Novel procedure for the synthesis of 1-hydroxy-1,1-bisphosphonic acids using phenols as medium

Article abstract of DOI:10.1080/00397910701578545

A facile synthetic route for the synthesis of bisphosphonates in phenols is described. Preparations of some of bisphosphonates, which are presently in clinical use such as risedronic acid and alendronate sodium, are synthesized following this new, simple method. This procedure can be useful for the synthesis of this class of bone-resorptive inhibitors in bulk quantities. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701578545

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Novel Procedure for the Synthesis of
1‐Hydroxy‐1,1‐bisphosphonic Acids using
Phenols as Medium
a
a
Divvela V. N. Srinivasa Rao , Ramesh Dandala , Garimella K. A. S. S.
a
a
a
b
Narayanan , Racha Lenin , M. Sivakumaran & Andra Naidu
a
Research and Development Department, Aurobindo Pharma Ltd.,
Hyderabad, Andhra Pradesh, India
b
Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, India
Published online: 14 Dec 2007.
To cite this article: Divvela V. N. Srinivasa Rao , Ramesh Dandala , Garimella K. A. S. S. Narayanan ,
Racha Lenin , M. Sivakumaran & Andra Naidu (2007): Novel Procedure for the Synthesis of
1‐Hydroxy‐1,1‐bisphosphonic Acids using Phenols as Medium, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 37:24, 4359-4365
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Synthetic Communications , 37: 4359–4365, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701578545
Novel Procedure for the Synthesis of
-Hydroxy-1,1-bisphosphonic Acids using
Phenols as Medium
1
Divvela V. N. Srinivasa Rao, Ramesh Dandala,
Garimella K. A. S. S. Narayanan, Racha Lenin, and
M. Sivakumaran
Research and Development Department, Aurobindo Pharma Ltd.,
Hyderabad, Andhra Pradesh, India
Andra Naidu
Jawaharlal Nehru Technological University, Kukatpally, Hyderabad,
India
Abstract: A facile synthetic route for the synthesis of bisphosphonates in phenols is
described. Preparations of some of bisphosphonates, which are presently in clinical
use such as risedronic acid and alendronate sodium, are synthesized following this
new, simple method. This procedure can be useful for the synthesis of this class of
bone-resorptive inhibitors in bulk quantities.
Keywords: alendronate, bisphosphonates, phenol, risedronic acid, sodium salt, zole-
dronic acid
INTRODUCTION
Bisphosphonates 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. Bisphosphonic acids are excellent antihypercalcemics
and as such are used as therapeutic agents of choice for the treatment of a
Received May 21, 2005
Address correspondence to Ramesh Dandala, Research and Development Depart-
ment, Aurobindo Pharma Ltd., 313, Bachupally, Hyderabad 500 072, Andhra
Pradesh, India. E-mail: rdandala@aurobindo.com
4
359

