The First 1-Hydroxypropylidenebisphosphonic Acid with 1,8-Naphthyridinone Substituent: Synthesis and Structure

Article abstract of DOI:10.1134/S1070363218090050

1-Hydroxy-3-(5,7-dimethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-1-yl)propylidenebisphosphonic acid has been synthesized. The structure of the acid and its precursors synthesized for the first time, 3-(5,7-dimethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-1-yl)propionic acid and the corresponding methyl ester, in the solid state and in the DMSO solution has been elucidated by means of vibrational (IR and Raman) and multinuclear (¹H, ¹³C, and ³¹P) NMR spectroscopy.

Full text of DOI:10.1134/S1070363218090050

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 9, pp. 1792–1799. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © G.V. Bodrin, M.P. Pasechnik, A.G. Matveeva, R.R. Aysin, S.V. Matveev, E.I. Goryunov, T.V. Strelkova, V.K. Brel, 2018, published
in Zhurnal Obshchei Khimii, 2018, Vol. 88, No. 9, pp. 1445–1452.
Dedicated to the 110th anniversary of M.I. Kabachnik’s birth
The First 1-Hydroxypropylidenebisphosphonic Acid
with 1,8-Naphthyridinone Substituent: Synthesis and Structure
G. V. Bodrina, M. P. Pasechnika, A. G. Matveevaa*, R. R. Aysina, S. V. Matveeva,
E. I. Goryunova, T. V. Strelkovaa, and V. K. Brela
a Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
ul. Vavilova 28, Moscow, 119991 Russia
*e-mail: phoc@ineos.ac.ru
Received June 28, 2018
Abstract―1-Hydroxy-3-(5,7-dimethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-1-yl)propylidenebisphosphonic
acid has been synthesized. The structure of the acid and its precursors synthesized for the first time, 3-(5,7-
dimethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-1-yl)propionic acid and the corresponding methyl ester, in the
solid state and in the DMSO solution has been elucidated by means of vibrational (IR and Raman) and
multinuclear (1H, 13C, and 31P) NMR spectroscopy.
Keywords: 1-hydroxy-3-(5,7-dimethyl-2-oxo-1,2-dihydro-1,8-maphthyridin-1-yl)propylidenebisphosphonic
acid, 3-(5,7-dimethyl-2-oxo-1,2-dihydro-1,8-maphthyridin-1-yl)propionic acid, methyl 3-(5,7-dimethyl-2-oxo-
1,2-dihydro-1,8-naphthyridin-1-yl)propionate
DOI: 10.1134/S1070363218090050
Bisphosphonates, especially nitrogen-containing
ones, form an important class of pharmacologically
active molecules which have been widely applied in
different fields of medicine [1–5]. Over three recent
decades, a series of inventions related to bisphosphonic
acids and their derivatives have been made, mainly
owing to the medicinal applications of these
compounds. The most prominent studies in this field
since 1970-ies have been performed in groups of
H. Fleisch (Switzerland), E. Breuer (Israel), F.H. Ebetino
(USA), Ch.E. McKenna, (USA), R.G.G. Russell
(Great Britain), P. Kafarski (Poland), M.I. Kabachnik
(Russia), and N.M. Dyatlova (Russia).
kidney, bone, and neurological diseases and cancer and
also as anti-inflammatory drugs [1, 5]. Certain bis-
phosphonates have exhibited herbicide [5, 8] and
antibacterial [9] properties.
Bisphosphonates exhibit strong affinity to metal
cations and are prone to hydrogen bonding [10]. They
have been successfully used as new ligands for the
formation of complexes with radioactive metals, which
can be used in magnetic resonance tomography and
radiotherapy [11] or as chelating agents for the
treatment of intoxication with metals [12].
Derivatives of 1,8-naphthyridine have been widely
used in biochemistry and medicine. The 1,8-
naphthyridine scaffold is found in many natural
species exhibiting a range of biological activity [13].
The coordination chemistry of 1,8-naphthyridine
derivatives has been rapidly developing owing to the
variety of applications of these compounds and their
complexes [13]. Such complexes with the cations of
majority of metals including lanthanides have been
studied to date [13, 14]. Derivatives of 1,8-
naphthyridine have been recognized for the prominent
ability to form hydrogen bonds [15].
