4-Hydroxy-2-quinolones 120. Synthesis and structure of ethyl 2-hydroxy-4-oxo-4H-pyrido-[1,2-a]pyrimidine-3-carboxylate

Article abstract of DOI:10.1007/s10593-007-0119-5

An improved method for the preparation and purification of ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carboxylates is proposed. According to ¹H and ¹³C NMR spectroscopic data the synthesized compounds exist in DMSO solution in the 2-hydroxy-4-oxo form while in the crystal (at least for the case of the unsubstituted derivative) X-ray analysis shows that it occurs in the bipolar 2,4-dioxo form.

Full text of DOI:10.1007/s10593-007-0119-5

Chemistry of Heterocyclic Compounds, Vol. 43, No. 6, 2007
4-HYDROXY-2-QUINOLONES
120*. SYNTHESIS AND STRUCTURE
OF ETHYL 2-HYDROXY-4-OXO-4H-PYRIDO-
[1,2-a]PYRIMIDINE-3-CARBOXYLATE
I. V. Ukrainets1, N. L. Bereznyakova1, G. P. Petyunin1,
I. A. Tugaibei1, V. B. Rybakov2, V. V. Chernyshev2, and A. V. Turov3
An improved method for the preparation and purification of ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]-
1
pyrimidine-3-carboxylates is proposed. According to H and 13C NMR spectroscopic data the
synthesized compounds exist in DMSO solution in the 2-hydroxy-4-oxo form while in the crystal (at least
for the case of the unsubstituted derivative) X-ray analysis shows that it occurs in the bipolar 2,4-dioxo
form.
Keywords: 2-aminopyridines, heterocyclic tricarbonylmethane derivatives, 2-hydroxy-4-oxo-
4H-pyrido[1,2-a]pyrimidine-3-carboxylic acids, esters, X-ray analysis.
Interest in 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives is principally due to their broad spectrum of
biological activity. Based on this molecular system there have been synthesized bicyclic diaza sugars which
inhibit β-glucosidase with high specificity [2]. 2-(Benzothiazol-2-yl) derivatives are novel, oral inhibitors of
human leukocyte elastase suitable for treating chronic obstructive illnesses of the lungs, asthma, emphysema,
cystic fibrosis, and various inflammatory reactions [3]. Substituted ethylenediamines containing the pyrido-
[1,2-a]pyrimidine fragment are effective in the fight against microbacterial infection, not just tubercular [4].
4-Oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamides find use as agents for the prophylaxis of gastric problems
arising from the use of nonsteroidal anti-inflammatory agents [5]. 2-Amino-4H-pyrido[1,2-a]pyrimidin-4-ones
actively inhibit the aggregation of human thrombocytes [6] and their analogs with a tetrazole fragment in
position 3 the synthesis of leukotrienes [7].
We have continued our work on preparative methods of synthesis and a study of the structure, chemical
reactivity, and biological properties of 4-hydroxy-2-quinolinones and heterocycles related to them. This report
concerns ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate.
_______
* For Communication 119 see [1]
__________________________________________________________________________________________
1National University of Pharmacy, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua.
2M. V. Lomonosov Moscow State University, Moscow 119899, Russia; e-mail: rybakov@biocryst.phys.msu.su.
3Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail: nmrlab@univ.kiev.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 864-876, June, 2007. Original article submitted February
20, 2006.
0009-3122/07/4306-0729©2007 Springer Science+Business Media, Inc.
729

A method for preparing ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1a) consists
of condensation of 2-aminopyridine 2a with triethylmethanetricarboxylate in refluxing bromobenzene [8]. To
avoid the formation of side product we proposed to use of a two fold excess of triethylmethanetricarboxylate and
a relatively large solvent volume. Chromatographic monitoring (although not totally clear) allowed the content
of the product to be checked and showed that the reaction is finished after 6 h. Removal of bromobenzene and
crystallization gave the ester 1 in 68% yield. Repeated attempts at the reported method and a fuller analysis of
the composition of the reaction mixture formed showed that unwanted chemical reactions could not all be
suppressed because about 20% of the 2-aminopyridine is used up in forming the side product of 2-hydroxy-
4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid pyridyl-2-amide (3a).
