Synthesis of novel uracil non-nucleosides analogues of 3,4-dihydro-2- alkylthio-6-benzyl-4-oxopyrimidines and 6-benzyl-1-ethoxymethyl-5- isopropyluracil

Article abstract of DOI:10.3184/030823407X210893

A series of new uracil non-nucleosides analogues of S-DABO's was synthesised by reaction of 5-alkyl-6-(p-chlorobenzyl)-2-thiouracils with chloroethyl dialkylamine hydrochloride, N-(2-chloroethyl)-pyrrolidine hydrochloride, N-(2-chloroethyl)-piperidine hyd

Full text of DOI:10.3184/030823407X210893

JOURNAL OF CHEMICAL RESEARCH 2007
MAY, 263–267
RESEARCH PAPER 263
Synthesis of novel uracil non-nucleosides analogues of
3,4-dihydro-2-alkylthio-6-benzyl-4-oxopyrimidines and
6-benzyl-1-ethoxymethyl-5-isopropyluracil
Nasser R. El-Brollosya*, Mohamed A. Al-Omara, Omar A. Al-Deeba, Ali A. El-Emama and
Claus Nielsenb
aDepartment of Pharmaceutical Chemistry, College of Pharmacy. King Saud University, Riyadh 11451, Saudi Arabia
bRetrovirus Laboratory, Department of Virology, State Serum Institute, DK-2300 Copenhagen, Denmark
A series of new uracil non-nucleosides analogues of S-DABO's was synthesised by reaction of 5-alkyl-6-
(p-chlorobenzyl)-2-thiouracilswithchloroethyldialkylaminehydrochloride, N-(2-chloroethyl)-pyrrolidinehydrochloride,
N-(2-chloroethyl)-piperidine hydrochloride or appropriate haloethers. Novel emivirine analogues were synthesised
by silylation of 5-alkyl-6-(p-chlorobenzyl)uracils and treatment with bromomethyl methyl ether, chloromethyl
ethyl ether or benzyl chloromethyl ether. Compounds 6-(p-chlorobenzyl)-5-ethyl-1-ethyloxymethyluracil (9e) and
1-benzyloxymethyl-6-(4-chlorobenzyl)-5-ethyluracil (9f) showed activity against wild-type HIV-1 strain III B in MT-4 cells.
Keywords: non-nucleosides, reverse transcriptase inhibitors, HIV drugs, S-DABOs, Emivirine analogues
O
N
O
N
O
N
Acquired immunodeficiency syndrome (AIDS) which is
caused by the human immunodeficiency virus type-1 (HIV-1),
has become a major worldwide pandemic. Three main
classes of compounds are used in the treatment of AIDS;
fusion inhibitors (FIs), protease inhibitors (PIs) and reverse
transcriptase inhibitors (RTIs). HIV-1 reverse transcriptase
(RT) is a key target for inhibition of HIV-1 replication and the
majority of drugs used clinically are RTIs.1-3
R
HN
HN
R1S
HN
O
S
O
HO
O
O
S-DABOs
Emivirine
HEPT
Fig. 1
RTIs can be divided into two groups; nucleoside reverse
transcriptase inhibitors (NRTIs), such as 3'-azido-3'-
deoxythymidine (AZT)4, 2',3'-dideoxycytidine (DDC)5 and
2',3'-dideoxyinosine (DDI)6, which act as chain terminators
to block the elongation of the HIV-1 viral DNA strand; and
non-nucleoside reverse transcriptase inhibitors (NNRTIs),
which in contrast to NRTIs, are highly specific as their binding
site is a hydrophobic pocket located approximately 10 Å from
polymerease active site.7 They bind allosterically forcing the
RT-subunit into an inactive conformation.8
but unfortunately in phase III clinical trials it was also found
to activate a liver enzyme in the P450 family which metabolises
protease inhibitors.14
Structure-activity relationship (SAR) studies on S-DABOs
showed that the presence of the C-2 alkylthio side chain is
a structural determinant for the antiviral activity of these
compounds. Unlike the length and type of substituent at C-2,
the substituents at C-5 have modulatory effects on potency.
However, modification of the pyrimidine base such as N-3
alkylation, shift of benzyl group from C-6 to C-5, decrease
or increase the distance between the pyrimidine and the
phenyl ring, or replacement of the C-6 benzyl with smaller
substituents have led to substantial loss of activity.12
Among the representatives of the NNRTIs, 1-[(2-
hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT)9,10
and S-DABOs, the thio analogues of dihydroalkyl-
oxybenzyloxopyrimidines (DABOs).11,12
In the present work, and as a part of our continuing interest
in the chemistry of NNRTIs,15-21 the synthesis and anti-HIV
evaluation of novel S-DABO and Emivirine analogues have
been investigated. Herein, we describe synthesis of new
S-DABOs bearing substituted aminoalkylthio and substituted
Although HEPT did not show very high activity against
HIV-1, it was considered as interesting lead compound for
the synthesis of new analogues. Among them 6-benzyl-
1-(ethoxymethyl)-5-isopropyluracil (Emivirine, formerly
MKC-442)13 which showed high activity against HIV-1,
Br
i. Zn, THF
O
CN
+
R
ii. K2CO3
iii. HCl
Cl
Cl
O
1
2
R
O
i. (NH2)2CS, NaOEt
ii. HCl
O
R
Cl
HN
O
O
S
N
H
3
4
2,3,4
a, R = CH3
b, R = C2H5
Scheme 1
* Correspondent. E-mail: brollosy@yahoo.com
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264 JOURNAL OF CHEMICAL RESEARCH 2007
R1
O
O
N
N
R1
.
HCl
Cl
R
Cl
R
Cl
R1
HN
HN
DMF / K2CO3
N
R1
S
N
H
S
4
5
R
R1
CH3 CH3
N
a
b
.
HCl
Cl
n
CH3 C2H5
R2
O
DMF / K2CO3
X
n
DMF / K2CO3
O
R
Cl
HN
O
N
n
S
N
R
Cl
HN
6
R
n
R2
O
S
N
n
a
b
c
d
CH3
C2H5
CH3
1
1
2
2
R
R2
n
2
1
1
7
a
b
c
CH3
CH3
CH3
C6H5
C2H5
C2H5 C6H5
Scheme 2
alkyloxyalkylthio moieties at C-2. The objective was to
investigate whether substitution with electron-rich groups at
C-2 of the pyrimidine ring could lead to an improved activity
against HIV-1. In addition, the synthesis of new HEPT
analogues would also provide information to the ongoing
investigation of the NNRTI binding site.