The presence of the P–C–P bonds in the
bisphosphonates makes them resistant to enzymatic
hydrolysis, and the nitrogen-containing group in the
alkylene linker between the bisphosphonate moieties
enhances the pharmacological activity of the
compounds in the treatment of bone diseases. The
most active bisphosphonates are these containing one
or two nitrogen atoms in the heteroaromatic fragment
linked to the geminal bisphosphonate moiety [1, 6, 7].
Bisphosphonates have been applied to the treatment of
1792

THE FIRST 1-HYDROXYPROPYLIDENEBISPHOSPHONIC ACID
1793
In view of the above mentioned, it can be expected
that the molecules containing both 1,8-naphthyridine
and bisphosphonate moieties will combine the
biological activity and coordination affinity to metal
cations.
spectroscopy in comparison with its derivatives
containing a neutral [С(O)OMe] or acidic [С(O)OH]
group as well as with 5,7-dimethyl-1,8-naphtyridin-
2(1Н)-one. To the best of our knowledge, the target
acid is the first example of 1-hydroxyalkylidene-
bisphosphonic acid with a 1,8-naphthyridine substituent.
This study aimed to synthesize a new bisphos-
phonic acid containing 1,8-naphthyridine substituent.
Structure of the acid in the solid state and in solutions
was investigated by means of vibrational (IR and
Raman) and multinuclear (1H, 13C, and 31P) NMR
Synthesis of 1-hydroxy-3-(5,7-dimethyl-2-oxo-1,2-di-
hydro-1,8-naphthyridin-1-yl)propylidenebisphosphonic
acid was performed according to the following
scheme.
O
O
(1) H3PO4
+
(2) NaOH
H2N
N
NH2
N
N
N
NH2
1
(1) H2SO4, NaNO2
(2) Na2CO3
CH2=CHC(O)OMe
[NaOH]
N
O
N
N
O
H
C(O)OMe
2
3
(1) H3PO3, PCl3
(2) H2O
AcOH, H2O
N
N
O
N
N
O
PO3H2
OH
PO3H2
C(O)OH
4
5
The starting compound, 2-amino-5,7-dimethyl-1,8-
naphthyridine 1, was prepared via the condensation of
pentane-2,4-dione with 2,6-diaminopyridine. The in
situ diazotization of aminonaphthyridine 1 with
nitrosylsulfuric acid at room temperature followed by
hydrolysis at 0°С afforded high yield of 5,7-dimethyl-
1,8-naphthyridin-2(1Н)-one 2, whose structure was
thus affording methyl 3-(5,7-dimethyl-2-oxo-1,2-
dihydro-1,8-naphthyridin-1-yl)propionate 3 in a high
yield (90%). It should be noted that to the best of our
knowledge this reaction is the first successful example
of the aza-Michael reaction of naphthyridinone 2,
which significantly extends the range of the
preparative use of this available heterocyclic reactant.
Hydrolysis of ester 3 in refluxing aqueous solution of
АсОН gave the corresponding 3-(5,7-dimethyl-2-oxo-
1,2-dihydro-1,8-naphthyridin-1-yl)propionic acid 4 in
close to quantitative yield. IR spectra of the solutions
of ester 3 and acid 4 contained the absorption band of
the heterocycle C=O bond at 1659 cm–1. The ν(C=O)
band of ester 3 was observed at 1734 cm–1 in the IR
spectrum, whereas the same vibrations in the spectrum
of acid 4 appeared at 1713 cm–1 (Table 1). The lower
frequency of the ν(C=O) vibration of acid 4 was due
to the formation of the H-bonds (as in the case of
1
confirmed basing on the data of IR as well as Н and
13С NMR spectroscopy. In particular, the ν(C=O)
vibration was observed at 1667 cm–1 [16], and the
stretching vibration of solvated N–H bond were
observed as a broad band with a maximum at 3100 cm–1
(Table 1). The 13С NMR signal assigned to the С=О
group of 1,8-naphthyridinone heterocycle was observed
at 163.3 ppm (Table 2).
Naphthyridinone 2 added at the C=C bond of
methyl acrylate at heating in the presence of NaOH,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1794
BODRIN et al.
Table 1. Data of vibrational spectra (cm–1) of compounds 2–5 in solid state and in DMSO solution
Co
mpo
und
no.
