Synthesis of 1-substituted-6-methyluracils.

Article abstract of DOI:10.1248/cpb.51.1025

A series of 6-methyl-1H-pyrimidin-2,4-diones bearing different substituents in the 1-position of the uracil ring were prepared starting from substituted ureas and diketene.

Full text of DOI:10.1248/cpb.51.1025

September 2003
Chem. Pharm. Bull. 51(9) 1025—1028 (2003)
1025
Synthesis of 1-Substituted-6-methyluracils
Rosa Maria NIETO, Alberto COELHO, Ana MARTÍNEZ, Angela STEFANACHI, Eddy SOTELO, and
*
Enrique RAVIÑA
Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Farmacia, Universidade de
Santiago de Compostela; 15782 Santiago de Compostela, Spain. Received February 14, 2003; accepted June 18, 2003
A series of 6-methyl-1H-pyrimidin-2,4-diones bearing different substituents in the 1-position of the uracil
ring were prepared starting from substituted ureas and diketene.
Key words uracil; diketene; piperazine
logically active molecules.14,15)
One of the most important goals in organic and medicinal
The piperazine function allows the step-by-step introduc-
tion of pharmacophoric moieties—a characteristic that repre-
sents one of the main advantages of this system in Medicinal
Chemistry. Several drugs acting on the CNS (Fluanisone,
Trazodone) or cardiovascular system (Urapidil, Prazosin)
contain a piperazine subunit. In this regard Urapidil is an an-
tihypertensive agent that incorporates both uracil and piper-
azine groups.
chemistry is the design and synthesis of molecules that have
value as therapeutic agents. In this regard, heterocyclic com-
pounds have proven to be versatile support structures that
offer a high degree of structural diversity. Among these com-
pounds uracils, together with purines and indoles, are proba-
bly the most representative examples of the so-called “privi-
leged structures” due to their significative presence in natural
structures.1,2)
As part of our drug discovery program directed toward the
synthesis of new uracil-based biologically active compounds,
we have prepared several new 6-methyluracil derivatives
bearing substituents at position 1. These compounds are at-
tractive starting materials for the preparation of highly sub-
stituted and heterofused uracil derivatives.
1-Substituted-6-methyluracils 3 were prepared by follow-
ing the general synthetic strategy shown in Chart 1.15,16) Re-
gioselective condensation of monosubstituted ureas 1 with
diketene was accomplished in pyridine at 0 °C to afford the
corresponding 3-substituted 1-acetoacetylureas 2 in excellent
yields. These compounds were isolated and characterised
(see Experimental part).
The uracil nucleus is a fundamental constituent of a large
number of natural products that have strategical biological
functions. This observation could explain the wide range of
biological actions shown by uracil derivatives. A significative
number of reports describing the pharmacological actions of
these compounds have been published, and this structure still
continues to attract the attention of medicinal and organic
chemists.3,4) As a result of the high degree of activity in this
field, a large number of compounds containing the uracil
moiety have been developed as drugs (Fig. 1). A range of bi-
ological actions have been reported for these compounds and
some of the most representative examples are antineoplas-
tic,5) antihypertensive,6) anti-inflammatory,7) antiviral,8,9) or
reverse transcriptase inhibitors.10—13)
On the other hand, the importance of piperazines in the
field of Medicinal Chemistry is also widely recognised. Par-
ticularly in recent years the piperazinone ring system has at-
tracted a great deal of attention in the search for pep-
tidomimetic conformationally constrained structures in bio-
Chart 1
Fig. 1. Several Pharmacologically Useful Agents Containing Uracil and Piperazine Moieties
To whom correspondence should be addressed. e-mail: qofara@usc.es
© 2003 Pharmaceutical Society of Japan

1026
Vol. 51, No. 9
Table 1. 1-Substituted-6-methyluracils 3a—e
Entry
R
Yield (%)
mp (°C)
3a
3b
3c
3d
3e
MeOCH2CH2
MeOCH2CH2CH2
PhCH2CH2
2-Furfuryl
NH(CH2CH2)2NCH2CH2
93
97
93
91
85
121—122
125—126
205—206
146—147
117—119 (dec)
Chart 3
procedure using boron tribromide. Replacement of the halo-
gen on this compound by treatment with 1-(benzyloxycar-
bonyl)piperazine and removal of the protecting group by hy-
drogenolysis gave compound 3e.
