Synthesis of new uracil non-nucleoside derivatives as potential inhibitors of HIV-1

Article abstract of DOI:10.1002/jhet.5570400203

6-(2-Phenylethyl) and 6-cyclohexyl 5-cyanouracils (1a,b) were synthesized and reacted with chloromethyl ethyl ether, benzyl chloromethyl ether, chloromethyl methyl sulfide and (2-acetoxyethoxy)methyl bromide. New uracil analogues of (S)-DHPA were synthesized by reaction of compounds (1a,b) with ((S)-2,2-dimethyl-1,3-dioxolane-4-yl) alkyl p-toluenesulfonate.

Full text of DOI:10.1002/jhet.5570400203

Mar-Apr 2003
213
Synthesis of New Uracil Non-nucleoside Derivatives
As Potential Inhibitors of HIV-1
Farag A. El-Essawy, Nasser R. El-Brollosy and Erik B. Pedersen*
Nucleic Acid Center , Department of Chemistry, University of Southern Denmark, Campusvej 55,
DK-5230 Odense M, Denmark
Claus Nielsen
Retrovirus Laboratory, Department of Virology, State Serum Institute, Artillerivej 5,
DK-2300 Copenhagen, Denmark
Received August 19, 2002
6-(2-Phenylethyl) and 6-cyclohexyl 5-cyanouracils (1a,b) were synthesized and reacted with
chloromethyl ethyl ether, benzyl chloromethyl ether, chloromethyl methyl sulfide and
(2-acetoxyethoxy)methyl bromide. New uracil analogues of (S)-DHPA were synthesized by reaction of
compounds (1a,b) with ((S)-2,2-dimethyl-1,3-dioxolane-4-yl) alkyl p-toluenesulfonate.
J. Heterocyclic Chem., 40, 213 (2003).
Scheme
1
In the fight against human immunodeficiency virus type
1 (HIV-1), the causative agent of the acquired immunode-
ficiency syndrome (AIDS), several classes of compounds
have been identified as highly specific inhibitors of HIV-1
[1]. Among the compounds, a cyclic 6-substituted uracil
derivative 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-
thymine (HEPT) is an HIV-1 specific reverse transcriptase
inhibitor [2]. This has led to the synthesis of many new
analogues [3-6] of which 6-benzyl-1-(ethoxymethyl)-5-
isopropyluracil (MKC-442) has been chosen as a candi-
date for clinical trials with AIDS patients [7]. Structure
activity relationship studies showed that a ring structure at
C-6 position of the pyrimidine moiety is an important
determinant for the anti-HIV-1 activity. On the other hand,
De Clercq et al. [8,9] reported the antiviral activity of (S)-
9-(2,3-dihydroxypropyl)adenine (S-DHPA). Several
viruses including vaccinia, HSV-1 and HSV-2 were inhib-
ited by (S)-DHPA. Several acyclonucleosides of DHPA
analogues were investigated [10]. Thus, in this report, as a
continuation of our interest, in this area [11], we describe a
practical synthesis of 5-cyano-6-phenylethyl and 6-cyclo-
hexyl analogues of HEPT and MKC-442.
The commercial aldehydes, 3-phenylpropanal and cyclo-
hexanecarboxaldehyde react with ethyl cyanoacetate and
urea according to the procedure of Kambe et al. [12], to
afford the uracil derivatives 1a,b. N-1 alkylation was
achieved when 5-cyano-6-(2-phenylethyl)uracil (1a) was
treated with sodium hydride and chloromethyl methylsul-
fide (2a) or benzyl chloromethyl ether (2c) in anhydrous
DMF. 5-Cyano-1-(methylthiomethyl)-6-(2-phenylethyl)-
uracil (3a) and 1-benzyloxymethyl-5-cyano-6-(2-
phenylethyl)uracil (3c) were obtained in 50% and 42%
yields, respectively. Alkylation with chloromethyl ethyl
ether (2b) afforded the corresponding N-1 alkylated 3b and
1,3-dialkylated 4b products in 53% and 33% yields, respec-
tively. On alkylation with 2-(acetoxyethoxy)methyl bromide
(2d) the corresponding 1,3-bis(acetoxyethoxymethyl)uracil

214
F. A. El-Essawy, N. R. El-Brollosy, E. B. Pedersen and C. Nielsen
Vol. 40
4d was obtained without observing the monoalkylated prod-
uct. 5-Cyano-6-cyclohexyluracil (1b) has more steric hin-
drance around N-1 than 1a. Therefore 1b upon reaction with
2a,c,d under the same reaction conditions gave the N-3 sub-
stituted compounds 5-cyano-6-cyclohexyl-3-(methylth-
iomethyl)uracil (5a), 3-benzyloxymethyl-5-cyano-6-cyclo-
hexyluracil (5c) and 3-(acetoxyethoxymethyl)-5-cyano-6-
cyclohexyluracil (5d), respectively. The product 5d was
deblocked with methanolic ammonia at room temperature to
give the 3-(2-hydroxylethoxymethyl) substituted uracil 7 in
60% yield (Scheme 1). Alkylation of 1b with chloromethyl
ethyl ether (2b) after treatment with NaH in anhydrous
DMF afforded again a 1,3-dialkylated product 6b together
with an N-3 monoalkylated product 5b. Due to steric hin-
drance by the 6-cyclohexyl group the N-1 monoalkylated
product was never observed.
