4-Hydroxy-2-quinolones 144*. alkyl-, arylalkyl-, and arylamides of 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and their diuretic properties

Article abstract of DOI:10.1007/s10593-008-0076-7

Alkyl-, arylalkyl-, and arylamides of 2-hydroxy-4-oxo-4H-pyrido[1,2-a] pyrimidine-3-carboxylic acid were prepared with a view to establishing a structure-biological activity relationship. A comparative analysis has been made of their diuretic properties and those of the structurally similar 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides. 2008 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-008-0076-7

Chemistry of Heterocyclic Compounds, Vol. 44, No. 5, 2008
4-HYDROXY-2-QUINOLONES
144*. ALKYL-, ARYLALKYL-, AND
ARYLAMIDES OF 2-HYDROXY-4-OXO-
4H-PYRIDO[1,2-a]PYRIMIDINE-
3-CARBOXYLIC ACID AND THEIR
DIURETIC PROPERTIES
I. V. Ukrainets1, I. A. Tugaibei2, N. L. Bereznyakova1,
V. N. Kravchenko1, and A. V. Turov3
Alkyl-, arylalkyl-, and arylamides of 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid
were prepared with a view to establishing a structure–biological activity relationship. A comparative
analysis has been made of their diuretic properties and those of the structurally similar 4-hydroxy-
2-oxo-1,2-dihydroquinoline-3-carboxamides.
Keywords: amides, 2-hydroxy-4-oxo-4H-pyrido-[1,2-a]pyrimidine-3-carboxylic acids, tricarbonyl-
methane heterocyclic derivatives, diuretic activity, X-ray structural analysis.
The problem of discovering novel classes of chemical substances capable of diuretic action, and
particularly important, those which are highly efficient and safe diuretic medicines has not lost its urgency even
over recent decades. Interesting substances investigated within this scheme are amidated 4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acids derivatives [2, 3]. Although for a long time high diuretic activity has
not been considered a characteristic of quinolone compounds, several of these materials proved extremely
promising and have been subjected to broad pharmacological investigation to this time. With this in mind we
have carried out the synthesis and biological screening to reveal the ability of the series of structurally related
2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid N-R-amides 1-3 to increase the diuretic kidney
function.
It was found that the alkylamides 1a-u (Table 1) can be prepared by the reaction of ethyl 2-hydroxy-4-oxo-
4H-pyrido[1,2-a]pyrimidine-3-carboxylate (4) with a two, or better three, fold excess of the corresponding
alkylamine in refluxing ethanol. It was initially proposed that it was necessary to use quite a large excess of the
_______
* For Communication 143 see [1].
__________________________________________________________________________________________
2
1National Pharmaceutical University, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. Kharkiv
Medicinal Academy of Postgraduate Education, Kharkiv 61176, Ukraine; e-mail: igor_doctor@rambler.ru.
1Taras Shevchenko National University, Kiev 01033, Ukraine, e-mail: nmrlab@univ.kiev.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 718-729, May, 2008. Original article submitted June 8,
2007.
0009-3122/08/4405-0565©2008 Springer Science+Business Media, Inc.
565

amine because of the clear acidic properties of the 2-OH group in ester 4 since at least an equimolar amount of
amine was tied up as the salt 5 but has not proved not strictly correct. The experiments carried out showed that
such ammonium salts are quite stable when formed under normal conditions and, in contrast to analogous salts
formed by 4-hydroxy-2-oxo-3-ethoxycarbonyl-1,2-dihydroquinolines [4], can be readily separated and
characterized.
