Synthesis of l-(alkoxymethyl)-5-benzyl-6-methyluracil as potential nonnucleoside HIV-1 RT inhibitors

Article abstract of DOI:10.1080/00397910600772850

1,3-Dibenzyl-6-methyl-5-zincbromomethyluracil 6 was prepared starting from 6-methyluracil 1. The cross-coupling reaction of benzylic zinc reagent 6 with PhI using bis(dibenzylideneacetone) palladium(0) and (o-furyl)3P as catalyst gave 1,3,5-tribenzyl-6-methyluracil 7. The N-1,N-3-dibenzyl group could be removed in dealkylation to give the 5-benzyl-6-methyluracil 8. It was N-1-alkylated with chloromethyl ethyl ether or chloromethyl benzyl ether to obtained the targets 9a and b. All synthesized compounds were tested for their inhibition of HIV-1 reverse transcriptase, and moderate activity were found for target compounds 9a and b and 5. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600772850

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Synthesis of
l‐(Alkoxymethyl)‐5‐benzyl‐6‐methyluracil as
Potential Nonnucleoside HIV‐1 RT Inhibitors
a
a
a
a
a
Yanli Chen , Ying Guo , Hua Yang , Xiaowei Wang & Junyi Liu
a
Department of Chemical Biology and State Key Laboratory of Natural and
Biomimetic Drugs, Peking University, Beijing, China
Version of record first published: 16 Feb 2007
To cite this article: Yanli Chen, Ying Guo, Hua Yang, Xiaowei Wang & Junyi Liu (2006): Synthesis of
l‐(Alkoxymethyl)‐5‐benzyl‐6‐methyluracil as Potential Nonnucleoside HIV‐1 RT Inhibitors, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:19,
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Synthetic Communications , 36: 2913–2920, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600772850
Synthesis of l-(Alkoxymethyl)-5-benzyl-6-
methyluracil as Potential Nonnucleoside
HIV-1 RT Inhibitors
Yanli Chen, Ying Guo, Hua Yang, Xiaowei Wang,
and Junyi Liu
Department of Chemical Biology and State Key Laboratory of Natural
and Biomimetic Drugs, Peking University, Beijing, China
Abstract: 1,3-Dibenzyl-6-methyl-5-zincbromomethyluracil 6 was prepared starting
from 6-methyluracil 1. The cross-coupling reaction of benzylic zinc reagent 6 with
PhI using bis(dibenzylideneacetone) palladium(0) and (o-furyl) P as catalyst gave
3
1,3,5-tribenzyl-6-methyluracil 7. The N-1,N-3-dibenzyl group could be removed in
dealkylation to give the 5-benzyl-6-methyluracil 8. It was N-1-alkylated with chloro-
methyl ethyl ether or chloromethyl benzyl ether to obtained the targets 9a and b. All
synthesized compounds were tested for their inhibition of HIV-1 reverse transcriptase,
and moderate activity were found for target compounds 9a and b and 5.
Keywords: HIV-1 reverse transcriptase, nonnucleoside reverse transcriptase
inhibitors, N-1-alkylated-5-benzyl-6-methyluracil
Since the discovery of the human immunodeficiency virus (HIV) as the
[1,2]
causative agent of acquired immunodeficiency syndrome (AIDS),
the potential targets for antiviral chemotherapy, HIV-1 reverse transcriptase
HIV-1 RT) and HIV-1 protease have been successful to date. Nucleoside
among
(
0
0
[3]
analogues, such as 3 -azido-3 -deoxythymidine (AZT), are useful drugs
against HIV. However, these compounds exhibit significant toxicity and
[
4]
viral resistance. Therefore, the development of very specific and highly
active nonnucleoside inhibitors of HIV-1 RT was envisioned to be the
potential solution for HIV-1 infection. Nonetheless, these agents also failed
Received in R.O.C. February 7, 2006
Address correspondence to Xiaowei Wang, Department of Chemical Biology and
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing
100083, China. E-mail: yanlichen79@hotmail.com
2
913

