
in their IR spectra, characteristic absorption bands corre-
sponding to the NH and O-acetyl groups at 3317–3324 and
1737–1740 cmꢁ1, respectively. Their 1H NMR spectra
showed the anomeric protons as doublets at d 5.49, 5.58,
and 5.60 with J coupling of 9.3, 9.4, and 9.2 Hz, respec-
tively, corresponding to a diaxial orientation of H-10 and
H-20 protons which are indicative of the b-configuration.
Deacetylation of 13a–c in a mixture of methanol and am-
monium hydroxide (25%) (1:1) at room temperature
Journal of Heterocyclic Chemistry
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September 2011
Synthesis and Antiviral Activity of New Substituted Pyrimidine Glycosides
1031
Figure 2. Synthesis of pyrimidine glycosides.
afforded the free nucleosides 14a–c in 83–90% yields. The
free nucleosides 14a–c showed, in their H NMR spectra,
the signals corresponding to the anomeric protons as dou-
(9.4, 9.6, and 9.5 Hz, respectively) clearly indicating that
these compounds have also the b-configuration.
Antiviral activity. The synthesized compounds were
tested for their antiviral activity against HBV using the
1
blets at d 5.36, 5.38, and 5.40 with J coupling constants
Journal of Heterocyclic Chemistry
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1032
M. M. M. Ramiz, W. A. El-Sayed, E. Hagag, and A. A. Abdel-Rahman
Vol 48
Figure 3. Glucosylation of cyanopyrimidines.
HepG2.2.2.15-cell line [35], a human hepatoplastoma
cell line producing HBV viral particles [36]. The cell
line was maintained in RPMI-1640 (Glutamax) (Gibco
BRL Life Technologies, Paisly Scotland) culture me-
dium containing 100 IU/mL nystatin (Gibco BRL Life
technologies), 380 lg/mL G418 (genetecin) (Gibco BRL
Life Technologies) and 10% fetal calf serum
(FCS)(Gibco BRL Life Technologies). The transferred
HEPG2.2.2.15 cells were kept in a tissue culture flask at
37ꢀC and 5% CO2. Subcultures were set up after a week by
trypsination [(10% versin/trypsin (Biochrome KG, Berlin
Germany)] and transferred to a 96-well tissue culture plate.
Serial dilutions of the test compounds were added to the
cell suspension and incubated for 6 days at 37ꢀC and 5%
CO2. The antiviral activity and cytotoxic effect of the test
compound was estimated by comparing the DNA content in
the culture supernatant and the viability of the cells with the
test compounds to those of HepG2.2.2.15 cells with no
compounds added to their supernatant (blank cells). The
drug lamivudine [(4-amino-1-[(2R,5S)-2-(hydroxymethyl)-
1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one), GlaxoS-
mithKline, Uxbridge, UK] which is a potent selective inhib-
itor of HBV replication has been used as a standard positive
control. Each compound was tested in triplicate.
DNA extraction. DNA extraction was done by incu-
bating 10 lL of diluted supernatant with 10 lL of 0.2M
NaOH at 37ꢀC for 1 h, then carefully adding 9.6 lL of
0.2M HCl followed by addition of 90 lL of Tris-EDTA
(TE) buffer [(2-amino-2-(hydroxymethyl)-1,3-propane-
diol-EDTA) (Gibco BRL Life Technologies)].
PCR-ELISA detection of HBV DNA. The DNA
content in the cell culture supernatant was determined
by PCR amplification of the HBV DNA using 1 lmol/L
of each of the following primers: HCID-1 primer (50-
GGAAAGAAGTCAGAAGGCA-30) and HCID-2 primer
(50-TTGGGGGAGGAGATTAGGTT-30), in a reaction
mixture containing 14 lL extracted supernatant, 4
mmol/L MgCl2, 10 lmol/L DIG-11-dUTP (Roche, Mu-
nich, Germany), 190 lmol/L dTTP, 200 lmol/L dATP,
dGTP, dCTP (Roche) 1.5 U Taq polymerase (Roche), in
a total volume 50 lL. PCR reaction conditions were: 32
cycles of 10 min at 94ꢀC, 30 s at 58ꢀC and 30 s at 72ꢀC
with a 3 s increment for each cycle in a Perkin Elmer
480 thermal cycler (Perkin Elmer, Waltham, MA). The
Journal of Heterocyclic Chemistry
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September 2011
Synthesis and Antiviral Activity of New Substituted Pyrimidine Glycosides
1033
1
Table 1
tor22 instrument (Bruker, Bremen, Germany). H NMR spectra
were recorded with a Varian Gemini spectrometer at 300 and
200 MHz with TMS as internal standard. Chemical shifts were
reported in d scale (ppm) relative to TMS as a standard and
the coupling constants (J values) are given in Hz. The progress
of the reactions was monitored by TLC using aluminum silica
gel plates 60 F245. EImass spectra were recorded with a HP
D5988 A 1000 MHz instrument (Hewlett, Packard, Palo Alto,
CA). Antiviral activity against HBV was tested at the Liver
Institute, Menoufia University, Shebien El-Kom Egypt.
Cytotoxic effect (CC50), inhibitory concentration (IC50), and selective
index (SI) of selected compounds.
HBV
DNA IC50 (lM)
Hep G2
2.2.15 CC50 (lM)
Compd.
SI
Lamivudine
6a
6b
<0.1
1.31
0.23
0.28
1.25
0.66
0.16
1.56
1.37
1.19
0.27
0.20
0.25
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>1000
>76
>417
>357
>80
>151
>625
>64
>73
>84
6c
9a
9b
9c
12a
12b
12c
14a
14b
14c
6-Aryl-5-cyanouracils (1a-c) [39]. A mixture of aromatic
aldehydes (0.1 mole), urea (6.0 g, 0.1 mole) ethyl cyanoacetate
(11.3 g, 0.1 mole) and anhydrous K2CO3 (13.8 g, 0.1 mole) in
absolute ethanol (150 mL) was refluxed for 20 h and then
cooled. The obtained potassium salt was filtered off as a color-
less solid. The potassium salt was dissolved in water at 80ꢀC,
filtered off and neutralized with glacial acetic acid. The precip-
itate was filtered off and washed with water. The precipitate
was crystallized from a water-acetone mixture to give 1a–c.
>370
>500
>400
Table 2
PCR product was detected by DIG-ELISA assay
(Roche). The optical density (OD) from DNA of the test
compound was compared to that of the blank culture.