Although these two synthetic routes do successfully lead
to compound 3e, the second pathway is a more general strat-
egy since it allows the efficient and quick synthesis of new
compounds by nucleophilic substitution of other piperazine
derivatives onto the 1-(2-bromoethyl)-6-methyl-1H-pyrimi-
dine-2,4-dione (9). The real value of the route shown in
Chart 2 is exemplified by the fact that these transformations
represent a model system that has been used during our cur-
rent research project aimed at the solid-phase synthesis of 4-
aminoalkyl-piperazines.20)
Chart 2
The structure of all compounds described here were con-
firmed by analytical and spectroscopic data. Work is cur-
Although most of the studies that describe a similar rently in progress in our Laboratory to prepare several new
process usually involve direct ring closure without isolation pharmacologically useful derivatives starting from uracils 3.
of 2, we decided to isolate these compounds since they are
Experimental
versatile synthons in their own right and can be used as start-
ing materials in the synthesis of other heterocyclic systems.
Melting points were determined on a Gallenkamp melting point apparatus
and are uncorrected. IR spectra were obtained using a Perkin-Elmer 1640
In a subsequent cyclization step the 6-methyl-1-substituted
uracils 3a—e were obtained as crystalline solids (after re-
crystallization from ethanol) in nearly quantitative yields
(Table 1) by treatment of the 3-substituted 1-acetoacetylureas
2 with a mixture of ethanol/acetic acid (3 : 1) and heating
under reflux.
Two synthetic strategies were developed for the prepara-
tion of the 1-(1Ј-piperazinyl-2-ethyl)uracil 3e (Chart 2, 3).
The regioselective nucleophilic substitution of 1-bromo-2-
chloroethane with 1-(benzyloxycarbonyl)piperazine 4 in ace-
tonitrile afforded the 1-(b-chloroethyl)-4-(benzyloxycar-
bonyl)piperazine 5 in high yield (Chart 2).
FTIR spectrophotometer with samples as potassium bromide pellets. The
NMR spectra were recorded on Bruker AM300 and XM500 spectrometers.
Chemical shifts are given as d values against tetramethylsilane as internal
standard and J values are given in Hz. Mass spectra were obtained on a Var-
ian MAT-711 instrument. The high resolution mass spectra were obtained on
an Autospec Micromass instrument. Elemental analyses were performed on
a Perkin-Elmer 240B apparatus at the Microanalysis Service of the Univer-
sity of Santiago de Compostela. The reactions were monitored by TLC with
2.5 mm Merck silica gel GF 254 strips, and the purified compounds each
showed a single spot; unless stated otherwise, iodine vapour and/or UV light
were used for detection of compounds. Commercially available starting ma-
terials and reagents were purchased from commercial sources and were used
without further purification.
1-Substituted-3-acetoacetylureas 2a—e. General Procedure Di-
ketene (2.10 ml, 27.7 mmol) was added slowly to a solution of the corre-
sponding urea 1a—e (27.7 mmol) in dry pyridine (15 ml) at 0 °C. The reac-
tion mixture was stirred under these conditions during 2 h, for a further 2 h
at room temperature and then heated at 60 °C (oil bath) during 4 h. The reac-
Transformation of 5 into the 1-(b-aminoethyl)-4-(benzyl-
oxycarbonyl)piperazine 6 was successfully achieved using
the classical conditions described for the Delepine reac-
tion.17,18) Thus, treatment of 5 with hexamethylenetetramine, tion mixture was cooled and concentrated to dryness under reduced pres-
sure. Ice was added to the oily residue and the resulting solid was collected
by filtration, washed with water and recrystallized from ethanol.