ν(С=O), ν(PO3H2),
ν(СO2)b ν(PO3H)c
ν(ОH),
ν(NH)
ν(С=O)cycle
Ramana
Naphthyridine rings
IR
Solvent
IR
1667
Ramana
IR IR
IR
2
DMSO
KBr
–
1614, 1597
–
3100
2950
1652, 1640 1645
1609, 1594, 1536, 1433, 1615, 1506,
1590, 1445,
1311
3
4
DMSO
KBr
1659
–
1610, 1588, 1550, 1440
–
1734
1664, 1650 1664, 1648 1610, 1588, 1545, 1438 1611, 1589, 1730
1552, 1296
DMSO
KBr
1659
1641,1660 1635
–
1610, 1588, 1545, 1439
1588, 1545, 1433
–
1713
2920, 2550
3000, 2670
1596, 1589, 1740,
1578, 1548, 1580,
1301
1400
5
DMSO
KBr
1659
–
1610, 1586, 1547, 1447
–
1196,
1010d, 956
1193, 1016, 3310,2700,
2740, 2250
1671, 1635 1659,1632 1535, 1468
1571, 1542,
1431, 1274
978,
2350, 2000
1110, 1076,
1041, 944
Raman spectra of the solutions were not recorded. b Symmetric and asymmetric vibrations of deprotonated СО2– group were observed in the
a
IR spectrum upon formation of the betaine structure (zwitter ion) of acid 4 in solid state. Deprotonated (РО3Н)– group appeared in the
c
zwitter ionic structure of acid 5. d In the spectrum of the solution in DMF.
carboxylic acids); the bands of ν(O–H) in the spectrum
of acid 4 were also typical of the associated carboxylic
acids [16].
marginal (within the experimental accuracy) deviation
of the positions of the observed carbon signals of
heterocyclic fragment of compounds 3 and 4 (Table 2),
in combination with the IR spectroscopy data (Table 1)
evidencing the molecular structure of acid 4 in the
solution.
The 1Н NMR spectra of compounds 3 and
4 contained, besides the signals typical of the dimethyl-
substituted 1,8-naphthyridine fragment, fairly distant
(by ~2 ppm) triplets assigned to the СН2 protons of the
ethylidene bridge separating the heterocyclic system
and the terminal ester (3) or carboxylic (4)
substituents. The singlet signals corresponding to the
carbon atoms of these methylene groups were
observed on the 13С NMR spectra of compounds 3 and
4. These spectra were also remarkable by a very
A method of transformation of terminal amino-
substituted carboxylic acids into the corresponding
nitrogen-containing 1-hydroxyalkylidenebisphosphonic
acids via simultaneous action of Н3РО3 and PCl3 has
been widely used earlier by M.I. Kabachnik et al. [17].
In this study we successfully extended this approach to
the case of acid 4, which was converted into the target
1-hydroxy-3-(5,7-dimethyl-2-oxo-1,2-dihydro-1,8-
naphthyridin-1-yl)propylidenebisphosphonic acid 5
under similar conditions; the product was isolated in
the yield of 35%.1 It should be noted that the use of
cheaper and available 85% H3PO4 at the last
phosphorylation stage instead of Н3РО3 earlier
exploited with 3-aminopropionic acids containing the
nitrogen atom in the piperidine or morpholine cycle
Table 2. Selected
13C NMR spectroscopy data for
compounds 2–5 in DMSO
δС, ppm
С7
Compound
С8a
С2
no.
2
3
4
5
150.04
149.08
149.08
148.81
160.00
159.48
159.53
159.54
163.28
162.05
162.06
162.36
1
About 26% of unreacted acid 4 could be isolated from the
reaction mixture.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

THE FIRST 1-HYDROXYPROPYLIDENEBISPHOSPHONIC ACID
1795
[18], failed in our case: the 31Р NMR spectrum of the
aqueous phase after the reaction showed only traces of
acid 5. Compound 5 was isolated as white fine-
crystalline substance stable in air and exhibiting high
decomposition temperature; its structure and
composition were confirmed by elemental analysis and
the data of IR and NMR spectroscopy. In particular,
the presence of two geminal phosphonic substituents in
the molecule of acid 5 was evidenced by the presence
of triplet splitting of carbon atoms of the СH2С(OH)·
[Р(О)(ОН)2]2 moiety with the corresponding spin-spin
coupling constants JCP. The positions of the signals of
the carbon nuclei of the heterocyclic part of the
molecule were practically identical to those in the
spectrum of compounds 2–4 (Table 2) evidencing the
molecular structure of acid 5. The IR spectrum
confirmed the existence of acid 5 in its neutral form in
the solution (Table 1): the bands of the naphthyridine
scaffold were similar to those of ester 3 and acid 4,
whereas the bands of the phosphonic groups cor-
responded to the ν(P=O) and ν[P–(OH)2] vibrations [20].