Results of inhibition of HBV replication by selected compounds.
Concentration
(lM)
HBV DNA in
supernatant
Compd.
Cytotoxicity
assay. 3-(3,5-Dimethylthiazole-2-yl)-
2,5-diphenyltetrazoliumbromide (MTT) (Sigma, St.
Louis, MO) is a colorless substrate that is transferred to
a colored product by any living cell but not by dead
cells. The assay utilizes this compound to test for the vi-
ability of the cells with the test compound added com-
pared to the viability of the blank cells [37].
Lamivudine
1.0
10.0
100.0
1.0
0.25
0.18
0.15
0.19
0.16
0.14
0.75
0.68
0.61
0.66
0.60
0.53
0.21
0.18
0.15
0.37
0.31
0.27
0.80
0.76
0.69
0.15
0.13
0.11
0.18
0.16
0.12
0.22
0.20
0.17
0.68
0.61
0.56
0.78
0.72
0.70
0.73
0.70
0.63
6a
10.0
100.0
1.0
10.0
100.0
1.0
10.0
100.0
1.0
6b
Calculation of IC50, CC50, and SI values. The 50%
inhibitory concentration (IC50) of an antiviral drug was
determined by plotting the DNA content of the serial
dilutions of the tested compound versus the concentra-
tion of this compound. The 50% cytotoxic effect (CC50)
was calculated from the average viability of the cells in
proportion to the concentration of the drug. The selec-
tive index (SI) could be calculated as CC50/IC50.
6c
9a
10.0
100.0
1.0
9b
10.0
100.0
1.0
10.0
100.0
1.0
Antiviral activity. The synthesized compounds were
tested for their antiviral activity against HBV using the
HepG2.2.2.15-cell line, a human hepatoplastoma cell
line producing HBV viral particles [38].
9c
12a
12b
12c
14a
14b
14c
10.0
100.0
1.0
The results of the viral screening against HBV of selected
compounds indicated that compounds 6b, 6c, 9b, 9c, 14a,
14b, and 14c showed moderate viral replication inhibition
and mild cytotoxicity with SI >417, >357, >151, >625,
>370, >500, and >400, respectively. On the other hand
compounds 6a, 9a, 12a, 12b, and 12c showed very low inhi-
bition and high cytotoxicity with SI >76, >80, >64, >73,
and >84, respectively (Tables 1 and 2).
10.0
100.0
1.0
10.0
100.0
1.0
10.0
100.0
1.0
10.0
100.0
1.0
EXPERIMENTAL
10.0
100.0
General. Melting points were determined using a Bu¨chi ap-
paratus. IR spectra (KBr) were recorded with a Bruker-Vec-
Journal of Heterocyclic Chemistry
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M. M. M. Ramiz, W. A. El-Sayed, E. Hagag, and A. A. Abdel-Rahman
Vol 48
5-Cyano-6-phenyluracil (1a). Yield: 40 %, m.p. 287–289ꢀC
and 100 mL of dry ether was added to the warm solution with
swirling and left for 12 h at 5ꢀC. The solid was collected by
filtration, washed with dry ether and dried well. Pure 2-acet-
amido-3,4,6-tri-O-acetyl-2-deoxy-a-D-glucopyranosyl chloride
(4) was obtained; yield 13 g, 76 %; m.p. 125–126ꢀC (lit. 70%,
m.p. 127–128ꢀC).
(lit. 34%, m.p. 286–287ꢀC).
5-Cyano-6-(4-methylphenyl)uracil (1b). Yield: 45%, m.p.
290–293ꢀC (lit. 39%, m.p. 295–296ꢀC).
5-Cyano-6-(4-methoxyphenyl)uracil (1c). Yield: 44%, m.p.
277–278ꢀC (lit. 40%, m.p. 276–277ꢀC).
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyrano-
syl)-6-aryl-5-cyano-2-(methylthio)-pyrimidin-4(1H)-ones (5a–
c). A mixture of 2-(methylthio)uracils 3a–c (5 mmol) and 50%
oil-immersed sodium hydride (0.24 g, 5 mmol) in DMF (30
mL) was stirred at 70–80ꢀC for 1 h and then cooled to room
temperature. a-Chloroacetamido sugar 4 (1.83 g, 5 mmol) was
added to the mixture, and stirred at 90ꢀC for 3–5 h. the mix-
ture was evaporated till dryness under reduced pressure and
the residue was recrystallized from absolute ethanol to give
5a–c in 76–81% yields.
6-Aryl-5-cyano-2-thiouracils (2a-c) [39]. A mixture of aro-
matic aldehydes (0.1 mole), thiourea (7.6 g, 0.1 mole) ethyl
cyanoacetate (11.3 g, 0.1 mole) and anhydrous K2CO3 (13.8 g,
0.1 mole) in absolute ethanol (150 mL) was refluxed for 19 h
and then cooled. The obtained potassium salt was filtered off
as yellow solid. The potassium salt was dissolved in water at
80ꢀC, filtered off and neutralized with glacial acetic acid. The
light yellow precipitate was filtered off and washed with water.
The precipitate was crystallized from a DMF-water mixture to
give 2a–c.
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranosyl)-
5-cyano-2-(methylthio)-6-phenylpyrimidin-4(1H)-one (5a). Yield
¼ 2.31 g, 81%; m.p. 190–191ꢀC. ir (KBr) m: 3310 (NH), 1738
5-Cyano-6-phenyl-2-thiouracil (2a). Yield: 45%; m.p. 296–
298ꢀC (lit. 40%; m.p. 246–247ꢀC).
5-Cyano-6-(4-methylphenyl)-2-thiouracil (2b). Yield: 50%;
m.p. 260–263ꢀC (lit. 42%; m.p. 245–246ꢀC).
5-Cyano-6-(4-methoxyphenyl)-2-thiouracil (2c). Yield: 52%,
m.p. 237–239ꢀC (lit. 44%, m.p. 236–237ꢀC).
6-Aryl-5-cyano-2-(methylthio)uracils (3a-c) [36]. A solution
of substituted 2-thiouracils 2a–c (0.05 mole), methyl iodide
(3.11 ml, 0.05 mole) and sodium hydroxide (2 g, 0.05 mole)
in water (50 mL) and ethanol (100 mL) was stirred at 60ꢀC
for 1 h. A white solid began to precipitate by cooling. The
solid was filtered off, washed with water, dried and recrystal-
lized from ethanol to give 3a–c in 88–92% yields.