Compound 1b was treated with NaH in anhydrous DMF
followed by (R)-2,2-dimethyl-1,3-dioxolan-4-methyl
toluene-4-sulfonate (8a), and the homologous 2-((S)-2,2-
dimethyl-1,3-dioxolan-4-yl)ethyl toluene-4-sulfonate (8b)
to afford the (S)-N-3 substituted uracil derivatives 9a,b.
Their deprotection was performed by treatment with aque-
ous acetic acid (80%) at room temperature to afford the
corresponding 5-cyano-6-cyclohexyl-3-((S)-2,3-dihydrox-
ypropyl)uracil (10a), and 5-cyano-6-cyclohexyl-3-((S)-
3,4-dihydroxybutyl)uracil (10b), respectively (Scheme 2).
Compound 10b was tosylated by reaction with tosyl chlo-
ride in dry pyridine at 4° to give the monotosylate 11 and
the ditosylate 12 after silica chromatography with
CHCl :EtOAc. The monotosylate 11 was treated with
3
sodium azide in dry DMF at 80° to afford the correspond-
ing 3-((S)-4-azido-3-hydroxybutyl)-5-cyano-6-cyclohexy-
luracil (13) in 60% yield which showed the azido group at
-1
2102 cm in the ir spectrum.
The N-1 alkylated compound 3b was confirmed by
nuclear overhouser effect (NOE) of Ph-CH -CH (4%) on
2
2
irradiation of OCH N, while on irradiation of the cyclo-
2
hexyl protons of compound 5b, no NOE enhancement of
OCH N was observed confirming N-3 alkylation in case of
2
the bulky cyclohexyl substitutent in the 6 position of the
13
uracil ring. C nmr spectra of compounds 3b, 5b, 4b and
6b showed OCH N at N-1 at lower field (73.20-74.13 ppm)
2
and OCH N at N-3 at higher field (70.63-71.46 ppm).
2
The test for activity against HIV-1 was performed in
MT4 cell cultures infected with either wild type HIV-1 or
strain N119 that harboured a substitution of cysteine for
tyrosine at position 181. No compounds exhibited activity
against HIV-1, except 1-benzyloxymethyl-5-cyano-6-(2-
Scheme 2

Mar-Apr 2003 Synthesis of New Uracil Non-nucleoside Derivatives As Potential Inhibitors of HIV-1
215
3.01-3.04 (m, 2 H, CH ), 3.07-3.12 (m, 2 H, CH ), (s, 2 H, CH ),
phenylethyl)uracil (3c) which showed activity (ED = 1.3
2
2
2
50
13
7.25-7.37 (m, 5 H, H
), 12.14 (s, 1 H, NH); C nmr (DMSO-
µM; CD = 25 µM) against wild type HIV-1.
arom
50
d ): δ 14.37 (CH ), 33.50 (CH ), 33.93 (CH ), 47.47 (CH ),
6
3
2
2
2
89.77 (C-5), 114.35 (CN), 126.00, 128.31, 128.52, 138.98 (Ar),
149.95 (C-2), 159.42 (C-4), 165.69 (C-6); EI ms: m/z 301 (M ).
EXPERIMENTAL
+.
5-Cyano-1-(ethoxymethyl)-6-(2-phenylethyl)uracil (3b).