ester 3 were split, the bands of the ester С=О and
double bonds of the naphthyridine cycle remained
unchanged (Table 1). That was likely due to the
interaction of the С=О and С–Н groups, since the
vibrations of the gauche- and anti-conformers of ester
3 were practically identical according to the simulation.
The simulation of acid 4 revealed that the energy
minimum corresponded to the structure with
intramolecular N···Н–О hydrogen bond, ν(С=О)
was 1784 cm–1. Frequencies of the ν(С=О) and ν(С=С)
vibrations of the cycle (1677, 1623 cm–1) and of the
vibrations of the naphthyridine cycle involving nitro-
gen atoms (1582, 1551, 1429, 1360, and 1315 cm–1)
for acid 4 and ester 3 were close, i. e. the formation of
the hydrogen bond practically did not affect the
frequencies of these vibrations.
The IR spectrum of solid acid 4 contained the bands
at 1580 and 1400 cm–1 probably corresponding to the
asymmetric and symmetric stretching vibrations of the
deprotonated СО2– group [16] and suggesting the
formation of the betaine structure with the proton
transfer to the nitrogen atom. At the same time, the
frequencies of the naphthyridine cycle remained
practically unchanged, probably due to the formation
of a strong ionic N–H+···–OOC bonding. Hence, the
simulated molecular structure with the hydrogen
bonding was not formed in the crystal, but a proton
transfer to the nitrogen atom occurred with the
formation of a ionic Н-bond. Moreover, a low-
frequency component of ν(С=О) appeared in the IR
and Raman spectra at about 1640 cm–1, i. e. a form of
the molecule with the endocyclic С=О group involved
in the H-bond formation exists. High-frequency part of
the spectrum contained broad bands with maxima at
2920 and 2670 cm–1 assignable to theν(ОН) and ν(NH)
vibrations, respectively [16]. Hence, solid specimen of
acid 4 contained zwitter ions with the N+−H···O−
hydrogen bond and the molecules with the hydrogen
bonding between the СООН and naphthyridine С=О
groups, in contrast to the solution in DMSO where the
dimers similar to the carboxylic acid ones were
formed. It should be noted that the existence of
polymorphic forms differing in the hydrogen bonding
type is characteristic of the majority of amino-
carboxylic acids [20].
IR spectra of the solid specimens of compounds 2–
5 significantly differed from their solutions spectra.
Therefore, we recorded the Raman spectra of the solid
specimens and performed quantum-chemical simula-
tion of the frequencies of the normal vibrations of
molecules of compounds 3 and 4.
The band of endocyclic С=О group was shifted to
lower frequency and split in the IR spectrum of solid
naphthyridine 2: its maximum was observed at
1640 cm–1, and the shoulder was found at 1652 cm–1; a
sufficiently strong band was observed in the Raman
spectrum at 1645 cm–1 due to the contribution from the
ν(С=С) mode (see the simulation below). The decrease
in the frequency of the ν(С=О) band was due to the
formation of the С=О···H–N hydrogen bond, this
interaction was in line with the presence of a broad
ν(NH) band at 2950 cm–1 (Table 1).
Quantum–chemical analysis of molecule 3 revealed
that the frequency of the vibration of the ester С=О
group equaled 1739 cm–1. The vibration of the
endocyclic С=О bond was combined with the C=C
bond vibration, with the corresponding frequencies
1669 [mainly ν(С=О)] 1617 cm–1 and [mainly ν(С=С)].
The frequencies of the vibrations involving nitrogen
atoms were 1580, 1546, 1429, 1360, and 1320 cm–1.
