Synthesis of methyl esters of 5-aroyl-6-aryl-2-oxo-1,2,3,6-tetra- hydropyrimidine-4-carboxylic acids

Article abstract of DOI:10.1007/s10593-009-0353-0

Methyl esters of 5-aroyl-6-aryl-2-oxo-1,2,3,6-tetrahydropyrimidine-4- carboxylic acids were synthesized from three component mixtures of methyl esters of aroylpyruvic acids, urea, and substituted benzaldehydes. 8-Hydroxy-4,5-diphenyl-3,4-dihydropyrimido[4

Full text of DOI:10.1007/s10593-009-0353-0

Chemistry of Heterocyclic Compounds, Vol. 45, No. 7, 2009
SYNTHESIS OF METHYL ESTERS
OF 5-AROYL-6-ARYL-2-OXO-1,2,3,6-TETRA-
HYDROPYRIMIDINE-4-CARBOXYLIC ACIDS
V. L. Gein1*, I. V. Krylova2, E. P. Tsypliakova1, A. R. Gaifullina1,
L. I. Varkentin1, and M. I. Vakhrin1
Methyl esters of 5-aroyl-6-aryl-2-oxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acids were synthesized
from three component mixtures of methyl esters of aroylpyruvic acids, urea, and substituted
benzaldehydes. 8-Hydroxy-4,5-diphenyl-3,4-dihydropyrimido[4,5-d]pyridazin-2(1H)-one was synthesized
by the reaction of 5-benzoyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidin-4-carboxylate with hydrazine
hydrate.
Keywords: hydrazine hydrate, 8-hydroxy-4,5-diphenyl-3,4-dihydropyrimido[4,5-d]-pyridazin-2(1H)-
one, substituted benzaldehydes, methyl esters of 5-aroyl-6-aryl-2-oxo-1,2,3,6-tetrahydropyrimidine-
4-carboxylic acids, urea, esters of aroylpyruvic acids.
The interaction of esters of acetylacetic acids with urea and substituted benzaldehydes led to the
formation of tetrahydropyrimidin-2-ones [1]. However the reaction of esters of acylpyruvic acids with mixtures
of urea and aromatic aldehydes was not studied.
O
OMe
O
O
OH
N
OH
O
O
H2NNH2
N
OMe
NH
O
+
+
1
R = R1 = H
Ph
H
H2N
NH2
R
NH
O
N
R1
2
4
H
R
N
H
O
Ph
3
R1
1a–f
2
1 а−d R = H, a R1 = H, b R1 = 3-MeO, c R1 = 3,4-(MeO)2, d R1 = 3-MeO, 4-OH, e, f R = Cl, e R1 = H, f R1 = 3-MeO
_______
* To whom correspondence should be addressed, e-mail: perm@pfa.ru, geinvl48@mail.ru.
1Perm State Pharmaceutical Academy, Perm 614990, Russia.
2Perm State Medicinal Academy, Perm 614000, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1046-1049, July, 2009. Original
article submitted June 5, 2008.
0009-3122/09/4507-0829©2009 Springer Science+Business Media, Inc.
829