O
O
O
HC(COOEt)3
R = 6-Me
N
N
Me
N
N
N
Me
R
H
H
NH2
NH
2a–f
N
HC(COOEt)3
Me
4
O
O
O
O
R1
N
N
N
N
OEt
OH
R
+
H
R
N
OH
N
3a–e
1a–e
1 а R = H, b R = 7-Cl, c R = 7-Me, d R = 8-Me, e R = 9-Me; 2 а R = H, b R = 5-Cl,
c R = 5-Me, d R = 4-Me, e R = 3-Me, f R = 6-Me; 3 а R = R1 = H, b R = 7-Cl,
R1 = 5-Cl, c R = 7-Me, R1 = 5-Me, d R = 8-Me, R1 = 4-Me, e R = R1 = 6-Me
With the aim of choosing more rational conditions for the synthesis of the ester 1a we have studied
several modifications of the method used in its preparation. We have varied both the molar ratio of reagents
entering into the reaction (from 10, 20, 50, and 100% excess of triethylmethanetricarboxylate) and the use of
added solvents with a broad range of boiling points (toluene, xylene, nitrobenzene). Experiments with a three
fold excess of pure triethylmethanetricarboxylate were also carried out.
From the overall series of experiments it was found that the best results could be achieved using
refluxing xylene and a two fold excess of triethylmethanetricarboxylate. It was not possible to avoid formation
of pyridyl-2-amide 3a in any of the experiments. However, this is a direct result of the direct amidation of the
initially formed heterocyclic ester 1a by 2-aminopyridine since, in the first place amide 3a is separated even
when carrying out the reaction in the comparatively low boiling toluene and, in the second, a thermal
intramolecular cyclization of the intermediate ethyl bis(pyridin-2-ylcarbamoyl)acetate needs much more forcing
conditions [9]. None the less, exchange of bromobenzene for xylene leads to some increase in the yield of the
target ester 1a and simultaneous lowering of the amount of the unwanted pyridyl-2-amide 3a.
Many substituted analogs 2b-e behave similarly to the 2-aminopyridine under the conditions of the
studied reaction. The corresponding ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylates 1b-e are
separated in good yields although specific feature are found in some cases. Thus the reaction of
triethylmethanetricarboxylate with 2-amino-3-methylpyridine (2e) gives the ester 1e exclusively. It is likely that
the amidation is suppressed by the neighboring methyl and amino groups in the aminopyridine 2e. In the case of
2-amino-6-methylpyridine (2f) the "normal" reaction scheme is also hindered by the methyl group but also
730

blocks access to the other reaction center (the pyridine nitrogen atom or more accurately to the cyclic imino form
NH group of the intermediate dicarbethoxyacetic acid pyridyl-2-amide). As a result, carrying out the reaction in
bromobenzene gives a mixture of methanetri-N-(6-methylpyridin-2-yl)carboxamide (4) and the 6-methylpyridyl-
1
2-amide 3e in the ratio 1: 1 (from H NMR data) whereas in refluxing xylene amide 3e proves to be the only
product of condensing triethylmethanetricarboxylate with compound 2f. It was interesting to find that it was not
possible to detect even traces of ethyl 2-hydroxy-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxlate in
any of the experiments. This situation allows us to suggest that the route to formation of the amides 3 is not
limited just to the variants discussed above.
Fig. 1. Atomic numbering and spatial structure for the molecule of ester 1a.
С6
О4
C7
С14
С13
C8
С4
N5
N1
С3
С12
С9
С11
С10
О11
С2
О2
O11b
Н1
O2b
Н1а
Fig. 2. System of intermolecular hydrogen bonds in the crystal of ester 1a.
731

It should be noted that the need to separate the reaction products arises in the majority of examples
independently of the reaction conditions. We have shown that the problem can be very efficiently resolved by
treatment of the reaction mixture with hot water or other solvent indicated in the Experimental section for which
amides 3 are virtually insoluble and the esters crystallize with an extremely high degree of purity.
All of the esters obtained 1a-e are colorless, crystalline materials, soluble in DMF and DMSO and of
low solubility in cold water but generally good in hot.