1-(2-Methoxyethyl)-3-acetoacetylurea (2a) This compound was pre-
pared by following the procedure described above. Yield 95%. mp 111—
followed by acid hydrolysis of the resulting complex, gave
the corresponding amine hydrochloride, which, after neutral-
ization, afforded amine 6 (Chart 2). In the next step, 6 was
112 °C (EtOH). IR (cmϪ1, KBr): 1665, 1582. 1H-NMR (CDCl3/TMS) d
(ppm), J (Hz): 10.20 (bs, 1H, NH), 8.43 (bs, 1H, NH), 3.52—3.40 (m, 6H,
3ϫCH2), 3.37 (s, 3H, OCH3), 2.20 (s, 3H, CH3). MS (70 eV) m/z (%): 202
(Mϩ, 44), 184 (100). High resolution (HR)-MS, m/z: Calcd for C8H14N2O4
(Mϩ): 202.2078, Found 202.2086.
1-(3-Methoxypropyl)-3-acetoacetylurea (2b) This compound was pre-
pared by following the procedure described above. Yield 95%. mp 120—
122 °C (EtOH). IR (cmϪ1, KBr): 3500—3000, 1685. 1H-NMR (CDCl3/
TMS) d (ppm), J (Hz): 10.25 (bs, 1H, NH), 8.52 (bs, 1H, NH), 3.54—3.35
(m, 9H, 3ϫCH2, OCH3), 2.27 (s, 3H, CH3), 1.89 (m, 2H, CH2). MS (70 eV)
m/z (%): 216 (Mϩ, 100), 198 (30). Anal. Calcd for C9H16N2O4: C, 49.99; H,
7.46; N, 12.96. Found: C, 50.21; H, 7.50; N, 13.09.
transformed into urea 7 by reaction with potassium iso-
cyanate.19) Acetoacetylation and subsequent dehydration of 7
were performed following the general route shown in Chart
1. Finally, the 1-[(1Ј-piperazinyl)-2-ethyl]-uracil 3e was ob-
tained by removing the benzyloxycarbonyl group in 8 by cat-
alytic hydrogenation.
Our second approach to prepare (3e) employed as a start-
ing material the readily obtainable 1-methoxyethyl-6-methyl-
1H-pyrimidin-2,4-dione (3a) (Chart 3). Hydrolysis of the
ether group on 3a and subsequent bromination of the inter-
mediate alcohol was accomplished in a high yielding one-pot
1-(2-Phenylethyl)-3-acetoacetylurea (2c) This compound was prepared

September 2003
1027
85%. mp 117—119 °C (dec) (i-PrOH). IR (cmϪ1, KBr): 3500—3000, 1684.
1H-NMR (CDCl3/TMS) d (ppm), J (Hz): 9.31 (bs, 1H, NH), 6.47 (bs, 1H,
NH), 5.53 (s, 1H, CH), 3.91 (m, 2H, CH2), 2.96 (m, 4H, 2ϫCH2), 2.63—
2.58 (m, 6H, 3ϫCH2), 2.21 (s, 3H, CH3). MS (70 eV) m/z (%): 238 (Mϩ,
10), 153 (25). Anal. Calcd for C11H18N4O2: C, 55.44; H, 7.61; N, 23.51.
Found: C, 55.47; H, 7.64; N, 23.49.
by following the procedure described above. Yield 93%. mp 114—115 °C
(EtOH). IR (cmϪ1, KBr): 3000, 1770, 1680. 1H-NMR (CDCl3/TMS) d
(ppm), J (Hz): 10.08 (bs, 1H, NH), 8.73 (bs, 1H, NH), 7.04—7.19 (m, 5H,
Ph), 2.79—3.41 (m, 6H, 3ϫCH2), 2.18 (s, 3H, CH3). MS (70 eV) m/z (%):
248 (Mϩ, 22), 230 (100). HR-MS, m/z: Calcd for C13H16N2O3 (Mϩ):
248.1161, Found 248.1180.