O
O
O
O
H2N–R
N
N
OEt
OEt
N
N
O
H2N–R
O
OH
H3N+–R
4
5a
H2N
O
R
O
N
O
R
N
N
N
N
H
H
R
OH
N
OH
1a–u
2a–f
O
O
N
N
N
H
N
OH
3
1 a R = CH2CH=CH2, b R = cyclo-C3H5, c R = C3H7, d R = C4H9, e R = i-C4H9, f R = C6H13,
g R = i-C3H7O(CH2)3, h R =PhCH2, i R = 2-ClC6H4CH2, j R = 4-ClC6H4CH2,
k R = 2-MeOC6H4CH2, l R = 4-MeOC6H4CH2, m R = 3,4-(MeO)2C6H3CH2, n R = PhCHMe,
o R = PhCH2CH2, p R = 2-ClC6H4CH2CH2, q R = 3,4-(MeO)2C6H3CH2CH2, r R = furfuryl,
s R = picolyl-2, t R = picolyl-3, u R = picolyl-4; 2 a R = H, b R = 2-F, c R = 3-F,
d R = 4-F, e R = 3-Cl, f R = 4-Cl, 5 a R = CH2CH2OH
In addition it is known [5] that blocking an o-OH group via salt formation markedly lowers the
reactivity of a neighboring ethoxycarbonyl group. From this it quite naturally followed that the low rate of
amidation of ester 4 (or more accurately its salt 5) needed no less than 25-30 h for completion despite the large
excess of amine. Only in the single example of 2-aminoethanol amongst all of the variety of amines used in this
study did the corresponding amide synthesis fail because the salt of ester 4 with this amino alcohol proved
extremely stable to subsequent amidation. A similar selective inertness (but only with relation to ammonia) has
been noted by us before in the ethyl 4-hydroxy-2-oxo- [4] and 4-chloro-2-oxo- [6] 1,2-dihydroquinoline-
3-carboxylates. Moreover, factors determining this observed effect were then identified not so much as the
properties of the individual functional groups or their reactivity but overall as the steric structure of the
interacting molecules approaching one another (as a key to a lock) and in this way forming extremely stable
adducts to further reaction. Most likely in the amidation ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-
3-carboxylate (4) by alkylamines of we are dealing with a similar effect maximaly showing up in the reaction
with 2-aminoethanol. Hence the course of the reaction of ester 4 with amines is not largely determined by the
acidity of the 2-OH group (pKa = 8.91 ± 0.01) but by the structural affinity of the starting components (although
a constructive role for the group giving the reacting molecules a suitable orientation in space is not in doubt).
566

TABLE 1. Characteristics of the 2-Hydroxy-4-oxo-4H-pyrido[1,2-a]-
pyrimine-3-carboxylic Acid N-R-Amides
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, Diuretic activity*,
mp, °C
% of control
%
C
H
N
58.86
58.77
1a
1b
1c
1d
1e
1f
C12H11N3O3
C12H11N3O3
C12H13N3O3
C13H15N3O3
C13H15N3O3
C15H19N3O3
C15H19N3O4
C16H13N3O3
C16H12ClN3O3
C16H12ClN3O3
C17H15N3O4
C17H15N3O4
C18H17N3O5
C17H15N3O3
C17H15N3O3
C17H14ClN3O3
C19H19N3O5
C14H11N3O4
C15H12N4O3
C15H12N4O3
C15H12N4O3
C15H11N3O3
C15H10FN3O3
C15H10FN3O3
C15H10FN3O3
C15H10ClN3O3
C15H10ClN3O3
Hypothiazide
4.63
4.52
4.60
4.52
5.21
5.30
5.85
5.79
5.73
5.79
6.72
6.62
6.18
6.27
4.35
4.44
3.61
3.67
3.75
3.67
4.58
4.65
4.74
4.65
4.90
4.82
4.81
4.89
4.95
4.89
4.04
4.10
5.11
5.18
3.95
3.89
4.13
4.08
4.17
4.08
4.02
4.08
3.87
3.94
3.44
3.37
3.42
3.37
3.31
3.37
3.28
3.19
3.24
3.19
—
17.05
17.13
17.06
17.13
16.88
16.99
16.16
16.08
16.00
16.08
14.59
14.52
13.66
13.76
14.34
14.23
12.68
12.74
12.81
12.74
12.83
12.92
12.85
12.92
11.73
11.82
