Синтез нових 1-гідроксі-1,1-бісфосфонових кислот
A synthetic method for the preparation of 1-hydroxyalkyl-1,1-bisphosphonic and 1-hydroxycycloalkyl-1,1-bisphosphonic acids, commonly known as dronic acids, has been developed. These compounds were obtained through the formation of the corresponding silyl derivatives at key stages of the synthesis. T...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
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Ukrainica Bioorganica Acta| _version_ | 1871193534987501568 |
|---|---|
| author | Kolodiazhna, Anastasiia O. Prysiazhnuk, Dmytro V. Sheiko, Serhiy Yu. |
| author_facet | Kolodiazhna, Anastasiia O. Prysiazhnuk, Dmytro V. Sheiko, Serhiy Yu. |
| author_institution_txt_mv | [
{
"author": "Anastasiia O. Kolodiazhna",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Dmytro V. Prysiazhnuk",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Serhiy Yu. Sheiko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Kolodiazhna, Anastasiia O. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:56Z |
| description | A synthetic method for the preparation of 1-hydroxyalkyl-1,1-bisphosphonic and 1-hydroxycycloalkyl-1,1-bisphosphonic acids, commonly known as dronic acids, has been developed. These compounds were obtained through the formation of the corresponding silyl derivatives at key stages of the synthesis. The developed method provides a simple and convenient approach for the preparation of hydroxybisphosphonates. The resulting compounds are promising substances with potential biological activity |
| doi_str_mv | 10.15407/bioorganica2025.02.046 |
| first_indexed | 2026-02-08T07:59:48Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
UDC 661.741+547.293/.294
DOI: https://doi.org/10.15407/bioorganica2025.02.046
46
Ukrainica Bioorganica Acta
www.bi oorgan ica . com.u a
RESEARCH ARTICLE
Synthesis of new 1-hydroxy-1,1-bisphosphonic acids
Anastasiia O. Kolodiazhna*, Dmytro V. Prysiazhnuk, Serhiy Yu. Sheiko
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: A synthetic method for the preparation of 1-hydroxyalkyl-1,1-bisphosphonic and 1-hydroxycycloalkyl-1,1-bisphosphonic acids,
commonly known as dronic acids, has been developed. These compounds were obtained through the formation of the corresponding silyl
derivatives at key stages of the synthesis. The developed method provides a simple and convenient approach for the preparation of
hydroxybisphosphonates. The resulting compounds are promising substances with potential biological activity.
Keywords: bisphosphonic acids; dronic acids; Arbuzov reaction; hydroxybisphosphonates.
Introduction
1-Hydroxy-1,1-bisphosphonic acids, also known as
dronic acids, are a class of bisphosphonic acids
characterized by a stable P-C-P fragment and occupy an
important place in medicinal chemistry due to their strong
affinity for bone mineral and resistance to enzymatic
hydrolysis. Their structural similarity to pyrophosphate
provides the ability to regulate bone metabolism, making
these compounds indispensable in the treatment of
osteoporosis, Paget’s disease, and oncological lesions of the
skeletal system.
Drugs containing the hydroxybisphosphonic fragment
are widely used in pharmacology and medicine. For
example, well-known pharmaceuticals such as Alendronic
acid (Alendra), Ibandronic acid (Bondronat), Zoledronic
acid (Zometa), and Risedronic acid (Atelvia) are
successfully and extensively applied in clinical practice for
the treatment of conditions such as postmenopausal
osteoporosis, skeletal damage in patients with breast cancer
Received:
Revised:
Accepted:
Published online:
03.10.2025
15.10.2025
10.11.2025
30.12.2025
Corresponding author. Tel.: +380-50-870-4187;
e-mail: nastya_k11@ukr.net (A.O. Kolodiazhna)
ORCID: 0000-0002-7990-7830
and metastatic bone lesions, complications following
surgical interventions and radiation therapy, and
malignancy-associated hypercalcemia (Figure 1) [1, 2, 3, 4].
In addition, the antiproliferative activity of dronic acids
against the causative agents of parasitic infections such as
malaria, leishmaniasis, and trypanosomiasis has recently
been actively investigated [5, 6, 7]. Beyond their clinical
applications, dronic acids also serve as valuable synthetic
intermediates, offering opportunities for the development of
new derivatives with a wide spectrum of biological
activities [8, 9] (Figure 1). Therefore, the development of
efficient and selective methods for their synthesis remains a
relevant and important challenge in modern chemistry and
pharmaceutical science.