Silylation of compounds 8a,b with N,O-bis-(trimethylsilyl)
acetamide (BSA) in anhydrous chloroform followed by
treatment with bromomethyl methyl ether, chloromethyl ethyl
ether or benzyl chloromethyl ether in the presence of cesium
iodide gave the Emivirine analogues 9a–f and their 1,3-bis-
alkylated derivatives 10a–d in 18–48% and 31–52% yields,
respectively.
The newly synthesised S-DABOs and Emivirine analogues
5b, 6a–d, 7a–d and 9b–f were tested against wild-type
HIV-1 strain III B in MT-4 cells. No compounds exhibited
activity against HIV-1 except 6-(p-chlorobenzyl)-5-ethyl-
1-ethyloxymethyluracil (9e) and 1-benzyloxymethyl-6-
(p-chlorobenzyl)-5-ethyluracil (9f) which showed activities
Results and discussions
p-Chlorophenylacetonitrile was reacted with ethyl 2-bromo-
propionate or ethyl 2-bromobutyrate in anhydrous THF in the
presence of activated zinc to give the corresponding 2-alkyl-
4-(p-chlorophenyl)-3-oxo esters 3a,b in good yields. 5-Alkyl-
6-(p-chlorobenzyl)-2-thiouracils (4a,b) were synthesised from
3a,b according to the procedure described by Danel et al.22 by
treatment with thiourea in boiling ethanol in the presence of
sodium ethoxide.
The NMR spectra of crude compound 3b showed an
impurity identified as another β-keto ester resulting from
self-condensation of ethyl 2-bromobutyrate. On reaction with
thiourea, this β-keto ester impurity also formed a pyrimidine
as an impurity in the raw material of 4b.23 However, pure
compound 4b was easily obtained by recrystallisation from
aqueous ethanol.
Compound 4a was treated with 2-chloroethyl dimethylamine
hydrochloride or 2-chloroethyl diethylamine hydrochloride
in DMF in the presence of anhydrous potassium carbonate
to afford 6-(p-chlorobenzyl)-2-dimethylaminoethylthio-5-
methyl-pyrimidin-4(3H)-one(5a)anditsdiethylaminoethylthio
derivative 5b in 55% and 68% yields, respectively.
Pyrrolidinylethylthio and piperidinylethylthiouracils 6a–d
were prepared in good yields from 4a,b by reaction with N-(2-
chloroethyl)-pyrrolidine hydrochloride or N-(2-chloroethyl)-
piperidine hydrochloride in DMF. On the other hand, the
S-DABOs analogues 7a–c were synthesised by treatment
of compounds 4a,b with bromoethyl ethyl ether or benzyl
chloromethyl ether in DMF in the presence of anhydrous
potassium carbonate.
(ED50 = 44 μM; CD50 = > 100 μM) and (ED50 = 5 μM; CD50
> 100 μM), respectively.
=
Virus and cells
The inhibitory activity against HIV-1 infection was evaluated
using MT-4 cells24 as target cells and the HIV-1 strain HTLV-
IIIB25 as infectious virus. The virus was propagated in H924
cells at 37°C, 5% CO2 using RPMI 1640 with 10% heat-
inactivated fetal calf serum (FCS) and antibiotics (growth
medium). Culture supernatant was filtered (0.45 nm),
aliquoted, and stored at –80°C until use.
Experimental
NMR spectra were recorded on a Varian Brüker AC 500 Ultra Shield
1
NMR spectrometer at 500 MHz for H and 125 MHz for 13C with
TMS as an internal standard. Chemical shifts are reported in ppm
(d), and signals are expressed as s (singlet), d (doublet), t (triplet),
q (quartet) or m (multiplet). Electron impact mass spectra were
recorded on Shimadzu GC-MS-QP 5000 instrument, all compounds
showed fragments corresponding to the typical pattern of chlorine
isotopes (35Cl and 37Cl). Melting points (uncorrected) were
determined on a Gallenkamp melting point apparatus. The progress of
reactions was monitored by TLC (DC-alufolio 60 F254) from Merck.
For column chromatography Merck silica gel (0.040–0.063 mm)
was used.
Ethyl 2-alkyl-4-(p-chlorophenyl)-3-oxobutyrates 3a and 3b: Zinc
dust (14 g) was activated by stirring with 4M HCl (30 cm3) for 5
min. The zinc dust was filtered, washed sequentially with H2O, EtOH
and dry Et2O then dried. The active zinc was suspended in dry THF
Desulfurisation of 2-thiouracils 4a,b was achieved by
reaction with boiling aqueous chloroacetic acid to give
5-alkyl-6-(p-chlorobenzyl)uracils (8a,b) in good yields.
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JOURNAL OF CHEMICAL RESEARCH 2007 265
O
O
R
Cl
R
Cl
10% aqu. ClCH2COOH
HN
HN
S
N
H
O
N
H
R
8
4
a
b
CH3
C2H5
O
N
O
R
Cl
R
Cl
R3
BSA, CsI, CHCl3
O
X
HN
R3
O
N
+
O
O
N
R3
O
R3
O
9
10
R
R3
R
R3
H
a
CH3
CH3
H
a
b
c
d
CH3
CH3
b
c
d
e
f
CH3
C6H5
H
CH3
H
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
CH3
C6H5
Scheme 2
(60 cm3) and heated to reflux. Afew drops of ethyl 2-bromopropionate
or ethyl 2-bromobutyrate were added and the mixture was refluxed
for 10 min. p-Chlorophenylacetonitrile (4.55 g, 0.03 mol) was added
in one portion and ethyl 2-bromopropionate or ethyl 2-bromobutyrate
(0.06 mol) was added dropwise. After the addition was completed,
the mixture was refluxed for 30 min, then it was diluted THF
(150 cm3) and quenched by addition of sat. aq. K2CO3 (60 cm3).
The mixture was stirred for 1 h at room temperature. The THF layer
was decanted and the residue was washed with THF (3 × 30 cm3).
The combined THF fractions were stirred with 10% aq. HCl (40 cm3)
for 30 min. The solution was concentrated under reduced pressure
and diluted with CH2Cl2 (100 cm3). The organic phase was washed
with sat. aq. NaHCO3 (2 × 60 cm3), dried (Na2SO4) and evaporated
under reduced pressure to give the product that was used for further
synthesis without purification.
Ethyl 4-(p-chlorophenyl)-2-methyl-3-oxobutyrate (3a): Faint
yellow oil26; yield 7.4 g (97%); 1H NMR (CDCl3, 500 MHz):
δ = 1.28 (t, J = 7.5 Hz, 3H, CH3), 1.34 (d, J = 7.0 Hz, 3H, CH3),
3.68 (q, J = 7.0 Hz, 1H, CH), 3.89 (s, 2H, CH2), 4.17 (q, J = 7.5 Hz,
2H, CH2); 7.14, 7.30 (2 × d, J = 8.0 Hz, 4H, Harom) ppm; 13C NMR
(CDCl3, 125 MHz): δ = 12.87 (CH3), 14.26 (CH3), 47.64 (CH2),
52.12 (CH2), 61.77 (CH), 128.69, 130.96, 131.89, 133.17 (Carom),
170.30 (CO), 202.87 (CO) ppm; MS (EI): m/z (%) = 254 (M+, 6), 208
(4), 152 (33), 129 (42), 125 (100).