2
914
Y. Chen et al.
to deal with viral resistance; it is necessary to continue the search for new and
more effective anti-HIV agents.
Nonnucleoside reverse transcriptase inhibitors (NNRTI) of HIV are a
very broad class of structurally diverse molecules. Within the group of non-
nucleoside inhibitors of HIV-1 RT, 1-[(2-hydroxyethoxy)methyl]-6-(phe-
[
5]
nylthio)thymine (HEPT) is one of the potential candidates for further
development in the search for an effective agent. Now, the new HEPT deriva-
tives such as MKC-442, GCA-186, and TNK-651 show greater inhibitory
[6]
effects than the parent compounds. Although extensive structure–activity
relationships on the anti-HIV activity have been performed, only a few inves-
tigations have dealt with the variation of the 5-substituent in the uracil ring.
Little or no information is available about 5-aromatic and 6-small substituents.
We therefore decided to synthesize N-I-alkylated, 5-benzyl, and 6-methyl
group uracils as examples of 5-bulky and 6-small substituents to find out
whether the new NNRTI type drugs display a high level of activity against
the clinically revant HIV mutant strains.
1-(Alkoxymethyl)-5-benzyl-6-methyluracil was prepared by 6-methyl-
uracil as a starting material (Scheme 1). For the preparation of the target
compounds 9, commercially available 6-methyluracil 1 was first hydroxy
methylated with an excess of HCHO in Ba(OH) to give 5-hydroxymethyl-
2
6
-methyluracil 2 in 80% yield, using the same conditions as used in the
[7]
synthesis of the corresponding uracil derivative. 1 Compound 2 reacted
with benzyl alcohol in aqueous HCI according to literature procedures to
give the 5-benzyloxymethyl-6-methyluracil 3 in 80% yield and then
Scheme 1.

1-(Alkoxymethyl)-5-benzyl-6-methyluracil
2915
underwent N-benzylation with 2 molar equivalents of sodium hydride and 2
molar equivalents of benzylbromide in dry DMF to furnish 1,3-dibenzyl-5-
benzyloxymethyl-6-methyluracil 4.
1
,3-Dibenzyl-5-bromomethyl-6-methyluracil 5 was prepared by treating
with 33% HBr solution in acetic acid in 57% yield. The zinc compound 6
was obtained via the slow addition of 5 to zinc powder previously activated
4
[8]
by treatment with 1,2-dibromoethane and trimethylsilychloride (TMSCI).
The compound 6 was easily converted to 1,3,5-tribenzyl-6-methyluracil 7
by treatment 6 with iodobenzene in THF in the presence of a
catalytic amount of bis(dibenzylideneaceton)palladium(0) [Pd(dba) ] and
2
[
9]
(o-furyl)3P (tfp) after 12 h at room temperature in 81% yield, together
with minor 1,3-dibenzyl-5,6-dimethyluracil.
The deprotection of the benzyl group for 7 was unsuccessful with usual
[
10]
[11]
[12]
[13]
reagents such as TiCl4,
or multiple products. However, deprotection with HCOONH –10%
CAN,
DDQ,
and TFA,
which gave no
4
[14]
Pd/C
deprotection at N-3 is preferable to that of at N-1; the preference at the
-position of deprotection is because of a more stable N-1-benzyl than that
at the 3-position. The alkylation gave the target compounds 9a and 9b in
afforded the pyrimidine 8 in 60% yield. It is noteworthy that the
3
[15]
6
7% and 71% yields, respectively, using standard conditions.
The compounds 3–5 and 7–9 were tested for antiviral activity against
HIV-1 RT using HIV antigen detection ELISA; only compounds 5
IC50 ¼ 26 mM), 9a (IC ¼ 30 mM), and 9b (IC ¼ 20 mM) showed
(
50
50
higher activity against HIV-1 RT than reference compound HEPT
IC50 ¼ 53 mM) but lower than nevirapine (IC50 ¼ 2 mM).
(
EXPERIMENTAL
Reactions were monitored by thin-layer chromatography (TLC). NMR spectra
1
were recorded on a JNM-AL-300 NMR spectrometer at 300 MHz for H NMR
1
3
and 75 MHz for C NMR with TMS as the internal standard. Mass spectra
were obtained, and the ionization methods used for the mass spectrometry
were desorption electron impact-ionization (EI). Melting points were deter-
mined on a X -type melting-point apparatus. IR was recorded on an Avatar
4
3
60 FT-IR spectrometer. Elemental analyses were performed on a Vario EL
III and were within +0.4% of the theoretical values. THF was distilled
from sodium/benzophenone prior to use. DMF and CH CN were dried and
freshly distilled over CaH2.
3
5
-Hydroxymethyl-6-methyluracil (2)
5
Ba(OH)2 8H O (1.5 g, 36.0 mmol) in water (20 mL). A solution of 37%
-Methyluracil (2.0 g, 15.9 mmol) was added to a filtered solution of
.
2

