Microwave-assisted efficient synthesis of bisphosphonate libraries: A useful procedure for the preparation of bisphosphonates containing nitrogen and sulfur

Article abstract of DOI:10.1007/s00044-012-0153-4

Microwave-assisted rapid and efficient procedure for the synthesis of bisphosphonate and their libraries is described in solvent-free medium. Bisphosphonates having nitrogen and sulfur are synthesized following this new procedure. This procedure is simple and can be useful for the generation of compound libraries of a class of bone-resorptive inhibitors such as N- and N-, S- containing bisphosphonates.

Full text of DOI:10.1007/s00044-012-0153-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:1624–1629
DOI 10.1007/s00044-012-0153-4
ORIGINAL RESEARCH
Microwave-assisted efficient synthesis of bisphosphonate libraries:
a useful procedure for the preparation of bisphosphonates
containing nitrogen and sulfur
•
Racha Lenin Rallabandi Madusudan Raju
•
•
Divvela V. N. Srinivasa Rao Uttam Kumar Ray
Received: 29 April 2011 / Accepted: 12 June 2012 / Published online: 1 July 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Microwave-assisted rapid and efficient proce-
dure for the synthesis of bisphosphonate and their libraries
is described in solvent-free medium. Bisphosphonates
having nitrogen and sulfur are synthesized following this
new procedure. This procedure is simple and can be useful
for the generation of compound libraries of a class of bone-
resorptive inhibitors such as N- and N-, S- containing
bisphosphonates.
and Geusens, 2001; Dunn and Goa, 2001). Recent studies
show that the BPs containing nitrogen along with sulfur are
emerging as excellent therapeutic agents for the treatment
of arthritis particularly rheumatoid. The pharmaceutical
importance of these molecules attracted many researchers
and developed several methods (Lorin and Jonathan, 1996;
Gallop et al., 1994; Pavia et al., 1993; Jung and Becksick-
inger, 1992; Dower and Fodor, 1991; Gold et al., 1995). But
many of these methods are suffering from drawbacks such
as long reaction time and isolation of products. Therefore,
we have developed a simple and efficient methodology for
the synthesis of BPs under microwave irradiation.
Keywords Bisphosphonates Á Phosphorous acid Á
Phosphorous trichloride Á Microwave-assisted
Trying for development of novel synthetic procedures is
desirable for the promising therapeutic areas to reach the
demand for rapid synthesis of compound libraries for
screening. Keeping this in view, we focused our attention
on the development of new procedures for the generation
of bisphosphonate libraries.
Introduction
Bisphosphonates (BPs) containing nitrogen are demon-
strated as potent inhibitors of bone-resorptive and highly
selective bone targeting agents (Abdou and Shaddy, 2009).
These are analogs of pyrophosphate in which the oxygen of
the P–O–P bond is replaced by a carbon atom, resulting
in a metabolically stable P–C–P structure (Abdou et al.,
2008). Over the past three decades, the discovery and
development of bisphosphonic acids and their related BPs
as a class of compounds for treatment of bone diseases has
been a fascinating saga in medicinal chemistry (McClung
Microwave-assisted heating under controlled conditions
has been shown to be invaluable technology for medicinal
chemistry and drug discovery applications (Baxendale
et al., 2002; Artmann et al., 2007; Appukkuttan and Eyc-
ken, 2006; Larhed and Hallberg, 2001; Wathey et al., 2002).
In recent years, microwave-assisted reactions have received
much attention because of their simplicity in operation,
enhanced reaction rates, and greater selectivity (Al Obeidi
et al., 2003; Kappe and Dallinger, 2006; Alcazar et al.,
2007; Varma 1999). In particular, solvent-free reactions
have gained popularity as they provide an opportunity to
work with open vessels (Zhang et al., 2007; Sinnwell and
Ritter, 2007; Barlow and Marder, 2003; Zhu et al., 2004;
Perelaer et al., 2006; Jhung et al., 2007; Millos et al., 2007;
Tsuji et al., 2005; Tompsett et al., 2006; Collins and
Leadbeater, 2007). This avoids use of organic solvents
and dramatically reduces reaction times, increases product
R. Lenin Á R. M. Raju (&)
Department of Chemistry, Osmania University, Hyderabad
500007, India
e-mail: rallabaldimr@yahoo.co.in
R. Lenin Á D. V. N. S. Rao Á U. K. Ray
Aurobindo Pharma Limited, Research Centre, 313, Bachupally,
Qutullapur Mandal, Hyderabad 500090, India
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Med Chem Res (2013) 22:1624–1629
1625
Scheme 1 Synthesis of
bisphosphonic acids and their
salts
O-Na+
OH
OH
OH
O
O
OH
OH
P
C
P
1. PCl3, H3PO3 / MW
80 oC, 3 min
P
aq. NaOH, H2O
0 oC, pH = 4.3
R
R C OH
R-COOH
2. H2O / MW
100 oC, 3 min
OH
P
OH
O
OH
O
3a-m
1a-m
2a-m
yields, and enhances product purities by reducing unwanted
side reactions compared to conventional heating methods.