(C-5), 128.89, 130.56, 131.92, 135.82 (Carom), 149.61 (C-6), 162.39
(C-4), 174.55 (C-2) ppm; MS (EI): m/z (%) = 266 (M+, 8).
6-(p-Chlorobenzyl)-5-ethyl-2-thiouracil (4b): White solid; yield
3.6 g (64%); m.p. 218–220°C; 1H NMR (CDCl3, 500 MHz): δ = 0.80
(t, J = 7.3 Hz, 3H, CH3), 2.23 (q, J = 7.3 Hz, 2H, CH2), 3.84 (s, 2H,
CH2), 7.26, 7.39 (2 × d, J = 8.0 Hz, 4H, Harom), 12.36 (bs, 2H, 2
× NH) ppm; 13C NMR (CDCl3, 125 MHz): δ = 13.39 (CH3), 18.19
(CH2), 34.25 (CH2), 117.03 (C-5), 129.06, 130.50, 131.88, 136.34
(Carom), 149.36 (C-6), 161.96 (C-4), 174.71 (C-2) ppm; MS (EI): m/z
(%) = 280 (M+, 42), 265 (9), 206 (5), 155 (39), 141 (3), 125 (61);
Anal. Calcd. for C13H13ClN2OS (280.77): C 55.6, H 4.7, N 10.0.
Found: C 55.5, H 4.6, N 9.7%.
6-(p-Chlorobenzyl)-2-(N,N-dialkylamino)ethylthio-5-methyl-
pyrimidin-4(3H)-ones 5a and 5b: 6-(p-Chlorobenzyl)-5-methyl-
2-thiouracil (4a, 0.266 g, 0.001 mol) was dissolved in anhydrous
DMF (3 cm3). Anhydrous potassium carbonate (0.304 g, 0.0022 mol)
was added followed by addition of chloroethyl dimethylamine
hydrochloride or chloroethyl diethylamine hydrochloride (0.0011
mol). The mixture was stirred at room temperature for 24 h, then was
diluted with H2O (100 cm3) and extracted with ether (3 × 50 cm3).
The combined organic extract was washed with H2O (3 × 50 cm3),
dried ( MgSO4) and evaporated under reduced pressure. The residue
was chromatographed on silica gel column with CHCl3 to afford 5a
and 5b.
Ethyl 4-(p-chlorophenyl)-2-ethyl-3-oxobutyrate (3b): Faint yellow
oil; yield 7.7 g (96%); 1H NMR (CDCl3, 500 MHz): δ = 0.93 (t,
J = 7.0 Hz, 3H, CH3), 1.26 (t, J = 7.5 Hz, 3H, CH3), 1.89 (m, 2H,
CH2), 3.46 (t, J = 7.5 Hz, 1H, CH), 3.80 (s, 2H, CH2), 4.18 (q,
J = 7.0 Hz, 2H, CH2), 7.14, 7.30 (2 × d, J = 8.0 Hz, 4H, Harom) ppm;
13C NMR (CDCl3, 125 MHz): δ = 12.84 (CH3), 13.53 (CH3), 18.47
(CH2), 42.02 (CH2), 60.72 (CH2), 61.98 (CH), 128.67, 130.99,
131.77, 133.17 (Carom), 162.56 (CO), 202.31 (CO) ppm; MS (EI): m/z
(%) = 268 (M+, 11), 222 (3), 213 (5), 186 (2), 152 (33), 143 (72), 125
(100).
5-Alkyl-6-(p-chlorobenzyl)-2-thiouracils 4a and 4b: Na (9.84 g,
0.434 mol) was dissolved in absolute EtOH (150 cm3). Thiourea
(22.84 g, 0.3 mol) was added and the mixture was heated to reflux.
Compounds 3a or 3b (0.02 mol) was added dropwise and the mixture
was refluxed for 90 min. The solvent was evaporated to dryness under
reduced pressure and the residue was redissolved in H2O (150 cm3).
The product was precipitated by addition of conc. HCl (16 cm3) and
then glacial acetic acid till pH = 4. The precipitate was filtered off,
washed with H2O dried and crystallised from aq. EtOH.
6-(p-Chlorobenzyl)-2-(N,N-dimethylamino)ethylthio-5-methyl-
pyrimidin-4(3H)-one (5a): White solid; yield 0.185 g (55%);
m.p. 136–138°C; H NMR (DMSO-d6, 500 MHz): δ = 1.93 (s, 3H,
1
CH3), 2.12 (s, 6H, 2 × CH3); 2.44 (br s, 2H, CH2), 3.12 (br s, 2H,
CH2), 3.83 (s, 2H, CH2), 7.26, 7.33 (2 × d, J = 8.0 Hz, 4H, Harom
)
ppm; 13C NMR (DMSO-d6, 125 MHz): δ = 10.86 (CH3), 28.22
(CH3), 39.56 (CH2), 45.07 (CH2), 58.61 (CH2), 115.64 (C-5), 128.70,
131.08, 131.36, 137.81 (Carom), 157.94 (C-6), 160.35 (C-4), 164.03
(C-2) ppm; MS (EI): m/z (%) = 337 (M+, 2), 322 (4), 291 (9), 267
(5), 248 (4), 220 (3), 192 (14), 143 (11), 125 (100); Anal. Calcd.
for C16H20ClN3OS (337.87): C 56.9, H 6.0, N 12.4. Found: C 56.9,
H 5.9, N 12.3%.
6-(p-Chlorobenzyl)-2-(N,N-diethylamino)ethylthio-5-methyl-
pyrimidin-4(3H)-one (5b): White solid; yield 0.25
g (68%);
m.p. 122–124°C; 1H NMR (CDCl3, 500 MHz): δ = 1.16 (t, J = 7.0 Hz,
6H, 2 × CH3), 2.03 (s, 3H, CH3), 2.76 (q, J = 7.0 Hz, 4H, 2 × CH2),
2.94–2.96 (m, 2H, CH2), 3.06–3.08 (m, 2H, CH2), 3.85 (s, 2H, CH2),
7.17, 7.25 (2 × d, J = 8.0 Hz, 4H, Harom), 13.51 (s, 1H, NH) ppm;
13C NMR (CDCl3, 125 MHz): δ = 10.38 (CH3), 10.72 (CH3), 31.27
(CH2), 40.22 (CH2), 47.13 (CH2), 55.17 (CH2), 117.68 (C-5), 128.51,
130.03, 132.16, 136.57 (Carom), 157.65 (C-6), 160.62 (C-4), 165.88
(C-2) ppm; MS (EI): m/z (%) = 365 (M+, 2), 354 (2), 330 (1), 297 (3),
192 (5), 125 (11), 99 (71); Anal. Calcd. for C18H24ClN3OS (365.92):
C 59.1, H 6.6, N 11.5. Found: C 59.0, H 6.6, N 11.4.