2
916
Y. Chen et al.
aqueous formaldehyde (4.1 mL, 54 mmol) was added, and the reaction
mixture was refluxed for a few minutes to dissolve the 6-methyluracil. The
reaction mixture was allowed to stir for 24 h at room temperature, and CO2
(
gas) was bubbled into the reaction mixture to precipitate BaCO . After fil-
3
tration, the water was evaporated, and the viscous residue was dissolved at
reflux in EtOH (20 mL). The desired product crystallized at room temperature
[
16]
as a pure white solid 2 (1.97 g, 80%); mp .3008C (lit.
mp .3008C). IR
H NMR (DMSO-d6):
2
1
1
(
KBr): 3414, 2933, 1704, 1665, 1447 cm
.
d ¼ 10.94 (s, IN, N3-H), 10.74 (s, 1H, NI-H), 4.52 (s, 1H, OH), 4.14
1
3
(
s, 2H, CH ), 2.12 (s, 3H, CH ). C NMR (DMSO-d ): d ¼ 64.2, 151.4,
2
3
6
1
50.9, 109.2, 62.8, 15.8. MS (EI, 70 eV): m/z (%) ¼ 127 (39), 138 (100),
þ
1
55 (38), 156 (70) [M ].
5
-Benzyloxymethyl-6-methyluracil (3)
A suspension of 5-hydroxymethyl-6-methyluracil 2 (2.0 g, 12.8 mmol) and
aqueous HCl (1 mL) in benzyl alcohol (50 mL) was refluxed for 1 h,
resulting in the formation I of a clear solution. After being cooled to
room temperature, the reaction mixture was poured into ether (250 mL).
The resulting fine precipitate was filtered and washed several times with
ether to give the pure product 3 (2.51 g, 80%); mp . 3008C. IR (KBr):
2
1
1
3
433. 1721, 1643, 1447, 1071 cm
.
s, IH, N3-H), 10.90 (s, lH, N1-H), 7.31 (s, 5H, Ph-H), 4.49 (s, 2H,
H NMR (DMSO-d ): d ¼ 11.04
6
(
CH ), 4.22 (s, 2H, CH ), 2.10 (s, 3H, CH ). C NMR (DMSO-d6):
1
3
2
2
3
d ¼ 164.1, 153.0, 150.8, 138.6, 128.2, 127.6, 127.4, 105.9, 71.2, 61.8,
1
5.9. MS (EI, 70 eV): m/z (%) ¼ 140 (100), 155 (5), 247 (0.25)
þ
[M þ H ]. Anal. calcd. for C H N O : C, 63.40; H, 5.73; N, 11.38.
Found: C, 63.20; H, 5.67; N, 11.15.
1
3 14 2 3
1,3-Dibenzyl-5-benzyloxymethyl-6-methyluracil (4)
A suspension of 5-benzyloxymethyl-6-methyluracil 3 (3.0 g, 12.2 mmol) in
dry DMF (40 mL) was treated portionwise with sodium hydride (1.16 g,
2
9.0 mmol, 60% in oil). After the end of gas evolution, the reaction mixture
was stirred for 1 h at room temperature and benzyl bromide (3.5 mL,
6.5 mmol) was slowly added. The reaction mixture was poured into water
120 mL), and the solvent was evaporated using a rotatory evaporator and
then a vacuum pump (0.1 mmHg). The residue was dissolved in EtOAc
60 mL) and was washed with water (30 mL). The aqueous phase was
2
(
(
extracted with EtOAc (2 ꢀ 25 mL), and the combined organic phase was
washed with brine and dried (MgSO ). After evaporation of the solvent, the
4
crude residue was purified by chromatography [petroleum ether

