Synthesis of annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442) using 1,3-oxazine-2,4(3H)-diones as key intermediates

Article abstract of DOI:10.1039/b005282p

Condensation of ethyl 3-phenyl-2-oxocyclopentanecarboxylate 5 with 2-(S-methylthio)isourea followed by hydrolysis with HC1 gave 6,7-dihydro-7-phenylcyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (10a). 7,8-Dihydro-8-phenyl-6H-cyclohexa[e][1,3]oxazine-2,4(3H,5H)-dione (10b) was synthesised by reacting 2-phenylcyclohexanone (9b) with N-(chlorocarbonyl) isocyanate. The oxazines 10a,b were reacted with ammonia to obtain the corresponding uracil derivatives 12a,b which after silylation were alkylated with diethoxymethane using trimethylsilyl triflate (TMS-triflate) as the catalyst or alkylated with chloromethyl ethyl ether to give annelated MKC-442 analogues 2,3 which are locked in a conformation close to the one of MKC-442. In spite of this, only moderate activities were found against HIV-1 for the annelated analogues of MKC-442. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b005282p

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Synthesis of annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-
isopropyluracil (MKC-442) using 1,3-oxazine-2,4(3H)-diones as
key intermediates
1
Janus S. Larsen,a Lene Christensen,a Gitte Ludvig,a Per T. Jørgensen,a Erik B. Pedersen*a
and Claus Nielsenb
a Department of Chemistry, University of Southern Denmark, Campusvej 55,
DK-5230 Odense M, Denmark
b Retrovirus Laboratory, Department of Virology, State Serum Institute, Artillerivej 5,
DK-2300 Copenhagen, Denmark
Received (in Cambridge, UK) 3rd July 2000, Accepted 17th July 2000
Published on the Web 18th August 2000
Condensation of ethyl 3-phenyl-2-oxocyclopentanecarboxylate 5 with 2-(S-methylthio)isourea followed by hydrolysis
with HCl gave 6,7-dihydro-7-phenylcyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (10a). 7,8-Dihydro-8-phenyl-6H-
cyclohexa[e][1,3]oxazine-2,4(3H,5H)-dione (10b) was synthesised by reacting 2-phenylcyclohexanone (9b) with
N-(chlorocarbonyl) isocyanate. The oxazines 10a,b were reacted with ammonia to obtain the corresponding
uracil derivatives 12a,b which after silylation were alkylated with diethoxymethane using trimethylsilyl triflate
(TMS-triflate) as the catalyst or alkylated with chloromethyl ethyl ether to give annelated MKC-442 analogues 2,3
which are locked in a conformation close to the one of MKC-442. In spite of this, only moderate activities were
found against HIV-1 for the annelated analogues of MKC-442.
Introduction
Since the synthesis of 1-[(2-hydroxyethoxy)methyl]-6-(phenyl-
thio)thymine (HEPT) by Miyasaka et al.1 in 1989, there has
been a growing interest in nonnucleoside reverse transcriptase
inhibitors. Although HEPT did not show very high activity
against HIV-1 it was considered an interesting lead compound
for the synthesis of new analogues, among them the 6-benzyl-1-
(ethoxymethyl)-5-isopropyluracil (MKC-442) 1.2 This com-
Fig. 1 1 Crystal structure of MKC-442 when bound to RT. 2 Struc-
pound showed high activity against HIV-1 and was chosen as
ture of cyclohexane-annelated MKC-442 analogue. 3 Structure of
a candidate for clinical trials with AIDS patients.3 MKC-442
cyclopentane-annelated MKC-442 analogue.
inhibits reverse transcriptase (RT) of the HIV-1 virus alloster-
ically, as it binds to the enzyme in a hydrophobic pocket outside
the active site and thereby changes the conformation of the
active site, making RT inactive. The inhibitor is mainly held in
place in the pocket by hydrogen bonds and hydrophobic bonds
to the nearby amino acids.
would be a key intermediate as in the synthesis of MKC-442 by
Danel et al.6 2-Phenyladipic acid 4 was prepared in 64% yield
according to the method of Baker and Jones7 by reaction of
phenylacetonitrile with diethyl carbonate under alkaline con-
ditions, followed by addition of 4-chlorobutyronitrile and
hydrolysis with conc. HCl. Compound 4 was reacted with
EtOH and H2SO4 to give the corresponding diester which was
then ring closed in a Dieckmann reaction to afford ethyl
3-phenyl-2-oxocyclopentanecarboxylate (5) using the same
conditions as Clark and Howes8 used in the synthesis of the
corresponding m-methoxy derivative (Scheme 1).