According to X-ray data carried out on ester 1a (Figs. 1 and 2, Tables 1 and 2) it was found that the
bicyclic fragment and atoms O(2) and O(4) lie in a single plane to within 0.02 Å. The alternating bonds in the
TABLE 1. Interatomic Distances (l) in the Structure of Ester 1a
Bond
l, Å
Bond
l, Å
N
(1)–C(10)
1.339(4)
1.386(4)
0.91(5)
C(7)–H(7)
C(8)–C(9)
C(8)–H(8)
C(9)–C(10)
C(9)–H(9)
0.9300
N(1)–C(2)
N(1)–H(1)
C(2)–O(2)
C(2)–C(3)
C(3)–C(4)
C(3)–C(11)
C(4)–O(4)
C(4)–N(5)
N(5)–C(10)
N(5)–C(6)
C(6)–C(7)
C(6)–H(6)
C(7)–C(8)
1.355(6)
0.9300
1.232(4)
1.441(4)
1.414(5)
1.472(5)
1.197(4)
1.500(5)
1.352(4)
1.381(5)
1.353(7)
0.9300
1.404(5)
0.9300
C(11)–O(11)
C(11)–O(12)
O(12)–C(13)
C(13)–C(14)
C(13)–H(13A)
C(13)–H(13B)
C(14)–H(14A)
C(14)–H(14B)
C(14)–H(14C)
1.199(5)
1.321(5)
1.431(5)
1.507(7)
0.9700
0.9700
0.9600
0.9600
1.402(7)
0.9600
TABLE 2. Valence Angles (ω) in the Structure of Ester 1a
Angle
ω, deg
Angle
C(7)–C(8)–H(8)
ω, deg
C(10)–N(1)–C(2)
C(10)–N(1)–H(1)
C(2)–N(1)–H(1)
O(2)–C(2)–N(1)
O(2)–C(2)–C(3)
N(1)–C(2)–C(3)
C(4)–C(3)–C(2)
C(4)–C(3)–C(11)
C(2)–C(3)–C(11)
O(4)–C(4)–C(3)
O(4)–C(4)–N(5)
C(3)–C(4)–N(5)
C(10)–N(5)–C(6)
C(10)–N(5)–C(4)
C(6)–N(5)–C(4)
C(7)–C(6)–N(5)
C(7)–C(6)–H(6)
N(5)–C(6)–H(6)
C(6)–C(7)–C(8)
C(6)–C(7)–H(7)
C(8)–C(7)–H(7)
C(9)–C(8)–C(7)
C(9)–C(8)–H(8)
125.9(3)
112(3)
121(3)
119.9
C(8)–C(9)–C(10)
C(8)–C(9)–H(9)
120.1(4)
120.0
117.1(3)
126.6(3)
116.2(3)
122.0(3)
119.0(3)
118.8(3)
130.9(4)
114.5(3)
114.6(3)
121.1(3)
122.3(3)
116.5(3)
120.4(4)
119.8
C(10)–C(9)–H(9)
120.0
N(1)–C(10)–N(5)
N(1)–C(10)–C(9)
118.9(3)
122.2(3)
118.9(3)
121.5(4)
125.2(4)
113.2(3)
117.7(4)
106.9(4)
110.3
N(5)–C(10)–C(9)
O(11)–C(11)–O(12)
O(11)–C(11)–C(3)
O(12)–C(11)–C(3)
C(11)–O(12)–C(13)
O(12)–C(13)–C(14)
O(12)–C(13)–H(13A)
C(14)–C(13)–H(13A)
O(12)–C(13)–H(13B)
C(14)–C(13)–H(13B)
H(13A)–C(13)–H(13B)
C(13)–C(14)–H(14A)
C(13)–C(14)–H(14B)
H(14A)–C(14)–H(14B)
C(13)–C(14)–H(14C)
H(14A)–C(14)–H(14C)
H(14B)–C(14)–H(14C)
110.3
110.3
110.3
108.6
119.8
109.5
119.3(4)
120.3
109.5
109.5
120.3
109.5
120.2(4)
119.9
109.5
109.5
732

fragment N(5)–C(6)–C(7)–C(8)–C(9)–C(10)–N(1) (bond length values N(5)–C(6) 1.381(5), C(7)–C(8) 1.402(7), C(9)–C(10)
1.404(5) Å are closer to a single bond and C(6)–C(7) 1.353(7), C(8)–C(9) 1.355(6), C(10)–N(1) 1.339(4) Å to a double
bond), the absence of a hydrogen atom on C(3) (it being actually found on the N(1) atom), and also the bond
lengths C(2)–C(3) 1.441(4), C(3)–C(4) 1.414(5), C(3)–C(11) 1.472(5) Å leads us to infer that ester 1a exists in the
O
O
O
O
O
O
–
OEt
OEt
OEt
N
N
N
+
+
–
O
OH
N
O
N
N
H
H
1a
6
5
crystal as an internal salt in which the positive charge is concentrated on the N(1) atom and the negative on the
(3) atom. The lengthening of the C(2)–O(2) bond 1.232(4) Å when compared with its mean value of 1.210 Å [10]
C
which also encourages the intermolecular hydrogen bond N(1)–H(1)···O(2b) (0.33-y, -0.66+x-y, z-0.3) H···O 2.01 Å,
N–H···O 149º and shortening of the C(2)–C(3) bond 1.441(4) Å compared with the mean value of 1.455 Å allow
us to propose that the molecular structure of ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate
(1a) is a resonance hybrid of the two bipolar structures 5 and 6 with a predominance of the 2,4-dioxo form 5.