Short reaction times make it ideal for rapid reaction
scouting and optimization. Compound libraries can then be
rapidly synthesized using this enabling technology. Thus,
microwave irradiation has become a powerful synthetic tool
for the rapid synthesis of a variety of biologically active
compounds under solvent-free conditions. Synthesis of
biologically active BPs achieved by several methods was
reported in literature. In reported procedures, synthesis of
BPs was carried out using organic solvents such as chlo-
robenzene, methanesulphonic acid (Kieczykowski et al.,
1995), sulfolane (Vijaykumar et al., 2005), ionic liquids
(Ferra et al., 2003), diphenyl ether (Despande and Luthra,
2006) and phenol (Rao et al., 2007a, b). The principal dif-
ficulty with all these procedures is using corrosive organic
solvents and long reaction times, resulting in low yield and
purities of the desired products. As part of our research,
we envisaged to develop a synthetic procedure for the
generation of high quality bisphosphonate libraries using
microwave.
compounds 1b–m to obtain products 2b–m in excellent
yields and in pure form without using any purification
methods. (Scheme 1; Table 1). When this reaction was
performed using silica gel as solid support and traditional
heating at 100 °C, black polymeric material was obtained
as a gummy mass.
Having set of optimal conditions in hand, herein we
report an efficient microwave-assisted solvent-free proce-
dure for the synthesis of bisphosphonate libraries. A mix-
ture of carboxylic acid 1, phosphorous acid (H3PO3),
phosphorous trichloride (PCl3) using silica gel as solid
support was irradiated in microwave unit at 80 °C for
3 min and the hydrolysis was carried out by addition
of water followed by irradiation at 100 °C for 3 min
(Scheme 1). After completion of hydrolysis, reaction mass
was filtered and water miscible solvent (ex: MeOH, EtOH,
acetone, etc.,) was added to the filtrate to get a solid. The
solid was filtered and dried in oven at 40–60 °C under
reduced pressure to obtain desired compound 2 in good to
excellent yields. Using this procedure bisphosphonic acids
2a–m are prepared.
The bisphosphonic acids 2a–m were converted into their
sodium salts using NaOH (1.2 eq.) in aqueous medium.
These salts precipitate as white solids upon addition of
MeOH or EtOH as co-solvent. Filtration and drying were
performed in oven at 60 °C under vacuum to obtain com-
pounds 3a–m in excellent yields (Table 1) in highly pure
form without using any purification techniques. This makes
the process simple convenient and time saving. Further the
generality of this facile reaction procedure could be estab-
lished for the generation of various bisphosphonate librar-
ies. Products obtained by this procedure were converted
into corresponding BPs in excellent yields (Table 1).
Results and discussion
We started our investigation with carboxylic acid 1a to
prepare bisphosphonic acid 2a and subsequent conversion
to its salt 3a. We first reacted compound 1a with phos-
phorous acid (H3PO3) and phosphorous trichloride (PCl3)
at various temperatures using microwave. Reactions per-
formed at 50 °C were very slow whereas reactions per-
formed at 100 °C were proceeded but the products
obtained were contaminated with many side products.
Decomposition was observed in the reactions performed at
above 100 °C. It was thought that phosphorous trichloride
is evaporated before the reaction takes place. Hence we
used silica gel as solid support, mixed the reagents uni-
formly, and studied the reaction at various temperatures in
microwave. We were delighted with the result when the
reaction was finished in 3 min at 80 °C which was con-
firmed by 31P NMR. Hydrolysis was also finished in 3 min
at 100 °C in microwave. Afterward workup product 2a was
obtained in very good yield and in pure form without
column chromatography. We applied this procedure to
Conclusion
In summary, herein we have demonstrated an efficient,
solvent-free, and microwave-assisted reaction procedure
for the preparation of various bisphosphonic acids and their
salts in highly pure form without using any purification
methods. This procedure is environmentally friendly and
useful for the synthesis of biologically important bis-
phosphonate libraries, valuable in drug discovery.