In the case of acid 5, the IR spectrum of the solid
specimen was the most different from the spectrum of
the solution: the number of the bands in the range of
phosphonic groups modes was increased, and the
The bands of the endocycle С=О bond vibration as
well as the stretching and nonplanar bending vibrations
of the CH groups in the IR and Raman spectra of solid
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1796
BODRIN et al.
bands of the naphthyridine cycle vibrations including
the ν(С=О) one were changed (Table 1). The shift of
the strongest Raman band in the spectrum of acid 5
(1274 cm–1) in comparison with the spectra of acid 4
and ester 3 (1301 and 1296 cm–1) was also remarkable.
Since the frequencies of the changed bands
corresponded to the vibrations with predominant
contribution from the unsubstituted nitrogen atom of
the naphthyridine scaffold (simulation data), it might
be suggested that the changes were due to its
protonation. In view of this, the appearance of
additional bands in the range of phosphonic groups
vibrations could be attributed to the deprotonation of
one of them. We therefore believe that acid 5 exists in
the form of zwitter ion in solid state. The more
significant change in the frequency of the
naphthyridine moiety vibrations in the zwitter ion of
acid 5 in comparison to that of acid 4 (Table 1), could
be due to different basicity of the phosphonate and
carbonate ions as well as to the formation of strong
hydrogen bonds between the bisphosphonate groups.
Intermolecular hydrogen bonds of this type have been
observed in structurally similar bisphosphonic acids
[5, 21]. Since both phosphonic groups (PO3H2 and
PO3H–) were involved in strong intermolecular H-
bonds, there was no sufficiently strong acceptor to
form a hydrogen bond with the betaine proton in the
crystal of acid 5, in contrast to that of acid 4. The C=O
and N–H+ groups were evidently involved in weaker
interactions. Hence, acid 5 exists in the form of
zwitter ion in the solid state, like majority of bis-
phosphonic acids with nitrogen-containing substituents
[5].
the bisphosphonic acid 5 and carboxylic acid 4 would
exhibit a range of biological activity and coordination
affinity towards metal cations.
EXPERIMENTAL
Organic solvents (“pure” or “chemically pure”
grade) were dried and purified via conventional
procedures. Deuterated dimethylsulfoxide (DMSO-d6)
from Acros was used as received.
1Н, 13С, and 31Р NMR spectra of 0.1 M. solutions in
DMSO-d6 were recorded using a Bruker AV-400
instrument [400.13 (1H), 100.61 (13C), and 161.98
(31Р) MHz] with internal (residual protons of non-
1
deuterated solvent for Н NMR and carbon atoms of
the deuterated solvent for 13С NMR) or external (85%
1
Н3РО4 for 31Р NMR) reference. The signals in the Н
and 13С NMR spectra were assigned using COSY,
HMQC, and HMBC two-dimensional heteronuclear
correlation spectra. IR spectra were recorded using a
Bruker Tensor 37 spectrometer (solid state: KBr
pellets, 4000–400 cm–1; solutions: 0.05 M. in DMSO-d6
and DMF, 4000–900 cm–1, CaF2 cell, optical path
length 0.062 mm]. Raman spectra (3500–100 cm–1)
were recorded using a Jobin-Yvon LabRAM 300
spectrometer equipped with a microscope and laser
CCD detector. The spectra were excited with a 632.8 nm
line of the He–Ne laser, the power not exceeding
2 mW. Melting points were measured in capillaries
using a short Anschütz thermometer in special heating
block. Elemental analysis was performed in the Labo-
ratory of Microanalysis, Nesmeyanov Institute of Organo-
element Compounds, Russian Academy of Sciences.
A similar feature (the existence of a molecular form
in the solution and of a zwitter ion in the solid state)
have been revealed in our study of bis(3-aminophenyl)
phosphinic acid [22]. At the same time, 1-hyd-
roxybisphosphonic acid with 1Н-pyrazolo[3,4-b]-
pyridine substituent exists in the molecular form both
in the solution and in the solid state [21]. These
examples illustrate the need for experimental study of
the ampholytes structure in the solid state and in
solutions.
Methyl acrylate (Acros, 99%) and phosphorus(III)
chloride (Acros, 98%) were freshly distilled before the
reaction. Phosphorous acid (Acros, 98%) was used as
received. Column chromatography was performed on
130–270 mesh, 60 Å silica gel (Aldrich) for column
chromatography.
2-Amino-5,7-dimethyl-1,8-naphthyridine 1 was syn-
thesized as described elsewhere [23].