5-Cyano-2-(methylthio)-6-phenyluracil (3a). Yield: 90%,
m.p. 267–269ꢀC (lit. 86%, m.p. 267ꢀC).
5-Cyano-6-(4-methylphenyl)-2-(methylthio)uracil (3b). Yield:
88%, m.p. 297–299ꢀC (lit. 86%, m.p. > 300ꢀC).
1
(C¼¼O), 1669 (C¼¼O), 2205 (CN) cmꢁ1; H NMR (DMSO-d6):
d ¼ 1.77 (s, 3 H, NHAc), 1.94, 1.99, 2.02 (3 s, 9 H, 3 OAc),
2.51 (s, 3 H, SCH3), 3.97-4.10 (m, 3 H, H-50, H-60), 4.50 (m,
1 H, H-20), 5.10 (m, 1 H, H-40), 5.25 (t, 1 H, J ¼ 9.5 Hz, H-
30), 5.70 (d, 1 H, J ¼ 9.5 Hz, H-10), 7.80 (d, 1 H, J ¼ 7.5 Hz,
NHAc), 7.32-7.40 (m, 5 H, ArAH). EI-MS: m/z ¼ 572 [Mþ].
Anal. Calcd for C26H28N4O9S (572.58): C 54.53, H 4.92, N
9.78. Found: C 54.44, H 4.67, N 9.99.
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranosyl)-
5-cyano-6-(4-methylphenyl)-2-(methylthio)pyrimidin-4(1H)-one
(5b). Yield ¼ 2.22 g, 76%; m.p. 212–213ꢀC. ir (KBr) m: 3314
(NH), 1740 (C¼¼O), 1672 (C¼¼O), 2205 (CN) cmꢁ1
;
1H nmr
(DMSO-d6): d ¼ 1.79 (s, 3 H, NHAc), 1.95, 1.99, 2.00 (3 s, 9
H, 3 OAc), 2.33 (s, 3 H, CH3), 2.50 (s, 3 H, SCH3), 3.95-4.15
(m, 3 H, H-50, H-60), 4.54 (m, 1 H, H-20), 5.19 (m, 1 H, H-40),
5.31 (t, 1 H, J ¼ 9.5 Hz, H-30), 5.74 (d, 1 H, J ¼ 9.6 Hz, H-
10), 7.19 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.35 (d, J ¼ 10.3 Hz,
2 H, ArAH), 7.82 (d, 1 H, J ¼ 7.5 Hz, NHAc). EI-MS: m/z ¼
586 [Mþ]. Anal. Calcd for C27H30N4O9S (586.61): C 55.28, H
5.15, N 9.55. Found: C 55.12, H 4.99, N 9.37.
5-Cyano-6-(4-methoxyphenyl)-2-(methylthio)uracil (3c). Yield:
92%, m.p. > 300ꢀC (lit. 87%, m.p. > 300ꢀC).
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-a-D-glucopyranosyl
chloride (4) [36]. Sodium (1.1 g, 47.5 mmol) was added in
small pieces to 50 mL of methanol in a round-bottomed flask
with cooling in an ice-bath. The solution was brought to 25ꢀC
and powdered 2-amino-2-deoxy-a-D-glucose hydrochloride
(10.45 g, 48.52 mmol) was added. The mixture was gently
swirled for 4–5 min, and then filtered through a Bu¨chner fun-
nel with very gentle suction. The filter was washed twice with
5-mL portions of methanol. The combined filtrate was treated
with 6 mL (63 mmol) of acetic anhydride, and the flask was
cooled under a tap for a few minutes to moderate the initial
reaction. The clear solution was kept for overnight at room
temperature and then refrigerated for 4 h at 0ꢀC to complete
crystallization. The product was filtered, washed with 10 mL
of methanol and then with three 5 mL portions of ether, and
dried well. The dried powder was placed in 250-mL round-bot-
tomed flask and treated with 20 mL of acetyl chloride which
was added drop wise through the top of the condenser with
vigorous stirring. The mixture was stirred for 48 h without
external heating at room temperature. Through the condenser,
80 mL of dichloromethane was added, then the solution was
poured with vigorous stirring onto 80 g of ice and 20 mL of
water. The organic solution was drawn off without delay into
a beaker containing ice and 80 mL of saturated sodium bicar-
bonate solution. The organic layer was dried over Na2SO4, fil-
tered, concentrated to 10 mL on a rotary evaporator at 50ꢀC,
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranosyl)-
5-cyano-6-(4-methoxyphenyl)-2-(methylthio)-pyrimidin-4(1H)-one
(5c) Yield ¼ 2.37 g, 79%; m.p. 233-234ꢀC. ir (KBr) m: 3312
1
(NH), 1742 (C¼¼O), 1669 (C¼¼O), 2207 (CN) cmꢁ1; H NMR
(DMSO-d6): d ¼ 1.78 (s, 3 H, NHAc), 1.94, 1.99, 2.02 (3 s, 9
H, 3 OAc), 2.53 (s, 3 H, SCH3), 3.48 (s, 3 H, OCH3), 3.91-
4.11 (m, 3 H, H-50, H-60), 4.53 (m, 1 H, H-20), 5.22 (m, 1 H,
H-40), 5.34 (t, 1 H, J ¼ 9.5 Hz, H-30), 5.72 (d, 1 H, J ¼ 9.4
Hz, H-10), 7.18 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.30 (d, J ¼
10.3 Hz, 2 H, ArAH), 7.77 (d, 1 H, J ¼ 7.5 Hz, NHAc). EI-
MS: m/z ¼ 602 [Mþ]. Anal. Calcd for C27H30N4O10S (602.61):
C 53.81, H 5.01, N 9.29. Found: C 53.66, H 4.87, N 9.17.
1-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)-6-aryl-5-cyano-
2-(methylthio)-pyrimidin-4(1H)-ones (6a-c). A solution of 5a-c
(0.5 g) in a 1:1 mixture (50 mL) of methanol and conc. ammo-
nia (25%) was stirred at room temperature for 2 h. The reac-
tion mixtures were concentrated under reduced pressure. The
residue were recrystallized from methanol to furnish the title
compounds 6a-c in 85-89% yields.