Results and Discussion
In most cases, hydroxybisphosphonic acids are obtained
using the so-called Merk method – the condensation of
carbonyl compounds with orthophosphoric acid in the
presence of phosphorus trichloride, followed by hydrolysis
[5, 6, 7]. However, this method has certain drawbacks, such
as harsh reaction conditions and rather low selectivity when
complex substrates are used. Another approach employed
for the synthesis of bisphosphonates is the phosphorylation
of carbonyl compounds (a modification of the
Arbuzov/Pudovik reaction), in which carbonyl compounds
react with alkyl phosphites and phosphorus sources (PCl₃,
POCl₃) [10]. Yet this method also has disadvantages,
© Kolodiazhna A.O. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
mailto:nastya_k11@ukr.net
https://orcid.org/0000-0002-7990-7830
A.O. Kolodiazhna et al.
47
NH2
OH
P P
O
OH
OH
O
HO
HO
N
OH
P P
O
OH
OH
O
HO
HO
OH
P P
O
OH
OH
O
HO
HO
N
N
OH
P P
O
OH
OH
O
HO
HO
N
Alendronic acid
(Alendronate)
Ibandronic acid
(Bondronat)
Zoledronic acid
(Zometa)
Risedronic acid
(Atelvia)
Figure 1. Examples of pharmaceutical preparations based on 1-hydroxy-1,1-bisphosphonic acids.
including the need for aggressive reagents and the
occurrence of side reactions. In our work, we obtained
a series of 1-hydroxyalkyl-1,1-bisphosphonic and 1-hydro-
xycycloalkyl-1,1-bisphosphonic acids using the method
described by Marc Lecouvey in 2001 [11] (Figure 2).
This method involves the reaction of acyl chlorides with
tris(trimethylsilyl) phosphite, resulting in the formation of
pentatrimethylsilyl derivatives of bisphosphonic acids as
intermediate products. Previously, this approach had been
used for the synthesis of dronic acids [5, 11].
In most cases, during the synthesis of
hydroxybisphosphonic acids, the pentasilylated interme-
diates are not isolated from the reaction mixture but are
directly subjected to the subsequent hydrolysis step. In our
work, however, we chose to isolate, purify, and characterize
all the intermediate tetrakis(trimethylsilyl)alkyl and
tetrakis(trimethylsilyl)cycloalkyl derivatives of bisphospho-
nic acids. These compounds also represent important
precursors for organic and organophosphorus synthesis.
Notably, these substances have not been previously isolated
or described.
For this purpose, we selected readily available
alkylcarboxylic and cycloalkylcarboxylic acids. In the first
stage of the synthesis, the alkylcarboxylic and
cycloalkylcarboxylic acids were converted into the
corresponding acid chlorides 1(a-g) by treatment with
thionyl chloride in the presence of dimethylformamide
(DMF) as a catalyst. The reaction was carried out at 30 °C
for 1 hour. After evaporation of the reaction mixture, the
obtained acid chlorides were dissolved in dry dichloro-
methane and, upon cooling to 0 °C, tris(trimethyl-
silyl) phosphite was added (Figure 3). The reaction mixture
was then stirred at room temperature for 3 hours. After
completion, dichloromethane was evaporated. To remove
the excess tris(trimethylsilyl) phosphite and by-products,
the resulting viscous oily residue was kept under high
vacuum (0.01 mm Hg) at 100-120 °C with vigorous stirring,
during which volatile components were collected in a liquid
nitrogen trap.
As a result, tetrakis(trimethylsilyl)alkyl and tetrakis-
(trimethylsilyl)cycloalkylalkyl derivatives of bis-
phosphonic acids were obtained as viscous liquids and
characterized using available physical methods (Figure 4
and 5). It should also be noted that the pentasilyl derivatives
of bisphosphonic acids are sensitive to moisture; therefore,
they must be stored under an inert gas atmosphere.