5,7-Dimethyl-1,8-naphthyridine-2(1Н)-one (2).
3.2 g (46.4 mmol) of NaNO2 was added in small
portions to a stirred solution of 6.74 g (38.9 mmol) of
aminonaphthyridine 1 in 50 mL of 96% H2SO4 at ~20°C.
The mixture was then stirred during 5 min and poured
onto 200 g of crushed ice. After 10 min, the reaction
mixture was alkalinized with saturated aqueous
solution of Na2CO3 to рН 9.0, then acidified with
In summary, we synthesized the first bisphosphonic
acid with 1,8-naphthyridinone substituent 5. The acid 5
and its precursor (acid 4) were shown to exist in the
molecular form in the solution in DMSO; in the solid
state, acid 5 existed in the form of betaine whereas
acid 4, like aminobenzoic acids, was a mixture of
neutral and zwitter ionic polymorphs. We expect that
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THE FIRST 1-HYDROXYPROPYLIDENEBISPHOSPHONIC ACID
1797
glacial АсОН to рН 5.0, and stored ~12 h at 0°С. The
С14Н16N2O3. Calculated, %: С 64.60; Н 6.20; N 10.76.
formed precipitate was separated, washed with water
(2×50 mL) and acetone (50 mL), and recrystallized
from ethanol. Yield 5.75 g (85%), mp 252–253°С (mp
250–251°С [24]). IR spectrum, ν, cm–1: 485, 547, 732,
792, 838, 856, 909, 929, 1195, 1240, 1310, 1433,
1502, 1536, 1594, 1609, 1640, 1652, 2950. Raman
spectrum, ν, cm–1: 127, 479, 668, 797, 1311, 1391,
3-(5,7-Dimethyl-2-oxo-1,2-dihydro-1,8-naphthyri-
din-1-yl)propionic acid (4). A solution of 3.7 g
(14.2 mmol) of ester 3 in a mixture of 100 mL of
distilled water and 25 mL of glacial АсОН was
refluxed during 7 h, and then kept during ~12 h at
room temperature. The precipitate was separated,
washed with diethyl ether (2×15 mL), and dried in a
vacuum (~12 mmHg) during 1 h at 100°С. Yield 3.33 g
(95%), mp 182–183°С (МеСN). IR spectrum, ν, cm–1:
488, 599, 792, 830, 857, 1152, 1204, 1330, 1379, 1400,
1433, 1488, 1545, 1580, 1588, 1641, 1660, 1740, 2670,
3000. Raman spectrum, ν, cm–1: 456, 547, 626, 978,
1129, 1193, 1249, 1301, 1353, 1375, 1548, 1578, 1589,
1596, 1635, 2930, 3076. 1Н NMR spectrum, δ, ppm (J,
1
1445, 1506, 1590, 1615, 1645, 2927, 3056. Н NMR
7
spectrum, δ, ppm (J, Hz): 2.46 s (3Н, СН3 ), 2.49 s
5
3
(3Н, СН3 ), 6.48 d (1Н, Н3, JHH = 9.6), 6.98 s (1H,
H6), 8.01 d (1Н, H4, 3JHH = 9.6), 11.95 s (1H, NH). 13С
5
7
NMR spectrum, δС, ppm: 18.0 (CH3 ), 24.5 (CH3 ),
111.4 (C4a), 120.0 (C6), 121.7 (C3), 136.3 (C4), 146.3
(C5), 150.0 (C8a), 160.0 (C7), 163.3 (C=O). Found, %:
C 68.96; H 5.71; N 16.17. C10H10N2O. Calculated, %:
С 68.95; Н 5.79; N 16.08.
5
7
Hz): 2.51 s (6Н, CH3 + СН3 ), 2.55 t (2Н, CH2COOH,
3JHH = 7.5), 4.58 t (2H, CH2N, 3JHH = 7.6), 6.60 d (1Н,
Methyl 3-(5,7-dimethyl-2-oxo-1,2-dihydro-1,8-
naphthyridin-1-yl)propionate (3). 5.75 g (33 mmol)
of naphthyridinone 2 and then 0.1 g (2.5 mmol) of
finely ground NaOH were added by portions to a
stirred solution of 4.75 g (55.2 mmol) of methyl
acrylate in 50 mL of anhydrous DMF under argon. The
mixture was heated at 100°С during 4 h, then 4.75 g
(55.2 mmol) of methyl acrylate was added, and the
mixture was heated during 4 h at the same temperature.