6-(p-Chlorobenzyl)-5-methyl-2-thiouracil (4a): White solid; yield
1
3.3 g (62%); m.p. 261–262°C (lit. 262–263°C)26; H NMR (CDCl3,
500 MHz): δ = 1.78 (s, 3H, CH3), 3.84 (s, 2H, CH2), 7.26, 7.38
(2 × d, J = 8.0 Hz, 4H, Harom), 12.28, 12.45 (2 × s, 2H, 2 × NH) ppm;
13C NMR (CDCl3, 125 MHz): δ = 10.33 (CH3), 34.65 (CH2), 111.93
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266 JOURNAL OF CHEMICAL RESEARCH 2007
5-Alkyl-6-(p-chlorobenzyl)-2-pyrrolidin-1-ylethylthiopyrimidin-
4(3H)-ones (6a,b) and 5-Alkyl-6-(p-chlorobenzyl)-2-piperidin-
66.72 (CH2), 69.33 (CH2), 116.80 (C-5), 128.51, 130.25, 132.31,
136.43 (Carom), 156.39 (C-6), 161.20 (C-4), 164.76 (C-2) ppm; MS
(EI): m/z (%) = 338 (M+, 2), 293 (2), 266 (37), 251 (2), 231 (4), 192
(5), 143 (3), 125 (18); Anal. Calcd. for C16H19ClN2O2S (338.85):
C 56.7, H 5.65, N 8.3. Found: C 56.5, H 5.5, N 8.1.
2-Benzyloxymethylthio-6-(p-chlorobenzyl)-5-methylpyrimidin-
4(3H)-one (7b): White solid; yield 0.255 g (66%); m.p. 185–186°C;
1H NMR (CDCl3, 500 MHz): δ = 2.01 (s, 3H, CH3), 3.91 (s, 2H, CH2),
4.57 (s, 2H, CH2), 5.43 (s, 2H, CH2), 7.18–7.28 (m, 9H, Harom), 12.34
(s, 1H, NH) ppm; 13C NMR (CDCl3, 125 MHz): δ = 10.31 (CH3),
39.86 (CH2), 71.23 (CH2), 71.83 (CH2), 117.41 (C-5), 127.21, 127.99,
128.52, 128.60, 130.26, 133.01, 137.12, 137.84 (Carom), 156.17
(C-6), 161.73 (C-4), 164.92 (C-2) ppm; MS (EI): m/z (%) = 386
(M+, 2), 356 (4), 339 (5), 295 (3), 280 (4), 267 (5), 143 (3), 125 (11),
91 (100); Anal. Calcd. for C20H19ClN2O2S (386.90): C 62.1, H 4.95,
N 7.2. Found: C 62.1, H 5.0, N 7.2.
2-Benzyloxymethylthio-6-(p-chlorobenzyl)-5-ethylpyrimidin-
4(3H)-one (7c): White solid; yield 0.244 g (61%); m.p. 236–238°C;
1H NMR (CDCl3, 500 MHz): δ = 1.06 (t, J = 7.0 Hz, 3H, CH3), 2.57
(q, J = 7.0 Hz, 2H, CH2), 3.91 (s, 2H, CH2), 4.34 (s, 2H, CH2), 5.21
(s, 2H, CH2), 7.16-7.40 (m, 9H, Harom), 12.31 (s, 1H, NH) ppm;
13C NMR (CDCl3, 125 MHz): δ = 13.21 (CH3), 18.77 (CH2), 39.67
(CH2), 70.85 (CH2), 71.15 (CH2), 122.64 (C-5); 127.44, 128.50,
128.55, 128.92, 130.37, 132.32, 136.77, 136.91 (Carom), 156.23
(C-6), 160.89 (C-4), 164.48 (C-2) ppm; MS (EI): m/z (%) = 400 (M+,
3), 371 (19), 357 (16), 338 (14), 306 (14), 280 (15), 248 (19), 190
(24), 155 (37); Anal. Calcd. for C21H21ClN2O2S (400.92): C 62.9,
H 5.3, N 7.0. Found: C 62.7, H 5.2, N 6.9%.
5-Alkyl-6-(p-chlorobenzyl)-uracils 8a and 8b: Compound 4a,b
(0.01 mol) was suspended in 10% aq. ClCH2CO2H (200 cm3).
The suspension was refluxed for overnight and filtered after cooling.
The precipitate was washed with H2O, cold EtOH then Et2O
and dried.
1-ylethylthiopyrimidin-4(3H)-ones (6c,d): To
a
solution of
compound 4a,b (0.001 mol) in anhydrous DMF (3 cm3), was added
anhydrous potassium carbonate (0.304 g, 0.0022 mol) followed by
N-chloroethylpyrrolidine hydrochloride or N-chloroethylpiperidine
hydrochloride (1.1 mmol). The mixture was stirred at room
temperature for 24 h, then was diluted with H2O (100 cm3) and
extracted with ether (3 × 50 cm3). The combined ether extract was
washed with H2O (3 × 50 cm3), dried ( MgSO4) and evaporated under
reduced pressure. The residue was chromatographed on silica gel
column with CHCl3 to give 6a–d.
6-(p-Chlorobenzyl)-5-methyl-2-pyrrolidin-1-ylethylthiopyrimidin-
4(3H)-ones (6a): White solid, yield 0.26 g (72%); m.p. 153-155°C;
1H NMR (CDCl3, 500 MHz): δ = 2.03-2.04 (m, 9H, CH3, 2 × CH2),
2.81-2.82 (m, 4H, 2 × CH2), 3.08-3.09 (m, 4H, 2 × CH2), 3.86 (s,
2H, CH2), 7.17, 7.25 (2 × d, J = 8.0 Hz, 4H, Harom), 12.31 (s, 1H,
NH) ppm; 13C NMR (CDCl3, 125 MHz): δ = 10.81 (CH3), 23.74,
54.15 (Cpyrrolidine), 31.71 (CH2), 40.21 (CH2), 58.87 (CH2), 117.53
(C-5), 128.52, 130.01, 132.12, 136.58 (Carom), 157.78 (C-6), 160.70
(C-4), 165.59 (C-2) ppm; MS (EI): m/z (%) = 363 (M+, 3), 291 (9),
266 (4), 234 (3), 192 (5), 163 (7), 143 (4), 125 (32); Anal. Calcd.
for C18H22ClN3OS (363.90): C 59.4, H 6.1, N 11.55. Found: C 59.2,
H 5.9, N 11.4.
