Rational synthesis of α-hydroxyphosphonic derivatives including dronic acids

Article abstract of DOI:10.1080/10426507.2018.1555537

New, green methods have been elaborated for the syntheses of α-hydroxyphosphonates and α-hydroxymethylenebisphosphonic derivatives (HMBPs, dronates). α-Hydroxyphosphonates were prepared via the Pudovik reaction, while the synthesis of HMBPs has been performed in the three-component reaction of carboxylic acids, phosphorus trichloride and phosphorus acid.

Full text of DOI:10.1080/10426507.2018.1555537

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Rational synthesis of α-hydroxyphosphonic
derivatives including dronic acids
Alajos Grün, Zita Rádai, Dávid Illés Sőregi-Nagy, István Greiner & György
Keglevich
To cite this article: Alajos Grün, Zita Rádai, Dávid Illés Sőregi-Nagy, István Greiner & György
Keglevich (2019): Rational synthesis of α-hydroxyphosphonic derivatives including dronic acids,
Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2018.1555537
To link to this article: https://doi.org/10.1080/10426507.2018.1555537
Published online: 09 Jan 2019.
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1555537
SHORT COMMUNICATION
Rational synthesis of a-hydroxyphosphonic derivatives including dronic acids
a,ꢀ
a
a
b
a
Alajos Gr u€ n , Zita R ꢀa dai , D ꢀa vid Ill ꢀe s S o} regi-Nagy , Istv ꢀa n Greiner , and Gy o€ rgy Keglevich
a
b
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary; Gedeon Richter
Plc, Budapest, Hungary
ABSTRACT
ARTICLE HISTORY
New, green methods have been elaborated for the syntheses of a-hydroxyphosphonates and
a-hydroxymethylenebisphosphonic derivatives (HMBPs, dronates). a-Hydroxyphosphonates were
prepared via the Pudovik reaction, while the synthesis of HMBPs has been performed in the three-
component reaction of carboxylic acids, phosphorus trichloride and phosphorus acid.
Received 28 September 2018
Accepted 30 November 2018
KEYWORDS
a-Hydroxymethylenebispho-
sphonates; a-hydroxy-
phosphonates; Pudovik
reaction; green syntheses;
sulfolane; ionic liquid
GRAPHICAL ABSTRACT
Introduction
a-Hydroxyphosphonic acids and related derivatives are of
[
1]
special importance due to their biological activity.
a-Hydroxymethylenebisphosphonic derivatives represent a
significant class within this family, as they are commercially
[
2]
available drugs against osteoporosis. Nowadays, environ-
mentally-friendly methods including suitable reagents and
solvents are in the focus. The application of ionic liquids
Scheme 1. Solvent-economic synthesis of a-hydroxyphosphonates via the
Pudovik reaction.
[
3]
(ILs) as solvents or additive is a new trend. During our
research targeting the synthesis of a-hydroxyphosphonates
and a-hydroxymethylenebisphosphonic derivatives, special
efforts were devoted to green chemical aspects.
Results and discussion
a-Hydroxyphosphonates are usually synthesized in the
Pudovik reaction of an oxo compound and dialkyl phos-
phite, under catalytic and solvent-free conditions. However,
in most of the cases, a considerable amount of organic
solvents is used during the work-up including extraction,
[
4,5]
column chromatography or recrystallization.
A new, solvent-economic variation of the Pudovik reac-
tion was elaborated by us. According to our new method,
for the triethylamine-catalyzed reaction of a substituted
[
6]
Scheme 2. Synthesis of dronic acid derivatives in sulfolane, or in the presence
of an IL additive, or using both agents.
benzaldehyde (1) and dialkyl phosphite, a minimal amount the crystallization of product 2 that could be separated by a
[
6,7]
of acetone was used. After the reaction was complete, some simple filtration (Scheme 1).
Although, a small quantity
n-pentane precipitant was added to the mixture, resulting in of acetone and pentane was used in the reaction, there was
CONTACT Alajos Gr u€ n
agrun@mail.bme.hu
ß 2018 Taylor & Francis Group, LLC