1-(Furfuryl)-3-acetoacetylurea (2d) This compound was prepared by
following the procedure described above. Yield 94%. mp 168—169 °C
(EtOH). IR (cmϪ1, KBr): 3500—3000, 1772, 1683. 1H-NMR (DMSO-
d6/TMS) d (ppm), J (Hz): 10.43 (bs, 1H, NH), 8.50 (bs, 1H, NH), 7.58 (s,
1H, CH), 6.39 (m, 1H, CH), 6.27 (m, 1H, CH), 4.37 (d, Jϭ2.6 Hz, 2H,
NCH2), 3.58 (s, 2H, CH2), 2.15 (s, 3H, CH3). MS (70 eV) m/z (%): 224 (Mϩ,
45), 140 (18). HR-MS, m/z: Calcd for C10H12N2O4 (Mϩ): 224.2134, Found
224.2139.
4-(2-Chloroethyl)piperazine-1-carboxylic Acid Benzyl Ester (5) To a
suspension of piperazine-1-carboxylic acid benzyl ester 4 (5.38 g, 24 mmol)
and K2CO3 (5.0 g, 40 mmol) in acetonitrile (55 ml) was added 1-bromo-2-
chloroethane (12 ml, 146.4 mmol). The mixture was flushed with argon for
5 min and then stirred at room temperature until the starting material had
been consumed (96 h, TLC monitoring). The solid was filtered off and the
filtrate was concentrated to dryness under reduced pressure to give an oil,
1
which was identified as 5. Yield 90%. H-NMR (CDCl3/TMS) d (ppm), J
1-[2-(1-Benzyloxycarbonylpiperazinyl)-1-ethyl]-3-acetoacetylurea (2e)
This compound was prepared by following the procedure described above.
Yield 88%. mp 196—197 °C (EtOH). IR (cmϪ1, KBr): 3000, 1760, 1680.
1H-NMR (CDCl3/TMS) d (ppm), J (Hz): 10.08 (bs, 1H, NH), 7.72 (bs, 1H,
NH), 7.35 (s, 5H, Ph), 5.13 (s, 2H, CH2), 3.54—3.47 (m, 6H, 3ϫCH2),
2.79—2.73 (m, 4H, 2ϫCH2), 2.44 (m, 4H, 2ϫCH2), 2.23 (s, 3H, CH3). MS
(70 eV) m/z (%): 390 (Mϩ, 56), 372 (89). HR-MS, m/z: Calcd for
C19H26N4O5 (Mϩ): 390.4337, Found 390.4368.
(Hz): 7.32 (s, 5H, Ph), 5.11 (s, 2H, OCH2), 3.56—3.48 (m, 6H, 3ϫCH2),
2.68 (t, Jϭ6.8 Hz, 2H, CH2), 2.47 (m, 4H, 2ϫCH2). MS (70 eV) m/z (%):
282 (Mϩ, 12), 233 (40). HR-MS, m/z: Calcd for C14H19N2O2Cl (Mϩ):
282.7656, Found 282.7670.
4-(2-Aminoethyl)piperazine-1-carboxylic Acid Benzyl Ester (6)
A
mixture of 4-(2-chloroethyl)piperazine-1-carboxylic acid benzyl ester (5)
(6.6 g, 23.3 mmol), KI (3.8 g, 23.3 mmol) and hexamethylenetetramine
(3.2 g, 23.3 mmol) in ethanol (120 ml) was flushed with argon for 5 min and
then stirred at room temperature until the starting material had been con-
sumed (113 h, TLC monitoring). The resulting precipitate was was filtered
off, dissolved in ethanol (420 ml) and the solution treated with concentrated
hydrochloric acid (37%) (30 ml). The reaction mixture was stirred at room
temperature until reaction was complete (36 h, TLC monitoring) and con-
centrated to dryness under reduced pressure. The residue was dissolved in
the minimum amount of water (120 ml) and the solution treated with 10%
NaOH until a pH of 7 was achieved. The mixture was then extracted with di-
ethyl ether (3ϫ30 ml), the organic phase was dried (Na2SO4) and concen-
trated to dryness under reduced pressure to give amine 6 as a white solid,
which was crystallized from i-PrOH. Yield 73%. mp 163—164 °C (i-PrOH).