6-(p-Chlorobenzyl)-5-ethyl-2-pyrrolidin-1-ylethylthiopyrimidin-
4(3H)-ones (6b): White solid; yield 0.285 g (75%); m.p. 142–144°C;
1H NMR (CDCl3, 500 MHz): δ = 1.01 (t, J = 7.3 Hz, 3H, CH3), 2.01–
2.02 (m, 4H, 2 × CH2), 2.47 (q, J = 7.3 Hz, 2H, CH2), 2.78–2.79
(m, 4H, 2 × CH2), 3.05–3.06 (m, 4H, 2 × CH2), 7.16, 7.24 (2 × d,
J = 8.0 Hz, 4H, Harom), 11.81 (s, 1H, NH) ppm; 13C NMR (CDCl3,
125 MHz): δ = 13.13 (CH3), 18.83 (CH2), 23.68, 54.11 (Cpyrrolidine),
31.05 (CH2), 39.50 (CH2), 58.72 (CH2), 123.36 (C-5), 128.40, 130.02,
132.03, 136.95 (Carom), 157.76 (C-6), 160.09 (C-4), 164.90 (C-2)
ppm; MS (EI): m/z (%) = 377 (M+, 3), 344 (2), 325 (2), 307 (2), 280
(3), 248 (2), 206 (2), 141 (4), 125 (9); Anal. Calcd. for C19H24ClN3OS
(377.93): C 60.4, H 6.4, N 11.1. Found: C 60.2, H 6.4, N 11.1.
6-(p-Chlorobenzyl)-5-methyl-2-piperidin-1-ylethylthiopyrimidin-
4(3H)-ones (6c): White solid; yield 0.27 g (72%); m.p. 137–139°C;
1H NMR (CDCl3, 500 MHz): δ = 1.55 (br s, 2H, CH2), 1.89–1.90 (m,
4H, 2 × CH2), 2.04 (s, 3H, CH3), 2.64–2.65 (m, 4H, 2 × CH2), 2.84
(t, J = 4.1 Hz, 2H, CH2), 3.06 (t, J = 4.1 Hz, 2H, CH2), 3.86 (s, 2H,
CH2), 7.18, 7.26 (2 × d, J = 8.0 Hz, 4H, Harom), 11.32 (s, 1H, NH)
ppm; 13C NMR (CDCl3, 125 MHz): δ = 10.84 (CH3), 23.97, 24.28,
55.44 (Cpiperdine), 29.97 (CH2), 40.21 (CH2), 61.71 (CH2), 117.79
(C-5), 128.54, 130.03, 132.17, 136.51 (Carom), 157.66 (C-6), 160.56
(C-4), 165.10 (C-2) ppm; MS (EI): m/z (%) = 377 (M+, 2), 356 (1),
342 (2), 318 (2), 291 (1), 192 (3), 163 (2), 143 (3), 125 (9), 111 (100);
Anal. Calcd. for C19H24ClN3OS (377.93): C 60.4, H 6.4, N 11.1.
Found: C 60.3, H 6.2 N 10.9%.
6-(p-Chlorobenzyl)-5-ethyl-2-piperidin-1-ylethylthiopyrimidin-
4(3H)-ones (6d): White solid; yield 0.301 g (77%); m.p. 119–121°C;
1H NMR (CDCl3, 500 MHz): δ = 1.02 (t, J = 7.4 Hz, 3H, CH3), 1.53
(br s, 2H, CH2), 1.86–1.87 (m, 4H, 2 × CH2), 2.48 (q, J = 7.4 Hz, 2H,
CH2), 2.62–2.63 (m, 4H, 2 × CH2), 2.81 (t, J = 4.0 Hz, 2H, CH2),
3.04 (t, J = 4.0 Hz, 2H, CH2), 3.83 (s, 2H, CH2), 7.16, 7.24 (2 × d,
J = 8.0 Hz, 4H, Harom), 10.97 (s, 1H, NH) ppm; 13C NMR (CDCl3,
125 MHz): δ = 13.15 (CH3), 18.88 (CH2), 23.96, 24.31, 55.40
(Cpiperidine), 29.93 (CH2), 39.54 (CH2), 61.63 (CH2), 123.62 (C-5),
128.44, 130.05, 132.09, 136.89 (Carom), 157.69 (C-6), 159.97 (C-4),
164.47 (C-2) ppm; MS (EI): m/z (%) = 391 (M+, 2), 354 (1), 307 (3),
218 (4), 170 (2), 149 (3), 111 (32); Anal. Calcd. for C20H26ClN3OS
(391.96): C 61.3, H 6.7, N 10.7. Found: C 61.3, H 6.7, N 10.6%.
General Procedure for Preparation of S-DABOs analogues 7a–7c:
To a solution of compound 4a,b (0.001 mol) in anhydrous DMF
(3 cm3), was added anhydrous potassium carbonate (0.152 g,
0.0011 mol) followed by addition of bromoethyl ethyl ether or benzyl
chloromethyl ether (0.0011 mol). The mixture was stirred at room
temperature for 24 h, then was diluted with H2O (100 cm3) and
extracted with ether (3 × 50 cm3). The combined ether extract was
washed with H2O (3 × 50 cm3), dried ( MgSO4) and evaporated under
reduced pressure. The residue was chromatographed on silica gel
column with CHCl3 to furnish 7a–c.
6-(p-Chlorobenzyl)-5-methyluracil (8a): White solid; yield 2.2 g
(88%); m.p. 285–287 (dec.); 1H NMR (DMSO-d6, 500 MHz):
δ = 1.75 (s, 3H, CH3); 3.74 (s, 2H, CH2), 7.28, 7.38 (2 × d, J = 8.0 Hz,
4H, Harom), 10.78, 11.03 (2 × s, 2H, 2 × NH) ppm; 13C NMR (DMSO-
d6, 125 MHz): δ = 10.12 (CH3), 35.15 (CH2), 105.78 (C-5), 129.03,
130.53, 131.87, 136.00 (Carom), 149.01 (C-6), 151.35 (C-2), 165.37
(C-4) ppm; MS (EI): m/z (%) = 250 (M+, 6), 235 (2), 224 (3), 215 (8),
196 (2), 173 (4), 138 (5), 125 (13); Anal. Calcd. for C12H11ClN2O2
(250.68): C 57.5, H 4.4, N 11.2. Found: C 57.3, H 4.4, N 11.0%.