€
A. GRUN ET AL.
2
Table 1. Yields and purities of dronic acid derivatives in sulfolane, or in the presence of an IL additive, or using both agents.
P-reagents (equiv.)
Dronic derivatives
Solvent or additive
Sulfolane
.1 equiv. [bmim][BF
Sulfolane
.6 equiv. [bmim][BF
PCl
3
H
3
PO
3
Purity (%)
Yield (%)
Ibandronate (4a)
3
3
2
2
2
2
2
2
2
2
2
2
2
2
100
99
100
99
99
100
100
83
90
74
75
93
58
66
0
4
]
]
Zoledronic acid (5a)
0
4
Sulfolane þ 0.6 equiv. [bmim][BF
4
]
Risedronic acid (6a)
Sulfolane
0
4
.6 equiv. [bmim][BF ]
no need for more solvent, as no purification steps
were necessary.
[2] Hudson, H. R.; Wardle, N. J.; Bligh, S. W. A.; Greiner, I.; Grun,
A.; Keglevich, G. N-Heterocyclic Dronic Acids: Applications
and Synthesis. Mini. Rev. Med. Chem. 2012, 12, 313–325.
The most often applied P-reagents in the synthesis of
a-hydroxymethylenebisphosphonic derivatives are phos-
phorus trichloride and phosphorous acid, and the preferred
solvent is methanesulfonic acid (MSA). But MSA is not con-
sidered an environmentally friendly solvent. The synthesis of
a few dronic acid derivatives was also performed in
sulfolane, or in the presence of an IL additive, or in the
[
3] R ꢀa dai, Z.; Keglevich, G. Synthesis and Reactions of
a-Hydroxyphosphonates. Molecules. 2018, 23, 1439–1468.
[
4] Rao, K. U. M.; Sundar, C. S.; Prasad, S. S.; Rani, C. R.; Reddy,
C. S. Neat Synthesis and Anti-oxidant Activity of
a-Hydroxyphosphonates. Bull. Korean Chem. Soc. 2011, 32,
3343–3347. DOI: 10.5012/bkcs.2011.32.9.3343.
[
5] Kong, D. L.; Liu, R. D.; Li, G. Z.; Zhang, P. W.; Wu, M. S. A
Rapid, Convenient, Solventless Green Approach for the
Synthesis of a-Hydroxyphosphonates by Grinding. Asian J.
Chem. 2014, 26,1246–1248. DOI: 10.14233/ajchem.2014.16606.
[
8]
combination of sulfolane/IL. This approach was extended
[
9]
to the synthesis of ibandronate (4a) and two representa-
[
10]
tives of the third generation agents zoledronic acid (4b)
and risedronic acid (4c)
[6] Keglevich, G.; R ꢀa dai, Z.; Kiss, N. Z. To Date the Greenest
Method for the Preparation of a-Hydroxyphosphonates from
Substituted Benzaldehydes and Dialkyl Phosphites. Green
Process. Synth. 2017, 6, 197–201.
[
11]
(Scheme 2, Table 1). The joint
use of the IL additive and sulfolane as the solvent was
synergetic affording highly valuable zoledronic acid in a
[
[
[
7] R ꢀa dai, Z.; Szeles, P.; Kiss, N. Z.; Heged u} s, L.; Windt, T.; Nagy,
V.; Keglevich, G. Green Synthesis and Cytotoxic Activity of
Dibenzyl a-Hydroxyphosphonates and a-Hydroxyphosphonic
Acids. Heteroatom Chem. 2018, e21436.
8] Nagy, D. I.; Gr u€ n, A.; Garadnay, S.; Greiner, I.; Keglevich, G.
Synthesis of Hydroxymethylenebisphosphonic Acid Derivatives
in Different Solvents. Molecules. 2016, 21, 1046–1065. DOI:
[
11]
record yield of 93%.
Funding
The above project was supported by the National Research
Development and Innovation Fund (K119202). Z. R ꢀa dai is grateful for
the fellowship provided by Chinoin–Sanofi Pharmaceuticals and J oꢀ zsef
10.3390/molecules21081046.
9] Nagy, D. I.; Gr u€ n, A.; Pavela, O.; Garadnay, S.; Greiner, I.;
Keglevich, G. Efficient Synthesis of Ibandronate in the Presence
of an Ionic Liquid. Lett. Drug. Des. Disc. 2018, 15,713–720.
DOI: 10.2174/1570180814666171027160324.
ꢀ
Varga Foundation. Z. R ꢀa dai was supported by the UNKP-18-3-IV-
BME-265 New National Excellence Program of the Ministry of
Human Capacities.
[
10] Nagy, D. I.; Gr u€ n, A.; L ꢀe vay, K.; Garadnay, S.; Greiner, I.;
Keglevich, G. Efficient Syntheses of Zoledronic Acid as an
Active Ingredient of a Drug against Osteoporosis. Synt. Comm.
2018, 48, 663–671. DOI: 10.1080/00397911.2017.1410894.
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