IR (cmϪ1, KBr): 3500—3000, 1770. 1H-NMR (CDCl3/TMS) d (ppm), J
(Hz): 7.35 (s, 5H, Ph), 5.13 (s, 2H, OCH2), 3.51 (m, 4H, 2ϫCH2), 2.78 (m,
2H, CH2), 2.43 (m, 6H, 3ϫCH2), 1.67 (s, 2H, NH2). MS (70 eV) m/z (%):
263 (25). Anal. Calcd for C14H21N3O2: C, 63.85; H, 8.04; N, 15.96. Found:
C, 63.88; H, 8.10; N, 15.99.
4-(2-Ureidoethyl)piperazine-1-carboxylic Acid Benzyl Ester (7) To a
suspension of 4-(2-aminoethyl)piperazine-1-carboxylic acid benzyl ester (6)
(0.70 g, 2.6 mmol) in water (70 ml) at 55 °C was added potassium isocyanate
(0.8 g, 10.6 mmol) in small portions. The reaction mixture was stirred and
heated (oil bath 100 °C) under argon until the starting material had been
consumed (4 h, TLC monitoring). The mixture was cooled to room tempera-
ture, extracted with methylene chloride (3ϫ30 ml) and the combined organic
phases organic phase were dried (Na2SO4). The solution was concentrated to
dryness under reduced pressure to give 0.41 g of the urea 7. Yield 50%. mp
132—134 °C (i-PrOH). IR (cmϪ1, KBr): 3500—3000, 1685, 1653, 1575. 1H-
NMR (CDCl3/TMS) d (ppm), J (Hz): 7.35 (m, 5H, Ph), 5.13 (m, 3H, OCH2,
NH), 4.65 (bs, 2H, NH2), 3.50 (m, 4H, 2ϫCH2), 3.24 (m, 2H, CH2), 2.48
(m, 2H, CH2), 2.42 (m, 4H, 2ϫCH2). MS (70 eV) m/z (%): 307 (Mϩ1, 10),
233 (100). Anal. Calcd for C15H22N4O3: C, 58.81; H, 7.24; N, 18.29. Found:
C, 58.93; H, 7.19; N, 18.28.
1-Substituted-6-methyl-1H-pyrimidin-2,4-diones 3a—e. General
Procedure
A solution of the 1-substituted-3-acetoacetylureas 2a—e
(2.6 mmol) in a mixture of ethanol/acetic acid (3 : 1) was stirred and heated
under reflux (oil bath 85 °C) under argon until the starting material had been
consumed (2—4 h, TLC monitoring). The reaction mixture was allowed to
cool and concentrated to dryness under reduced pressure. The resulting solid
was purified by recrystallization (i-PrOH). Yield 85—97%.
1-(2-Methoxyethyl)-6-methyl-1H-pyrimidin-2,4-dione (3a) This com-
pound was prepared by following the procedure described above. Yield 93%.
mp 121—122 °C (i-PrOH). IR (cmϪ1, KBr): 3500—3000, 1684. 1H-NMR
(CDCl3/TMS) d (ppm), J (Hz): 9.89 (bs, 1H, NH), 5.51 (s, 1H, CH), 3.96 (t,
Jϭ5.0 Hz, 2H, CH2), 3.56 (t, Jϭ5.0 Hz, 2H, CH2), 3.28 (s, 3H, CH3), 2.27
(s, 3H, CH3). MS (70 eV) m/z (%): 184 (Mϩ, 68). Anal. Calcd for
C8H12N2O3: C, 52.17; H, 6.57; N, 15.21. Found: C, 52.21; H, 6.55; N, 15.29.