1
Nmr Spectra were recorded at 300 MHz for H and 75 MHz
13
This compound was obtained as colorless crystals, yield 0.16 g
for C on a Varian Gemini 2000 NMR 300 MHz spectrometer or
on a Bruker AC-250 FT spectrometer at 250 MHz for H and at
62.9 MHz for C; δ values are in ppm relative to tetramethylsi-
1
1
(53%); mp 197-200°; H nmr (DMSO-d ): δ 1.13 (t, 3 H, J = 7.0
6
13
Hz, CH ), 2.94-2.98 (m, 2 H, CH ), 2.99-3.04 (m, 2 H, CH ),
3
2
2
3.58 (q, 2 H, J = 7.0 Hz, CH ), 5.57 (s, 2 H, CH ), 7.23-7.38 (m,
lane as an internal standard. EI mass spectra were recorded on a
Finnigan MAT SSQ 710. MALDI mass spectra were recorded on
a Kratos MS50RF spectrometer. Analytical silica gel (tlc) was
2
2
13
5 H, H
), 12.09 (s, 1 H, NH); C nmr (DMSO-d ): δ 14.76
arom
6
(CH ), 33.82 (CH ), 33.87 (CH ), 64.21 (CH ), 73.20 (CH ),
3
2
2
2
2
89.74 (C-5), 114.25 (CN), 126.61, 128.16, 128.58, 139.31 (Ar),
performed on Merck precoated 60 F
plates. The silica gel
254
150.27 (C-2), 159.09 (C-4), 166.58 (C-6). HRms (MALDI): m/z
(0.040 x 0.063 mm) used for column chromatography was pur-
chased from Merck.
+
322 (M + Na ): Anal. Calcd. for C
H N NaO : 322.1162.
16 17 3 3
Found: 322.1166.
General Procedure for the Preparation of 5-Cyano-6-substituted
1-Benzyloxymethyl-5-cyano-6-(2-phenylethyl)uracil (3c).
Uracils (1a,b).
This compound was obtained as colorless crystals, yield 0.15 g
A mixture of ethyl cyanoacetate (10.6 g, 0.1 mole), an appropri-
ate aldehyde (0.1 mole), urea (6 g, 0.1 mole) in absolute ethanol
(100 ml) containing anhydrous potassium carbonate (13.82 g, 0.1
mole) was heated under reflux for 5 hours. The potassium salt of
1a,b that precipitates during the reaction was collected by filtration
and washed with ethanol. The crude salt was dissolved in warm
water and after cooling the solution was acidified with acetic acid,
and the precipitate was collected by filtration, washed with water,
dried, and recrystallised from acetic acid to give 1a,b.
1
(42%); mp 160-163°; H nmr (DMSO-d ): δ 2.80-2.86 (m 2 H,
6
CH ), 2.91-2.97 (m, 2 H, CH ), 4.59 (s, 2 H, CH ), 5.29 (s, 2 H,
2
2
2
13
CH ), 7.20-7.38 (m, 10 H, H
); C nmr (DMSO-d ): δ 33.02
2
arom
6
(CH ), 34.03 (CH ), 69.76 (CH ), 70.99 (CH ), 86.21 (C-5),
2
2
2
2
114.12 (CN), 126.54, 127.28, 127.46, 128.12, 128.16, 128.49,
137.81, 139.05 (Ar), 149.89 (C-2), 160.32 (C-4), 164.79 (C-6).
+
HRms (MALDI): m/z 384 (M + Na ): Anal. Calcd. for
C H N NaO : 384.1324. Found: 384.1325.
22 21
3
3
5-Cyano-6-cyclohexyl-3-(methylthiomethyl)uracil (5a).
5-Cyano-6-(2-phenylethyl)uracil (1a).
This compound was obtained as colorless crystals, yield 0.1 g
(37%); mp 246-249°; H nmr (deuteriochloroform): δ 1.28-1.89
This compound was obtained as yellow crystals, yield 6.3 g
1
1
(26%); mp 294-296°; H nmr (DMSO-d ): δ 2.81-2.85, 2.93-2.98
6
(m, 10 H, 5 x CH ), 2.13 (s, 3 H, CH ), 2.91-2.99 (m, 1 H, CH),
(2 x m, 4 H, 2 x CH ), 7.22-7.35 (m, 5 H, H
), 11.73 (brs, 2 H,
2
3
2
arom
13
13
4.99 (s, 2 H, CH ), 10.42 (bs, 1 H, NH); C nmr (deuteriochlo-
2 x NH); C nmr (DMSO-d ): δ 33.11, 34.04 (2 x CH ), 86.45
2
6
2
roform): δ 16.64 (CH ), 25.13, 25.48, 29.52, 42.30 (C
),
(C-5), 114.33 (CN), 126.53, 128.21, 128.51, 139.09 (Ar), 149.85
(C-2); 161.08 (C-4), 165.63 (C-6); EI ms: m/z 241(M ).
3
cyclohexyl
+.
44.98 (CH ), 87.84 (C-5), 112.75 (CN), 151.24 (C-2), 159.47 (C-
2
+
4), 167.12 (C-6). HRms (MALDI): m/z 302 (M + Na ): Anal.