Compound 5 was reacted with thiourea and sodium in EtOH
using the method of Danel et al.6 to give the 2-thio analogue 6
in only 4% yield. In an attempt to obtain a better yield, the
reaction was carried out in different solvents (MeOH and
EtOH) and bases (NaH and tBuOK), but without any success.
In an alternative route compound 5 was reacted with guanidine
carbonate9 in EtOH to give the 2-amino-7-phenyl-6,7-dihydro-
5H-cyclopenta[d]pyrimidin-4(3H)-one 7, but again in a poor
yield (11%), indicating that the cyclic β-keto ester 5 was quite
unreactive towards nucleophiles and therefore this strategy was
abandoned without further optimisation.
Structure–activity relationships (SAR) studies of HEPT-
derivatives have shown, that an ethyl or isopropyl group in the
C-5 position of the pyrimidine ring is important for antiviral
activity.4 This substituent forces Tyr 181 of the enzyme to make
a 180Њ rotation and thereby making it favourable for interaction
with the 6-benzyl group of the inhibitor. In this paper we
investigate the effect of fixing the orientation of the phenyl
group in MKC-442 by synthesising annelated compounds 2 and
3 with rigid structures to fix the position of the aromatic ring.
The crystal structure of MKC-442 bound in the RT5 (Fig. 1)
makes it likely that the position of the aromatic ring and angle
to the plan of the pyrimidine ring in MKC-442 and in the two
annelated analogues are very similar. It was therefore interest-
ing to find out whether fixing the orientation of the aromatic
ring in an MKC-442 type structure, could improve the activity
against HIV-1.
The difficulties in the above mentioned reactions made us
look for an alternative synthetic route. Ross et al.10 have shown
that reasonable yields of 2-amino-1,3-oxazine-4(3H)-ones
were obtained by reaction of 2-(S-methylthio)isourea with non-
Results and discussion
In order to synthesise the cyclopentane annelated compound 3,
a conventional route was chosen in which the β-keto ester 5
DOI: 10.1039/b005282p
J. Chem. Soc., Perkin Trans. 1, 2000, 3035–3038
This journal is © The Royal Society of Chemistry 2000
3035

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Scheme 1
cyclic β-keto esters in aqueous KOH. The reaction of 5 under
conditions,15 using trimethylsilyl trifluoromethanesulfonate
(TMS-triflate) as a Lewis acid catalyst. This gave 3 in 67% yield
(Scheme 3).
the same conditions gave 51% yield of 2-amino-7-phenyl-6,7-
dihydrocyclopenta[e][1,3]oxazin-4(5H)-one 8 which was easily
converted to the corresponding 7-phenyl-6,7-dihydrocyclo-
penta[e][1,3]oxazine-2,4(3H,5H)-dione 10a by treatment with 3
M HCl under reflux (Scheme 2).
Scheme 3
Compound 12b was silylated using N,O-bis(trimethylsilyl)
acetamide (BSA) in CHCl3 followed by coupling with chloro-
methyl ethyl ether6 to give 2 in 53% yield.
Scheme 2
Biological activity
The compounds 2,3,6–8,10–12 were tested for their activity
against HIV-1 in MT-4 cells using HIV antigen detection
ELISA for quantifying expression of HIV in culture medium.
Only compound 2 (ED50 = 29 µM, CD50 > 100 µM) and 3
(ED50 = 36 µM, CD50 > 100 µM) showed activity against
HIV-1, but at considerably higher concentrations than the
reference compound MKC-442 (ED50 = 0.005 µM).
The cyclohexyl annelated compound 2 was synthesised via
the 1,3-oxazine-2,4(3H)-dione 10b as intermediate but using
another synthetic pathway for the intermediate. The com-
mercially available 9b was reacted with N-(chlorocarbonyl)
isocyanate11 to give a mixture of products 10b and 11 in 30%
and 25% yield, respectively. 2-Phenylcyclopentanone 9a could
likewise be used for the synthesis of 10a and was easily obtained
by reacting cyclopentanone with phenylmagnesium bromide
followed by treatment with sulfuric acid to give 1-phenylcyclo-
pentene,12 which was oxidized using formic acid and hydrogen
peroxide.13 Unfortunately, the reaction of 9a with N-(chloro-
carbonyl)isocyanate gave 10a in 12% yield, only.