1-(3-Methoxypropyl)-6-methyl-1H-pyrimidin-2,4-dione
(3b) This
compound was prepared by following the procedure described above. Yield
97%. mp 125—126 °C (i-PrOH). IR (cmϪ1, KBr): 3000, 1655. 1H-NMR
(CDCl3/TMS) d (ppm), J (Hz): 10.07 (bs, 1H, NH), 5.56 (s, 1H, CH) 3.92 (t,
Jϭ7.3 Hz, 2H, CH2O), 3.40 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 2.28 (s,
3H, CH3), 1.94 (m, 2H, CH2). MS (70 eV) m/z (%): 198 (Mϩ, 78). Anal.
Calcd for C9H14N2O3: C, 54.53; H, 7.12; N, 14.13. Found: C, 54.72; H, 7.09;
N, 14.21.
1-(2-Phenylethyl)-6-methyl-1H-pyrimidin-2,4-dione (3c) This com-
pound was prepared by following the procedure described above. Yield 93%.
,
mp 205—206 °C (i-PrOH). IR (cmϪ1 KBr): 1673, 1482. 1H-NMR
(CDCl3/TMS) d (ppm), J (Hz): 9.90 (bs, 1H, NH), 7.36—7.29 (m, 3H, Ph),
7.23—7.14 (m, 2H, Ph), 5.48 (s, 1H, CH), 4.00 (t, Jϭ7.1 Hz, 2H, CH2), 2.98
(t, Jϭ7.1 Hz, 2H, CH2), 2.16 (s, 3H, CH3). MS (70 eV) m/z (%): 230 (Mϩ,
33), 104 (100). Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17.
Found: C, 67.98; H, 6.09; N, 12.18.
1-(Furfuryl)-6-methyl-1H-pyrimidin-2,4-dione (3d) This compound
was prepared by following the procedure described above. Yield 91%. mp
146—147 °C (i-PrOH). IR (cmϪ1, KBr): 1684, 1560, 1499. 1H-NMR
(CDCl3/TMS) d (ppm), J (Hz): 9.41 (bs, 1H, NH), 7.36 (s, 1H, CH), 6.39
(m, 1H, CH), 6.34 (m, 1H, CH), 5.57 (s, 1H, CH), 5.01 (s, 2H, CH2), 2.40 (s,
3H, CH3). MS (70 eV) m/z (%): 206 (Mϩ, 20), 81 (100). HR-MS, m/z: Calcd
for C10H10N2O3 (Mϩ): 206.1981, Found 206.1998.
1-[2-(1-Benzyloxycarbonylpiperazinyl)-1-ethyl]-6-methyl-1H-pyrim-
idin-2,4-dione (8). Method B To a suspension of the piperazine-1-car-
boxylic acid benzyl ester (0.15 g, 0.81 mmol) and K2CO3 (0.11 g, 0.81
mmol) in acetonitrile, was slowly added a solution of 1-(2-bromoethyl)-6-
methyl-1H-pyrimidine-2,4-dione (0.20 g, 0.81 mmol) in acetonitrile (3 ml).