R Cl
O P
P
OSiMe3
OSiMe3
O OSiMe3
OSiMe3
OSiMe3O
R
P
P
OH
O OH
OH
OHO
R
OH
nP(OSiMe3)3
R = Alk, Ar
MeOH
Figure 2. Lecouvey method for obtaining 1-hydroxy-1,1-bisphosphonic acids.
Figure 3. Synthesis of 1-hydroxyalkyl-1,1-bisphosphonic and 1-hydroxycycloalkyl-1,1-bisphosphonic acids.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
48
Figure 4. 1H and 13С NMR spectra of tetrakis(trimethylsilyl)ethyl(trimethyloxy) bisphosphonate.
At the next stage of our experiment, all the obtained
tetrakis(trimethylsilyl)alkyl and tetrakis(trimethylsilyl)-
cycloalkyl derivatives of bisphosphonic acids were
subjected to hydrolysis using a solution of 5 equivalents of
methanol in dry diethyl ether. The reaction proceeded at
room temperature over 12 hours.
After evaporation of the solvents, the residues yielded 1-
hydroxyalkyl-1,1-bisphosphonic and 1-hydroxycycloalkyl-
1,1-bisphosphonic acids, which were converted into their
ammonium salt forms by treatment with an aqueous
ammonia solution. In all cases, the yields were quantitative,
and the bisphosphonic acids were obtained with a chemical
A.O. Kolodiazhna et al.
49
Figure 5. 1H and 13С NMR spectra of hexyldronic acid.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
50
P
P
OH
O OH
OH
O OH
OH
P
P
OH
O OH
OH
O OH
OH
P
P
OH
O OH
OH
O OH
OH
P
P
OH
O OH
OH
O OH
OH
P
P
OH
O OH
OH
O OH
OH
P
P
OH
O OH
OH
O OH
OH
P
P
OH
O OH
OH
O OH
OH
3a 3b 3c 3d
3e 3f 3g
Figure 6. The obtained 1-hydroxyalkyl-1,1-bisphosphonic and 1-hydroxycycloalkyl-1,1-bisphosphonic acids.
purity of no less than 90%, as confirmed by available
physical methods such as ¹H, ¹³C, and ³¹P NMR
spectroscopy, as well as LCMS analysis (Figure 5).
Thus, for the first time, tetrakis(trimethylsilyl)alkyl and
tetrakis(trimethylsilyl)-[cycloalkyl(trimethoxy)methyl]
derivatives of bisphospho-nic acids 2a-g were obtained and
characterized, along with the corresponding 1-hydroxy-
alkyl-1,1-bisphosphonic and 1-hydroxycycloalkyl-1,1-
bisphosphonic acids 3a-g. Some of these compounds (3a-c)
had been described previously, while the remaining ones
(3d-g) were characterized for the first time (Figure 6).
Conclusions
Thus, in this work, we obtained and characterized
tetrakis(trimethylsilyl)[alkyl(trimethoxy)methyl] and tetra-
kis(trimethylsilyl)[cycloalkyl(trimethoxy)methyl] deriva-
tives of bisphosphonic acids, as well as 1-hydroxyalkyl-1,1-
bisphosphonic and 1-hydroxycycloalkyl-1,1-bisphosphonic
acids.
To achieve this goal, we carried out the bisphospho-
rylation reaction of the corresponding acid chlorides of
carboxylic acids. All obtained tetrakis(trimethylsilyl)-
[alkyl(trimethoxy)methyl] and tetrakis(trimethylsilyl)-
[cycloalkyl(trimethoxy)methyl] derivatives of bisphospho-
nic acids, along with the 1-hydroxyalkyl-1,1-bisphosphonic
and 1-hydroxycycloalkyl-1,1-bis-phosphonic acids, were
characterized using all available physicochemical methods.
All the silylated derivatives and compounds 3d–g were
synthesized for the first time with high chemical yields.
Thus, pentasilyl bisphosphonates and 1-hydroxy-1,1-
bisphosphonic acids were obtained – promising compounds
with potential biological activity and valuable building
blocks for the synthesis of new pharmaceuticals and
physiologically active substances.
Experimental section
All solvents were purified according to standard
procedures. All starting materials were obtained from
Enamine LTD or other commercial sources. Melting points
were measured using an MPA 100 OptiMelt automated
melting point system.