The carbonyl group of the ester substituent at atom C(3) is slightly non-planar with that of the bicycle
(torsional angle O(11)–C(11)–C(3)–C(2) -16.39º). Such a position of the ester substituent leads to a marked repulsion
between the negative charged oxygen which produces a marked increase in the valence angles O(4)–C(4)–C(3) to
130.9(4) and O(2)–C(2)–C(3) to 126.6(3)º. Shortening of the intramolecular contact H(6)···O(4) also occurs 2.29 Å
(sum of van der Waal radii 2.46 Å [11]). The ethyl substituent in the ester function occurs in an ap-position
relative to the C(3)–C(11) bond and atom C(14) in an ap-conformation relative to the bond C(11)–O(12) (torsional
angles C(13)–O(12)–C(11)–C(3) 176.1 and C(14)–C(13)–O(12)–C(11) -176.1º). An interesting system of intermolecular
N(1)–H(1)···O(2b) and N(1)–H(1)···O(11b) hydrogen bonds is formed thanks to which three molecules are located and
held around a third order axis (Fig. 2).
Hence the X-ray analytical results show that in at least one of the synthesized 3-ethoxycarbonyl-
2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidines (in fact ester 1a) it exists in the bipolar 2,4-dioxo form in the
crystal state.
Mass spectrometric analysis of the structure of esters 1a-e leads to a similar conclusion. It was found that
these compounds form molecular ions under electron impact which fragment by a single scheme as discussed for
ester 1a. The low intensity for the peaks of both the molecular ion and subsequent fragment ions through to the
peak fragment with m/z 121 suggest that, for the 2,4-dioxo form, the probability of initial decomposition of the
ester group is much lower than fission of the C(4)–N and C(2)–C(3) bond which leads to the formation of a
protonated isocyanate with m/z 121 (evidently further isomerizing to the more stable aromatic
oxadiazolopyridine ion.
Attempts to check the purity of esters 1a-e on an instrument package consisting of a gas chromatograph
and mass spectrometer detector proved unsuccessful because of the ready decomposition of the compounds
studied in transition to the gaseous phase. In order to increase the volatility they were converted to the
2-trimethylsilyoxy derivatives which allowed us to confirm the chromatographic purity of the compounds
synthesized and also to record completely the mass spectrometric behavior of modified samples when compared
with the starting esters 1a-e. Blocking of the 2-hydroxy groups (i.e. effectively removing the potential of esters
1a-e for tautomeric conversion) leads to total suppression of the primary fragmentation of the pyrido[1,2-a]-
pyrimidine ring.
733

.
+
O
O
O
–
N
OEt
+
N
H
234 (6.2%)
– OEt
+
O
N
O
NH+
N
O
N
OH
121 (100%)
189 (3.6%)
– CO
.
+
O
N
+
O
N
N
N
OH
121 (100%)
162 (15.8%)
– CO
+
.
+
O
N
N
OH
N
N
121 (100%)
134 (4.1%)
However, the ester 1a has been reported in the literature as the 2-hydroxy-4-oxopyrido[1,2-a]pyrimidine
derivative [8]. Analysis of the 1H NMR spectra of esters 1a-e shows that all of them are of a single type and, in
principle, consistent with either of the possible tautomeric forms. In other words it did not prove possible to
interpret the structure of the compounds obtained in solution on the basis of just this data. For example it is
proposed that in the 1H NMR spectrum of ester 1a the hydroxyl signal occurs at lowest field at 12.30 ppm. This
signal is strongly broadened. At the same time the signal for the residual water at 3.3 ppm is broadened. This
points to a quite rapid proton exchange between the hydroxyl proton and water. The presence of such an
exchange is a major obstacle in correlating the experiments since the hydroxyl proton has time to relax fully
during the pulse sequence mixing time. Hence a correlation for the hydroxyl group is not found in the HMBC
spectrum and it was not possible to localize it in the spectrum. The aromatic proton signals gave a pattern in the
spectrum typical of a pyridine. The pyridine H-6 signal was found at lowest field at 8.89 ppm. Its chemical shift
is governed on the one hand by the presence of a neighboring heterocyclic nitrogen atom and on the other by the
oxygen electron pair at C(4). The H-8 signal is found at quite low field at 8.16 ppm and this is formally a
13
γ-pyridine. The remaining two aromatic protons fall together at 7.35 ppm. The assignment of signals in the C
734

.
+
O
N
O
O
O
N
O
N
OEt
N
OEt
– Me
+
O
Si
291 (25%)
– C2H4
Si
306 (31%)
– OEt
O
+
O
N
O
O
N
N
OH
+
O
N
O
Si
Si
263 (100%)
– CO2
261 (69%)
– CO
.
+
O
O
N
N
N
+
O
N
O
Si
Si
219 (20%)
234 (30%)
NMR spectrum was made on the basis of an HMBC correlation spectrum. In this case there are few signals and
the protonated carbon atoms can be assigned on the basis of the presence of residual correlations via one bond
and the quaternary carbon atoms on the basis of the correlation through 2-3 chemical bonds (Table 3).