6-(p-Chlorobenzyl)-5-ethyluracil (8b): White solid; yield 2.15 g
1
(81%); m.p. 261–263°C; H NMR (DMSO-d6, 500 MHz): δ = 0.81
(t, J = 7.4 Hz, 3H, CH3), 2.23 (q, J = 7,4 Hz, 2H, CH2), 3.84 (s, 2H,
CH2), 7.28, 7.38 (2 × d, J = 8.0 Hz, 4H, Harom), 10.76, 11.04 (2 × s,
2H, 2 × NH) ppm; 13C NMR (DMSO-d6, 125 MHz): δ = 14.00 (CH3),
18.05 (CH2), 34.73 (CH2), 111.94 (C-5), 129.02, 130.45, 131.21,
136.42 (Carom), 148.70 (C-6), 151.39 (C-2), 164.95 (C-4) ppm; MS
(EI): m/z (%) = 264 (M+, 100), 249 (82), 206 (31), 181 (42), 178 (18),
139 (65), 125 (66); Anal. Calcd. for C13H13ClN2O2 (264.71): C 59.0,
H 4.95, N 10.6. Found: C 58.7, H 4.9, N 10.4.
Emivirine analogues (9a–f) and their 1,3- bis-alkylated derivatives
(10a–d): N,O-Bis(trimethylsilyl)acetamide (BSA) (0.87 cm3, 0.0035
mol) was added to a suspension of 8a,b (0.001 mol) in anhydrous
CHCl3 (20 cm3) and the mixture was stirred at room temperature under
nitrogen. After a clear solution was obtained (10 min), the appropriate
haloethers namely, bromomethyl methyl ether, chloromethyl ethyl
ether or benzyl chloromethyl ether (0.015 mol) and CsI (0.26 g,
0.001 mol) were added. The reaction mixture was stirred at room
temperature under nitrogen for 3–4 h. Sat. aq. NaHCO3 (20 cm3)
was added and mixture was extracted with CH2Cl2 (3 × 50 cm3).
The organic phase was collected, dried ( MgSO4) and evaporated
under reduced pressure. The residue was chromatographed on silica
gel column using CHCl3 to give 9a–f and 10a–d.
6-(p-Chlorobenzyl)-5-methyl-1-methyloxymethyluracil (9a): White
solid; yield 0.062 g (21%); m.p. 201–202°C; 1H NMR (CDCl3,
500 MHz): δ = 2.05 (s, 3H, CH3), 3.45 (s, 3H, CH3), 3.78 (s, 2H,
CH2), 5.37 (s, 2H, CH2), 7.21, 7.31 (2 × d, J = 8.0 Hz, 4H, Harom),
10.01 (s, 1H, NH) ppm; 13C NMR (CDCl3, 125 MHz): δ = 10.79
(CH3), 35.91 (CH2), 57.91 (CH3), 71.81 (CH2), 107.47 (C-5), 129.26,
130.04, 133.23, 133.67 (Carom), 146.51 (C-6), 152.57 (C-2), 164.01
(C-4) ppm; MS (EI): m/z (%) = 294 (M+, 5), 279 (7), 264 (6), 251
(62), 229 (3), 199 (5), 125 (17); C14H15ClN2O3 (294.73): C 57.05,
H 5.1, N 9.5. Found: C 56.8, H 5.0, N 9.3%.
6-(p-Chlorobenzyl)-2-ethyloxyethylthio-5-methylpyrimidin-
4(3H)-one (7a): White solid; yield 0.213 g (63%); m.p. 169–171°C;
1H NMR (CDCl3, 500 MHz): δ = 1.19 (t, J = 7.1 Hz, 3H, CH3), 2.07
(s, 3H, CH3), 3.26 (t, J = 6.0 Hz, 2H, CH2), 3.51 (q, J = 7.1 Hz, 2H,
CH2), 3.61 (t, J = 6.0 Hz, CH2), 3.84 (s, 2H, CH2), 7.17, 7.26 (2 × d,
J = 8.0 Hz, 4H, Harom); 12.36 (s, 1H, NH) ppm; 13C NMR (CDCl3,
125 MHz): δ = 10.64 (CH3), 15.04 (CH3), 30.74 (CH2), 40.20 (CH2),
6-(p-Chlorobenzyl)-1-ethyloxymethyl-5-methyluracil (9b): White
1
solid; yield 0.090 g (29%); m.p. 214–215°C; H NMR (CDCl3, 500
MHz): δ = 1.18 (t, J = 7.0 Hz, 3H, CH3), 2.02 (s, 3H, CH3), 3.61
(q, J = 7.0 Hz, 2H, CH2), 4.15 (s, 2H, CH2), 5.15 (s, 2H, CH2), 7.07,
PAPER: 07/4507

JOURNAL OF CHEMICAL RESEARCH 2007 267
7.29 (2 × d, J = 8.0 Hz, 4H, Harom), 9.54 (s, 1H, NH) ppm; 13C NMR
(CDCl3, 125 MHz): δ = 10.91 (CH3), 14.99 (CH3), 33.41 (CH2),
65.03 (CH2), 72.82 (CH2), 111.07 (C-5), 128.67, 129.42, 133.29,
133.31 (Carom), 149.10 (C-6), 151.73 (C-2), 163.55 (C-4) ppm; MS
(EI): m/z (%) = 308 (M+, 3), 262 (6), 249 (4), 227 (32), 215 (4), 143
(5), 125 (18); Anal. Calcd. for C15H17ClN2O3 (308.76): C 58.35,
H 5.55, N 9.1. Found: C 58.1, H 5.5, N 8.9%.
1-Benzyloxymethyl-6-(p-chlorobenzyl)-5-methyluracil (9c): White
solid; yield 0.152 g (41%); m.p. 128–129°C; 1H NMR (CDCl3,
500 MHz): δ = 2.01 (s, 3H, CH3), 4.13 (s, 2H, CH2), 4.66 (s, 2H,
CH2), 5.23 (s, 2H, CH2), 7.01–7.36 (m, 9H, Harom), 9.67 (s, 1H, NH)
ppm; 13C NMR (CDCl3, 125 MHz): δ = 10.92 (CH3), 33.43 (CH2),
71.71 (CH2), 72.79 (CH2), 111.15 (C-5), 127.89, 128.23, 128.67,
129.42, 130.04, 133.18, 133.32, 137.11 (Carom), 148.92 (C-6), 151.77
(C-2), 163.53 (C-4) ppm; MS (EI): m/z (%) = 370 (M+, 2), 264 (5),
215 (3), 201 (7), 143 (2), 125 (14), 91 (100), 77 (16); Anal. Calcd.
for C20H19ClN2O3 (370.83): C 64.8, H 5.2, N 7.55. Found: C 64.7,
H 5.1, N 7.2%.