¹H and ¹³C NMR spectra were recorded in CDCl₃ on an
“Avance III” 500 MHz spectrometer (“Bruker,” Germany)
at ambient temperature. Chemical shift values (δ) are
reported in parts per million (ppm) relative to
tetramethylsilane (TMS) as the internal standard. Signal
multiplicities are denoted as s (singlet), d (doublet), dd
(doublet of doublets), t (triplet), m (multiplet), br (broad
signal), and q (quartet). Coupling constants (J) are given in
hertz (Hz). All reagents and solvents were used without
special purification. All reactions were carried out in
glassware dried over flame or in a drying oven. The
progress of the reactions was monitored by analytical thin-
layer chromatography (TLC) on silica gel 60F254 plates
(“Merck,” Germany), and the products were visualized
using anisaldehyde. The purity of all compounds was
determined by TLC and NMR analysis.
Synthesis
General procedure for the synthesis of tetra-
kis(trimethylsilyl)[alkyl(trimethoxy)methyl] bisphosphona-
tes and tetrakis(trimethylsilyl)[cycloalkyl(trimethoxy)-
methyl] bisphosphonates 2a-g.
To a pure alkylcarboxylic or cycloalkylcarboxylic acid
(0.017 mol, 1 eq.) were added a few drops of DMF
(catalyst), and the mixture was cooled while thionyl
chloride (0.019 mol, 1.2 eq.) was added dropwise. The
reaction mixture was stirred at 40 °C for 30 minutes (until
gas evolution ceased). After completion, the reaction
mixture was evaporated, and the resulting acid chloride of
the alkylcarboxylic or cycloalkylcarboxylic acid was used
in the next step without further purification.
At the next stage, the obtained acid chlorides (0.017 mol,
1 eq.) were dissolved in dry methylene chloride (70 mL),
cooled to 0 °C, and tris(trimethylsilyl) phosphite (17.6 mL,
0.527 mol, 3.1 eq.) was added dropwise. The reaction
mixture was stirred overnight at room temperature. Upon
completion, the reaction mixture was evaporated and kept
under high vacuum (0.05 mm Hg) at 100-110 ºC to remove
volatile impurities.
A.O. Kolodiazhna et al.
51
The residue consisted of tetrakis(trimethylsilyl)[alkyl-
(trimethoxy)methyl] bisphosphonates and tetrakis(trime-
thylsilyl)[cycloalkyl(trimethoxy)methyl] bisphosphonates
as clear colorless oils.
Tetrakis(trimethylsilyl)[ethyl(trimethoxy)methyl] bisphos-
phonate 2a.
Colorless oil. Yield 65%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 2.06-1.92 (m, 2H), 1.09-1.05 (m, 3H), 0.30 (s,
36H, Si(OMe3)12), 0.20 (s, 9H). NMR 31Р (160 MHz,
СDCl3, 25 ºC) δ 2.43. NMR 13С (125.7 MHz, СDCl3, 25 ºC)
δ 79.81, 78.50, 77.19 (t, J = 164.67, Hz) 8.86, 2.83, 1.36,
1.16, 0.59.
Tetrakis(trimethylsilyl)[propyl(trimethoxy)methyl] bisphos-
phonate 2b.
Colorless oil. Yield 75%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 1.91-1.80 (2Н, m, СН2), 1.59-1.50 (2Н, m, СН2),
0.86 (3Н, t, J = 7.5, СН3), 0.28 (36Н, s, Si(OMe3)12), 0.16
(9Н, s, Si(OMe3)3). NMR 31Р (160 MHz, СDCl3, 25 ºC) δ
2.33. NMR 13С (125.7 MHz, СDCl3, 25 ºC) δ 79.58, 78.25,
76.92 (t, J = 166.25, Hz), 37.74, 17.09, 14.59, 1.30, 0.59.
Tetrakis(trimethylsilyl)[hexyl(trimethoxy)methyl] bisphos-
phonate 2c.
Colorless oil. Yield 77%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 1.96-1.94 (2Н, m, СН2), 1.64-1.52 (2Н, m, СН2),
1.35-1.21 (4Н, m, СН2-СН2), 0.89 (3Н, t, J = 9, СН3), 0.30
(36Н, s, Si(OMe3)12), 0.19 (9Н, s, Si(OMe3)3). Спектр
ЯМР 31Р (160 MHz, СDCl3, 25 ºC) δ 2.35. NMR 31Р (160
MHz, СDCl3, 25 ºC) δ 79.59, 78.26, 76.93 (t, J = 166.25,
Hz), 35.64, 32.63, 23.55, 22.36, 14.07, 1.40, 0.91.