13.66
13.58
13.68
13.58
12.13
12.22
11.30
11.38
14.65
14.73
18.83
18.91
18.98
18.91
18.95
18.91
15.03
14.94
14.10
14.04
13.95
14.04
14.01
14.04
13.26
13.31
13.22
13.31
—
132-134
185-187
140-142
151-153
166-168
139-141
104-106
198-200
192-194
159-161
181-183
162-164
173-175
146-148
140-142
155-157
168-170
207-209
202-204
189-191
213-215
217-219
264-266
253-255
258-260
263-265
291-293
—
83
71
75
78
76
73
70
84
82
85
80
84
81
68
83
86
80
82
76
79
81
78
75
80
84
81
83
—
-21.6
+ 7.8
-0.4
58.71
58.77
58.20
58.29
59.68
59.76
59.66
59.76
62.38
62.27
59.10
59.01
65.14
65.08
58.20
58.28
58.33
58.28
62.85
62.76
62.82
62.76
60.77
60.84
65.92
66.01
66.07
66.01
59.48
59.40
61.67
61.78
58.86
58.95
60.77
60.81
60.86
60.81
60.88
60.81
63.96
64.05
60.29
60.20
60.15
60.20
60.12
60.20
+ 36.7
-21.1
-72.3
-10.0
-21.5
+ 3.0
-17.9
-52.5
-12.3
-24.0
+ 4.1
+ 10.4
-20.5
-33.6
+ 15.4
-28.5
-3.5
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
1u
2a
2b
2c
2d
2e
2f
-0.7
+ 6.5
+ 2.6
+ 18.4
-4.7
57.15
57.07
57.00
57.07
+ 20.8
+ 26.3
+ 48.0
—
_______
* a + signifies an increase and a – signifies an inhibition of diuresis
relative to the control taken as 100%.
567

For comparison the pKa of the 4-OH group in ethyl 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates
is about 8.6 [7] and similar complications did not arise in their amidation with the exception of the case of
ammonia reported above. It was interesting that the stable salts formed by the alkylamides 1a-u at the 2-OH
group were not observed and their separation would not necessarily demand acidification of the reaction
medium. As will be shown below the amides 1a-u form a totally different system of intramolecular hydrogen
bonds to those in the starting ester 4 [8]. It is possible that such a change in the acidity of the 2-OH group is the
reason for its lowering by several order such that, for example, the pKa of the 2-phenylethylamide 1o is as low as
10.32 ± 0.02.
1
We have measured the H and 13C NMR spectra of the salt 5a to determine its structure and it became
1
clear that the starting components had reacted in the ratio 1:1. In addition we carried out H–13C heteronuclear
correlation experiments through one (HMQC) and through 2-3 (HMBC) chemical bonds. Although the proton
spectrum contained all of the signals for the heterocyclic and monoethanolamine fragments all of the active (OH
and NH2) protons exchanged with water present in the solvent to give a single broad signal at 3.4 ppm. Such a
spectrum appearance did not make it possible to define a clear structure for the compound obtained. A salt
structure is more likely for this in which the hydroxyl group proton of the heterocycle migrates to the basic
amino group of the monoethanolamine to form an ionized compound. As an alternative we can also consider that
the monoethanolamine fragment occurs as a substituent in the heterocyclic ring. We considered that the HMBC
spectrum could determine the true structure of the compound formed. If it is a salt the signals of the
monoethanolamine fragment would not correlate with the carbon atoms of the heterocycle since the bonding
between them is not covalent. If dealing with substitution such a correlation has to occur.