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Med Chem Res (2013) 22:1624–1629
Table 1 Microwave-promoted
synthesis of bisphosphonates
Compound
a
1a-h
2a-h
3a-3h
Yield (%)
72
b
76
c
65
78
d
e
f
67
78
g
86
82
h
Materials and methods
spectrometer. IR spectra were measured with a Perkin-
Elmer Spectrum One FT-IR spectrometer.
Chemistry
General method for the preparation of BPs 1a–m to 3a–m
Microwave-assisted synthesis was carried out in an Initia-
torTM 2.0 single mode MW at 2.45 GHz (Biotage AB,
Uppsala). The reactions were performed in sealed vessels
equipped with a teflon-coated stirred bar and under an
argon atmosphere. A variable power was employed to
reach the temperature desired and then to maintain it in the
vessel during the period of time programmed. 1H, 13C, and
31P NMR spectra were recorded with a Bruker AM 300, 75,
and 121.5 mHz NMR spectrometer, which provided all the
necessary data for the full SCIEX-API 2000 mass
A mixture of 3-(4-methyl pentylamino)-propionic acid
(5 g, 2.38 mmol), phosphorous acid (5.87 g, 7.16 mmol),
phosphorous trichloride (16.4 g, 11.93 mmol), and silica
gel (5 g) were mixed thoroughly and subjected to micro-
wave irradiation for 3 min at 80 °C. After completion of
starting material as confirmed by 31P NMR, water (50 mL)
was added to the resulting reaction mixture and again
subjected to microwave irradiation for 3 min at 100 °C.
The resulting reaction mixture was cooled to room
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Med Chem Res (2013) 22:1624–1629
1627
Table 1 continued
Compound 1i-m
2i-m
3i-3m
Yield (%)
i
81
j
81
k
l
80
72
m
79
temperature and filtered and the cake was washed with
water (10 mL). The filtrate was added to methanol (80 mL)
and stirred well for 1 h and precipitated bisphosphonic acid
was filtered and washed with methanol (10 mL) to obtain
product 2a (yield 3.8 g).
21.85, 23.56, 28.20, 39.74, 53.24, 56.7, 72.56; 31P NMR
(D2O, 121.5 mHz, d, ppm): 17.69; MS (ESI, m/z): 318.0
[M-H]?.
1-Hydroxy-3-(pentylamino)-propylidene bisphophosnic
acid monosodium (3b)
A stirred mixture of the above-obtained bisphosphonic
acid 2a (3 g) in water (30 mL) was adjusted to pH 4.3 by
adding 40 % NaOH solution (*2 mL) at 0 °C to obtain a
clear solution. To this clear solution methanol (45 mL) was
added and continued stirring for 1 h at 0 °C and precipi-
tated solid was filtered and dried to obtain bisphosphonate
sodium salt 3a (2.85 g). All the products were confirmed
by its IR, 1H NMR, 13C NMR, 31P NMR, and mass spectral
data.
Yield: 76 %; white solid; spectroscopic analysis: IR (KBr)
1
v
max/cm-1: 3680, 2951, 2430, 1470, 1400, 102 cm-1; H
NMR (D2O, 300 mHz, d, ppm): d 0.80 (t, J = 6.6 Hz, 3H),
1.23–1.27 (m, 4H), 1.54–1.59 (m, 2H), 2.14–2.27 (m, 2H),
2.90–2.95 (m, 2H), 3.23–3.27 (m, 2H); 13C NMR (D2O,
75.5 mHz, d, ppm): 13.38, 21.82, 25.66, 28.17, 29.95,
44.45, 48.06, 72.78; 31P NMR (D2O, 121.5 mHz, d, ppm):
18.23; MS (ESI, m/z): 304.2 [M-H]?.
Results for individual compounds
6-Amino-1-hydroxyhexylidene)-bisphosphonic acid
monosodium (neridronate sodium, 3c)
[1-Hydroxy-3-(methylpentylamino)-propylidene]-
bisphosphonic acid monosodium (ibandronate sodium, 3a)
Yield: 65 %; white solid; spectroscopic analysis: IR (KBr)
1
Yield: 72 %; white solid; spectroscopic analysis: IR (KBr)
1
v
max/cm-1: 3275, 2889, 1640, 1470, 1266, 952 cm-1; H
v
max/cm-1: 3166, 2962, 2320, 1667, 1259, 1034 cm-1; H
NMR (D2O, 300 mHz, d, ppm): 1.28–1.35 (m, 2H), 1.50–
1.63 (m, 2H), 1.73–1.77 (m, 2H), 1.81–1.88 (m, 2H), 2.85–
2.95 (m, 2H); 13C NMR (D2O, 75.5 mHz, d, ppm): 23.48,
26.7, 34.1, 39.61, 76.26; 31P NMR (D2O, 121.5 mHz, d,
ppm): 19.4; MS (ESI, m/z): 276.1 [M-H]?.