5.44 (s, 2H, CH2), 7.06, 7.31 (2 × d, J = 8.0 Hz, 4H, Harom) ppm;
13C NMR (CDCl3, 125 MHz): δ = 13.69 (CH3), 19.74 (CH2), 32.85
(CH2), 57.11 (CH3), 57.97 ((CH3), 72.68 (CH2), 74.99 (CH2), 116.48
(C-5), 128.65, 129.41, 133.30, 133.74 (Carom), 147.18 (C-6), 152.61
(C-2), 162.54 (C-4) ppm; MS (EI): m/z (%) = 352 (M+, 4), 337 (2),
309 (4), 277 (9), 248 (11), 220 (7), 204 (3), 155 (7), 125 (12); Anal.
Calcd. for C17H21ClN2O4 (352.81): C 57.9, H 6.0, N 7.9. Found:
C 57.5, H 5.8, N 7.7.
1,3-Bis-(ethyloxymethyl)-6-(p-chlorobenzyl)-5-ethyluracil (10d):
1
Colourless oil; yield 0.167 g (44%); H NMR (CDCl3, 500 MHz):
δ = 1.05 (t, J = 7.5 Hz, 3H, CH3), 1.16 (t, J = 7.0 Hz, 3H, CH3),
1.24 (t, J = 7.2 Hz, 3H, CH3); 2.45 (q, J = 7.5 Hz, 2H, CH2), 3.59
(q, J = 7.0 Hz, 2H, CH2), 3.69 (q, J = 7.2 Hz, 2H, CH2), 4.12
(s, 2H, CH2), 5.12 (s, 2H, CH2), 5.47 (s, 2H, CH2), 7.06, 7.30 (2 × d,
J = 8.0 Hz, 4H, Harom) ppm; 13C NMR (CDCl3, 125 MHz): δ = 13.69
(CH3), 15.00 (CH3), 15.19 (CH3), 19.74 (CH2), 32.88 (CH2), 65.12
(CH2), 65.95 (CH2), 71.17 (CH2), 73.51 (CH2), 116.36 (C-5), 128.68,
129.35, 133.22, 133.85 (Carom), 147.23 (C-6), 152.52 (C-2), 162.58
(C-4) ppm; MS (EI): m/z (%) = 380 (M+, 2), 336 (9), 323 (5), 277
(16), 255 (7), 248 (9), 220 (4), 169 (11), 141 (6), 125 (27); Anal.
Calcd. for C19H25ClN2O4 (380.87): C 59.9, H 6.6, N 7.4. Found:
C 59.8, H 6.5, N 7.1%.
6-(p-Chlorobenzyl)-5-ethyl-1-methyloxymethyluracil (9d): White
1
solid; yield 0.055 g (18%), m.p. 171–172°C; H NMR (CDCl3, 500
MHz): δ = 1.08 (t, J = 7.0 Hz, 3H, CH3), 2.52 (q, J = 7.0 Hz, 2H,
CH2), 3.39 (s, 3H, CH3), 3.78 (s, 2H, CH2), 5.34 (s, 2H, CH2), 7.22,
7.30 (2 × d, J = 8.0 Hz, 4H, Harom), 9.82 (s, 1H, NH) ppm; 13C NMR
(CDCl3, 125 MHz): δ = 13.70 (CH3), 18.88 (CH2), 35.38 (CH2),
57.93 (CH3), 71.71 (CH2), 113.59 (C-5), 129.25, 130.08, 133.29,
133.68 (Carom), 146.14 (C-6), 152.49 (C-2), 163.50 (C-4) ppm; MS
(EI): m/z (%) = 308 (M+, 4), 293 (3), 278 (3), 265 (27), 153 (5), 125
(17); Anal. Calcd. for C15H17ClN2O3 (308.76): C 58.35, H 5.55,
N 9.1. Found: C 58.1, H 5.4, N 8.9%.
The financial support of the Research Centre of the College
of Pharmacy, King Saud University (Project # C.P.R.C. 163),
is greatly appreciated.
Received 25 February 2007; accepted 5 May 2007
Paper 07/4507 doi: 10.3184/030823407X210893
6-(p-Chlorobenzyl)-5-ethyl-1-ethyloxymethyluracil (9e): White
1
solid; yield 0.126 g (39%); m.p. 135–136°C; H NMR (CDCl3, 500
MHz): δ = 1.08 (t, J = 7.5 Hz, 3H, CH3), 1.18 (t, J = 7.0 Hz, 3H,
CH3), 2.45 (q, J = 7.5 Hz, 2H, CH2); 3.60 (q, J = 7.0 Hz, 2H, CH2),
4.14 (s, 2H, CH2), 5.12 (s, 2H, CH2), 7.07, 7.29 (2 × d, J = 8.0 Hz,
4H, Harom), 9.60 (s, 1H, NH) ppm; 13C NMR (CDCl3, 125 MHz):
δ = 13.74 (CH3), 15.00 (CH3), 19.18 (CH2), 32.83 (CH2), 65.06
(CH2), 72.76 (CH2), 117.11 (C-5), 128.66, 129.38, 133.28, 133.83
(Carom), 148.54 (C-6), 151.83 (C-2), 163.17 (C-4) ppm; MS (EI): m/z
(%) = 322 (M+, 3), 265 (4), 249 (3), 241 (19), 228 (2), 213 (4), 125
(16); Anal. Calcd. for C16H19ClN2O3 (322.79): C 59.5, H 5.9, N 8.7.
Found: C 59.35, H 5.8, N 8.5%.
References
1
2
3
4
H. Mitsuya, R. Yarchoan and S. Broder, Science, 1990, 249, 1533.
E. De Clercq, Trends Pharmacol. Sci., 1990, 11, 198.
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H. Mitsuya, K.J. Weinhold, P.A. Furman, M.H. St. Clair, S.N. Lehrman,
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6
H. Mitsuya and S. Broder, Proc. Natl. Acad. USA, 1986, 83, 1911.
R.Yarchoan,H.Mitsuya,R.V.Thomas,J.M.Pluda,N.R.Hartman,C.F.Perno,
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412.