Table 1. Characteristics of Methyl Esters of 5-Aroyl-6-aryl-2-oxo-1,2,3,6-
tetrahydropyrimidine-4-carboxylic Acids 1a-f
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
(АсОН)
Yield, %
C
N
H
1а
1b
1c
1d
1e
1f
С19Н16N2O4
С20Н18N2O5
С21Н20N2O6
С20Н18N2O6
С19Н15ClN2O4
С20Н16ClN2O5
67.79
67.84
69.48
69.35
64.02
63.63
62.91
62.82
62.01
61.54
64.01
63.24
8.27
8.33
8.17
8.09
7.14
7.07
7.24
7.33
7.32
7.56
7.54
7.38
4.96
4.80
5.32
5.24
4.99
5.08
4.59
4.74
4.12
4.08
4.57
4.25
176-177
160-162
134-136
210-212
190-191
191-193
79
64
61
52
63
55
We have established that on fusing methyl esters of aroylpyruvic acids with a mixture of an aromatic
aldehyde and urea at 130-150°C for 30 min methyl esters of 5-aroyl-6-aryl-2-oxo-1,2,3,6-tetrahydropyrimidine-
4-carboxylic acids 1a-f are formed.
The compounds obtained, 1a-f, are colorless or yellow crystalline compounds, soluble in general
organic solvents, but insoluble in water (Table 1).
The IR spectra of these compounds contain absorptions bands for ester carbonyl groups at 1720-1736,
lactam carbonyl groups at 1688-1720, ketone carbonyl groups at 1640-1656, and N–H stretches of two amino
groups in positions 1 and 3 of the pyrimidine ring at 3208-3240 and 3304-3376 cm-1 (Table 2).
1
In the H NMR spectra of compounds 1a-f signals of the methoxy group protons are observed in the
3.15-3.28 range, signals of aromatic protons in the 6.50-7.60 range, signals of the protons bonded to nitrogen
atoms in the 7.70-7.93 and 9.00-9.20 ranges, signals of the methyne proton at positions 4 of the pyrimidine ring
in the 5.22-5.35 range, and also signals of the methoxy group protons (for compounds 1b-d, f) in the 3.60-3.70
range and of the OH group (for compound 1d) at 8.80 ppm (Table 2).
The presence of the β-dicarbonyl systems in the methyl esters of 5-aroyl-6-aryl-1,2,3,6-tetrahydro-
pyrimidine-4-carboxylic acids allows the discussion of compounds 1a-f as suitable reagents for the synthesis of
condensed heterocyclic systems.
In fact reaction of 5-benzoyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-4-carboxylate 1a with
hydrazine hydrate at 170-180°C gave 8-hydroxy-4,5-diphenyl-3,4-dihydropyrimido[4,5-d]pyridazin-2(1H)-one
(2) as a colorless crystalline substance, soluble in common organic solvents, but insoluble in water. It gave a
cherry color with ethanolic FeCl3 solution.
EXPERIMENTAL
1
IR spectra of nujol mulls were recorded with a UR-20 instrument. H NMR spectra of DMSO-d6
solutions with TMS as internal standard were recorded on a Fourier BS-567 A (100 MHz) instrument.
Methyl esters of 5-Aroyl-6-aryl-2-oxo-1,2,3,6-tetrhydropyrimidine-4-carboxylic Acids 1a-f
(General Method). A mixture of a methyl ester of an aroylpyruvic acid (0.01 mol), urea (0.01 mol), and an
aromatic aldehyde (0.01 mol) was fused at 135-150°C until evolution of the gas ceased. The reaction mixture
was treated with ethanol, the precipitate was filtered off and recrystallized from conc. AcOH.
830

831

8-Hydroxy-4,5-diphenyl-3,4-dihydropyrimido[4,5-d]pyridazin-2(1H)-one (2). A mixture of methyl
5-benzoyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-4-carboxylate (1a) (0.01 mol) and 98% hydrazine
hydrate (0.01 mol) was heated at 170-180°C until evolution of gas ceased. The reaction mixture was treated with
ethanol, the precipitate was filtered off and recrystallized from a mixture of conc. AcOH and DMF. Yield 1.81 g
(57%); mp 295-297°C (mixture of AcOH–DMF). IR spectrum, ν, cm-1: 1710 (CONH), 3210 (1-NH), 3358
(3-NH). 1H NMR Spectrum, δ, ppm, (J, Hz): 5.30 and 5.31 (1H, d, J = 3.3, H-4); 7.05 (10H, m, arom); 7.83 (1H,
s, H-1); 9.20 (1H, br. s, H-3); 13.20 (1H, s, OH). Found, %: C 67.95; 67.94; H 4.40; 4.33; N 17.69, 17.64.
C18H14N4O2. Calculated, %: C 67.92; H 4.43; N 17.60.
REFERENCE
1.
Ch. V. Reddy, M. Mahech, P. V. K. Raju, T. R. Babu, and V. V. N. Reddy, Tetrahedron Lett., 43, 2657
(2002).
832