NMR (D2O, 300 mHz, d, ppm): 0.78 (t, J = 6.9 Hz, 3H),
1.23–1.26 (m, 4H), 1.60–1.62 (m, 2H), 2.21–2.30 (m, 2H),
2.74 (s, 3H), 2.94–2.98 (m, 1H), 3.06–3.12 (m, 2H), 3.43–
3.47 (m, 1H); 13C NMR (D2O, 75.5 mHz, d, ppm): 13.43,
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Med Chem Res (2013) 22:1624–1629
(4-Amino-1-hydroxybutylidene)-bisphosphonic acid
monosodium (alendronate sodium, 3d)
1-Hydroxy-2-(2-pyridinyl) ethylidene bisphosphonic acid
monosodium (3i)
Yield: 78 %; white solid; spectroscopic analysis: IR (KBr)
1
Yield: 81 %; white solid; spectroscopic analysis: IR (KBr)
1
v
max/cm-1: 2925, 2225, 1770, 1417, 1377, 104 cm-1; H
v
max/cm-1: 3256, 2435, 2112, 1656, 1248, 1059 cm-1; H
NMR (D2O, 300 mHz, d, ppm): 1.90–1.92 (m, 4H), 2.93
(m, 2H); 13C NMR (D2O, 75.5 mHz, d, ppm): 22.8, 31.0,
40.3, 74.82; 31P NMR (D2O, 121.5 mHz, d, ppm): 18.7;
MS (ESI, m/z): 248.0 [M-H]?.
NMR (D2O, 300 mHz, d, ppm): 3.61 (t, J = 13.0 Hz, 2H),
7.71–7.78 (m, 1H), 7.85 (d, J = 8.1 Hz, 1H), 8.26 (d,
J = 7. 8 Hz, 1H), 8.48 (d, J = 5.4 Hz, 1H); 13C NMR
(D2O, 75.5 mHz, d, ppm): 37.5, 71.5, 125.1, 130.1, 141.0,
145.5, 152.1; 31P NMR (D2O, 121.5 mHz, d, ppm): 16.87;
MS (ESI, m/z): 281.9 [M-H]?.
3-(Amino-1-hydroxypropylidene)-bisphosphonicacid
monosodium (pamidronate sodium, 3e)
1-Hydroxy-2-(4-pyridylmercapto) ethylidene
bisphosphonic acid monosodium (3j)
Yield: 67 %; white solid; spectroscopic analysis: IR (KBr)
1
v
max/cm-1: 3192, 2322, 1630, 1509, 1286, 915 cm-1; H
Yield: 81 %; white solid; spectroscopic analysis: IR (KBr)
max/cm-1: 3256, 2310, 1633, 1483, 1279, 1064, 956 cm-1
;
NMR (D2O, 300 mHz, d, ppm): 2.15–2.29 (m, 2H), 3.16–
3.27 (m, 2H); 13C NMR (D2O, 75.5 mHz, d, ppm): 31.3,
36.6, 73.08; 31P NMR (D2O, 121.5 mHz, d, ppm): 18.45;
MS (ESI, m/z): 236.1 [M?H]?.
v
1H NMR (D2O, 300 mHz, d, ppm): 3.70 (t, J = 11.7 Hz,
2H), 7.75 (d, J = 5.7 Hz, 2H), 8.25 (d, J = 5.4 Hz, 2H) 13
C
NMR (D2O, 75.5 mHz, d, ppm): 36.9, 72.9, 122.4, 139.1,
165.5; 31P NMR (D2O, 121.5 mHz, d, ppm): 16.85; MS
(ESI, m/z): 315.9 [M?H]?.