In order to synthesise the N-1 substituted uracils 2 and 3,
the oxazines 10a,b were reacted with concentrated aqueous
ammonia to give 12a,b in 73% and 100% yield, respectively.14
Compound 12a was then silylated with 1,1,1,3,3,3-hexa-
methyldisilazane (HMDS) in the presence of (NH4)2SO4 and
reacted with diethoxymethane under standard Vorbrüggen
Conclusion
We have developed new routes for the synthesis of the target
compounds 2 and 3 as the already known procedures gave very
low yields. The target compounds were synthesised from the
corresponding 1,3-oxazine-2,4(3H)-diones which were syn-
thesised using two new strategies. Unfortunately the annelated
compounds did not show antiviral activities in the nanomolar
range as does MKC-442 and therefore we conclude that these
compounds are not able to induce the Tyr 181 switch.
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J. Chem. Soc., Perkin Trans. 1, 2000, 3035–3038

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2-Amino-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazin-4(5H)-
one 8
Experimental
1H NMR spectra were recorded on a Varian Gemini 2000
NMR spectrometer at 300 MHz for H and 62.9 MHz for 13C
1
2-(S-Methylthio)isourea (1.36 g, 9.77 mmol) was dissolved in
10 mL H2O and 1.15 g (20.5 mmol) KOH was added. Under
stirring 2.03 g (9.74 mmol) ethyl 3-phenyl-2-oxocyclopentane-
carboxylate 5 was added and the inhomogenous mixture was
stirred for 18 h at room temp. The mixture was filtered and the
solid was washed with H2O and Et2O. White crystals (0.99 g,
with TMS as an internal standard. EI mass spectra were
recorded on a Finnigan MAT SSQ 710. FAB mass spectra were
recorded on a Kratos MS 50 RF. Thin-layer chromatography
(TLC) analyses were carried out on TLC plates 60 F254 and
for preparative TLC silica gel 60 PF254/366 were used, both
purchased form Merck and were visualized with UV-light. The
silica gel (0.040–0.063 mm) used for column chromatography
was purchased from Merck. Microanalyses were carried out at
the H. C. Ørsted Institute, Copenhagen. Preparative HPLC was
performed on a Waters Delta Pak 300 A, 10 µm 305 × 7 mm
semi-prep HPLC column.
1
51%); mp 208–210 ЊC; H NMR (DMSO): δ = 1.87 (1H, m,
Ha-6), 2.59 (3H, m, Hb-6, H-5), 3.17 (1H, s, H-7), 4.30 (2H, m,
NH2), 7.22–7.69 (5H, m, Ph). 13C NMR (DMSO): δ = 24.70
(C-5), 30.11 (C-6), 48.33 (C-7), 116.08 (C-4a), 127.07, 127.50,
128.83, 141.24 (Ph), 160.33 (C-2), 164.52 (C-7a), 167.24 (C-4);
MS (EI) m/z 228 (Mϩ).
7-Phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-
dione 10a
Ethyl 3-phenyl-2-oxo-cyclopentanecarboxylate 5
Na (3.79 g, 0.165 mol) Na was dissolved in 100 mL absolute
EtOH and the excess EtOH was removed in vacuo, 200 mL dry
toluene and 23.0 g (0.099 mol) diethyl 2-phenyladipate were
added under N2. The mixture was refluxed for 1 week and after
cooling to room temp. the mixture was acidified with acetic acid
to pH 5. The organic fraction was washed with H2O and
NaHCO3 and dried over Na2SO4. The product was an orange
2-Amino-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazin-4(5H)-
one 8 (0.27 g, 12.1 mmol) was dissolved in 8 mL 3 M HCl under
stirring. The heterogeneous mixture was heated to reflux for 1 h,
then cooled and filtered. The solid was washed well with H2O
1
(0.19 g, 69%); mp >240 ЊC; H NMR (DMSO): δ = 1.89 (1H,
m, Ha-6), 2.54 (3H, m, Hb-6, H-5), 4.26 (1H, m, H-7), 7.23–7.36
(5H, m, Ph), 11.76 (1H, s, NH). 13C NMR (DMSO): δ = 23.73
(C-5), 30.52 (C-6), 48.52 (C-7), 112.62 (C-4a), 127.39, 127.86,
1
oil (12.8 g, 67%); H NMR (CDCl3): δ = 1.31 (3H, m, CH3),
2.30 (4H, m, 2 × CH2), 3.41 (2H, m, 2 × CH), 4.23 (2H, m,
CH2), 7.18–7.38 (5H, m, Ph). 13C NMR (CDCl3): δ = 13.95
(CH3), 24.83 (CH2), 29.06 (CH2), 53.80 (CH), 55.02 (CH), 61.32
(CH2O), 127.13, 128.10, 128.61, 138.14 (Ph), 169.33 (COOEt),
128.95, 140.61 (Ph), 149.40 (C᎐O), 161.05 (C᎐O), 168.24
᎐
᎐
(C-7a); C13H11NO3 (229.24): Calc. C, 68.11; H, 4.84; N, 6.11.