8.89
H
4.12
O
O
H2
C
7.35
8.16
130.24
N
166.02
O
154.27
90.23
H
116.77
14.84
CH3
60.04
1.20
147.62
N
159.90
OH
144.21
H
115.97
12.30
H
7.35
The assignment of the C(4) signal follows from its correlation with proton H-6. The bridging carbon atom
between the two heterocyclic nitrogen atoms can be assigned by the correlation with atoms H-6,8 and H-9. The
ester group carbonyl carbon can be assigned from its correlation with the methylene group proton signal. A
correlation could not be observed for two carbon atoms. Since these occur in the unassigned spectrum at 90.23
and 159.90 ppm the first must be the C(3) carbon atom and the second C(2).
735

TABLE 3. Correlations Identified for Ester 1a
НМBC,
one bond
δ, ppm
HMBC, 2–3 chemical bonds
12.30
8.89
8.16
7.35
4.12
1.20
—
130.24
—
154.27, 147.62, 144.21, 116.77
147.62, 130.24
144.21
116.77, 115.97
60.04
147.62, 130.24, 116.77, 115.97
166.02, 14.84
14.84
60.04
13
The C NMR spectra of esters 1a-e also proved to be similar and a detailed study showed that the C(2)
and C(9) signals had a width 3-4 time greater than the width of the remainder. These signals correspond to the
carbon atoms placed close to the N(1) atom.
Signal broadening is frequently associated with the presence of exchange processes, from which it
follows that in esters 1a-e the hydrogen is most likely not fixed at the hydroxyl group 2-OH but the equilibrium
shown in the scheme of the two tautomeric forms occurs, even though this fact is not an unambiguous
confirmation of the presence of such an equilibrium.
Additional useful information also comes from comparison of experimental and calculated 13C NMR
spectra. The calculations carried out for the two tautomers using several programs showed that the calculated
spectra of the 2-hydroxy form are the closest to reality. The carbon atom in position 3 of the
pyrido[1,2-a]pyrimidines are specially indicative in this scheme. Their mean value for the 2-hydroxy form is
89.4 ppm while for all of the remaining tautomers it is about 65 ppm. In the experimental spectra the indicated
signals are found in the 90 ppm region and so it is logical to suggest that the synthesized compounds are
principally in the 2-hydroxy forms in DMSO solution.
EXPERIMENTAL
1
13C NMR spectra of the esters 1a-e, H NMR and also the heteronuclear HMBC spectrum of ester 1a
were obtained on a Varian Mercury-400 spectrometer (100 and 400 MHz respectively). The 1H NMR spectra of
the remaining compounds were taken on a Varian Mercury VX-200 (200 MHz) instrument using DMSO-d6
solvent. In all cases the internal standard was TMS. The mass spectra of esters 1a-e were obtained on a Varian
1200L spectrometer in full scanning mode in the range 45-550 m/z and EI ionization 70 eV. Chromato mass
spectra were recorded on a Hewlett Packard 5890/5972 instrument in full scanning mode in the range 35-700
m/z and EI ionization 70 eV. To increase their volatility the esters 1a-e were converted to the 2-trimethylsilyloxy
derivatives using N,O-bis(trimethylsilyl)trifluoroacetamide and chromatographed on a Hewlett Packard 5MS
column of length 25 m, internal diameter 0.2 mm, stationary phase polysiloxane (5% diphenylpolysiloxane, 95%
dimethylpolysiloxane) of thickness 0.33 µm, and helium gas carrier. Commercial 2-aminopyridines and
triethylmethanetricarboxylate from Fluka were used in this work.
Ethyl 2-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1a). A solution of 2-amino-
pyridine 2a (0.94 g, 0.01 mol) and triethylmethanetricarboxylate (4.21 g, 0.02 mol) in xylene (10 ml,
commercial mixture of isomers) was refluxed for 1-1.5 h allowing the liberated ethanol to evaporate through the
reflux condenser. It was then cooled and hexane (50 ml) was added. After 2-3 h the crystals separated were
filtered off, washed with hexane, and dried (major amounts of unreacted triethylmethanetricarboxylate were
readily regenerated from the filtrate). The compound obtained was treated with boiling water and filtered. The
ester 1a crystallized from the filtrate. Yield 1.78 g (76%); mp 220-222ºC (water). 1H NMR spectrum, δ, ppm (J,
Hz): 12.30 (1H, br. s, OH); 8.89 (1H, dd, J = 7.4 and 1.0, H-6); 8.16 (1H, td, J = 7.8 and 1.4, H-8); 7.41-7.32
736

13
(2H, m, H-7,9); 4.12 (2H, q, J = 7.0, OCH2); 1.20 (3H, t, J = 7.0, CH3). C NMR spectrum, δ, ppm: 166.02
(CO2), 159.90 (C(2)), 154.27 (C(4)), 147.62 (C(9a)), 144.21 (C(8)), 130.24 (C(6)), 116.77 (C(7)), 115.97 (C(9)), 90.23
(C(3)), 60.04 (OCH2), 14.84 (CH3). Mass spectrum, m/z (Irel, %): 234 [M]+ (6.2), 189 [M-OEt]+ (3.6), 162
[M-COOC2H4]+ (15.8), 134 [M-COOC2H4-CO]+ (4.1), 121 (100). Mass spectrum of 2-trimethylsilyl derivative,
m/z (Irel, %): 306 [M]+ (31), 291 [M-Me]+ (25), 263 [M-Me-C2H4]+ (100), 261 [M-OEt]+ (69), 234 [M-OEt-CO]+
(30), 233 [M-OEt-CO]+ (58), 219 [M-Me-C2H4-CO2]+ (20), 206 (38).