8.57
H
4.05
O
O
H
H
6.79
7.59
128.3
156.0
111.7
H
H
H
168.3
N
O
59.6
93.2
1.18
15.0
H
H
138.0
150.3
2.82
H
N
168.0
O
H
122.0
H
N+
H
H
59.2
H
42.4
6.96
H
OH
H
3.54
1
All of the heteronuclear H–13C HMQC and HMBC correlations found are given in Table 2. With their
help we could achieve a secure assignment of the signals in the carbon spectrum and deduce the structure of the
compound. Hence the presence of an HMBC correlation between the methylene group protons in the ester
fragment and the carbon atom signal at 168.3 ppm allows us to assign this signal to the carbonyl group of this
substituent despite the fact that it is extremely close to a further signal at 168.0 ppm in the spectrum. Similarly
the presence of an HMBC correlation for the H-6 proton at 8.57 ppm and the carbon atom signal at 156.0 ppm
shows that this is the carbonyl C-4 carbon. The signal assignments made in this way are shown in the scheme
and the arrows show the basis for the HMBC correlations.
The signals for which HMBC correlations were not observed proved to be those with chemical shifts of
168.0 and 93.2 ppm. We assign these to the C-2 and C-3 atoms of the pyrido[1,2-a]pyrimidine ring respectively
and these are in agreement with the 13C nuclea chemical shifts for compounds of similar structure studied by us
before [8].
568

TABLE 2. Heteronuclear 1H–13C Correlations Found for Salt 5a
δ, ppm
НМQC
HMBC
8.57
7.59
6.96
6.79
4.05
3.54
2.82
1.18
128.3
138.0
122.0
111.7
59.6
156.0; 150.3; 138.0; 111.7
150.3; 128.3
150.3; 111.7
128.3; 122.0
168.3; 15.0
42.4
59.2
42.4
15.0
59.2
59.6
As is evident from data in Table 2 HMBC correlations between the protons signals of the
monoethanolamine and the carbon signals of the heterocyclic system are absent. From this we can deduce the
studied compound 5a has the structure of a salt. An additional supporting argument came from the spectrum
measured in trifluoroacetic acid. In this solvent [for protonsof the monoethanolamine two signals for each type
of the methylene groups] were observed in the intensity ratio 2:1. This suggests that an equilibrium is
established in this solvent between compound 5a and the salt of monoethanolamine and trifluoroacetic acid.
In contrast to the alkyl- and arylalkylamines, anilines don't show sterical affinity to ester 4 hence the
corresponding 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid anilides 2a-f (Table 1) were
formed in good yields using an equimolar ratio of reagents but under more rigid conditions. Evidently this
method is also applicable to the synthesis of hetarylamides although not specifically considered in this report but
the pyridin-2-ylamide 3 tested in biological investigation as an azabiostere of the anilide 2a (was obtained by
condensation of the 2-aminopyridine with triethylmethanetricarboxylate as a side product [8]).
All of the alkylamides 1 and anilides 2 are colorless crystalline materials virtually insoluble in cold
water, poorly in hot, and moderately soluble in DMF ad DMSO at room temperature. The structure in all of the
1
cases was confirmed by H NMR spectroscopy (Table 3) and, in the case of the 2-methoxybenzylamide 1k
additionally by X-ray analytical analysis (see Figure 1 and Tables 4, 5). The bicyclic fragment of the molecule
of this compound and the O(1), O(2), C(9), O(3), N(3), and C(10) atoms lie in a single plane within an accuracy of 0.01
Å which is due to the formation of strong intramolecular hydrogen bonds O(1)–H(10)···O(3): H···O 1.43 Å, O–H···O
157º ad N(3)–H(3N)···O(2): H···O 1.91 Å, N–H···O 140º. This same reason leads to a marked redistribution of
Fig. 1. Structure of the amide 1k molecule with atomic numbering.