Found: C, 67.89; H, 4.90; N, 5.78%; MS (EI) m/z: 229 (Mϩ).
210.15 (C᎐O); MS (EI) m/z 232 (Mϩ).
᎐
General procedure for preparation of annelated-1,3-oxazine-
2,4(3H)-diones 10a and 10b
1,2,6,7-Tetrahydro-7-phenyl-2-thioxo-5H-cyclopenta[d]-
pyrimidin-4(3H)-one 6
The appropriate ketone (10 mmol) was mixed with 12 mmol of
N-(chlorocarbonyl) isocyanate in a 100 ml 3-necked flask fitted
with a septum, a condenser and the mixture was heated at 58 ЊC
for 1 h under a nitrogen atmosphere. After additional heating at
130 ЊC for 2 h and cooling to room temperature, the mixture
was taken up in 100 ml EtOAc and the organic phase was
washed with sat. aq. NaHCO3, (2 × 50 ml to remove traces of
HCl) followed by washing with 2 × 50 ml H2O. The organic
phase was dried (Na2SO4) and evaporated in vacuo to an oily
product which was purified by silica gel column chrom-
atography with EtOAc–petroleum ether (60–80 ЊC) 1:1 to give
the products 10 and 11.
Na (0.5 g, 21.6 mmol) Na was dissolved in 30 mL 99.9% EtOH.
Ethyl 3-phenyl-2-oxocyclopentanecarboxylate 5 (1.00 g, 4.30
mmol) was added together with 1.31 g (17.2 mmol) thiourea
and the mixture was refluxed for 22 h. EtOH was removed in
vacuo and the remaining solid was dissolved in 20 mL H2O. The
solution was acidified with conc. HCl and extracted with Et2O
(3 × 10 mL), dried (Na2SO4) and evaporated in vacuo. The
resulting oil was purified by column chromatography (10%
ethyl acetate in petroleum ether→ethyl acetate) and followed by
preparative TLC (50% ethyl acetate in petroleum ether) which
1
gave an orange oil (0.047 g, 4%); H NMR (DMSO): δ = 1.46
(2H, m, H-5), 2.58 (2H, m, H-6), 4.07 (1H, m, H-7), 7.14–7.40
(5H, m, Ph). 13C NMR (DMSO): δ = 25.22 (C-5), 31.49 (C-6),
49.36 (C-7), 115.24 (C-4a), 126.35, 127.26, 128.51, 142.44 (Ph),
160.19 (C-7a), 160.75 (C-4), 176.51 (C-2); MS (EI) m/z 244
(Mϩ).
7-Phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-
dione 10a. (0.22g, 12%) Spectral data and melting point were
the same as above where 10a was prepared from 8.
7,8-Dihydro-8-phenyl-6H-cyclohexa[e][1,3]oxazine-
2,4(3H,5H)-dione 10b. White solid (1.22 g, 30%); mp 181–
183 ЊC; 1H NMR (CDCl3): δ = 1.70 (2H, m, 2 × H-6), 1.85 (2H,
m, 2 × H-5), 2.50 (2H, m, 2 × H-7), 3.80 (1H, m, H-8), 7.20–
7.47 (5H, m, Ph), 9.54 (1H, br s, NH). 13C NMR (CDCl3):
δ = 18.03 (C-6), 20.63 (C-7), 31.71 (C-5), 43.03 (C-8), 111.32
(C-4a), 128.21, 129.33, 130.51, 140.17 (Ph), 147.81 (C-2), 163.15
(C-8a), 163.88 (C-4); MS (EI) m/z 243 (Mϩ); C14H13NO3
(243.26): Calc. C, 69.12; H, 5.39; N, 5.76. Found: C, 69.21; H,
5.42; N, 5.59%.