4
360
D. V. N. S. Rao et al.
[1]
number of diseases characterized by abnormal calcium metabolism. Bispho-
sphonates [in particular, 1-hydroxy-2-(pyridinyl)ethylidene bisphosphonic
acid (risedronic acid, 2a), 1-hydroxy-2-(1-imidazolyl) ethylidene bisphospho-
nic acid (zoledronic acid, 2d), 3-amino-1-hydroxypropylidene bisphosphonic
acid (pamidronic acid, 2e), and 4-amino-1-hydroxy-butylidene bisphosphonic
acid (alendronic acid, 2f)] and their salts are used for the treatment of Paget’s
bone disease and osteoporosis.
RESULTS AND DISCUSSION
[
2–6]
There are several methods reported
-hydroxy alkylidene bisphosphonates. 1-Hydroxy alkylidene bisphospho-
in the literature for the synthesis of
1
nates and their pharmacologically active salts were prepared from the corre-
sponding carboxylic acids with phosphorous acid and phosphorous
[
2]
[3]
trichloride, in solvents such as chlorobenzene, methanesulphonic acid,
[
4]
[5]
[6]
sulfolane, ionic liquids, and diphenyl ether. All these processes have
some disadvantages associated with their use, such as solid and unstirrable
mass formation, which prevents uniform mixing. It is difficult to adapt these
processes to an industrial scale, because the reaction mixture of the phospho-
nation step is not homogenous and tends to solidify, preventing stirring and
leading to inconsistent yields. Methanesulphonic acid is helpful for solubil-
[3]
izing the reaction mass but, as reported, involves safety risks in that this
solvent gives rise to uncontrollable exothermic reactions, when the tempera-
ture of the reacting mixtures exceeds 858C. Moreover, all processes may be
suitable for preparation of small quantities of material but not practical for
even pilot-scale preparation. Because of the therapeutic importance of this
class of compounds, it became essential to develop an efficient and practical
synthesis. We herein report a novel phenol-mediated procedure (Scheme 1),
which circumvents these problems. Further, the solvent used can be
recovered and recycled using known methods, which makes this procedure
suitable for large-scale production.
The appropriate carboxylic acid is taken and treated with phosphorous
trichloride and phosphorous acid in phenolic compounds such as phenol, p-
nitrophenol, or p-cresol. By conducting the reaction in a phenolic medium,
the reaction mass remains fluid, thus allowing complete conversion of the
starting material, providing excellent yields and purity of bisphosphonates,
and making the process safe and convenient. During the preparation of alen-
dronate sodium (2f), phenol was used for the reaction as a solvent. After com-
pletion of hydrolysis, the phenol layer was separated and fractionally distilled
to obtain pure phenol (more than 99%). When p-nitrophenol and p-cresol were
used as reaction solvents, these were recovered from the mother liquor by
simply removing the solvents, followed by isolation from water. Further,
the generality of this facile reaction was established by converting some

1-Hydroxy-1,1-bisphosphonic Acids
4361
Scheme 1.
carboxylic acids to the corresponding bisphosphonates 2a–g in good yields
Table 1).
Herein we have demonstrated a novel phenol-mediated reaction
(
procedure for the preparation of various bisphosphonic acids and their
sodium salts, suitable on a pilot scale. This approach is general, and it will
be useful for the synthesis of various bisphosphonates.
EXPERIMENTAL
Solvents and reagents were obtained from commercial sources and used
without purification. The IR spectra were recorded in the solid state as KBr
1
dispersion using a Perkin-Elmer FT-IR spectrometer. The H NMR and
1
3
C NMR spectra were recorded on a Bruker 300-MHz spectrometer. The
chemical shifts are reported in d ppm relative to TMS. The mass spectra
were recorded on API 2000 Perkin-Elmer PE-SCIEX mass spectrometer.
1
(
-Hydroxy-2-(3-pyridinyl)ethylidene Bisphosphonic Acid
Risedronic Acid, 2a): Typical Procedure
A mixture of 3-pyridylacetic acid (1a, 500.0 g, 3.65 mol), phosphorus acid
897.8 g, 10.95 mol), and p-nitrophenol (3000 g) was heated to 658C, and phos-
phorus trichloride (1731 g, 12.59 mol) was slowly added over a period of 3 h at
5–708C. The reaction mass was stirred at 65–708C for 5 h and then cooled to
(
6

4
362
D. V. N. S. Rao et al.
Table 1. Iodine-catalyzed synthesis of tetrahydrobenzo[b]pyran derivatives
a
Entry
Products
Time (h)
3.2
Yield (%)
92
Mp (8C)
[
10]
4
a
231 (233
)
[
10]
4
b
3.5
88
208 (207–209
)
[
[
[
10]
10]
10]
4
4
4
c
d
e
3.5
3.6
4.0
90
90
85
199 (198–200
211 (208–210
133 (130–132
)
)
)
[
10]
4
4
f
3.8
4.0
85
86
130 (130–132
215 (210–212
)
)
[
10]
g
[
11]
4
h
3.8
80
209 (206–208
)
a
Refers to isolated yield.