The solvent was removed in a vacuum, the residue was
dissolved in 60 mL of benzene and filtered through 6.0 g
of silica gel, the carrier was washed with benzene
(2×20 mL). The organic filtrates were combined and
concentrated to half of the volume; 50 mL of
cyclohexane was added, and the mixture was kept
during ~12 h at 20°C. The precipitate was separated,
washed with hexane (2×25 mL), and dried in a vacuum
(~12 mmHg) during 2 h at 70°С. Yield 7.7 g (90%),
mp 102.0–102.5°С (benzene–cyclohexane). IR spec-
trum, ν, cm–1: 488, 620, 791, 833, 860, 908, 1149, 1159,
1188, 1199, 1248, 1317, 1374, 1438, 1545, 1588, 1610,
1650, 1664, 1730. Raman spectrum, ν, cm–1: 447, 488,
546, 631, 871, 976, 1128, 1190, 1250, 1263, 1296,
1334, 1375, 1552, 1589, 1611, 1648, 1664, 2929,
Н3, 3JHH = 9.6), 7.05 s (1H, H6), 8.03 d (1Н, H4, 3JHH
=
9.5), 12.35 s (1H, OH). 13С NMR spectrum, δС, ppm:
5
7
18.2 (CH3 ), 25.0 (CH3 ), 32.7 (CH2N), 36.9
(CH2CH2N), 112.3 (C4a), 120.1 (C6), 120.7 (C3), 135.1
(C4), 147.0 (C5), 149.1 (C8a), 159.5 (C7), 162.1 (C2), 173.0
(COOH). Found, %: С 63.51; Н 5.78; N 11.43.
С13Н14N2О3. Calculated, %: С 63.40; Н 5.73; N 11.38.
1-Hydroxy-3-(5,7-dimethyl-2-oxo-1,2-dihydro-1,8-
naphthyridin-1-yl)propylidenebisphosphonic acid
(5). A solution of 5.5 g (40 mmol) of PCl3 in 5 mL of
PhCl was added dropwise under argon at stirring to a
mixture of 4.92 g (20 mmol) of acid 4, 3.3 g (40 mmol)
Н3РО3, and 15 mL of PhCl heated at 100°С. The
mixture was heated during 4 h at the same temperature
and then cooled down to ambient. The solvent was
decanted off, the residue was kept in a vacuum
(~12 mmHg) during 0.5 h at 25ºC, then 30 mL of
water was added, and the mixture was heated on a
boiling water bath during 30 min. After cooling to
ambient, the aqueous layer was decanted2 and kept
during 14 days at 0°С. The powder precipitate was
separated, recrystallized from 70% АсОН, washed
with ice water and acetone (10 mL each), and dried in
a vacuum (~12 mmHg) during 3 h at 145°С. Yield 2.0 g
(35%, with respect to reacted acid 4), decomp. >240°С.
IR spectrum, ν, cm–1: 424, 480, 511, 628, 780, 847, 881,
916, 944, 978, 1016, 1041, 1076, 1110, 1193, 1230,
1248, 1271, 1371, 1468, 1535, 1635, 1671, 2000, 2350,
2700, 3310. Raman spectrum, ν, cm–1: 286, 448, 483,
1
3088. Н NMR spectrum, δ, ppm (J, Hz): 2.51 s (6Н,
5
7
CH3 + СН3 ), 2.63 t (2Н, CH2CH2N, 3JHH = 7.4), 3.56
3
s (3H, CH3O), 4.62 t (2H, CH2N, JHH = 7.4), 6.61 d
(1Н, Н3, JHH = 9.6), 7.06 s (1H, H6), 8.04 d (1Н, H4,
3
5
3JHH = 9.7). 13С NMR spectrum, δС, ppm: 18.2 (CH3 ),
7
25.0 (CH3 ), 32.7 (CH2N), 36.9 (CH2CH2N), 51.9
(CH3O). 112.3 (C4a), 120.1 (C6), 120.7 (C3), 135.1 (C4),
147.1 (C5), 149.1 (C8a), 159.5 (C7), 162.1 (C2), 171.9
[C(O)OMe]. Found, %: С 64.69; Н 6.19; N 10.73.