Tetrakis(trimethylsilyl)[heptyl(trimethoxy)methyl] bisphos-
phonate 2d.
Colorless oil. Yield 85%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 1.95-1.81 (2Н, m, СН2), 1.62-1.53 (2Н, m, СН2),
1.32-1.25 (6Н, m, (СН2)3), 0.89 (3Н, t, J = 8.5, СН3), 0.31
(36Н, s, Si(OMe3)12), 0.20 (9Н, s, Si(OMe3)3). NMR 31Р
(160 MHz, СDCl3, 25 ºC) δ 2.38. NMR 13С (125.7 MHz,
СDCl3, 25 ºC) δ 79.57, 78.24, 76.91 (t, J = 166.25, Hz),
34.17, 31.33, 28.77, 24.82, 22.47, 13.97, 0.78, 0.5.
Tetrakis(trimethylsilyl)[cyclobutyl(trimethoxy)methyl]
bisphosphonate 2e.
Colorless oil. Yield 67%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 3.72 (1Н, m, СН), 2.35-1.74 (6Н, m, (СН2)3), 0.22
(42Н, s, Si(OMe3)15). NMR 31Р (160 MHz, СDCl3, 25 ºC) δ
3.33. NMR 13С (125.7 MHz, СDCl3, 25 ºC) δ 79.57, 78.24,
76.91 (t, J = 166.25, Hz), 24.2, 24.14, 17.83, 0.88, 0.54.
Tetrakis(trimethylsilyl)[cyclopentyl(trimethoxy)methyl]
bisphosphonate 2f.
Colorless oil. Yield 65%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 2.5 (1Н, m, СН), 1.87-1.48 (8Н, m,(СН2)4), 0.24
(42Н, s, Si(OMe3)15). NMR 31Р (160 MHz, СDCl3, 25 ºC) δ
2.86NMR 13С (125.7 MHz, СDCl3, 25 ºC) δ 78.47, 77.17,
75.87 (t, J = 162.5, Hz), 28.52, 26.01, 25.40, 0.88.
Tetrakis(trimethylsilyl)[cyclohexyl(trimethoxy)methyl] bis-
phosphonate 2g.
Colorless oil. Yield 65%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 3.01-2.94 (1Н, m, СН), 2.08-1.64 (10Н, m,
(СН2)5), 0.45-0.28 (42Н, s, Si(OMe3)15). NMR 13С (125.7
MHz, СDCl3, 25 ºC) δ 2.09. NMR 31Р (160 MHz, СDCl3,
25 ºC) δ 78.70, 77.38, 76.06 (t, J = 165, Hz), 27.62, 25.65,
25.38.
General procedure for the synthesis of 1-hydroxyalkyl-1,1-
bisphosphonic and 1-hydroxycycloalkyl-1,1-bisphosphonic
acids 3a-g.
Tetrakis(trimethylsilyl)[alkyl(trimethoxy)methyl] bis-
phosphonates and tetrakis(trimethylsilyl)[cycloalkyl(tri-
methoxy)methyl] bisphosphonates 2a-g (0.01 mol, 1 eq.)
were dissolved in dry dimethyl ether, and methanol (0.1
mol, 10 eq.) was added. The reaction mixture was stirred at
room temperature overnight. Upon completion, the solvent
was evaporated, and the residue was converted into the
ammonium salt form by treatment of the aqueous solution
of the bisphosphonic acid with an excess of aqueous
ammonia. The water was then evaporated, and the resulting
white or slightly yellow precipitate was purified by washing
with a 1:1 mixture of isopropanol and chloroform. As a
result, the ammonium salts of 1-hydroxyalkyl-1,1-
bisphosphonic and 1-hydroxycycloalkyl-1,1-bisphosphonic
acids 3a-g were obtained.
1-Hydroxypropyl-1,1-bisphosphonic acid ammonium salt
3a.