569

570

571

TABLE 4. Bond Lengths (l) in the Amide 1k Structure
Bond
l, Å
Bond
l, Å
O
(1)–C(8)
1.323(2)
1.257(2)
1.417(3)
1.336(2)
1.382(2)
1.329(2)
1.415(3)
1.394(3)
1.408(2)
1.468(2)
1.381(2)
1.391(3)
1.388(3)
O(2)–C(6)
O(4)–C(16)
N(1)–C(1)
N(2)–C(1)
N(2)–C(6)
N(3)–C(10)
C(2)–C(3)
C(4)–C(5)
C(7)–C(8)
C(10)–C(11)
C(11)–C(16)
C(13)–C(14)
C(15)–C(16)
1.234(2)
1.372(2)
1.330(2)
1.375(2)
1.440(2)
1.451(2)
1.352(3)
1.341(3)
1.402(2)
1.505(2)
1.391(2)
1.374(3)
1.382(2)
O(3)–C(9)
O(4)–C(17)
N(1)–C(8)
N(2)–C(5)
N(3)–C(9)
C(1)–C(2)
C(3)–C(4)
C(6)–C(7)
C(7)–C(9)
C(11)–C(12)
C(12)–C(13)
C(14)–C(15)
electron density in the molecule which is revealed in lengthening of the O(2)–C(6) bonds 1.234(2) and O(3)–C(9)
1.257(2) Å when compared with their mean value of 1.210 Å [9] and also the N(1)–C(1) 1.330(2) and C(7)–C(8)
1.402(2) Å bonds (mean values 1.313 and 1.331 Å respectively). The O(1)–C(8) 1.323(2), N(1)–C(8) 1.336(2), and
C(6)–C(7) 1.408(2) Å bonds are shortened when compared with their mean values of 1.333, 1.376, and 1.455 Å.
It should be noted that the intramolecular hydrogen bonds in the molecule of amide 1k are stronger than
those reported by us previously for the structurally closely related 2-hydroxy-8-methyl-4-oxo-4H-pyrido-
[1,2-a]pyrimidine-3-carboxylic acid diethylaminoethylamide [10]. As a result of this the C(1)–N(1) and N(1)–C(8)
bonds become virtually equal in length. Attention is also drawn to the marked difference in the strength of the two
intramolecular hydrogen bonds giving a basis for confirming that the predominant contribution to delocalization
relates to the very strong O–H···O bond. Hence the geometry of the substance studied can be represented as a
resonance hybrid of the two canonical structures 1k and 6, the main contribution to which relates somewhat
differently to the case of the above mentioned diethylaminoethylamide the bizwitterionic form 6.
TABLE 5. Valence Angles (ω) in the Amide 1k Structure
Angle
ω, deg
Angle
ω, deg.
C(16)–O(4)–C(17)
118.2(2)
121.5(2)
117.6(2)
123.5(2)
116.8(2)
120.3(2)
120.8(2)
117.1(2)
118.8(2)
121.8(2)
120.5(2)
120.8(2)
119.4(2)
118.2(2)
118.0(2)
119.4(2)
119.4(2)
115.4(1)
C(1)–N(1)–C(8)
116.8(2)
120.9(2)
122.6(2)
119.7(2)
121.1(2)
119.5(2)
128.0(2)
114.9(2)
119.4(2)
114.4(2)
125.1(2)
119.8(2)
115.3(2)
123.8(2)
121.4(2)
120.4(2)
123.5(2)
121.2(2)
C(1)–N(2)–C(5)
C(5)–N(2)–C(6)
N(1)–C(1)–N(2)
N(2)–C(1)–C(2)
C(2)–C(3)–C(4)
C(4)–C(5)–N(2)
O(2)–C(6)–N(2)
C(8)–C(7)–C(6)
C(6)–C(7)–C(9)
O(1)–C(8)–C(7)
O(3)–C(9)–N(3)
N(3)–C(9)–C(7)
C(12)–C(11)–C(16)
C(16)–C(11)–C(10)
C(14)–C(13)–C(12)
C(16)–C(15)–C(14)
O(4)–C(16)–C(11)
C(1)–N(2)–C(6)
C(9)–N(3)–C(10)
N(1)–C(1)–C(2)
C(3)–C(2)–C(1)
C(5)–C(4)–C(3)
O(2)–C(6)–C(7)
C(7)–C(6)–N(2)
C(8)–C(7)–C(9)
O(1)–C(8)–N(1)
N(1)–C(8)–C(7)
O(3)–C(9)–C(7)
N(3)–C(10)–C(11)
C(12)–C(11)–C(10)
C(11)–C(12)–C(13)
C(13)–C(14)–C(15)
O(4)–C(16)–C(15)
C(15)–C(16)–C(11)
572

OMe
OMe
+
HN
O
HN
O
–
N
O
N
O
+
–
N
OH
N
OH
1k
6
The methoxyphenyl substituent in amide 1k is placed almost perpendicularly to the C(9)–N(3) bond
(torsional angle C(9)–N(3)–C(10)–C(11) 80.3(2)º) and this is due to the repulsion between the aromatic ring and the