5-Cyano-6-cyclohexyluracil (1b).
Calcd. for C H N NaO S: 302.0934. Found: 302.0943.
13 17
3
2
This compound was obtained as yellow crystals, yield 8.5 g
5-Cyano-6-cyclohexyl-3-(ethoxymethyl)uracil (5b).
1
(39%); mp 284-286°; H nmr (DMSO-d ): δ 1.17-1.25, 1.66-1.82
6
This compound was obtained as colorless crystals, yield 0.12 g
(43%); mp 194-195°; H nmr (deuteriochloroform): δ 1.18 (t, 3
(2 x m, 10 H, 5 x CH ), 2.66-2.73 (m, 1 H, CH), 11.70 (brs, 2 H,
2
1
13
2 x NH); C nmr (DMSO-d ): δ 24.61, 25.35, 28.35, 42.40
6
H, J = 7.0 Hz, CH ), 1.33-1.94 (m, 10 H, 5 x CH ), 2.94-2.99 (m,
(cyclohexyl), 85.11 (C-5), 114.53 (CN), 150.05 (C-2), 161.34 (C-
3
2
+.
1 H, CH), 3.63 (q, 2 H, J = 7.0 Hz, CH ), 5.39 (s, 2 H, CH ), 10.7
4), 169.46 (C-6); EI ms: m/z 219 (M ).
2
2
13
(s, 1 H, NH); C nmr (deuteriochloroform): δ 15.05 (CH ),
3
General Procedure for the Preparation of Compounds 3a-c, 4b,d,
5a-d and 6b.
25.01, 25.48, 29.44, 42.32 (C
), 66.23 (CH ), 70.63
cyclohexyl
2
(CH ), 87.58 (C-5), 112.80 (CN), 151.62 (C-2), 159.81 (C-4),
2
+
167.60 (C-6). HRms (MALDI): m/z 300 (M + Na ): Anal. Calcd.
To a stirred solution of 1a,b (1 mmole) in dry N,N-dimethyl-
formamide (10 ml), 0.04 g (1 mmole) of sodium hydride (60%
dispersion in mineral oil) was added. When liberation of hydro-
gen had ceased (1 hour), the appropriate ether (2a-d, 1.1 mmoles)
was added, and the reaction mixture was stirred at room tempera-
ture for 10-15 hours. The solvent was evaporated in vacuo, and
the compounds were purified by silica gel column chromatogra-
phy with chloroform:ethyl acetate (2:1, v/v). Fractions with
dialkylated derivatives 4b,d and 6b were eluated faster than their
mono-alkylated counterparts 3a-c and 5a-d.
for C H N NaO : 300.1319. Found: 300.1327.
14 19
3
3
3-(Benzyloxymethyl)-5-cyano-6-cyclohexyluracil (5c).
This compound was obtained as colorless crystals, yield
1
0.17 g (50%); mp 139-142°; H nmr (deuteriochloroform): δ
1.26-1.89 (m, 10 H, 5 x CH ), 2.87-2.95 (m, 1 H, CH), 4.69 (s,
2
2 H, CH ), 5.48 (s, 2 H, CH ), 7.23-7.44 (m, 5 H, H ), 10.33
2
2
arom
13
(brs, 1 H, NH); C nmr (deuteriochloroform): δ 25.02, 25.44,
29.39, 42.26 (C ), 70.62 (CH ), 72.68 (CH ), 87.68 (C-
cyclohexyl
2
2
5), 112.77 (CN), 127.36, 127.92, 128.36, 137.33 (Ar), 151.40
5-Cyano-1-(methylthiomethyl)-6-(2-phenylethyl)uracil (3a).
(C-2), 159.85 (C-4), 167.51 (C-6). HRms (MALDI): m/z 362
+
(M + Na ): Anal. Calcd. for C
H N NaO : 362.1475. Found:
This compound was obtained as colorless crystals, yield 0.15 g
19 21 3 3
1
362.1482.
(50%); mp 228-230°; H nmr (DMSO-d ): δ 2.24 (s, 3 H, CH ),
6
3

216
F. A. El-Essawy, N. R. El-Brollosy, E. B. Pedersen and C. Nielsen
Vol. 40
3-[(2-Acetoxyethoxy)methyl]-5-cyano-6-cyclohexyluracil (5d).
General Procedure for the Preparation of Compounds (9a,b).