White solid. Yield 90%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 1.85-1.72 (2Н, m, СН2), 0.89 (3Н, t, J = 9,5 Hz,
СН3). NMR 31Р (160 MHz, СDCl3, 25 ºC) δ 18.91. NMR
13С (125.7 MHz, СDCl3, 25 ºC) δ 75.67, 74.61, 73.55 (t, J =
132.5 Hz), 26.64, 8.45.
1-Hydroxybutyl-1,1-bisphosphonic acid ammonium salt 3b.
White solid. Yield 91%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 1.82-1.70 (2Н, m, СН2), 1.47-1.38 (2Н, m, СН2),
0.78 (3Н, t, J = 9 Hz, СН3). NMR 31Р (160 MHz, СDCl3,
25 ºC) δ 18.90. NMR 13С (125.7 MHz, СDCl3, 25 ºC) δ
75.22, 74.24, 73.26 (t, J = 156,6 Hz), 35.93, 17.09, 14.13.
1-Hydroxyhexyl-1,1-bisphosphonic acid ammonium salt 3c.
White solid. Yield 87%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 1.73-1.62 (2Н, m, СН2), 1.37-1.29 (2Н, m, СН2),
1.13-1.03 (4Н, m, (СН2)2), 0.65 (3Н, t, J = 8.5 Hz, СН3).
NMR 31Р (160 MHz, СDCl3, 25 ºC) δ 18.01. NMR 13С
(125.7 MHz, СDCl3, 25 ºC) δ 75.49, 74.43, 73.38 (t, J =
132.5 Hz), 33.87, 32.13, 23.4, 21.93, 13.52.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
52
1-Hydroxyheptyl-1,1-bisphosphonic acid ammonium salt
3d.
White solid. Yield 82%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 1.86-1.75 (2Н, m, СН2), 1.47-1.40 (2Н, m, СН2),
1.35-1.15 (6Н, m, (СН2)3), 0.75 (3Н, t, J = 9 Hz, СН3).
NMR 31Р (160 MHz, СDCl3, 25 ºC) δ 18.7. NMR 13С
(125.7 MHz, СDCl3, 25 ºC) δ 75.51, 74.45, 73.39 (t, J =
168.96 Hz), 33.85, 31.08, 29.53, 23.66, 22.12, 13.47.
1-Hydroxycyclobutyl-1,1-bisphosphonic acid ammonium
salt 3e.
White solid. Yield 70%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 2.94-2.84 (1Н, m, СН), 1.95-1.43 (6Н, m, (СН2)3).
NMR 31Р (160 MHz, СDCl3, 25 ºC) δ 17.74. NMR 13С
(125.7 MHz, СDCl3, 25 ºC) δ 75.9, 74.84, 73.78 (t, J =
132.5 Hz), 38.27, 23.68, 17.96.
1-Hydroxycyclopentyl-1,1-bisphosphonic acid ammonium
salt 3f.
White solid. Yield 651H NMR (СDCl3, 500 MHz, 25 ºC)
δ 2.29-2.17 (1Н, m, СН), 1.65-1.59 (2Н, m, СН2), 1.48-1.27
(6Н, m, (СН2)3), NMR 31Р (160 MHz, СDCl3, 25 ºC) δ
18.64. NMR 13С (125.7 MHz, СDCl3, 25 ºC) δ 76.56, 75.52,
74.48 (t, J = 130 Hz), 43.29, 27.39, 24.5
1-Hydroxycyclohexyl-1,1-bisphosphonic acid ammonium
salt 3g.
White solid. Yield 68%. 1H NMR (СDCl3, 500 MHz,
25 ºC) δ 2.75-2.69 (1Н, m, СН), 1.76-1.36 (10Н, m,
(СН2)5NMR 31Р (160 MHz, СDCl3, 25 ºC) δ 19.74. NMR
13С (125.7 MHz, СDCl3, 25 ºC) δ 77.63, 76.68, 75.73 (t, J =
118.87 Hz), 44.29, 27.77, 27.23, 26.43, 25.79, 24.91.
Notes
Acknowledgments. We would like to thank Enamine
Ltd. for the material and technical support for the synthetic
part of this work. The authors thank all the brave defenders
of Ukraine who stood against the russian full-scale invasion
and made this publication possible.
The authors declare no conflict of interest.
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Синтез нових 1-гідрокси-1,1-бісфосфонових кислот
А.О. Колодяжна, Д.В. Присяжнюк, С.Ю. Шейко.