1-(Alkoxymethyl)-5-benzyl-6-methyluracil
2917
(60–908C)–EtOAc, 4:1], providing the desired product 4 (2.95 g, 57%) as
colorless oil.
2
1 1
IR (KBr): 3432, 1700, 1649, 702 cm . H NMR (CDCl ): d ¼ 7.51–
3
7
.11 (m, 15H, 3Ph-H), 5.19 (s, 2H, N3-CH ), 5.13 (s, 2H, N1-CH ), 4.53
2
2
(
s, 2H, CH ), 4.43 (s, 2H, CH ), 2.20 (s, 3H, CH ). MS (EI, 70 eV): m/z
2 2 3
þ
(
%) ¼ 91 (100), 299 (28), 320 (22), 321 (3), 427 (1) [M þ H ].
-Bromomethyl-1,3-dibenzyl-6-methyluracil (5)
5
Dry 1,4-dioxane (7.85 mL) and 33% HBr-AcOH (3.7 mL 9.7 mmol) were
added to 1,3-dibenzyl-5-benzyloxy-6-methyluracil 4 (2.0 g, 4.69 mmol),
resulting in the formation of a clear solution. The reaction mixture was
stirred for 12 h at room temperature, and the solvent was removed by
vacuum to afford an oily residue that crystallized after the addition of a few
drops of ether. It was filtrated and washed with ether (1.5 mL) to give
product 5 (1.1 g, 59%), which was analytically pure; mp 89–918C. IR
2
1
(
KBr): 3429, 1701, 1649, 1455, 699 cm
1
.
H NMR (CDCl ): d ¼ 7.52–7.12 (m, 10H, Ph-H), 5.20 (s, 2H, N3-CH ),
3
2
5
.19 (s, 2H, Nl-CH ), 4.46 (s, 2H, CH ), 2.27 (s, 3H, CH ). Ms (EI, 70 eV): m/
2 2 3
þ
z (%) ¼ 91 (100), 319 (17), 399 (0.1) [M þ H ].
The Zinc Reagent (6)
A dry 50-mL three-necked flask equipped with a nitrogen inlet, a nitrogen
venthole, and a thermometer was charged with zinc dust (0.85 g, 13.1 mmol).
The flask was flushed with nitrogen, and 1,2-dibromoethane (0.038 mL) in
THF (1 mL) was added. The zinc suspension was heated three times to
reflux with a heat gun for ca. 30 s and was allowed to cool to room tempera-
ture. TMSCl (0.13 mL) was added, and the reaction mixture was stirred for
5
min and cooled to 08C with an ice bath. The 5-bromomethyl-1,3-
dibenzyl-6-methyluracil 5 (1.45 g, 3.6 mmol) in THF: (6 mL) was slowly
added using a syringe pump (1 drop every 5 s), and the reaction mixture
was stirred for another 30 min at room temperature after the end of the
addition. After completion of the reaction, THF (6 mL) was added, and the
zinc was allowed to settle for 1–2 h at rt.
1
,3,5-Tribenzyl-6-methyluracil (7)
A dry three-necked flask equipped with a nitrogen inlet, a nitrogen venthole,
and thermometer was charged with Pd-(dba) (19.2 mg, 0.9 mol%) and tfp
2
(15.33 mg, 1.8 mol%) followed by THF (1.7 mL). The initial red color dis-
appeared after 1 min, leading to a yellow solution. The PhI (0.15 mL) was