2-Amino-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-
4(3H)-one 7
Ethyl 3-phenyl-2-oxocyclopentanecarboxylate 5 (2.20 g, 9.47
mmol) and 1.71 g (9.49 mmol) guanidine carbonate were
dissolved in 10 mL 99.9% EtOH and refluxed for 18 h. EtOH
was evaporated in vacuo. The resulting brown oil was dissolved
in 10 mL H2O and the solution was neutralised with ice cold
acetic acid. An orange solid precipitated and was further puri-
fied by recrystallisation from EtOH (0.23 g, 11%); mp >240 ЊC
1
(decomp.); H NMR (DMSO): δ = 1.80 (1H, m, Ha-6), 2.52
6,7-Dihydro-4a-phenyl-5H-cyclohexa[e][1,3]oxazine-2,4(3H,
1
(3H, m, Hb-6, H-5), 3.97 (1H, t, J = 7.47 Hz, H-7), 6.40 (2H, s,
NH2), 7.10–7.28 (5H, m, Ph), 10.64 (1H, s, NH). 13C NMR
(DMSO): δ = 25.43 (C-5), 32.01 (C-6), 52.08 (C-7), 111.53
(C-4a), 126.26, 128.11, 128.40, 144.17 (Ph), 156.59 (C-2),
160.96 (C-7a), 172.24 (C-4); C13H13N3Oؒ0.2H2O (230.87):
Calc. C, 67.63; H, 5.85; N, 18.20. Found: C, 67.85; H, 5.73; N,
17.85%; MS (EI) m/z 227 (Mϩ).
4aH)-dione 11. White solid (1.09 g, 25%); mp 134–137 ЊC; H
NMR (CDCl3): δ = 1.28 (2H, m, CH2), 1.53 (2H, m, CH2),
2.20–2.45 (2H, m, CH ), 6.01 (1H, t, J 2.0 Hz, CH᎐), 7.33–7.47
᎐
2
(5H, m, Ph), 8.62 (1H, br s, NH). 13C NMR (CDCl3): δ = 16.82
(C-6), 23.13 (C-7), 33.58 (C-5), 49.33 (C-4a), 115.81 (C-8),
127.76, 128.22, 129.12, 137.39 (Ph), 143.93 (C-2), 147.58 (C-8a),
171.04 (C-4); MS (EI) m/z 243 (Mϩ).
J. Chem. Soc., Perkin Trans. 1, 2000, 3035–3038
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7-Phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4(1H,
3H)-dione 12a. 7-Phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-
2,4(3H,5H)-dione 10a was dissolved in 4.5 mL 12 M NH4OH.
The mixture was refluxed for 18 h, cooled and filtered and the
solid was washed well with H2O (71 mg, 73%); mp >250 ЊC;
1H NMR (DMSO): δ = 1.85 (1H, m, Ha-6), 2.55 (3H, m, Hb-6,
H-5), 4.14 (1H, d, J 7.3 Hz, H-7), 7.17–7.37 (5H, m, Ph), 10.88
(1H, s, NH), 10.96 (1H, s, NH). 13C NMR (DMSO): δ = 25.46
(C-5), 32.24 (C-6), 49.18 (C-7), 110.92 (C-4a), 127.03, 127.53,
128.81, 142.10 (Ph), 152.71 (C-7a), 156.86 (C-2), 162.44 (C-4);
C13H12N2O2ؒ0.2H2O (231.85): Calc. C, 67.35; H, 5.39; N, 12.08.
Found: C, 67.63; H, 5.18; N, 11.97%; MS (EI) m/z 228 (Mϩ).
(1.33 mmol), 5 mL HMDS and 5 mg (NH4)2SO4 was heated
under reflux for 2 h. The mixture was allowed to cool to room
temp. and the excess HMDS was removed in vacuo. The result-
ing oil was dissolved in 5 mL dry acetonitrile and the mixture
was stirred at Ϫ35 ЊC. TMS-triflate (0.22 mL, 1.22 mmol) was
added to the solution, followed by dropwise addition of
diethoxymethane (13.2 mmol). The mixture was stirred for 3 h
and 5 mL ice cold saturated aqueous NaHCO3 was added. The
solution was coevaporated with 2 × 25 mL EtOH to almost
dryness. The resulting solid was dissolved in 100 mL dry Et2O
and stirred for 1 h. The solution was filtered and the organic
phase was dried (Na2SO4) and purified either by silica column
chromatography (2% MeOH in CH2Cl2); White solid (0.26 g,
67%); mp 140–143 ЊC; 1H NMR (DMSO): δ = 1.06 (3H, t,
J 7.1 Hz, CH3), 1.80 (1H, m, Ha-6), 2.58 (3H, m, Hb-6, H-5),
3.38 (2H, m, CH2), 4.36 (1H, d, J 10.5 Hz, NCH2), 4.47 (1H, d,
J 7.2 Hz, H-7), 5.12 (1H, d, J 10.3 Hz, NCH2), 7.17–7.37 (5H,
m, Ph), 11.33 (1H, s, NH). 13C NMR (DMSO): δ = 14.48
(CH3), 25.28 (C-5), 32.69 (C-6), 49.12 (C-7), 63.50 (CH2), 72.04
(CH2), 114.24 (C-4a), 126.85, 127.06, 128.18, 141.68 (Ph),
152.62 (C-2), 156.26 (C-7a), 161.30 (C-4); MS (EI) m/z: 286
(Mϩ).