carbamide group [shortened intramolecular contacts H(12)···C(9) 2.76 Å (sum of van der Waal radii [11] 2.87 Å),
H(12)···N(3) 2.53 (2.67 Å)] and is coplanar to N(3)–C(10) bond (torsional angle N(3)–C(10)–C(11)–C(12) = -3.7(3)º). The
methoxy group deviates from the plane of the aromatic ring (torsional angle C(17)–O(4)–C(16)–C(15 9.4(3)º) as a
result of the repulsion between the methyl group atoms and the benzene ring (shortened intramolecular contacts
H
(15)···C(17) 2.50 (2.87), H(15)···H(17b) 2.26 (2.34), H(15)···H(17a) 2.24 (2.34), H(17a)···C(15) 2.77 (2.87), and H(17b)···C(15)
2.69 (2.87 Å)).
A study of the diuretic properties of all of the 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-
3-carboxylic acid N-R-amides 1-3 has been made in parallel and in comparison with hypothiazide by a standard
method [12] using white, nonpedigree male mice of mass 180-200 g. The studied compounds were introduced
per os at a dose of 40 mg/kg (the effective dose of hypothiazide) as a fine aqueous suspension stabilized by
Tween-80. All laboratory animals received an aqueous charge through a stomach probe based on 25 mg/kg. The
urinary secretion was measured over 4 h. Comparing the data in Table 1 for the pharmacological study of
amides 1-2 with the results of our previous work it should be noted that exchange of the 4-hydroxy-2-oxo-
1,2-dihydroquinoline ring for the 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine is accompanied by a marked
lowering of diuretic activity in the majority of cases hence the search for potential diuretics can be identified as
of little promise. Principally such a conclusion relates to the alkyl and arylalkylamides 1a-u. The pyridin-
2-ylamide 3 also shows activity at a level of only +8.4% when compared to the control and almost no difference
to the unsubstituted anilide 2a. In the series of substituted anilides 2b-f against a background of the overall
tendency to fall, the dependence of the diuretic effect on the substituent in the aromatic ring is preserved as in
the 4-hydroxy-2-oxoquinoline analogs. Thus amongst the monofluoroanilides the most active is the meta isomer
2c while the diuresis is always expressed more clearly in the para-substituted compound for the chloro
derivatives.
EXPERIMENTAL
1H NMR spectra for the N-R-amides 1 and 2 were recorded on a Varian Mercury VX-200 instrument
1
(200 MHz). The H and 13C NMR spectra and also the heteronuclear HMQC and HMBC experiments were
carried out on a Varian Mercury-400 spectrometer (400 and 100 MHz respectively). All 2D experiments were
carried out with gradient selection of useful signals. The mixing times in the pulse sequence were respectively
2-3
1JCH = 140 and
J
CH
= 8 Hz. The numbers of increments in the HMQC and HMBC experiments were 128 and
400 respectively. In all cases the solvent used was DMSO-d6 and the internal standard TMS. The study of the
acid-base equilibrium was carried out using method [13] with 80% aqueous dioxane solvent. Preparation of a
mixed solvent used freshly distilled bidistillate freed from CO2 and dioxane for UV from the Labscan company.