This compound was obtained as colorless crystals, yield 0.1 g
(33%); mp 159-161°; H nmr (deuteriochloroform): δ 1.31-1.91
To a stirred solution of 1b (0.22 g, 1 mmole) in dry N,N-
dimethylformamide (10 ml), 0.04 g (1mmole) of sodium hydride
(60% dispersion in mineral oil) was added. After evolution of
hydrogen has completed (1 hour), the appropriate 2,2-dimethyl-
1,3-dioxolane-4-yl alkyl p-toluenesulfonate (8a,b, 1.1 mmoles)
was added in one portion, and the reaction mixture was stirred for
additional 8-10 hours at 100°. The reaction mixture was cooled to
room temperature, and the solvent was evaporated in vacuo. The
compounds were purified by silica gel column chromatography
with chloroform:ethyl acetate (95:5, v/v).
1
(m, 10 H, 5 x CH ), 2.06 (s, 3 H, CH ), 2.94 (m, 1 H, CH), 3.84
2
3
(t, 2 H, J = 4.9 Hz, CH ), 4.18 (t, 2 H, J = 4.9 Hz, CH ), 5.43 (s, 2
2
2
13
H, CH ), 10.32 (brs, 1 H, NH); C nmr (deuteriochloroform): δ
2
20.80 (CH ), 25.01, 25.43, 29.47, 42.29 (C
), 63.11
3
cylclohexyl
(CH ), 68.79 (CH ), 71.06 (CH ), 87.76 (C-5), 112.70 (CN),
2
2
2
151.26 (C-2), 159.85 (C-4), 167.67 (C-6), 170.84 (CO). HRms
+
(MALDI): m/z 358 (M + Na ): Anal. Calcd. for C H N NaO :
16 21
3
5
358.1373. Found: 358.1380.
1,3-Bis(ethoxymethyl)-5-cyano-6-(2-phenylethyl)uracil (4b).
5-Cyano-6-cyclohexyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-
ylmethyl)uracil (9a).
This compound was obtained as colorless crystals, yield 0.15 g
1
(42%); mp 124-126°; H nmr (deuteriochloroform): δ 1.19, 1.22 (2
This compound was obtained as colorless crystals, yield 0.2 g
1
x t, 6 H, J = 7.0 Hz, 2 x CH ), 3.04-3.09 (m, 2 H, CH ), 3.17-3.23
(17%); mp 123-125°; H nmr (deuteriochloroform): δ 1.21 (s, 3
3
2
(m, 2 H, CH ), 3.64, 3.65 (2 x q, 4 H, J = 7.0 Hz, 2 x CH ), 5.35 (s,
H, CH ), 1.47 (s, 3 H, CH ), 1.23-1.91 (m, 10 H, 5 x CH ), 2.94-
2
2
3
3
2
13
2 H, CH ), 5.42 (s, 2 H, CH ), 7.24-7.37 (m, 5 H, H ): C nmr
3.05 (m, 1 H, CH), 3.79 (dd, 1 H, J = 5.3, 8.9 Hz, CH ), 3.88 (dd,
2
2
arom
2
(deuteriochloroform): δ 14.95, 15.08 (2 x CH ), 34.24 (CH ),
1 H, J = 4.9, 12.9 Hz, CH ), 4.06 (dd, 1 H, J = 6.4, 8.8 Hz, CH ),
3
2
2
2
34.90 (CH ), 65.90, 66.34 (2 x CH ), 71.46 (CH ), 74.43 (CH ),
4.24 (dd, 1 H, J = 7.3, 12.9 Hz, CH ), 4.42-4.51 (m, 1 H, CH),
10.55 (brs, 1 H, NH); C nmr (deuteriochloroform): δ 25.08,
2
2
2
2
2
13
90.93 (C-5), 113.17 (CN), 127.22, 128.31, 128.95, 138.37 (Ar),
+.
150.88 (C-2), 158.77 (C-4), 165.40 (C-6); EI ms: m/z 357 (M ).
26.65, 29.47, 42.21 (C
), 25.29 (CH ), 25.45 (CH ), 44.23
cyclohexyl
3 3
(CH ), 67.46 (CH ), 72.46 (CH), 87.85 (C-5), 109.87 (C(CH ) ),
112.87 (CN), 151.78 (C-2), 159.70 (C-4), 166.90 (C-6).
2
2
3 2
1,3-Bis(ethoxymethyl)-5-cyano-6-cyclohexyluracil (6b).
This compound was obtained as colorless crystals, yield 0.11 g
5-Cyano-6-cyclohexyl-3-[2-((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)ethyl]uracil (9b).