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Розроблено синтетичний метод отримання 1-гідроксиалкіл-1,1-бісфосфонової та 1-гідроксициклоалкіл-1,1-бісфосфонової кислот,
широко відомих як дронові кислоти. Ці сполуки були отримані шляхом утворення відповідних силільових похідних на ключових стадіях синтезу.
Розроблений нами метод забезпечує простий та зручний підхід до отримання гідроксибісфосфонатів. Отримані сполуки є перспективними
речовинами з потенційною біологічною активністю.
Ключові слова: біcфосфонові кислоти; дронові кислоти; реакція Арбузова; гідроксибісфосфонати.
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| id | oai:ojs2.bioorganica.com.ua:article-123 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:15Z |
| publishDate | 2025 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/e3/097e800c70dbc3ec8544da3f9d1106e3.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-1232026-07-19T14:56:56Z Synthesis of new 1-hydroxy-1,1-bisphosphonic acids Синтез нових 1-гідроксі-1,1-бісфосфонових кислот Kolodiazhna, Anastasiia O. Prysiazhnuk, Dmytro V. Sheiko, Serhiy Yu. bisphosphonic acids dronic acids Arbuzov reaction hydroxy bisphosphonates біcфосфонові кислоти дронові кислоти реакція Арбузова гідроксибісфосфонати A synthetic method for the preparation of 1-hydroxyalkyl-1,1-bisphosphonic and 1-hydroxycycloalkyl-1,1-bisphosphonic acids, commonly known as dronic acids, has been developed. These compounds were obtained through the formation of the corresponding silyl derivatives at key stages of the synthesis. The developed method provides a simple and convenient approach for the preparation of hydroxybisphosphonates. The resulting compounds are promising substances with potential biological activity Розроблено синтетичний метод отримання 1-гідроксиалкіл-1,1-бісфосфонової та 1-гідроксициклоалкіл-1,1-бісфосфонової кислот, широко відомих як дронові кислоти. Ці сполуки були отримані шляхом утворення відповідних силільових похідних на ключових стадіях синтезу. Розроблений нами метод забезпечує простий та зручний підхід до отримання гідроксибісфосфонатів. Отримані сполуки є перспективними речовинами з потенційною біологічною активністю V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2025-12-31 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/123 10.15407/bioorganica2025.02.046 Ukrainica Bioorganica Acta; Vol. 20 No. 2 (2025): Ukrainica Bioorganica Acta; 46-52 Ukrainica Bioorganica Acta; Том 20 № 2 (2025): Ukrainica Bioorganica Acta; 46-52 1814-9766 1814-9758 10.15407/bioorganica2025.02 en https://bioorganica.com.ua/index.php/journal/article/view/123/107 Copyright (c) 2025 Anastasiia O. Kolodiazhna, Dmytro V. Prysiazhnuk, Serhiy Yu. Sheiko https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | біcфосфонові кислоти дронові кислоти реакція Арбузова гідроксибісфосфонати Kolodiazhna, Anastasiia O. Prysiazhnuk, Dmytro V. Sheiko, Serhiy Yu. Синтез нових 1-гідроксі-1,1-бісфосфонових кислот |
| title | Синтез нових 1-гідроксі-1,1-бісфосфонових кислот |
| title_alt | Synthesis of new 1-hydroxy-1,1-bisphosphonic acids |
| title_full | Синтез нових 1-гідроксі-1,1-бісфосфонових кислот |
| title_fullStr | Синтез нових 1-гідроксі-1,1-бісфосфонових кислот |
| title_full_unstemmed | Синтез нових 1-гідроксі-1,1-бісфосфонових кислот |
| title_short | Синтез нових 1-гідроксі-1,1-бісфосфонових кислот |
| title_sort | синтез нових 1-гідроксі-1,1-бісфосфонових кислот |
| topic | біcфосфонові кислоти дронові кислоти реакція Арбузова гідроксибісфосфонати |
| topic_facet | bisphosphonic acids dronic acids Arbuzov reaction hydroxy bisphosphonates біcфосфонові кислоти дронові кислоти реакція Арбузова гідроксибісфосфонати |
| url | https://bioorganica.com.ua/index.php/journal/article/view/123 |
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