2
1.3 g (25.5%) of unreacted acid 4 was isolated from the tar
residue via recrystallization from 20% AcOH.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1798
BODRIN et al.
Kafarski, P., Lejczak, B., and Forlani, G., Heteroatom.
Chem., 2000, vol. 11, no. 7, p. 449. doi 10.1002/1098-
1071(2000) 11:7<449::AID-HC3>3.0.CO;2-V
612, 817, 1110, 1206, 1232, 1250, 1274, 1380, 1431,
1542, 1571, 1632, 1659, 2931, 3073. 1Н NMR
spectrum, δ, ppm (J, Hz): 2.25 t. t (2H, CH2CH2N,
3
7
3JHH = 7.0, JHP = 14.6), 2.51 s (3Н, СН3 ), 2.54 s (3Н,
9. Leon, A., Liu, L., Yang, Y., Hudock, M.P., Hall, P.,
Yin, F.,Studer, D., Puan, K.-J., Morita, C.T., and
Oldfield, E., J. Med. Chem., 2006, vol. 49, no. 25,
p. 7331. doi 10.1021/ jm060492b
10. Matczak-Jon, E. and Videnova-Adrabińska, V., Coord.
Chem. Rev., 2005, vol. 249, nos. 21–22, p. 2458. doi
10.1016/j.ccr.2005.06.001; Galezowska, J. and
Gumienna-Kontecka, E., Coord. Chem. Rev., 2012,
vol. 256, p. 105. doi 10.1016/j.ccr.2011.07.002
11. Motaleb, H.A., It, I., El-Tawoosy, M., and Mohamed, M.I.,
J. Label. Compd. Radiopharm., 2017, vol. 60, no. 11,
p. 542. doi 10.1002/jlcr.3532; Aufaure, R., Hardoin, J.,
Millot, N., Motte, L., Lalatonne, Y., and Guénin, E.,
Chem. Eur. J., 2016, vol. 22, no. 45, p. 16022. doi
10.1002/chem.201602899; Neves, M., Teixeira, F.C.,
Antunes, I., Majkowska, A., Gano, L., and Santos, A.C.,
Appl. Radiat. Isot., 2011, vol. 69, p. 80.
5
3
СН3 ), 4.67 t (2Н, CH2N, JHH = 6.7), 6.63 d (1Н, Н3,
3JHH = 9.5), 6.93 br. s (5Н, ОН), 7.07 s (1H, H6), 8.05
d (1Н, H4, 3JHH = 9.5). 13С NMR spectrum, δС, ppm (J,
5
7
Hz): 18.2 s (CH3 ), 24.6 (CH3 ), 32.6 s (CH2N), 36.5 t
2
1
(CH2CH2N, JCP = 7.7), 72.1 t [C(OH), JCP = 147.1],
112.6 s (C4a), 120.3 s (C6), 120.7 s (C3), 135.2 s (C4),
147.4 s (C5), 148.8 s (C8a), 159.5 s (C7), 162.4 (C=O).
31Р NMR spectrum: δР 19.1 ppm. Found, %: С 39.62;
Н 4.59; N 6.99; Р 15.54. С13Н18N2О8Р2. Calculated, %:
С 39.81; Н 4.63; N 7.14; Р 15.79.
Quantum-chemical simulation of the frequency and
geometry of the normal vibrations at the RIJCOSX
[25] TPSS [26] D3 [27] Def2-TZVP [28] theory level
was performed using ORCA software [29].
12. Kontecka, E.G., Jezierska, J., Lecouvey, M., Leroux, Y.,
and Kozlowski, H., J. Inorg. Biochem., 2002, vol. 89,
p. 13; Crisponi, G., Nurchi, V.M., and Pivetta, T.,
J. Inorg. Biochem., 2008, vol. 102, p. 209.
Spectral studies were performed at the Center of
Study of Molecular Structure, Institute of Organo-
elemental Compounds, Russian Academy of Sciences.
13. Litvinov, V.P., Adv. Heterocycl. Chem., 2006, vol. 91,
p. 189; Margiotta, N., Savino, S., Gandin, V., Marzano, C.,
and Natile, G., Chem. Med. Chem., 2014, vol. 9,
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Hoffman, J.M., Habecker, C.N., Pietruszkiewicz, A.M.,
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CONFLICT OF INTERESTS
No conflict of interests was declared by the authors.
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