1-Hydroxy ethylidine bisphosphonic acid monosodium
(etidronate sodium, 3f)
1-Hydroxy-2-(1-imidazolyl) ethylidene bisphosphonic acid
monosodium (zoledronate sodium, 3k)
Yield: 78 %; white solid; spectroscopic analysis: IR (KBr)
v
max/cm-1: 3148, 2026, 1620, 1382, 1216, 1052, 951 cm-1;1H
NMR (D2O, 300 mHz, d, ppm): d 1.3 (s, 3H). 13C NMR (D2O,
75.5 mHz, d, ppm): 2.8, 62.7; 31P NMR (D2O, 121.5 mHz, d,
ppm): 17.5; MS (ESI, m/z): 207.2 [M?H]?.
Yield: 80 %; white solid; spectroscopic analysis: IR (KBr)
1
v
max/cm-1: 3160, 2765, 1586, 1491, 1371, 1053 m-1; H
NMR (D2O, 300 mHz, d, ppm): 4.54–4.63 (m, 2H), 7.27
(s, 1H), 7.43(s, 1H), 8.62 (s, 1H); 13CNMR (D2O, 75.5 mHz,
d, ppm): 53.6, 71.4, 118.8, 124.5, 136.6; 31P NMR (D2O,
121.5 mHz, d, ppm): 14.63; MS (ESI, m/z): 273.2 [M?H]?.
1-Hydroxy-2-(3-pyridinyl)-ethylidene bisphosphonic acid
monosodium (risedronate sodium, 3g)
1-Hydroxy-2-(2-methyl-1-imidazolyl)-ethylidene
bisphosphonic acid monosodium (3l)
Yield: 86 %; white solid; spectroscopic analysis: IR (KBr)
1
v
max/cm-1: 3368, 2151, 1690, 1568, 1349, 1133 cm-1; H
NMR (D2O, 300 mHz, d, ppm): 3.35 (t, J = 12.0 Hz, 2H),
7.81 (dd, J = 8.1, 5.5 Hz, 1H), 8.46 (d, J = 6.6 Hz, 2H),
8.63 (s, 1H); 13C NMR (D2O, 75.5 mHz, d, ppm): 36.3,
73.9, 125.1, 137.2, 141.1, 145.4, 145.2, 145.8; 31P NMR
(D2O, 121.5 mHz, d, ppm): 18.1; MS (ESI, m/z): 282.1
[M-H]?.
Yield: 72 %; white solid; spectroscopic analysis: IR (KBr)
1
v
max/cm-1: 3208, 1891, 1609, 1341, 1246, 984 cm-1; H
NMR (D2O, 300 mHz, d, ppm): 2.38 (s, 3H), 4.31–4.38
(m, 2H),6.78(s, 1H), 7.22(s, 1H); 13CNMR (D2O, 75.5 mHz,
d, ppm): 11.2, 50.6, 73.5, 116.9, 124.1, 145.9;31P NMR (D2O,
121.5 mHz, d, ppm): 15.23; MS (ESI, m/z): 286.0 [M-H]?.
1-Hydroxy-2-(4-pyridinyl)-ethylidene bisphosphonic acid
monosodium (3h)
1-Hydroxy-2-(1-imidazolyl) propylidene bisphosphonic
acid monosodium (3m)
Yield: 82 %; white solid; spectroscopic analysis: IR (KBr)
1
Yield: 79 %; white solid; spectroscopic analysis: IR (KBr)
1
v
max/cm-1: 3448, 3107, 2134, 1644, 1344, 1091 cm-1; H
v
max/cm-1: 3216, 2283, 1580, 1472, 1266, 971 cm-1; H
NMR (D2O, 300 mHz, d, ppm): 3.33 (t, J = 12.3 Hz, 2H),
7.37 (d, J = 5.7, Hz, 2H), 8.43 (d, J = 5.7 Hz, 2H); 13C
NMR (D2O, 75.5 mHz, d, ppm): 40.1, 76.3, 129.5, 140.5,
159.5; 31P NMR (D2O, 121.5 mHz, d, ppm): 17.16; MS
(ESI, m/z): 282.0 [M–H]?.
NMR (D2O, 300 mHz, d, ppm): 2.39 (m, 2H), 4.47 (d,
J = 7.6 Hz, 2H), 7.31 (s, 1H), 7.45 (s, 1H), 8.67 (s, 1H);
13C NMR (D2O, 75.5 mHz, d, ppm): 34.8, 46.0, 72.9,
120.0, 122.2, 135.0; 31P NMR (D2O, 121.5 mHz, d, ppm):
18.09; MS (ESI, m/z): 285.0 [M-H]?.
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Acknowledgments RL, DVNSR, and UKR are grateful to Aurob-
indo Pharma Limited (APL) Research Centre for supporting this
study. The authors’ also thank Dr. N. Murali for his encouragement
and support.
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