1
(33%); mp 119-120°; H nmr (deuteriochloroform): δ 1.19, 1.20
(2 x t, 6 H, J = 7.0 Hz, 2 x CH ), 1.33-2.26 (m, 10 H, 5 x CH ),
3
2
3.01-3.06 (m, 1 H, CH), 3.62, 3.64 (2 x q, 4 H, J = 7.0 Hz, 2 x
This compound was obtained as colorless crystals, yield 0.1 g
(66%); mp 189-191°; H nmr (deuteriochloroform): δ 1.30 (s, 3
13
1
CH ), 5.41 (s, 2 H, CH ), 5.49 (s, 2 H, CH ); C nmr (deuteri-
2
2
2
ochloroform): δ 14.94, 15.04 (2 x CH ), 24.75, 26.10, 28.89,
H, CH ), 1.36 (s, 3 H, CH ), 1.30-1.99 (m, 10 H, 5 x CH ), 2.90-
3
3
3
2
40.92 (C
), 65.32, 66.33 (2 x CH ), 71.49, 74.13 (2 x
3.01 (m, 1 H, CH
), 3.53-3.58 (m, 2 H, CH ), 3.93-4.27
cyclohexyl
2
cyclohexyl
2
13
CH ), 87.85 (C-5), 113.76 (CN), 150.95 (C-2), 159.59 (C-4),
(m, 5 H, CH, CH CH ), 10.68 (brs, 1 H, NH); C nmr (deuteri-
2
2
2
+
170.23 (C-6). HRms (MALDI): m/z 358 (M + Na ): Anal. Calcd.
ochloroform): δ 25.15, 26.81, 29.46, 42.15 (C
), 25.44,
cyclohexyl
for C H N NaO : 358.1737. Found: 358.1750.
25.45 (2 x CH ), 31.02 (CH ), 38.72 (CH ), 69.03 (CH ), 73.94
17 25
3
4
3
2
2
2
(CH), 87.68 (C-5), 109.05 (C (CH ) ), 112.97 (CN), 151.68 (C-
2), 159.74 (C-4), 166.72 (C-6).
3 2
1, 3-Bis[(2-acetoxyethoxy)methyl]-5-cyano-6-(2-
phenylethyl)uracil (4d).
General Procedure for the Deprotection of Compounds (9a,b).
This compound was obtained as an viscous oil, yield 0.2 g
1
(45%); H nmr (deuteriochloroform): δ 2.00 (s, 3 H, CH ), 2.06
Compound 9a or 9b (1mmole) was dissolved in 80% aqueous
acetic acid (10 ml) and the solution was stirred overnight at room
temperature. The volatiles were evaporated in vacuo and the
residue was coevaporated with water (3 x 5 ml), and finally with
ethanol (3 x 5 ml). The compounds 10a,b were purified by silica
gel column chromatography with chloroform:methanol (95:5, v/v).
3
(s, 3 H, CH ), 3.05-3.11 (m, 2 H, CH ), 3.16-3.22 (m, 2 H, CH ),
3
2
2
3.85-3.89 (m, 4 H, OCH CH O), 4.18-4.23 (m, 4 H,
2
2
OCH CH O), 5.42 (s, 2 H, CH ), 5.46 (s, 2 H, CH ), 7.26-7.37
2
2
2
2
13
(m, 5 H, H
); C nmr (deuteriochloroform): δ 20.26, 20.74 (2
arom
x CH ), 34.23, 34.63 (2 x CH ), 90.94 (C-5), 112.96 (CN),
3
2
127.17, 128.21, 128.88, 138.19 (Ar), 150.48 (C-2), 158.62 (C-4),
5-Cyano-6-cyclohexyl-3-((S)-2,3-dihydroxypropyl)uracil (10a).
165.36 (C-6), 170.54, 170.73 (2 x COCH ). HRms (MALDI):
3
+
This compound was obtained as a colorless viscous oil, yield
m/z 496 (M + Na ): Anal. Calcd. for C H N NaO : 496.1690.
23 27
3
8
1
61 mg (60%); H nmr (DMSO-d ): δ 1.17-1.91 (m, 10 H, 5 x
Found: 496.1672.
6
CH ), 2.67-2.72 (m, 1 H, CH), 3.67-3.91 (m, 5 H, CH, 2 x CH ),
2
2
5-Cyano-6-cyclohexyl-3-(2-hydroxyethoxymethyl)uracil (7).
13
4.78 (brs, 2 H, 2 x OH); C nmr (DMSO-d ): δ 24.73, 25.40,
6
Compound 5d (60 mg, 0.2 mmole) was dissolved in 50%
methanolic ammonia (10 ml) and the mixture was stirred for 5
hours at 50-60°. The solvent was evaporated in vacuo and the
residue was purified by silica gel column chromatography with
28,64, 42.50 (C
(CH), 83.89 (C-5), 115.37 (CN), 151.69 (C-2), 161.41 (C-4),
169.19 (C-6). HRms (MALDI): m/z 316 (M + Na ): Anal. Calcd.