1-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)-5-cyano-2-(meth-
ylthio)-6-phenylpyrimidin-4(1H)-one (6a). Yield ¼ 0.33 g, 85%;
m.p. 263-264ꢀC. ir (KBr) m: 3412-3380 (OH), 3311 (NH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis and Antiviral Activity of New Substituted Pyrimidine Glycosides
1035
1674 (C¼¼O), 2205 (CN) cmꢁ1
;
1H NMR (DMSO-d6): d ¼
1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-5-cyano-2-(meth-
ylthio)-6-phenylpyrimidin-4(1H)-one (8a). Yield ¼ 2.23 g, 78
%; m.p. 166-168ꢀC. ir (KBr) m: 1736 (C¼¼O), 1668 (C¼¼O),
1.68 (s, 3 H, NHAc), 3.16-3.25 (m, 2 H, H-60), 3.42-3.50 (m, 2
H, H-40, H-50), 3.73 (m, 1 H, H-30), 3.84 (m, 1 H, H-20), 5.18-
5.31 (m, 3 H, 3 OH), 5.38 (d, 1 H, J ¼ 9.5 Hz, H-10), 7.35-
7.40 (m, 5 H, ArAH), 7.92 (d, 1 H, J ¼ 8.5 Hz, NHAc). EI-
MS: m/z ¼ 446 [Mþ]. Anal. Calcd for C20H22N4O6S (446.47):
C 53.80, H 4.96, N 12.54. Found: C 53.60, H 4.81, N 12.32.
1-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)-5-cyano-6-(4-
methyl- phenyl)-2-(methylthio)-pyrimidin-4(1H)-one (6b). Yield
¼ 0.34 g, 89%; m.p. 274-275ꢀC. ir (KBr) m: 3418-3385 (OH),
1
2204 (CN) cmꢁ1; H NMR (DMSO-d6): d ¼ 2.02, 2.03, 2.04,
2.07 (4 s, 12 H, 4 OAc), 2.50 (s, 3 H, SCH3), 4.09 (m, 2 H,
0
H-60), 4.22 (m, 1 H, H-50), 5.06 (t, 1 H, J3 ,4 ¼ 9.5 Hz, H-40),
0
5.16 (t, 1 H, J2 ,3 ¼ 9.2 Hz, H-20), 5.58 (t, 1 H, J2 ,3 ¼ 9.3
0
0
0
0
Hz, H-30), 6.42 (d, 1 H, J1 ,2 ¼ 8.2 Hz, H-10), 7.35-7.40 (m, 5
0
0
H, ArAH). EI-MS: m/z
¼
446 [Mþ]. Anal. Calcd for
C26H27N3O10S (573.57): C 54.44, H 4.74, N 7.32. Found: C
54.23, H 4.61, N 7.25.
3316 (NH), 1670 (C¼¼O), 2202 (CN) cmꢁ1; H NMR (DMSO-
1
d6): d ¼ 1.69 (s, 3 H, NHAc), 2.30 (s, 3 H, CH3), 2.51 (s, 3
H, SCH3), 3.19-3.26 (m, 2 H, H-60), 3.40-3.50 (m, 2 H, H-40,
H-50), 3.77 (m, 1 H, H-30), 3.89 (m, 1 H, H-20), 5.21-5.31 (m,
3 H, 3 OH), 5.39 (d, 1 H, J ¼ 9.6 Hz, H-10), 7.23 (d, J ¼ 10.3
Hz, 2 H, ArAH), 7.39 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.90 (d,
1 H, J ¼ 8.5 Hz, NHAc). EI-MS: m/z ¼ 460 [Mþ]. Anal.
Calcd for C21H24N4O6S (460.50): C 54.77, H 5.25, N 12.16.
Found: C 54.63, H 5.11, N 12.02.
1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-5-cyano-6-
(4-methylphenyl)-2-(methylthio)-pyrimidin-4(1H)-one (8b). Yield
¼ 2.31 g, 79%; m.p. 166-168ꢀC. ir (KBr) m: 1738 (C¼¼O),
1666 (C¼¼O), 2205 (CN) cmꢁ1
;
1H NMR (DMSO-d6): d ¼
1.99, 2.02, 2.04, 2.06 (4 s, 12 H, 4 OAc), 2.38 (s, 3 H,
CH3), 2.52 (s, 3 H, SCH3), 4.11 (m, 1 H, H-60), 4.29 (m, 1
H, H-50), 5.11 (m, 1 H, H-40), 5.25 (m, 1 H, H-20), 5.61 (m,
1 H, H-30), 6.44 (d, 1 H, J1 ,2 ¼ 8.1 Hz, H-10), 7.20 (d, J ¼
0
0
1-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)-5-cyano-6-(4-
methoxy-phenyl)-2-(methylthio)-pyrimidin-4(1H)-one (6c). Yield
¼ 0.35 g, 88%; m.p. 260-262ꢀC. ir (KBr) m: 3429-3387 (OH),
10.3 Hz, 2 H, ArAH), 7.40 (d, J ¼ 10.3 Hz, 2 H, Ar-H). EI-
MS: m/z ¼ 587 [Mþ]. Anal. Calcd for C27H29N3O10
S
(587.60): C 55.19, H 4.97, N 7.15. Found: C 54.98, H 4.81,
N 7.05.
3317 (NH), 1671 (C¼¼O), 2205 (CN) cmꢁ1
;
1H nmr (DMSO-
d6): d ¼ 1.69 (s, 3 H, NHAc), 2.50 (s, 3 H, SCH3), 3.29-3.50
(m, 7 H, H-40, H-50, H-60, OCH3), 3.75 (m, 1 H, H-30), 3.85
(m, 1 H, H-20), 5.20-5.35 (m, 3 H, 3 OH), 5.35 (d, 1 H, J ¼
9.5 Hz, H-10), 7.23 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.37 (d, J ¼
10.3 Hz, 2 H, ArAH), 7.91 (d, 1 H, J ¼ 8.5 Hz, NHAc). EI-
MS: m/z ¼ 476 [Mþ]. Anal. Calcd for C21H24N4O7S (476.50):
C 52.93, H 5.07, N 11.75. Found: C 52.79, H 4.87, N 11.59.