1-Hydroxy-1,1-bisphosphonic Acids
4363
5
08C. Precooled water (5000 ml) was added cautiously over a period of 1 h, and
the contents were heated to reflux for 10 h. The reaction mass temperature was
cooled to 108C, and methanol (7500 ml) was added. The precipitated product
was stirred at 0–58C for 2 h. The product was filtered, washed with water
(500 ml), and dried to get 952.5 g (87%) of 2a monohydrate as a white solid.
IR (KBr): 1184, 1073 cm
21
;
1
H NMR (300 MHz, D O/NH ): d 3.26
2 3
(
t, J ¼ 12.1 Hz, 2H), 7.55 (dd, J ¼ 8.2, 5.5 Hz, 1H), 8.18 (d, J ¼ 5.5 Hz,
1
3
1
d 36.5, 73.8, 125.3, 137.1, 141.3, 145.3, 145.4, 146.1; P NMR (D O/NH ):
d 18.1; mass: 282.0 (M 2 1). Anal. calcd. for C H NO P : C, 27.92; H,
7
H), 8.32 (d, J ¼ 5.5 Hz, 1H), 8.51 (s, 1H); C NMR (75 MHz, D O/NH ):
2
3
3
1
2 3
þ
13
8 2
4
.35; N, 4.65. Found: C, 27.64; H, 4.29; N, 4.69.
1
-Hydroxy-2-(2-pyridinyl)ethylidene Bisphosphonic Acid (2b)
This compound was prepared in a way similar to 2a, using 2-pyridylacetic acid
(1b, 10.0 g, 72.99 mmol) and p-cresol, as a white monohydrate solid; yield:
21 1
8.1 g (82%). IR (KBr): 1215, 1058 cm ; H NMR (300 MHz, D O/NH ):
2 3
1
d 3.28 (t, J ¼ 12.1 Hz, 2H), 7.16–7.20 (dd, J ¼ 7.4, 6.0 Hz, 1H), 7.43–7.46
(
d, J ¼ 7.4 Hz, 1H), 7.63–7.68 (dd, J ¼ 8.5, 7.4 Hz, 1H), 8.28
1
3
(
d, J ¼ 5.2 Hz, 1H); C NMR (75 MHz, D O/NH ): d 37.7, 73.2, 125.0,
2 3
3
1
1
29.6, 140.8, 145.6, 153.4; P NMR (D O/NH ): d 17.2; mass: 282.1
2 3
þ
(M 2 1). Anal. calcd. for C H NO P : C, 27.92; H, 4.35; N, 4.65. Found:
C, 15.10; H, 5.50; N, 4.20.
7
13
8 2
1
-Hydroxy-2-(4-pyridinyl)ethylidene Bisphosphonic Acid (2c)
This compound was prepared in a way similar to 2a, using 4-pyridylacetic acid
(1c, 10.0 g, 72.99 mmol) and p-nitrophenol, as a white monohydrate solid;
yield: 17.8 g (81%). IR (KBr): 1162, 1058 cm
2
1
1
; H NMR (300 MHz,
D O/NH ): d 3.14 (t, J ¼ 12.1 Hz, 2H), 7.37 (d, J ¼ 4.4, 1.7 Hz, 2H),
2
3
1
3
8
.23–8.25 (dd, J ¼ 4.4, 1.7 Hz, 2H); C NMR (75 MHz, D O/NH ): d
2
3
3
1
3
9.5, 74.3, 128.3, 143.4, 155.4; P NMR (D O/NH ): d 18.2; mass: 282.1
2 3
þ
M 2 1). Anal. calcd. for C H NO P : C, 27.92; H, 4.35; N, 4.65. Found:
7 13 8 2
(
C, 27.76; H, 4.61; N, 4.72.
1
(
-Hydroxy-2-(1-imidazolyl)ethylidene Bisphosphonic Acid
Zoledronic Acid, 2d)
This compound was prepared in a way similar to 2a, using 1-imidazolylacetic
acid (1d, 10.0 g, 79.36 mmol) and p-cresol, as a white solid; yield: 17.2 g
2
1
1
(
80%). IR (KBr): 1179, 1093 cm ; H NMR (300 MHz, D O/NH ): d
2 3
1
.63–4.66 (m, 2H), 7.34 (s, 1H), 7.48 (s, 1H), 8.68 (s, 1H); C NMR
3
4

