3
40 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
Simple Syntheses of Isouramil and Isobarbituric
Acid$
E. J. Behrman
1998, 340±341$
Department of Biochemistry, The Ohio State University, Columbus, OH 43210, USA
Peroxodisulfate oxidations of uracil and 6-aminouracil followed by hydrolysis led to efficient syntheses of isobarbituric
acid and isouramil.
Isouramil (4-amino-5,6-dihydroxypyrimidin-2-one, II) is the
aglycone of convicine which, together with the aglycone
The purity of compounds II and III was established by
agreement of their molar absorption coecients with litera-
ture values.
1,2
of vicine, are the causative agents of favism. These pyrimi-
dines are also reported to have therapeutic eects in the
2
Experimental
treatment of malaria and cancer.
Isouramil has been synthesized by nitrosation of 2,4,5-
Isouramil-5-O-sulfonate I.Ð2 g (0.016 mol) of 4-amino-2,6-
dihydroxypyrimidine (Aldrich) was dissolved in water (20 ml) con-
taining NaOH (1.6 g, 0.04 mol). The solution was cooled on ice
and then sodium peroxodisulfate (3.8 g, 0.016 mol) was added in
portions over 15 min with stirring. The solution was brought to
3
,4
trihydroxypyrimidine followed by reduction,
condensation of urea with a 2-cyano-2-alkoxyacetic acid
and by
5
ester. The latter route is lengthy and the former requires
the relatively expensive isobarbituric acid (ca. $50 per g).
22 8C and allowed to stand overnight. The orange solution was
6
Hurst attempted the synthesis of isouramil via the Elbs oxi-
cooled on ice and then concentrated HCl (4 ml, 0.048 mol) was
added with stirring. The precipitate which formed after a few
minutes was ®ltered o, washed with cold water and then cold 95%
ethanol to yield 2.4±2.7 g (55±62%) of crude I after air-drying.
Crystallization from 50% ethanol yielded colorless needles, mp
dation of 6-amino-2,4-dihydroxypyrimidine (ca. $1 per g.)
He reported that the intermediate 4-amino-6-hydroxy-
pyrimidin-2-one 5-hydrogensulfate I failed to give a satis-
factory elemental analysis. There were also diculties in
hydrolysis of the sulfate ester.
>
300 8C. Tests for chloride were negative. Titration with KOH
gave an equivalent weight of 27025 (calc. for the trihydrate, 277)
Found: C, 17.4; H, 2.8; N, 14.9. Calc. for C O:
SÁ3H
C, 17.3; H, 3.9; N, 15.1%). IR(Nujol): 3430, 3325, 3200, 1700, 1625,
(
4
H
5
N
3
O
6
2
�
1
�1
1
410, 1280, 1250, 1155, 1060, 840, 720 cm . UV (ꢀmax/nm, e/M
�
1
cm ): 224 (4700), 270 (17 100) (in 0.1 M HCl).
Potassium Salt of I.ÐCompound I (270 mg, 0.001 mol) was dis-
solved in water (5 ml). The pH was brought to about 10 with 1 M
aqueous KOH. The solution was evaporated to dryness and the
residue was recrystallized from 50% ethanol to yield small white
crystals, mp >300 8C (Found: C, 17.15; H, 1.24; N, 14.54. Calc. for
C
4
H
3.5
K
1.5
N
3
O
6
S: C, 17.14; H, 1.26; N, 14.99%. IR (Nujol): 3455,
Modi®cation of Hurst's procedure has led to an easy
route to isouramil. The crude sulfate ester I was recrystal-
lized to give a product which had the theoretical carbon and
nitrogen analyses for the trihydrate; the analysis for hydro-
gen was unacceptably low. The equivalent weight also
suggested a trihydrate. Conversion into the potassium salt,
however, yielded material which gave a satisfactory analysis.
Hydrolysis of I to isouramil II cannot be carried out as
usual in hot aqueous HCl because of concomitant hydrolysis
of the amino group. Zav'yalov and Pokhvisneva reported
success by using concentrated HCl at room temperature
for the related pyrimidine, divicine-5-O-sulfonate (2,4-
diamino-6-hydroxypyrimidine 5-hydrogensulfate). Isouramil-
3
1
415, 3340, 3290, 3180, 1730, 1650, 1530, 1360, 1265, 1235, 1150,
055, 840, 760, 720 cm . UV (ꢀmax/nm, e/M cm ): 222 (4600),
�1
�1
�1
�
1
270 (17 000) (in water). The strong IR bands around 1050 cm are
characteristic of sulfate esters.
Isouramil II.ÐCrude I (1 g) was dissolved in 48% aqueous HBr
(10 ml). The solution was kept at 22 8C. It began to deposit crystals
of isouramil after about 3 h. After 5 h the reaction mixture was
cooled to 5 8C and allowed to stand overnight. The crystals were
®ltered o, washed with 48% HBr, water and 95% ethanol. Air-
drying gave 0.38 g (60% yield) of isouramil with spectra in agree-
3
7
4
ment with those reported by Bien et al. (IR) and Davoll and
5
Laney (UV).
Isobarbituric Acid III.ÐUracil (3.16 g, 0.028 mol) was dissolved
in water (30 ml) containing NaOH (3 g). The solution was cooled
on ice and then sodium peroxodisulfate (7.16 g, 0.03 mol) was
added in portions with stirring during 1 h. The homogeneous
solution was allowed to stand at 22 8C overnight. The pH was
adjusted to about 7.5 with concentrated HCl. This solution was
allowed to stand for 2±3 d at 22 8C during which time uracil
slowly precipitated (1 g). After removal of the uracil by ®ltration,
one-half volume of concentrated HCl was added and the solution
heated to boiling for 10 min. Isobarbituric acid (2 g) precipitated in
the cold. This crude material contained about 14% uracil. The
yield of isobarbituric acid was 49% after correction for this or
71% after taking into account the uracil initially recovered. Crystal-
lization was ineective in separating uracil and isobarbituric
acid. However, the remaining uracil can be removed by trituration
with the solvent recommended for chromatographic separations in
5-O-sulfonate I is insoluble in concentrated HCl. However,
48% aqueous HBr dissolves this material easily and gives a
good yield of the hydrolysis product, II.
I also report an improved route to isobarbituric acid III
which ought to lower its cost. Elbs oxidations of uracil
(ca. 20 cents per g) had been previously carried out but with
an overall yield of III of 9% or without reported yield.
8
6
If one avoids isolation of the sulfate ester, then III can
be obtained in crude form in about 50% yield. The
impurity is uracil which is dicult to remove by crystalliza-
tion. However, trituration with aqueous ammoniacal pro-
pan-2-ol extracts the uracil. Pure isobarbituric acid can
then be recovered from the residue by acidi®cation and
recrystallization.
7,8
this system, propan-2-ol±concentrated ammonia±water (7:1:2)
Five-hundred milligram lots were stirred with about 10 ml of this
mixture at 22 8C for 30 min. TLC on cellulose showed only uracil
in the ®ltrate. The residue was ®ltered o, washed with fresh
solvent and ®nally 95% ethanol. This material was clean by TLC
and was recrystallized from dilute HCl to yield III in about 70%
yield with spectral characteristics in agreement with the literature
8
values.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research(S), 1998, Issue 1]: there is there-
fore no corresponding material in J. Chem. Research(M).
I thank Dr. G. E. Means for interesting me in isouramil.
Behrman