Compounds 1b-e were prepared by the preceding method.
Ethyl 7-Chloro-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1b). Yield 70%;
1
mp 203-205ºC (ethanol). H NMR Spectrum, δ, ppm (J, Hz): 12.66 (1H, br. s, OH), 8.88 (1H, d, J = 2.4, H-6);
8.23 (1H, dd, J = 8.3 and 2.4, H-8); 7.38 (1H, d, J = 9.3, H-9); 4.14 (2H, q, J = 7.1, OCH2); 1.21 (3H, t, J = 7.1,
CH3). 13C NMR spectrum, δ, ppm: 165.90 (CO2), 160.50 (C(2)), 153.72 (C(4)), 147.12 (C(9a)), 143.76 (C(8)),
127.84 (C(9)), 123.15 (C(6)), 118.86 (C(7)), 90.03 (C(3)), 60.26 (OCH2); 14.80 (CH3). Mass spectrum, m/z (Irel, %):
268 [M]+ (34.6), 223 [M-OEt]+ (4.7), 196 [M-COOC2H4]+ (27.7), 168 [M-COOC2H4-CO]+ (59.6), 155 (100).
Mass spectrum of 2-trimethylsilyloxy derivative, m/z (Irel, %): 340 [M]+ (38), 325 [M-Me]+ (30), 297 [M-Me-
C2H4]+ (100), 295 [M-OEt]+ (62), 268 [M-OEt-CO]+ (37), 267 [M-OEt-CO]+ (51), 253 [M-Me-C2H4-CO2]+ (26),
240 (30). In both cases the m/z value refers only to the 35Cl isotope. Found, %: C 49.30; H 3.47; N 10.35.
C11H9ClN2O4. Calculated, %: C 49.18; H 3.38; N 10.43.
Ethyl 2-Hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1c). Yield 77%;
1
mp 207-209ºC (water). H NMR spectrum, δ, ppm (J, Hz): 12.31 (1H, br. s, OH); 8.73 (1H, s, H-6); 8.05 (1H,
dd, J = 8.6 and 1.6, H-8); 7.30 (1H, d, J = 8.9, H-9); 4.13 (2H, q, J = 7.2, OCH2); 2.36 (3H, s, CH3); 1.21 (3H, t,
13
J = 7.1, CH2CH3). C NMR spectrum, δ, ppm: 166.11(CO2), 159.82 (C(2)), 154.20 (C(4)), 146.19 (C(9a)); 146.08
(C(8)), 127.72 (C(6)), 126.55 (C(7)), 115.60 (C(9)), 90.22 (C(3)), 60.04 (OCH2), 17.88 (CH(3)), 14.83 (OCH2CH3).
Mass spectrum, m/z, (Irel, %): 248 [M]+ (35.9), 203 [M-OEt]+ (18.9), 176 [M-COOC2H4]+ (42.7), 148
[M-COOC2H4-CO]+ (61.5), 135 (100). Mass spectrum of 2-trimethylsilyloxy derivative, m/z (Irel, %): 320 [M]+
(37), 305 [M-Me]+ (33), 277 [M-Me-C2H4]+ (100), 275 [M-OEt)+ (60), 248 [M-OEt-CO]+ (34), 247 [M-OEt-
CO]+ (52), 233 [M-Me-C2H4-CO2]+ (26), 220 (34). Found, %: C 58.19; H 4.94; N 11.36. C12H12N2O4.
Calculated, %: C 58.06; H 4.87; N 11.28.