), 43.66 (CH ), 64.16 (CH ), 68.18
cyclohexyl
2 2
+
for C H N O Na: 316.1268. Found: 316.1264.
14 19
3 4
chloroform:methanol (95:5, v/v) as the eluent to give 7 (30 mg,
5-Cyano-6-cyclohexyl-3-((S)-3,4-dihydroxybutyl)uracil (10b).
1
60%) as a colorless viscous oil; H nmr (DMSO-d ): δ 1.19-1.81
6
(m, 10 H, 5 x CH ), 2.64-2.68 (m, 1 H, CH), 3.41-3.47 (m, 2 H,
This compound was obtained as a colorless viscous oil, yield
2
1
CH ), 3.58-3.62 (m, 2 H, CH ), 4.62 (br s, 1 H, OH), 5.11 (s, 2 H,
60 mg (86%); H nmr (DMSO-d ): δ 1.18-1.81(m, 10 H, 5 x
2
2
6
13
CH ); C nmr (DMSO-d ): δ 24.64, 25.31, 28.39, 42.50
CH ), 2.68-2.72 (m, 1 H, CH), 3.21-3.45 (m, 3 H, CH, CH ),
2
6
2
2
(C
), 60.06 (CH ), 70.19 (CH ),71.58 (NCH O), 84.39
3.70-3.79, 3.89-3.98 (2 x m, 2 H, CH ), 4.53 (brs, 2 H, 2 x OH);
cyclohexyl
2
2
2
2
13
(C-5), 114.77 (CN), 150.78 (C-2), 160.91 (C-4), 169.38 (C-6).
C nmr (DMSO-d ): δ 24.14, 24.88, 27.86, 41.75 (C
),
6
cyclohexyl

Mar-Apr 2003 Synthesis of New Uracil Non-nucleoside Derivatives As Potential Inhibitors of HIV-1
217
30.68 (CH ), 37.70 (CH ), 65.33 (CH ), 69.11 (CH), 84.42 (C-5),
collected by filtration, and washed with ice-water. The product
was recrystallised from ethanol as colorless crystals, 0.03 g
2
2
2
114.15 (CN), 149.53 (C-2), 159.95 (C-4), 167.09 (C-6). HRms
+
-1 1
(MALDI): m/z 330 (M + Na ): Anal. Calcd. for C H N O Na:
(60%); mp 129-131°; ir (KBr): CN 2232, N 2102 cm ; H nmr
15 21
3
4
3
330.1424. Found: 330.1422.
(deuteriochloroform): δ 1.12-1.94 (m, 12 H, 6 x CH ), 2.90-2.98
2
(m, 1 H, CH), 3.25-3.30 (m, 2 H, CH ), 3.71 (brs, 1 H, OH), 4.09-
2
Toluene-4-sulfonic Acid (S)-4-(5-Cyano-6-cyclohexyluracil-3-
yl)-2-hydroxybutyl Ester (11).
13
4.16 (m, 2 H, CH ), 9.81 (brs, 1 H, NH); C nmr (deuteriochlo-
2
roform): δ 25.13, 25.47, 29.71, 42.16 (C
), 32.15 (CH ),
cyclohexyl
2
4-Toluenesulfonyl chloride (0.29 g, 1.5 mmoles) was added to
an ice cooled solution of compound 10b (0.19 g, 0.75 mmole) in
dry pyridine (10 ml) and left it to stand overnight at 4°, and then
4 hours at room temperature. The pyridine was evaporated in
vacuo, and the resulting gum was purified by silica gel column
chromatography with chloroform:ethyl acetate (1:1, v/v) to give
11, yield 0.17 g (48%), and 12 yield 0.2 g (40%).
38.36 (CH ), 56.35 (CH ), 67.98 (CH), 87.73 (C-5), 112.77
2
2
(CN), 151.19 (C-2), 160.62 (C-4), 166.99 (C-6). HRms
+
(MALDI): m/z 638 (M + Na – N ): Anal. Calcd for
2
C H N O Na: 327.1428. Found: 327.1429.
15 20
4 3
REFERENCES AND NOTES
1
Compound 11 has H nmr (deuteriochloroform): δ 1.21-1.93
(m, 12 H, 6 x CH ), 2.46 (s, 3 H, CH ), 2.91-2.99 (m, 1 H, CH),
[ ] A research center funded by The Danish National
2
3
3.25 (brs, 1 H, OH), 3.82-3.85 (m, 1 H, CH), 3.94 (d, 2 H, J = 5.1
Research Foundation for studies on nucleic acid chemical biology.