2,3,4,6-Tetra-O-acetyl-a-D-glucopyranosyl bromide (7)
[40]. Glucose pentaacetate (12 g, 30.76 mmol) was dissolved in
dry dichloromethane (24 mL) and placed in a 250-mL conical
flask fitted with a glass stopper. Hydrogen bromide solution in
acetic acid (24 mL) (45%, w/w HBr) was added and the reac-
tion mixture was allowed to stand at room temperature for 2.5
h. The mixture was poured into ice-water and the flask was
washed with dichloromethane. The organic layer was separated
and washed with several portions of saturated aqueous NaHCO3
until no effervescence occurs. The organic layer was washed
with water, dried over Na2SO4, filtered and evaporated under
reduced pressure. The residue was dissolved in dry ether, heat-
ing to 40ꢀC and light petroleum (b.p. 40-60ꢀC) was added
slowly until a slight persistent cloudiness was occurred. A little
amount of dry ether was added to give a clear solution which
was left to cool slowly to room temperature and finally refriger-
ated. The purified product was filterted off and dried well to
give 7, yield 11 g, 87%; m.p. 85-86ꢀC (lit. 88%, m.p. 88-89ꢀC).
The product should be stored in refrigerator without delay.
1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-6-aryl-5-cyano-
2-(methylthio)-pyrimidin-4(1H)-ones (8a-c). 2-(Methylthio)ura-
cils 3a-c (5 mmol) were suspended in 25 mL dry DMF at
room temperature. To this suspension 0.26 g NaH (50%, 5
mmol) was added and the mixture was stirred at 70-80ꢀC for
0.5 h and cooled to room temperature. 2,3,4,6-Tetra-O-acetyl-
a-D-glucopyranosyl bromide (7) (2.26 g, 5.5 mmol) was
added, and the mixture was stirred at room temperature for 3 h
until the starting material was consumed (TLC) and then fil-
tered. The residue resulted from evaporation of the filtrate
under reduced pressure was purified by recrystallization from
absolute ethanol to afford 8a-c in 78-83 yields.
1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-5-cyano-6-(4-
methoxyphenyl)-2-(methylthio)-pyrimidin-4(1H)-one (8c). Yield
¼ 2.50 g, 83%; m.p. 189-191ꢀC. ir (KBr) m: 1742 (C¼¼O),
1
1670 (C¼¼O), 2206 (CN) cmꢁ1; H nmr (DMSO-d6): d ¼ 1.98,
2.02, 2.05, 2.08 (4 s, 12 H, 4 OAc), 2.53 (s, 3 H, SCH3), 3.48
(s, 3 H, OCH3), 4.17 (m, 1 H, H-60), 4.32 (m, 1 H, H-50),
5.21-5.30 (m, 2 H, H-20, H-40), 5.66 (m, 1 H, H-30), 6.43 (d, 1
H, J1 ,2 ¼ 8.3 Hz, H-10), 7.25 (d, J ¼ 10.3 Hz, 2 H, Ar-H),
7.43 (d, J ¼ 10.3 Hz, 2 H, ArAH). EI-MS: m/z ¼ 603 [Mþ].
Anal. Calcd for C27H29N3O11S (603.60): C 53.72, H 4.84, N
6.96. Found: C 53.60, H 4.80, N 7.08.
0
0
1-(b-D-Glucopyranosyl)-6-aryl-5-cyano-2-(methylthio)-pyri-
midin-4(1H)-ones (9a-c). A solution of 8a-c (0.5 g) in a 1 : 1
mixture (50 mL) of methanol and conc. ammonia (25%) was
stirred at room temperature for 2 h. The reaction mixtures
were concentrated under reduced pressure. The residue were
recrystallized from methanol to give 9a-c in 88-92% yields.
1-(b-D-Glucopyranosyl)-5-cyano-2-(methylthio)-6-phenylpyri-
midin-4(1H)-one (9a). Yield ¼ 0.32 g, 92 %; m.p. 170-171
ꢀC. ir (KBr) m: 3432-3386 (OH), 1670 (C¼O), 2205 (CN)
cmꢁ1
;
1H NMR (DMSO-d6): d ¼ 2.51 (s, 3 H, SCH3), 3.28-
3.31 (m, 4 H, H-30, H-40, H-50, H-60), 3.50 (m, 1 H, H-60),
3.64 (m, 1 H, H-20), 4.50 (brs, 1 H, 60-OH), 5.00 (brs, 1 H, 40-
OH), 5.45 (m, 2 H, 20-OH, 30-OH), 5.74 (d, J1 ,2 ¼ 7.8 Hz, þH-
10), 7.30-7.40 (m, 5 H, ArAH). EI-MS: m/z ¼ 405 [M ].
Anal. Calcd for C18H19N3O6S (405.42): C 53.32, H 4.72, N
10.36. Found: C 53.09, H 4.63, N 10.17.
0
0
1-(b-D-Glucopyranosyl)-5-cyano-6-(4-methylphenyl)-2-(meth-
ylthio)-pyrimidin-4(1H)-one (9b). Yield ¼ 0.32 g, 90 %; m.p.
198-199ꢀC. ir (KBr) m: 3434-3389 (OH), 1672 (C¼¼O), 2207
(CN) cmꢁ1
;
1H NMR (DMSO-d6): d ¼ 2.38 (s, 3 H, CH3),
2.50 (s, 3 H, SCH3), 3.35-3.45 (m, 5 H, H-30, H-40, H-50, H-
60), 3.66 (m, 1 H, H-20), 4.52 (brs, 1 H, 60-OH), 5.07 (brs, 1
H, 40-OH), 5.50 (m, 2 H, 20-OH, 30-OH), 5.75 (d, J1 ,2 ¼ 7.5
Hz, H-10), 7.25 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.45 (d, J ¼
10.3 Hz, 2 H, Ar-H). EI-MS: m/z ¼ 419 [Mþ]. Anal. Calcd
for C19H21N3O6S (419.45): C 54.40, H 5.04, N 10.01. Found:
C 54.28, H 4.89, N 9.89.
0
0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1036
M. M. M. Ramiz, W. A. El-Sayed, E. Hagag, and A. A. Abdel-Rahman
Vol 48
40), 7.21 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.41 (d, J ¼ 10.3 Hz,
2 H, Ar-H). EI-MS: m/z ¼ 587 [Mþ]. Anal. Calcd for
C27H29N3O10S (587.60): C 55.19, H 4.97, N 7.15. Found: C
54.02, H 4.77, N 7.00.
1-(b-D-Glucopyranosyl)-5-cyano-6-(4-methoxyphenyl)-2-(meth-
ylthio)-pyrimidin-4(1H)-one (9c). Yield ¼ 0.31 g, 88 %; m.p.