Ethyl 2-Hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1d). Yield 72%; mp
1
231-233ºC (water). H NMR spectrum, δ, ppm (J, Hz): 12.26 (1H, br. s, OH); 8.78 (1H, d, J = 7.1, H-6); 7.22
(1H, dd, J = 7.0 and 1.5. H-7); 7.11 (1H, s, H-9); 4.12 (2H, q, J = 7.1, OCH2); 2.44 (3H, s, CH3); 1.20 (3H, t,
13
J = 7.1, CH2CH3). C NMR spectrum, δ, ppm: 166.03 (CO2), 159.89 (C(2)),156.98 (C(4),154.20 (C(9a)), 146.97
(C(8)), 126.59 (C(7)), 118.78 (C(6)), 114.03 (C(9)), 89.73 (C(3)), 59.95 (OCH2), 21.88 (CH3), 14.85 (OCH2CH3).
Mass spectrum, m/z (Irel, %): 248 [M]+ (35.4), 203 [M-OEt]+ (23.4), 176 [M-COOC2H4]+ (59.1), 148 [M-
COOC2H4-CO]+ (41), 135 (100). Mass spectrum of the 2-trimethylsilyloxy derivative, m/z (Irel, %): 320 [M]+
(40), 305 [M-Me]+ (36). 277 [M-Me-C2H4]+ (100), 275 [M-OEt]+ (55), 248 [M-OEt-CO]+ (39), 247 (M-OEt-
CO)+ (48), 233 (M-Me-C2H4-CO2)+ (21), 220 (27). Found, %: C 58.12; H 4.75; N 11.17. C12H12N2O4.
Calculated, %: C 58.06; H 4.87; N 11.28.
Ethyl 2-Hydroxy-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1e). Yield 84%;
1
mp 189-191ºC (acetone). H NMR spectrum, δ, ppm (J, Hz): 1.247 (1H, br. s, OH); 8.82 (1H, d, J = 7.1, H-6);
7.97 (1H, dd, J = 7.1 and 1.0, H-8); 7.26 (1H, d, J = 7.0, H-7); 4.23 (2H, q, J = 7.1, OCH2); 2.41 (3H, s, CH3);
13
1.25 (3H, t, J = 7.1, CH2CH3). C NMR spectrum, δ, ppm: 169.14 (CO2), 159.17 (C(2)), 155.49 (C(4)), 150.08
(C(9a)), 141.04 (C(8)), 127.40 (C(6)), 120.21 (C(9)), 116.00 (C(7)), 89.43 (C(3)), 61.00 (OCH2), 17.73 (CH3), 14.73
(OCH2CH3). Mass spectrum, m/z (Irel, %): 248 [M]+ (32.2), 203 [M-OEt]+ (23.4), 176 [M-COOC2H4]+ (56.3),
148 [M-COOC2H4-CO]+ (65.6), 135 (100). Mass spectrum of the 2-trimethylsilyloxy derivative, m/z (Irel, %):
320 [M]+ (33), 305 [M-Me]+ (30), 277 [M-Me-C2H4]+ (100), 275 [M-OEt]+ (54), 248 [M-OEt-CO]+ (28), 247
[M-OEt-CO]+ (49), 233 [M-Me-C2H4-CO2]+ (32), 220 (36). Found, %: C 58.20; H 4.96; N 11.22. C12H12 N2O4.
Calculated, %: C 58.06; H 4.87; N 11.28
737

X-Ray Investigation of Ethyl 2-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1a).
Crystals of ester 1a are trigonal (water). At 20ºC: a = b = 25.475(8), c = 8.662(7) Å, α = β = 90º, γ = 120º,
V = 4868(4) Å3, Mr 234.2 1, Z = 18, space group R3c, dcalc = 1.438 g/cm3, µ(MoKα) = 0.946 mm-1,
F(000) = 2196. The parameters for the unit cell and intensities of 3200 reflections (1180 independent,
Rint = 0.113) were measured and refined for 25 reflexes in the angle range θ 28-30º on a CAD4 diffractometer
(CuKα radiation, graphite monochromator, ω-scanning). The diffraction experiment was carried out on a crystal of
linear dimensions 4.0×0.2×0.2 mm (3.47 ≤ θ ≤ 74.91º), index range h, k, l: 0 ≤ h ≤ 31, -31 ≤ k ≤ 27, -10 ≤ l ≤ 0).
The structure was solved by a direct method using the SHELXTL program package [12]. The positions
of the hydrogen atoms were calculated geometrically and refined isotropically. The structure was refined in F2
full matrix least squares analysis in the anisotropic approximation for non-hydrogen atoms to wR2 = 0.115 for
1180 reflections (R1 = 0.049, S = 1.089). The full crystallographic information has been placed in the Cambridge
structural data bank (reference CCDC no. 297490). The spatial positions of the atoms in the molecule of the
investigated compound and their numbering are given in Fig. 1 obtained using the ORTEP3 program [13].
Individual interatomic distances are given in Table 1 and valence angles in Table 2.