The titrant was 0.01 molar aqueous KOH solution freed from CO2. The concentration of the titration solution
was 0.0005 molar at the neutral point. The potentiometric titration was carried out on a SevenEasy S-20-K
Mettler Toledo stationary pH meter using an InLab 413 combination electrode at 25ºC. Titrations were
performed three times for each compound. The accuracy of the obtained results was estimated by mathematic
statistics [14].
573

2-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic Acid Alkylamides 1a-u (General
Method). The corresponding alkylamine (0.03 mol) was added to a solution of ethyl 2-hydroxy-4-oxo-
4H-pyrido-[1,2-a]pyrimidine-3-carboxylate 4 (2.34 g, 0.01 mol) in ethanol (10 ml) and refluxed for 30 h. The
reaction mixture was cooled, the precipitated amide 1a-u filtered, carefully washed with ether, and dried.
X-ray Structural Study. Crystals of the amide 1k are monoclinic (ethanol), at 20ºC: a = 7.877(1),
b = 10.303(1), c = 18.885(2) Å, β = 101.19(1)º, V = 1503.4(2) Å3, Mr = 325.32, Z = 4, space group P2/n,
dcalc = 1.437 g/cm3, µ(MoKα) = 0.105 mm-1, F(000) = 680. Unit cell parameters and intensities of 6319
reflections (2607 independent with Rint = 0.021) were measured on an Xcalibur-3 diffractometer (MoKα
radiation, CCD detector, graphite monochromator, ω scanning to 2θmax = 50º).
The structure was solved by a direct method using the SHELXTL program package [15]. The positions
of the hydrogen atoms were revealed from electron density difference synthesis and refined isotropically. The
structure was refined in F2 full matrix least squares analysis in the anistropic approximation for non-hydrogen
atoms to wR2 = 0.093 for 2549 reflections (R1 = 0.035 for 1457 reflections with F > 4σ(F), S = 0.883). The full
crystallographic information has been placed in the Cambridge structural database (reference CCDC 650598).
Interatomic distances and valence angles are given in Tables 4 and 5.
2-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic Acid Anilides 2a-f (General Method).
A mixture of compound 4 (2.34 g, 0.01 mol), the corresponding aniline (0.01 mol), and DMF (1 ml) was stirred
and held for 15 min at 160ºC. After cooling, ethanol (10-15 ml) was added and triturated carefully. The
precipitated anilides 2a-f were filtered off, washed with alcohol, dried, and crystallized from DMF.
2-Hydroxyethyl-1-ammonium 3-Ethoxycarbonyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-olate (5a).
2-Aminoethanol (0.9 ml, 0.015 mol) was added to a solution of compound 4 (2.34 g, 0.01 mol) in ethanol
(20 ml) and carefully stirred. A white precipitate formed immediately after mixing the reagents. It was filtered
off, carefully washed with ethanol, and dried. For the separation of salts of ester 4 with other alkylamines it was
1
necessary to dilute the reaction mixture with ether. Yield 2.8 g (95%); mp 226-228ºC. H NMR spectrum, δ,
ppm (J, Hz): 8.57 (1H, d, J = 6.8, H-6); 7.59 (1H, t, J = 7.2, H-8); 6.96 (1H, d, J = 8.8, H-9); 6.79 (1H, t, J = 6.8,
H-7); 4.05 (2H, q, J = 7.2, OCH2CH3); 3.54 (2H, t, J = 5.2, OCH2CH2N); 2.82 (2H, t, J = 5.2, OCH2CH2N); 1.18
(3H, t, J = 7.2, CH3). 13C NMR spectrum, δ, ppm: 168.3 (CO2), 168.0 (C(2)), 156.0 (C(4)), 150.3 (C(9a)), 138.0
(C(8)), 128.3 (C(6)), 122.0 (C(9)), 111.7 (C(7)), 93.2 (C(3)), 59.6 (OCH2CH3), 59.2 (OCH2CH2N), 42.4
(OCH2CH2N), 15.0 (CH3). Found, %: C 52.97; H 5.92; N 14.34. C11H9N2O4·C2H8NO. Calculated, %: C 52.88;
H 5.80; N 14.23.
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