218-220ꢀC. ir (KBr) m: 3435-3388 (OH), 1677 (C¼¼O), 2207
(CN) cmꢁ1
;
1H NMR (DMSO-d6): d ¼ 2.50 (s, 3 H, SCH3),
3.39-3.52 (m, 8 H, H-30, H-40, H-50, H-60, OCH3), 3.63 (m, 1
H, H-20), 4.48 (brs, 1 H, 60-OH), 5.05 (brs, 1 H, 40-OH), 5.55
1-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-5-cyano-6-(4-
methoxyphenyl)-2-(methylthio)-pyrimidin-4(1H)-one (11c). Yield
¼ 1.99 g, 66 %; m.p. 205-206ꢀC. ir (KBr) m: 1744 (C¼¼O),
(m, 2 H, 20-OH, 30-OH), 5.77 (d, J1 ,2 ¼ 7.7 Hz, H-10), 7.25
(d, J ¼ 10.3 Hz, 2 H, ArAH), 7.47 (d, J ¼ 10.3 Hz, 2 H, Ar-
H). EI-MS: m/z ¼ 435 [Mþ]. Anal. Calcd for C19H21N3O7S
(435.45): C 52.40, H 4.86, N 9.64. Found: C 52.27, H 4.80, N
9.53.
0
0
1669 (C¼¼O), 2207 (CN) cmꢁ1
;
1H NMR (DMSO-d6): d ¼
2.01, 2.03, 2.05, 2.16 (4 s, 12 H, 4 OAc), 2.49 (s, 3 H, SCH3),
3.50 (s, 3 H, OCH3), 3.88-3.96 (m, 1 H, H-50), 4.10-4.19 (m, 2
H, H-60), 4.73 (d, 1 H, J1 ,2 ¼ 7.4 Hz, H-10), 5.10-5.20 (m, 2
0
0
H, H-20, H-30), 5.37 (dd, 1 H, J3 ,4 ¼ 3.5 Hz, J4 ,5 ¼ 1.2 Hz,
H-40), 7.22 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.40 (d, J ¼ 10.3
Hz, 2 H, ArAH). EI-MS: m/z ¼ 603 [Mþ]. Anal. Calcd for
C27H29N3O11S (603.60): C 53.72, H 4.84, N 6.96. Found: C
53.63, H 4.77, N 6.88.
0
0
0
0
2,3,4,6-Tetra-O-acetyl-a-D-galactopyranosyl bromide (10)
[41]. Galactose pentaacetate (12 g, 30.76 mmol) was dissolved
in dry dichloromethane (24 mL) and placed in a 250-mL coni-
cal flask fitted with a glass stopper. Hydrogen bromide solution
in acetic acid (24 mL) (45%, w/w HBr) was added and the
reaction mixture was allowed to stand at room temperature for
2.5 h. The mixture was poured into ice-water and the flask
was washed with dichloromethane. The organic layer was sep-
arated and washed with several portions of saturated aqueous
NaHCO3 until no effervescence occurs. The organic layer was
washed with water, dried over Na2SO4, filtered and evaporated
under reduced pressure. The residue was dissolved in dry
ether, heating to 40ꢀC and light petroleum (b.p. 40-60ꢀC) was
added slowly until a slight persistent cloudiness was occurred.
A little amount of dry ether was added to give a clear solution
which was left to cool slowly to room temperature and finally
refrigerated. The purified product was filtered off and dried
well to give 10 (10 g, 79%). The product should be stored in
refrigerator without delay.
1-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-6-aryl-5-cyano-
2-(methylthio)-pyrimidin-4(1H)-ones (11a-c). 2-(Methylthio)ura-
cils 3a-c (5 mmol) were suspended in 25 mL dry DMF at
room temperature. To this suspension 0.26 g NaH (50%, 5
mmol) was added and the mixture was stirred at 70-80ꢀC for
0.5 h and cooled to room temperature. 2,3,4,6-Tetra-O-acetyl-
a-D-galactopyranosyl bromide (10) (2.26 g, 5.5 mmol) was
added, and the mixture was stirred at room at room tempera-
ture for 3 h until the starting material was consumed (TLC)
and then filtered. The residue resulted from evaporation of the
filtrate under reduced pressure was purified by recrystallization
from absolute ethanol to afford 11a-c in 66-71 yields.
1-(b-D-Galactopyranosyl)-6-aryl-5-cyano-2-(methylthio)-pyr-
imidin-4(1H)-ones (12a-c). A solution of 11a-c (0.5 g) in a 1 :
1 mixture (50 mL) of methanol and conc. ammonia (25%) was
stirred at room temperature for 2 h. The reaction mixtures
were concentrated under reduced pressure. The residue were
recrystallized from methanol to give 12a-c in 78-80% yields.
1-(b-D-Galactopyranosyl)-5-cyano-2-(methylthio)-6-phenyl-
pyrimidin-4(1H)-one (12a). Yield ¼ 0.28 g, 80%; m.p. 210-
211ꢀC. ir (KBr) m: 3435-3385 (OH), 1665 (C¼¼O), 2204 (CN)
cmꢁ1
;
1H nmr (DMSO-d6): d ¼ 2.50 (s, 3 H, SCH3), 3.42-
3.49 (m, 3 H, H-20, H-30, H-50), 3.65-3.71 (m, 2 H, H-60), 3.88
(m, 1 H, H-40), 4.48 (m, 1 H, H-10), 4.70 (brs, 1 H, 60-OH),
5.05 (brs, 1 H, 40-OH), 5.50 (m, 2 H, 20-OH, 30-OH), 7.30-
7.40 (m, 5 H, ArAH). EI-MS: m/z ¼ 405 [Mþ]. Anal. Calcd
for C18H19N3O6S (405.42): C 53.32, H 4.72, N 10.36. Found:
C 53.22, H 4.60, N 10.24.
1-(b-D-Galactopyranosyl)-5-cyano-6-(4-methylphenyl)-2-
(methylthio)-pyrimidin-4(1H)-one (12b). Yield ¼ 0.28 g,
80%; m.p. 237-239ꢀC. ir (KBr) m: 3436-3388 (OH), 1667 (C¼¼O),
1
2206 (CN) cmꢁ1; H nmr (DMSO-d6): d ¼ 2.33 (s, 3 H, CH3),
2.52 (s, 3 H, SCH3), 3.52-3.69 (m, 5 H, H-20, H-30, H-50, H-60),
3.90 (m, 1 H, H-40), 4.54 (m, 1 H, H-10), 4.74 (brs, 1 H, 60-OH),
5.15 (brs, 1 H, 40-OH), 5.55 (m, 2 H, 20-OH, 30-OH), 7.24 (d, J ¼
10.3 Hz, 2 H, ArAH), 7.44 (d, J ¼ 10.3 Hz, 2 H, ArAH). EI-MS:
m/z ¼ 419 [Mþ]. Anal. Calcd for C19H21N3O6S (419.45): C 54.40,
H 5.04, N 10.01. Found: C 54.32, H 4.95, N 9.94.