2-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid pyrid-2-ylamide (3a). The residue
of water insoluble material on the filter (see the example of the synthesis of ester 1a) was dried. Yield 0.2 g
(14%); mp 250-252ºC (DMF). 1H NMR spectrum, δ, ppm: 14.15 (1H, s, OH); 12.00 (1H, s, NH); 8.97-7.10 (8H,
m, Harom.).
Compounds 3b-e were prepared similarly.
7-Chloro-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid 5-chloropyrid-2-ylamide
(3b). Yield 19%; mp 316-318ºC (DMF). 1H NMR spectrum, δ, ppm: 14.01 (1H, s, OH); 12.03 (1H, s, NH);
9.00-7.52 (6H, m, Harom.). Found, %: C 47.77; H 2.41; N 20.32. C14H8Cl2N4O3. Calculated, %: C 47.89; H 2.30;
N 20.19.
2-Hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid 5-methylpyrid-2-ylamide
1
(3c). Yield 11%; mp 324-326ºC (DMF). H NMR spectrum, δ, ppm: 14.43 (1H, s, OH); 11.86 (1H, s, NH);
8.82-7.44 (6H, m, Harom.); 2.42 (3H, s, CH3); 2.26 (3H, s, CH3). Found, %: C 61.85; H 4.47; N 18.20.
C16H14N4O3. Calculated, %: C 61.93; H 4.55; N 18.05.
2-Hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid 4-methypyrid-2-ylamide
(3d). Yield 8%; mp >340ºC (DMF). 1H NMR, δ, ppm: 14.30 (1H, s, OH); 11.94 (1H, s, NH); 8.90-7.00 (6H, m,
Harom.); 2.43 (3H, s, CH3); 2.31 (3H, s, CH3). Found, %: C 61.80; H 4.43; N 18.13. C16H14N4O3. Calculated, %:
C 61.93; H 4.55; N 18.05
2-Hydroxy-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid 6-methylpyrid-2-ylamide
1
(3e). Yield 26%; mp 226-228ºC (DMF). H NMR spectrum, δ, ppm: 14.15 (1H, s, OH); 11.96 (1H, s, NH);
8.03-6.92 (6H, m, Harom.); 2.91 (3H, s, CH3); 2.40 (3H, s, CH3). Found, %: C 61.81; H 4.67; N 18.00.
C16H14N4O3. Calculated, %: C 61.93; H 4.55; N 18.05.
REFERENCES
1.
I. V. Ukrainets, N. L. Bereznyakova, V. A. Parshikova, and S. V. Shishkina, Khim. Geterotsikl. Soedin.,
856 (2007). [Chem. Heterocycl. Сотр., 43, 722 (2007)]
2.
3.
D. D. Dhavale, M. M. Matin, T. Sharma, and S. G. Sabharwal, Bioorg. Med. Chem., 12, 4039 (2004).
M. Varga, Z. Kapui, S. Batori, L. T. Nagy, L. Vasvari-Debreczy, E. Mikus, K. Urban-Svabo, and
P. Aranyi, Eur. J. Med. Chem., 38, 421 (2003).
4.
M. N. Protopopova, R. E. Lee, R. A. Slayden, C. E. Barry, and L. Einck, WO Patent 03096989 (2003).
http://ep.espacenet.com
5.
I. Hermecz, J. Sipos, L. Vasvari-Debreczy, K. Gyires, and Z. Kapui, Acta Physiol. Hung., 80, 225 (1992).
738

6.
7.
G. Roma, M. Di. Braccio, G. Leoncini, and B. Aprile, Farmaco, 48 1225 (1993).
Y. Hamasaki, M. Zaitu, K. Tsuji, M. Miyazaki, R. Hayasaki, E. Muro, S. Yamamoto, I. Kobayashi, M.
Matsuo, T. Ichimaru, and S. Miyazaki, Int. J. Immunopharmacol., 22, 483 (2000).
A. Kutyrev and T. Kappe, J. Heterocycl. Chem., 34, 969 (1997).
I. V. Ukrainets, O. V. Gorokhova, L. V. Sidorenko, and N. L. Bereznyakova, Khim. Geterotsikl. Soedin.,
1191 (2006). [Chem. Heterocycl. Comp., 42, 1032 (2006)].
8.
9.
10.
11.
12.
H.–B. Burgi and J. D. Dunitz, Struct. Correl., Vol. 2, VCH, Weinheim (1994), p. 741.
Yu. V. Zefirov, Krystallografiya, 42, 936 (1997).
G. M. Sheldrick, SHELXTL PLUS PC Version. A System of Computer Programs for the Determination
of Crystal Structure from X ray Diffraction Data, Revision 5.1 (1998).
13.
L. J. Farrugia, J. Appl. Crystallogr., 30, 565 (1997).
739