2
918
Y. Chen et al.
added followed by the compound 6 obtained in foregoing reaction. The
reaction mixture was stirred for 12 h at room temperature and worked up by
pouring in aqueous saturated NH Cl solution and extracting with EtOAc.
4
The organic phase was washed with brine and dried (MgSO ), and the
4
residual oil obtained after evaporation of the solvent was purified by flash
chromatography [petroleum ether (60–908C)/EtOAc, 5:1] to give the
product 7 as a pale yellow oil (0.43 g, 30%).
1
H NMR (CDCl ): d ¼ 7.52–7.12 (m, 15H, Ph-H), 5.22 (s, 2H, N3-CH ),
3
2
5
.16 (s, 2H, N3-CH ), 3.85 (S, 2H, CH ), 2.15 (s, 3H, CH ). MS (EI, 70 eV):
2 2 3
þ
m/z (%) ¼ 91 (100), 305 (82), 396 (73), 397 (15) [M þ H ].
-Benzyl-6-methyluracil (8)
HCO NH (0.66 g, 10.5 mmol), dry methanol (6 mL), and 10% Pd/C (0.8 g)
5
2
4
were added to compound 7 (0.23 g, 0.58 mmol). The mixture was allowed
reflex for 5 days. It was then cooled to room temperature and passed
through celite, washing extensively with methanol. Removal of MeOH and
purification by column chromatography using CHCl -MeOH (9:1) as
3
solvent for elution afforded 8 (75.3 mg, 60%) as white solid; mp 221–2228C.
21 1
IR (KBr): 3428, 2927, 1732, 1636, 530 cm . H NMR (DMSO-d ):
6
d ¼ 11.02 (s, 1H, N3-H), 10.74 (s, IH, Nl-H), 7.27–7.15 (m 5H, Ph-H),
1
3
2
.58 (s, 2H, CH ), 2.09 (s, 3H, CH ). C NMR (DMSO-d ): d ¼ 164.5,
2
3
6
1
50.8, 149.1, 140.3, 128.3, 127.9, 125.8, 108.1, 29.2, 16.2. MS (EI, 70 eV):
þ
m/z (%) ¼ 91 (32), 215 (50), 216 (100), 217 (18) [M þ H ]. Anal. calcd.
for C H N O : C, 66.65; H, 5.59; N, 12.96. Found: C, 66.30; H, 5.67; N,
1
2 12 2 2
12.65.
1-(Ethoxymethyl)-5-benzyl-6-methyluracil (9a)
Compound 8 (15 mg, 0.07 mmol) was suspended in CH CN (1 mL), and
3
bis(trimethylisily)acetamide (BSA) (38 mL, 0.16 mmol) was added to the
suspension. The mixture became clear after stirring at room temperature
for 10 min. Chloromethyl ethyl ether (14 mL, 0.08 mmol) was added to
the solution, and stirring continued until no change in the amount of the
starting material could be noticed on TLC. After evaporation of the
solvent in vacuo, the resulting syrup was purified by column chromato-
graphy using CHCl -MeOH (9:1) to afford 9a (12.8 mg, 67%) as white
3
crystals; mp 101–1028C.
1
H NMR (CDCl ): d ¼ 9.13 (s, 1H, N3-H), 7.30–7.16 (m, 5H, Ph-H),
3
5
.33 (s, 2H, CH ), 3.82 (s, 2H, CH ), 3.65 (q, J ¼ 6.9 Hz, 2H, CH ), 2.35
3 3 3
2
2
2
1
3
(
s, 3H, CH ), 1.20 (t, J ¼ 6.9 Hz, 3H, CH ). C NMR (CDCl ): d ¼ 163.3,
1
51.6, 150.6, 139.3, 128.5, 128.0, 126.2, 112.5, 73.1, 64.9, 30.7, 15.7, 15.1.
MS (EI, 70 eV): m/z (%) ¼ 59 (100), 215 (52), 274 (70), 275 (15)

1-(Alkoxymethyl)-5-benzyl-6-methyluracil
2919
þ
[
M þ H ]. Anal. calcd. for C H N O : C, 65.68; H, 6.61; N, 10.22. Found:
1
5 18 2 3
C, 65.49; H, 6.80; N, 9.88.
l-(Benzyloxymethyl)-5-benzyl-6-methyluracil (9b)
Compound 8 (16.2 mg, 0.075 mmol) was suspended in CH CN (1 mL), and
3
bis(trimethylisily)acetamide (BSA) (41 mL, 0.17 mmol) was added to the
suspension. The mixture became clear after stirring at room temperature for
1
0 mm. Chloromethyl benzyl ether (17 mL, 0.08 mmol) was added to the
solution, and stirring continued until no change in the amount of the
starting material could be noticed on TLC. After evaporation of the solvent
in vacuo, the resulting syrup was purified by column chromatography using
CHCl -MeOH (9:1) to afford 9b (19.4 mg, 77%) as white crystals; mp
3
1
52–1538C.
IR (KBr): 3434, 1668, 1461 cm . H NMR (CDCl ): d 9.24 (s, 1H, N3-
H), 7.37–7.16 (m, 10H, Ph-H), 5.43 (s, 2H, CH ), 4.66 (s, 2H, CH ), 3.80
2
1 1
3
2
2
1
3
(s, 2H, CH ), 2.34 (s 3H CH ). C NMR (CDCl ): d 163.2, 151.6, 150.4,
2 3 3
1
3
39.2, 137.1, 128.7, 128.5, 128.4, 128.0, 127.7, 126.2, 112.6, 73.1, 71.7,
0.6, 15.8 MS (EI, 70 eV): m/z (%) ¼ 77 (16), 91 (100), 215 (38), 336
þ
(17), 337 (4) [M þ H ]. Anal. calcd. for C H N O : C, 71.41; H, 5.99; N,
2
0 20 2 3
8
.33. Found: C, 71.17; H, 6.00; N, 7.95.
ACKNOWLEDGMENTS
This research was supported by the 985 program of the Ministry of Education
of China.
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