103
uncorrected. Elemental analysis indicated by the symbols
of the elements were within ± 0.4% of the theoretical
values.
5.1.3. Hydroxymetabolite 5-(2-hydroxyethyl)-5-
isobutylbarbituric acid A3
This synthesis was performed in four steps.
2-bromoethyltetrahydropyranylether:
5.1. Chemistry
Bromoethanol (125 g, 1 mol) was dissolved into dihy-
dropyran (84 g, 1 mol). Two drops of hydrochloric acid
were added. The mixture was stirred at 20 °C for 3 h.
Sodium hydroxide (10%) 100 mL was added. The or-
ganic solution was extracted with diethylether and dried
(sodium sulfate). The solvent was evaporated and the
residue was purified by distillation under reduced pres-
sure. Yield: 80%.
Diethyl 2-ethylmalonate, urea, transcutol (diethylene-
glycol monoethylether), ethyl acetate, petroleum ether,
diethylether and chloroform were commercial products.
5.1.1. 5-Ethyl-5-isobutylbarbituric acid A1
5-Ethyl-5-isobutylbarbituric acid A1 was prepared ac-
cording to the standard method [10]: condensation of
urea with diethyl 2-ethyl-2-isobutylmalonate in alkaline
medium. Yield: 64%. Anal. (C, H, N) C10O3H16N2.
1H-NMR (DMSO-d6) δ ppm: 0.75 (m, 9H, 2CH3 isobutyl
and CH3 ethyl); 1.5 (m, 1H, CH isobutyl); 1.75 (q, 4H,
2CH2); 11.5 (s, 2H exch. D2O, 2NH).
Alkylation of diethyl 2-isobutyl malonate:
Sodium (9.2 g, 0.4 mol) was dissolved in 300 mL of
dry ethanol [11]. After cooling, diethyl 2-isobuyl mal-
onate (54 g, 0.25 mol) was added. The mixture was
stirred at 80 °C for 18 h. After cooling, the solvent was
evaporated. The residue was dissolved in water. The
organic phase was extracted with diethylether and dried
(sodium sulfate). The solvent was evaporated and the
residue was purified by column chromatography (silica:
Kieselgel 60 Merck; solvent: diethylether/petroleum
ether 10:100). Yield: 70%.
5.1.2. 5-Ethyl-5-(2-hydroxy-2-methylpropyl)-
barbituric acid A2
Method 1: chromic oxidation of A1:
5-Ethyl-5-(2-hydroxy-2-methylpropyl)barbituric acid
A2 was prepared from A1 by chromic oxidation in acetic
medium according to the method described in [6]. Yield:
20%. Anal. (C, H, N) C10H16O4N2. 1H-NMR (DMSO-d6)
δ ppm: 0.7 (t, 3H, CH3); 1.05 (s, 6H, 2CH3); 1.65 (q, 2H,
CH2); 2.1 (s, 2H, CH2); 4.5 (s, 1H, OH); 11.15 (s, 2H
exch. D2O, 2NH).
Condensation of alkylmalonate with urea:
The tetrahydropyranylether of 5-(2-hydroxyethyl)-5-
isobutylbarbituric acid was prepared according to the
standard method [10]. Yield: 52%. Anal. (C, H, N)
1
C15H24O5N2. H-NMR (DMSO-d6) δ ppm: 0.9 (d, 6H,
2CH3 isobutyl); 1 (m, 1H, CH isobutyl); 1.5 (m, 6H,
3CH2); 1.8 (d, 2H, CH2); 2.1 (d, 2H, CH2); 3.3 (m, 2H,
CH2); 3.6 (t, 2H, CH2); 4.5 (s, 1H, CH); 11.4 (s, 2H exch.
D2O, 2NH).
Hydrolysis of the tetrahydropyranylether of 5-(2-
hydroxyethyl)-5-isobutylbarbituric acid:
Method 2: oxidation of 5-ethyl-5-(2-methylpropenyl)-
barbituric acid:
5-Ethyl-5-(2-methylpropenyl)barbituric acid was pre-
pared according to the standard method: condensation of
urea with diethyl 2-ethyl-2-methylpropenyl malonate in
alkaline medium [10].
Pyranylether (4.84 g, 0.0155 mol) was dissolved into
300 mL dry ethanol [11]. Sulfuric acid (128 mL) was
then added to the mixture, which was heated (20 °C)
without stirring for 24 h. Then 100 mL of water were
added. The mixture was cooled at 4 °C for 48 h. The
compound was filtered and then dried. Yield: 70%. Anal.
(C, H, N) C10H16O4N2. 1H-NMR (DMSO-d6) δ ppm: 0.8
(d, 6H, 2CH3); 1.5 (m, 1H, CH); 1.8 (d, 2H, CH2); 2 (t,
2H, CH2); 3.3 (t, 2H, CH2O); 4.5 (s, 1H exch. D2O, OH);
11.4 (s, 2H exch. D2O, 2NH).
Diethyl 2-ethyl-2-methylpropenyl malonate (40 g,
0.165 mol) was added to (13.22 g, 0.220 mol) of urea in
the reactant obtained by action of sodium (9.4 g,
0.408 mol) on dry ethanol (260 mL) [11]. The mixture
was stirred at 80 °C for 16 h. After cooling, the solvent
was evaporated and the residue was dissolved in water
and hydrochloric acid was added dropwise. The precipi-
tate was filtered and crystallized from water. Yield: 87%.
1
Anal. (C, H, N) C10H14O3N2. H-NMR (DMSO-d6) δ
ppm: 0.75 (t, 3H, CH3 ethyl); 1.55 (s, 3H, CH3–C=); 1.8
(q, 2H, CH2 ethyl); 3.25 (s, 2H, –CH2–C=); 4.6 (s, 1H,
H–C=); 4.8 (s, 1H, H–C=); 11.5 (s, 2H exch. D2O, 2NH).
5-Ethyl-5-(2-methylpropenyl)barbituric acid (8.61 g,
0.041 mol) was dissolved in 25 mL acetic acid (95%).
The flask was placed in a boiling water bath. Sulfuric acid
(5mL) was added, and the mixture stirred for 30 min.
After cooling, the solid residue was filtered and crystal-
lized from water/ethanol. Yield: 70%.
5.1.4. 5-(2-Oxoethyl)-5-isobutylbarbituric acid A4
This synthesis was performed in three steps.
Alkylation of diethyl 2-(1,3-dioxolyl)-2-isobutyl-
malonate:
Sodium (18.4 g, 0.8 mol) was dissolved in 450 mL dry
ethanol [11]. After cooling, diethyl 2-isobutylmalonate
(108 g, 0.5 mol) was added. The mixture was stirred at