1-Benzyloxymethyl-6-(p-chlorobenzyl)-5-ethyluracil (9f): White
7
A.L. Hopkins, J. Ren, R.M. Esnouf, B.E. Willcox, E.Y. Jones, C. Ross,
T. Miyasaka, R.T. Walker, H. Tanaka, D.K. Stammers and D.I. Stuart,
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1
solid; yield 0.185 g (48%); m.p. 137–138°C; H NMR (CDCl3, 500
MHz): δ = 1.05 (t, J = 7.0 Hz, 3H, CH3), 2.43 (q, J = 7.0 Hz, 2H, CH2),
4.12 (s, 2H, CH2), 4.66 (s, 2H, CH2), 5.20 (s, 2H, CH2), 7.02–7.39 (m,
9H, Harom), 9.61 (s, 1H, NH) ppm; 13C NMR (CDCl3, 125 MHz): δ
= 13.76 (CH3), 19.16 (CH2), 32.85 (CH2), 71.85 (CH2), 72.80 (CH2),
117.18 (C-5), 127.59, 128.07, 128.52, 128.67, 129.39, 133.31, 133.68,
137.21 (Carom), 148.35 (C-6), 151.87 (C-2), 163.12 (C-4) ppm; MS
(EI): m/z (%) = 384 (M+, 2), 370 (2), 356 (2), 333 (2), 278 (5), 201 (7),
125 (12), 91 (100), 77 (13); Anal. Calcd. for C21H21ClN2O3 (384.86):
C 65.5, H 5.5, N 7.3. Found: C 65.5, H 5.5, N 7.2%.
1,3-Bis-(methyloxymethyl)-6-(p-chlorobenzyl)-5-methyluracil
(10a): White solid; yield 0.145 g (43%); m.p. 92–93°C; 1H NMR
(CDCl3, 500 MHz): δ = 2.03 (s, 3H, CH3), 3.41 (s, 3H, CH3), 3.48
(s, 3H, CH3), 4.12 (s, 2H, CH2), 5.12 (s, 2H, CH2), 5.45 (s, 2H, CH2),
7.05, 7.28 (2 × d, J = 8.0 Hz, 4H, Harom) ppm. 13C NMR (CDCl3,
125 MHz): δ = 11.51 (CH3), 33.41 (CH2), 57.05 (CH3), 57.94 (CH3),
72.77 (CH2), 75.06 (CH2), 110.52 (C-5), 128.66, 129.26, 133.28,
133.32 (Carom), 147.69 (C-6), 152.57 (C-2), 163.02 (C-4) ppm; MS
(EI): m/z (%) = 338 (M+, 4), 295 (6), 234 (7), 211 (5), 199 (8), 155
(11), 125 (14); Anal. Calcd. for C16H19ClN2O4 (338.79): C 56.7,
H 5.65, N 8.3. Found: C 56.5, H 5.5, N 8.0%.
8
9
R. Esnouf, J. Ren, C. Ross, Y. Jones, D. Stammers and D. Stuart, Nature
Struct. Biol., 1995, 2, 303.
M. Baba, H. Tanaka, E. De Clercq, R. Pauwels, J. Balzarini, D. Schols,
H. Nakashima, C.F. Perno, R.T. Walker and T. Miyasaka, Biochem.
Biophys. Res. Commun., 1989, 165, 1375.
10 T. Miyasaka, H. Tanaka, M. Baba, H. Hayakawa, R.T. Walker, J. Balzarini
and E. De Clercq, J. Med. Chem., 1989, 32, 2507.
11 M. Artico, S. Massa, A. Mai, M.E. Marongiu, G. Pira, E. Tramontano and
P. La Colla, Antiviral Chem. Chemother., 1993, 4, 361.
12 A. Mai, M. Artico, G. Sbardella, S. Massa, A.G. Loi, E. Tramontano,
P. Scano and P. La Colla, J. Med. Chem., 1995, 38, 3258.
13 H. Tanaka, H. Takashima, M. Ubasawa, K. Sekiya, N. Inouye, M. Baba,
S. Shigeta, R.T. Walker, E. De Clercq and T. Miyasaka, J. Med. Chem.,
1995, 38, 2860.
14 G.M. Szczech, P. Furman, G.R. Painter, D.W. Barry, K. Borroto-Esoda,
T.B. Grizzle, M.R. Blum, J.P. Sommadossi, R. Endoh, T.M. Yamamoto
and C. Moxham, Antimicrob. Agents Chemother., 2000, 44, 123.
15 N.R. El-Brollosy, P.T. Jorgensen, B. Dahan, A.M. Boel, E.B. Pedersen
and C. Nielsen, J. Med. Chem., 2002, 45, 5721.
16 N.R. El-Brollosy, E.B. Pedersen and C. Nielsen, Arch. Pharm. Pharm.
Med. Chem., 2003, 336, 236.
17 F.A. El-Essawy, N.R. El-Brollosy, E.B. Pedersen and C. Nielsen,
J. Heterocyclic Chem., 2003, 40, 213.
18 M. Wamberg, E.B. Pedersen, N.R. El-Brollosy and C. Nielsen, Bioorg.
Med. Chem., 2004, 12, 1141.
19 E.R. Sorensen, N.R. El-Brollosy, P.T. Jorgensen, E.B. Pedersen and
C. Nielsen, Arch. Pharm. Life. Sci., 2005, 338, 299.
1,3-Bis-(ethyloxymethyl)-6-(p-chlorobenzyl)-5-methyluracil (10b):
Colourless oil; yield 0.19 g (52%); 1H NMR (CDCl3, 500 MHz):
δ = 1.17 (t, J = 7.0 Hz, 3H, CH3), 1.22 (t, J = 7.1 Hz, 3H, CH3), 2.22
(s, 3H, CH3), 3.51 (m, 4H, 2 × CH2), 4.13 (s, 2H, CH2), 4.77 (s, 2H,
CH2), 4.90 (s, 2H, CH2), 7.06, 7.31 (2 × d, J = 8.0 Hz, 4H, Harom
)
ppm; 13C NMR (CDCl3, 125 MHz): δ = 11.50 (CH3), 14.97 (CH3),
15.17 (CH3), 33.45 (CH2), 65.08 (CH2), 65.92 (CH2), 71.26 (CH2),
73.59 (CH2), 110.42 (C-5), 128.69, 129.38, 133.26, 133.38 (Carom),
147.73 (C-6), 152.48 (C-2), 163.06 (C-4) ppm; MS (EI): m/z (%) =
366 (M+, 3), 322 (18), 309 (11), 279 (8), 263 (24), 241 (9), 234 (22),
211 (3), 199 (16), 169 (7), 125 (23); Anal. Calcd. for C18H23ClN2O4
(366.84): C 58.9, H 6.3, N 7.6. Found: C 59.1, H 6.1, N 7.45%.
1,3-Bis-(methyloxymethyl)-6-(p-chlorobenzyl)-5-ethyluracil (10c):
Colourless oil; yield 0.11 g (31%); 1H NMR (CDCl3, 500 MHz):
δ = 1.05 (t, J = 7.0 Hz, 3H, CH3), 2.45 (q, J = 7.0 Hz, 2H, CH2), 3.40
(s, 3H, CH3), 3.49 (s, 3H, CH3), 4.10 (s, 2H, CH2), 5.08 (s, 2H, CH2),
20 N.R. El-Brollosy, C. Nielsen and E.B. Pedersen, Monatsh. Chem., 2005,
136, 1247.
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PAPER: 07/4507