1-(b-D-Galactopyranosyl)-5-cyano-6-(4-methoxyphenyl)-2-
(methylthio)-pyrimidin-4(1H)-one (12c). Yield ¼ 0.28 g, 78
%; m.p. 243-245ꢀC. ir (KBr) m: 3439-3388 (OH), 1667
1-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-5-cyano-2-
(methylthio)-6-phenylpyrimidin-4(1H)-one (11a). Yield
¼
2.03 g, 71 %; m.p. 143-144ꢀC. ir (KBr) m: 1737 (C¼¼O), 1662
1
(C¼¼O), 2207 (CN) cmꢁ1; H nmr (DMSO-d6): d ¼ 2.51 (s, 3
(C¼¼O), 2205 (CN) cmꢁ1
;
1H NMR (DMSO-d6): d ¼ 2.02,
H, SCH3), 3.50-3.65 (m, 5 H, H-20, H-30, H-50, H-60), 3.93 (m,
1 H, H-40), 4.50 (m, 1 H, H-10), 4.77 (brs, 1 H, 60-OH), 5.19
(brs, 1 H, 40-OH), 5.59 (m, 2 H, 20-OH, 30-OH), 7.21 (d, J ¼
10.3 Hz, 2 H, ArAH), 7.45 (d, J ¼ 10.3 Hz, 2 H, ArAH). EI-
MS: m/z ¼ 435 [Mþ]. Anal. Calcd for C19H21N3O7S (435.45):
C 52.40, H 4.86, N 9.64. Found: C 52.33, H 4.77, N 9.49.
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyrano-
syl)-6-aryl-5-cyanopyrimidin-4(1H)-ones (13a-c). A mixture of
6-aryl-5-cyanouracils 1a-c (5 mmol) and 50% oil-immersed so-
dium hydride (0.24 g, 5 mmol) in DMF (30 ml) was stirred at
70-80ꢀC for 1 h and then cooled to room temperature. a-Chlor-
oacetamido sugar 4 (1.83 g, 5 mmol) was added to the mixture,
and stirred at 90ꢀC for 3-5 h. the mixture was evaporated till
dryness under reduced pressure and the residue was recrystallized
from absolute ethanol to give 13a-c in 75-80% yields.
2.03, 2.07, 2.17 (4 s, 12 H, 4 OAc), 2.51 (s, 3 H, SCH3), 3.86-
3.92 (m, 1 H, H-50), 4.06-4.18 (m, 2 H, H-60), 4.70 (d, 1 H,
J1 ,2 ¼ 7.4 Hz, H-10), 5.00 (m, 1 H, H-30), 5.18 (m, 1 H, H-
0
0
20), 5.36 (dd, 1 H, J3 ,4 ¼ 3.4 Hz, J4 ,5 ¼ 1.1 Hz, H-40), 7.30-
7.40 (m, 5 H, ArAH). EI-MS: m/z ¼ 446 [Mþ]. Anal. Calcd
for C26H27N3O10S (573.57): C 54.44, H 4.74, N 7.32. Found:
C 54.27, H 4.51, N 7.20.
0
0
0
0
1-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-5-cyano-6-(4-
methylphenyl)-2-(methylthio)-pyrimidin-4(1H)-one (11b). Yield
¼ 2.02 g, 69 %; m.p. 163-164ꢀC. ir (KBr) m: 1740 (C¼¼O),
1
1667 (C¼¼O), 2204 (CN) cmꢁ1; H nmr (DMSO-d6): d ¼ 2.00,
2.03, 2.05, 2.14 (4 s, 12 H, 4 OAc), 2.33 (s, 3 H, CH3), 2.50
(s, 3 H, SCH3), 3.86-3.98 (m, 1 H, H-50), 4.10-4.18 (m, 2 H,
H-60), 4.74 (d, 1 H, J1 ,2 ¼ 7.5 Hz, H-10), 5.15-5.20 (m, 2 H,
0
0
H-20, H-30), 5.33 (dd, 1 H, J3 ,4 ¼ 3.3 Hz, J4 ,5 ¼ 1.0 Hz, H-
0
0
0
0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis and Antiviral Activity of New Substituted Pyrimidine Glycosides
1037
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyrano-
syl)-5-cyano-6-phenylpyrimidin-4(1H)-one (13a). Yield ¼ 2.11
g, 78 %; m.p. 150-151ꢀC. ir (KBr) m: 3317 (NH), 1737(C¼¼O),
1-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)-5-cyano-6-(4-
methoxy- phenyl)-pyrimidin-4(1H)-one (14c). Yield ¼ 0.32 g,
83%; m.p. 290-292ꢀC. ir (KBr) m: 4362-3995 (OH), 3324
1
1668 (C¼¼O), 2203 (CN) cmꢁ1; H nmr (DMSO-d6): d ¼ 1.75
(NH), 1674 (C¼¼O), 2207 (CN) cmꢁ1
;
1H nmr (DMSO-d6): d
(s, 3 H, NHAc), 1.94, 1.99, 2.00 (3 s, 9 H, 3 OAc), 3.95-4.11
(m, 3 H, H-50, H-60), 4.54 (m, 1 H, H-20), 5.15 (m, 1 H, H-40),
5.30 (m, 1 H, H-30), 5.49 (d, 1 H, J ¼ 9.3 Hz, H-10), 7.77 (d,
1 H, J ¼ 7.5 Hz, NHAc), 7.37-7.47 (m, 5 H, ArAH). EI-MS:
m/z ¼ 542 [Mþ]. Anal. Calcd for C25H26N4O10 (542.50): C
55.35, H 4.83, N 10.32. Found: C 55.21, H 4.77, N 10.13.