Hz,CH ), 4.07-4.09 (m, 2 H, CH ), 7.34 (d, 2 H, J = 8.2 Hz,
*
To whom correspondence should be addressed.
2
2
13
H
), 7.75 (d, 2 H, J = 8.2 Hz, H
); C nmr (deuteriochlo-
[1] E. De Clercq, Med. Res. Rev., 13, 229 (1993).
[2] T. Miyasaka, H. Tanaka, M. Baba, H. Hayakawa, R. T.
Walker, J. Balzarini and E. De Clercq, J. Med. Chem., 32, 2507
(1989).
[3] J. Balzarini, A. Karlsson and E. De Clercq, Mol.
Pharmacol., 44, 694, (1993).
[4] M. Baba, S. Yuasa, T. Niwa, M. Yamamoto, S. Yabuuchi,
H. Takashima, M. Ubasawa, H. Tanaka, T. Miyasaka, R. T. Walker, J.
Balzarini, E. De Clercq and S. Shigeta, Biochem. Pharmacol., 45,
2507 (1993).
[5] T. Miyasaka, H. Tanaka, E. De Clercq, M. Baba, R. T.
Walker and M. Ubasawa, European Patent, EP449726A1 (1991);
Chem. Abstr., 116, 41986 (1991).
[6] T. Miyasaka, H. Tanaka, E. De Clercq, M. Baba, R. T.
Walker and M. Ubasawa, European Patent, EP420763A2 (1991);
Chem. Abstr., 115, 158838 (1991).
[7] M. Baba, H. Tanaka, T. Miyasaka, S. Yuasa, M. Ubasawa;
R. T. Walker and E. De Clercq, Nucleosides Nucleotides, 14, 575
(1995).
arom
arom
roform): δ 21.66 (CH ), 25.13, 25.47, 29.67, 42.19 (C
),
3
cyclohexyl
30.77 (CH ), 38.15 (CH ), 66.67 (CH ), 73.03 (CH), 87.59 (C-5),
2
2
2
112.89 (CN), 127.92, 129.98, 132.37, 145.22 (C
), 151.07 (C-
arom
2), 160.66 (C-4), 167.09 (C-6). HRms (MALDI): m/z 484 (M +
+
Na ): Anal. Calcd for C
H N O SNa: 484.5263. Found:
22 27 3 6
484.5262.
1
Compound 12 has H nmr (deuteriochloroform): δ 1.26-2.09
(m, 12 H, 6 x CH ), 2.45, 2.46 (2 x s, 6 H, 2 x CH ), 2.90-2.98
2
3
(m, 1 H, CH), 3.90-3.92 (m, 2 H, CH ), 4.02-4.11 (m, 2 H, CH ),
2
2
4.68-4.71 (m, 1 H, CH), 7.26-7.35 (m, 4 H, H
), 7.66-7.70 (m,
arom
13
4 H, H
), 9.95 (s, 1 H, NH); C nmr (deuteriochloroform): δ
arom
21.69 (2 x CH ), 25.25, 25.48, 29.65, 42.24 (C
), 28.65
3
cyclohexyl
(CH ), 37.37 (CH ), 68.84 (CH ), 76.58 (CH), 87.51 (C-5),
2
2
2
112.98 (CN), 127.92, 127.93, 129.99 132.04, 132.94, 145.38
(C
), 150.83 (C-2), 159.88 (C-4), 167.07 (C-6). HRms
arom
+
(MALDI): m/z 638 (M
+
Na ): Anal. Calcd. for
C H N O S Na: 638.7147. Found: 638.2998.
29 33
3 8 2
[8] E. De Clercq and A. Holy, J. Med Chem., 22, 510 (1979).
[9] E. De Clercq, J. Descamps, P. De Somer and A. Holy,
Science, 200, 563 (1978).
[10] A. A. Rahman and M. T. Aal, Pharmazie, 53, 377 (1998).
[11] K. Danel, E. Larsen and E. B. Pedersen, Synthesis, 934
(1995).
3-((S)-4-Azido-3-hydroxybutyl)-5-cyano-6-cyclohexyluracil
(13).
A mixture of compound 11 (1 mmole) and sodium azide (1
mmole) in dry N,N-dimethylformamide (5 ml) was heated for 2
hours at 80°. The solvent was removed in vacuo and the remain-
ing syrup was triturated with ice-water. A white precipitate was
[12] S. Kambe, K. Saito and H. Kishi, Synthesis, 287 (1979).