The reaction mixture was flushed with argon for 5 min and then stirred at
room temperature under argon until the starting material had been consumed
(48 h, TLC monitoring). The solvent was evaporated under reduced pressure
to give a solid residue, which was purified by column chromatography on
silica gel. Yield 82%. mp 208—210 °C (i-PrOH). IR (cmϪ1, KBr): 1696,
1-[2-(1-Benzyloxycarbonylpiperazinyl)-4-ethyl]-6-methyl-1H-pyrim-
idin-2,4-dione (8). Method A This compound was prepared by follow-
ing the procedure described above. Yield 89%. mp 231—233 °C (acetoni-
1
trile). IR (cmϪ1, KBr): 3500—3000, 1765, 1680. H-NMR (CDCl3/TMS) d
1
(ppm), J (Hz): 9.72 (bs, 1H, NH), 7.33 (s, 5H, Ph), 5.52 (s, 1H, CH), 5.11 (s,
2H, OCH2), 3.90 (t, Jϭ6.4 Hz, 2H, NCH2), 3.49 (m, 4H, 2ϫNCH2), 2.61 (t,
Jϭ6.4 Hz, 2H, NCH2), 2.49 (m, 4H, 2ϫCH2), 2.27 (s, 3H, CH3). MS (70 eV)
m/z (%): 372 (Mϩ, 15), 233 (70).
1669. H-NMR (CDCl3/TMS) d (ppm), J (Hz): 9.30 (bs, 1H, NH), 7.30—
7.35 (m, 5H, Ph), 5.45 (s, 1H, CH), 5.11 (s, 2H, CH2), 3.80 (t, Jϭ6.6 Hz,
2H, CH2), 3.26 (m, 4H, 2ϫNCH2), 2.46 (t, Jϭ6.6 Hz, 2H, NCH2), 2.32 (m,
4H, 2ϫCH2), 2.16 (s, 3H, CH3). MS (70 eV) m/z (%): 353 (Mϩ1, 25). Anal.
Calcd for C17H28N4O4: C, 57.94; H, 8.01; N, 15.90. Found: C, 58.02; H,
8.12; N, 15.87.
6-Methyl-1-[2-(1-piperazinyl)-4-ethyl]-1H,3H-pyrimidin-2,4-dione
(3e) To a solution of 8 (0.26 g, 0.64 mmol) in dry methylene chloride
(15 ml) was added a catalytic amount of palladium on charcoal. The mixture
was stirred at room temperature under a hydrogen atmosphere until the start-
ing material had disappeared (24 h, TLC monitoring). The reaction mixture
was filtered through celite and evaporation of the solvent under reduced
pressure gave a solid residue, which was purified by recrystallization. Yield
1-(2-Bromoethyl)-6-methyl-1H-pyrimidine-2,4-dione (9) To a solu-
tion of 1-methoxyethyl-6-methyluracil (0.30 g, 1.51 mmol) in dry methylene
chloride (20 ml) at 0 °C was slowly added a solution of boron tribromide
(3.02 ml, 3.03 mmol). The reaction mixture was stirred under argon during
2 h and then at room temperature until the starting material had been con-

1028
Vol. 51, No. 9
sumed (TLC monitoring). The reaction mixture was treated with ammonium
acetate (0.23 g, 3.03 mmol) and the solvent was evaporated under reduced
pressure. The resulting residue was purified by column chromatography on
silica gel. Yield 93%. mp 235—236 °C (i-PrOH). IR (cmϪ1, KBr): 1693,
5) Kennedy B. J., Torkelson J. L., Torlakovic E., Cancer, 85, 2265—
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1
1662. H-NMR (CDCl3/TMS) d (ppm), J (Hz): 9.85 (bs, 1H, NH), 5.60 (s,
1H, CH), 4.17 (t, Jϭ6.63 Hz, 2H, CH2), 3.61 (t, Jϭ6.63 Hz, 2H, CH2), 2.30
(s, 3H, CH3). MS (70 eV) m/z (%): 246 (Mϩ, 12), 167 (30), 140 (70). Anal.
Calcd for C7H9BrN2O2: C, 36.07; H, 3.89; Br, 34.28; N, 12.02. Found: C,
36.09; H, 3.94; Br, 34.31; N, 12.01.
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Acknowledgements This work was supported by the Spanish Intermin- 12) Perry C. M., Faulds D., Drugs, 53, 657—680 (1997).
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