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyrano-
syl)-5-cyano-6-(4-methylphenyl)-pyrimidin-4(1H)-one (13b). Yield
¼ 2.22 g, 80 %; m.p. 242-243ꢀC. ir (KBr) m: 3319 (NH),
¼ 1.73 (s, 3 H, NHAc), 3.39-3.58 (m, 8 H, H-30, H-40, H-50,
H-60, OCH3), 3.88 (m, 1 H, H-20), 5.20-5.30 (m, 3 H, 3 OH),
5.40 (d, 1 H, J ¼ 9.5 Hz, H-10), 7.21 (d, J ¼ 10.3 Hz, 2 H,
ArAH), 7.39 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.90 (d, 1 H, J ¼
8.5 Hz, NHAc). EI-MS: m/z ¼ 446 [Mþ]. Anal. Calcd for
C20H22N4O8 (446.41): C 53.81, H 4.96, N 12.55. Found: C
53.60, H 4.83, N 12.33.
REFERENCES AND NOTES
1738 (C¼¼O), 1668 (C¼¼O), 2205 (CN) cmꢁ1
;
1H nmr
(DMSO-d6): d ¼ 1.76 (s, 3 H, NHAc), 1.97, 2.00, 2.05 (3 s,
9 H, 3 OAc), 2.36 (s, 3 H, CH3), 4.25-4.45 (m, 4 H, H-20,
H-50, H-60), 5.20-5.30 (m, 1 H, H-40), 5.43 (m, 1 H, H-30),
5.58 (d, 1 H, J ¼ 9.4 Hz, H-10), 7.21 (d, J ¼ 10.3 Hz, 2 H,
Ar-H), 7.39 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.80 (d, 1 H, J
¼ 7.5 Hz, NHAc). EI-MS: m/z ¼ 556 [Mþ]. Anal. Calcd
for C26H28N4O10 (556.52): C 56.11, H 5.07, N 10.06.
Found: C 56.00, H 4.89, N 9.97.
[1] Brown, D. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1996;
Vol. 3, Chapter 2. 13.
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Caldwell, J.; Zondler, H.; Walter, H.; Havenhand, M.; He, Y. Bioorg
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S. Bioorg Med Chem 2005, 13, 4645.
1-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranosyl)-
5-cyano-6-(4-methoxyphenyl)-pyrimidin-4(1H)-one (13c). Yield
¼ 2.14 g, 75 %; m.p. 263-264ꢀC. ir (KBr) m: 3324 (NH), 1740
(C¼¼O), 1672 (C¼¼O), 2206 (CN) cmꢁ1; 1H nmr (DMSO-d6): d ¼
1.78 (s, 3 H, NHAc), 1.96, 1.99, 2.02 (3 s, 9 H, 3 OAc), 3.53 (s, 3
H, OCH3), 4.07-4.19 (m, 3 H, H-50, H-60), 4.33 (m, 1 H, H-20),
5.32 (m, 1 H, H-40), 5.50 (t, 1 H, J ¼ 9.5 Hz, H-30), 5.60 (d, 1 H, J
¼ 9.2 Hz, H-10), 7.19 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.33 (d, J ¼
10.3 Hz, 2 H, ArAH), 7.79 (d, 1 H, J ¼ 7.5 Hz, NHAc). EI-MS:
m/z ¼ 572 [Mþ]. Anal. Calcd for C26H28N4O11 (572.52): C 54.54,
H 4.92, N 9.78. Found: C 54.32, H 4.81, N 9.57.
1-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)-6-aryl-5-
cyano-pyrimidin-4(1H)-ones (14a-c). A solution of 13a-c
(0.5 g) in a 1:1 mixture (50 mL) of methanol and conc. ammo-
nia (25%) was stirred at room temperature for 8 h. The
reaction mixtures were concentrated under reduced pressure.
The residue were recrystallized from methanol to give 14a-c in
83-90% yields.
[5] Chang, L. C. W.; Spanjersberg, R. F.; von Frijtag Drabbe
Kunzel, K.; Mulder–Krieger, T.; Van DenHout, G.; Beukers, M. W.;
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H. J.; Weber, O.; Kraemer, T.; Niewoehner, U.; Pleiss, U.; Stoltefuss, J.;
Graef, E.; Koletzki, D.; Masantschek, R. N. A.; Reimann, A.; Jaeger, R.;
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1-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)-5-cyano-6-phe-
nyl-pyrimidin-4(1H)-one (14a). Yield ¼ 0.34 g, 90%; m.p.
276-277ꢀC. ir (KBr) m: 4351-3986 (OH), 3315 (NH), 1668
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1
(C¼¼O), 2204 (CN) cmꢁ1; H nmr (DMSO-d6): d ¼ 1.68 (s, 3
[14] Hegab, M. I.; Hassan, N. A.; Rashad, A. E.; Fahmy, A. A.;
Abdel Megeid, F. M. E. Phosphorus Sulfur Silicon Relat Elem 2007,
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H, NHAc), 3.32-3.50 (m, 4 H, H-40, H-50, H-60), 3.77-4.88 (m,
2 H, H-20, H-30), 5.16-5.26 (m, 3 H, 3 OH), 5.36 (d, 1 H, J ¼
9.4 Hz, H-10), 7.30-7.40 (m, 5 H, ArAH), 7.90 (d, 1 H, J ¼
8.5 Hz, NHAc). EI-MS: m/z ¼ 416 [Mþ]. Anal. Calcd for
C19H20N4O7 (416.39): C 54.80, H 4.84, N 13.45. Found: C
54.60, H 4.71, N 13.37.
1-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)-5-cyano-6-(4-
methyl- phenyl)-pyrimidin-4(1H)-one (14b). Yield ¼ 0.34 g,
88%; m.p. 288-289ꢀC. ir (KBr) m: 4360-3990 (OH), 3317
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Mukund, V.; Srinivasan Kumar, V. Tetrahedron 2008, 64, 10214.
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(NH), 1669 (C¼¼O), 2205 (CN) cmꢁ1
;
1H nmr (DMSO-d6): d
¼ 1.69 (s, 3 H, NHAc), 2.38 (s, 3 H, CH3), 3.19-3.29 (m, 4 H,
H-40, H-50, H-60, 3.70-3.80 (m, 2 H, H-20, H-30), 5.15-5.21 (m,
3 H, 3 OH), 5.38 (d, 1 H, J ¼ 9.6 Hz, H-10), 7.22 (d, J ¼ 10.3
Hz, 2 H, ArAH), 7.41 (d, J ¼ 10.3 Hz, 2 H, ArAH), 7.88 (d,
1 H, J ¼ 8.5 Hz, NHAc). EI-MS: m/z ¼ 430 [Mþ]. Anal.
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Found: C 55.68, H 5.04, N 12.92.
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DOI 10.1002/jhet