5,6,7,8-Tetrahydro-8-phenylcyclohexa[d]pyrimidine-2,4(1H,
3H)-dione 12b. 5,6,7,8-Tetrahydro-8-phenyl-2H-cyclohexa[e]-
[1,3]oxazine-2,4(3H)-dione 10b (1.20 g, 4.9 mmol) was sus-
pended in 50 ml of conc. NH4OH and the mixture was refluxed
overnight. Evaporation of the solvent in vacuo and subsequent
washing with Et2O (50 ml) gave 12b in 100% yield; mp 191–
193 ЊC; 1H NMR (DMSOd-6): δ = 1.25–2.50 (6H, m, H-5, H-6,
H-7), 3.75 (1H, m, CHPh), 7.25 –7.41 (5H, m, Ph), 10.20 (1H, s,
NH), 10.95 (1H, s, NH). 13C NMR (DMSO-d6): 16.38 (C-6),
20.62 (C-7), 30.67 (C-5), 41.68 (C-8), 108.06 (C-4a), 126.61,
128.10, 142.42 (Ph), 148.70 (C-8a), 151.15 (C-2), 164.65 (C-4);
MS (EI) m/z 242 (Mϩ).
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1-Ethoxymethyl-8-phenyl-5,6,7,8-tetrahydrocyclohexa[d]-
pyrimidine-2,4(1H,3H)-dione 2. To a suspension of 12b (0.55 g,
2.27 mmol) in dry CHCl3 was added N,O-bis(trimethylsilyl)-
acetamide (BSA) (0.56 ml, 4.54 mmol) and the stirring was
continued until all the starting material had dissolved. Then
(chloromethyl) ethyl ether (0.21 ml, 2.27 mmol) was added and
the reaction mixture was stirred until TLC showed no change in
amount of starting material. After evaporation of the solvent
in vacuo the product was chromatographed on a silica gel
column to obtain the pure N-1 alkylated product 2 as a yellow
solid (0.36 g, 53%); mp 201–206 ЊC; C17H20N2O3 (300.36): Calc.
C, 67.98; H, 6.71; N, 9.33. Found: C, 67.70; H, 6.87; N, 9.21%;
1H NMR (CDCl3): δ = 1.16 (3H, t, J 7 Hz, CH3), 1.52 (2H, m,
2 × H-6), 2.01 (2H, m, 2 × H-5), 2.46 (1H, m, H-7), 2.70 (1H,
m, H-7), 3.56 (2H, m, CH2O), 4.33 (1H, m, H-8), 4.50 (1H, d, J
11 Hz, NCH2), 5.43 (1H, d, J 11 Hz, NCH2), 7.10–7. 36 (5H, m,
Ph), 9.28 (1H, s, NH); 13C NMR (CDCl3): δ = 14.95 (CH3),
15.23 (C-6), 21.55 (C-5), 31.11 (C-7), 39.69 (C-8), 64.97
(OCH2), 71.78 (NCH2), 112.37 (C-4a), 127.35, 127.84, 129.09,
141.36 (Ph), 149.96 (C-8a), 152.02 (C-2), 163.50 (C-4); MS (EI)
m/z 300 (Mϩ).
13 P. H. Mazzocchi and C. H. Kim, J. Med. Chem., 1982, 25,
1473.
1-Ethoxymethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]-
pyrimidine-2,4(1H,3H)-dione 3. A mixture of 7-phenyl-6,7-
14 H. Skulnick and W. Wierenga, Heterocycles, 1985, 23, 1685.
15 H. Vorbrüggen, K. Krolikiewicz and B. Bennua, Chem. Ber., 1981,
114, 1234.
dihydro-5H-cyclopenta[d]pyrimidine-2,4(1H,3H)-dione
12a
3038
J. Chem. Soc., Perkin Trans. 1, 2000, 3035–3038