4
364
D. V. N. S. Rao et al.
3
1
(
NH ): d 16.1; mass: 271.0 (M 2 1). Anal. calcd. for C H N O P : C,
75 MHz, D O/NH ): d 53.0, 73.2, 118.5, 124.2, 136.1; P NMR (D O/
2
3
2
þ
3
5 10 2 7 2
22.07; H, 3.70; N, 10.30. Found: C, 22.31; H, 3.72; N, 10.18.
(3-Amino-1-hydroxypropylidene)bisphosphonic Acid (Pamidronic
Acid, 2e)
This compound was prepared in a way similar to 2a, using 3-aminopropionic
acid (1e, 10.0 g, 112.36 mmol) and p-cresol, as a white solid; yield: 14.9 g
2
1 1
(
(
57%). IR (KBr): 1152, 987 cm ; H NMR (300 MHz, D O): d 2.17–2.28
2
1
m, 2H), 3.24 (m, 2H); C NMR (75 MHz, D O): d 30.8, 36.2, 72.5;
3
2
3
1
þ
P NMR (D O): d 18.5; mass: 234.1 (M 2 1). Anal. calcd. for
2
C H NO P : C, 15.33; H, 4.72; N, 5.96. Found: C, 15.41; H, 4.83; N, 5.88.
3
11
7 2
(
(
4-Amino-1-hydroxybutylidene)bisphosphonic Acid Monosodium
Alendronate Sodium, 2f)
This compound was prepared in a way similar to 2a, using 4-aminobutanoic
acid (1f, 10.0 g, 97.09 mmol) and phenol, but pH was adjusted to 4.3 with
40% sodium hydroxide solution before diluting with methanol. The product
was filtered and dried to get the trihydrate product as a white solid; yield:
2
1
1
5.8 g (50%). IR (KBr): 1176, 1064 cm ; H NMR (300 MHz, D O): d
1
1
4
2
1
.89–1.92 (m, 4H), 2.92 (m, 2H); C NMR (75 MHz, D O): d 22.5, 30.9,
3
2
3
1
0.2, 73.8; P NMR (D O): d 18.6; mass: 248.1 (M 2 1). Anal. calcd. for
þ
2
C H NNaO P : C, 14.78; H, 5.58; N, 4.31. Found: C, 15.10; H, 5.50; N, 4.20.
4
18
10 2
(6-Amino-1-hydroxyhexylidene)bisphosphonic Acid (Neridronic
Acid, 2g)
This compound was prepared in a way similar to 2a, using 6-aminohexanoic
acid (10.0 g, 76.34 mmol) and p-cresol, as a white solid; yield: 11.2 g (53%).
2
1 1
IR (KBr): 1147, 996 cm ; H NMR (300 MHz, D O): d 1.29–1.33 (m, 2H),
2
1
.51–1.61 (m, 2H), 1.73–1.78 (m, 2H), 1.82–1.87 (m, 2H), 2.90–2.94
31
1
m, 2H); C NMR (75 MHz, D O): d 23.4, 26.6, 26.8, 34.0, 39.5, 74.5;
3
( P
NMR (D O): d 19.5; mass: 276.0 (M 2 1). Anal. calcd. for C H NO P :
2
þ
2
6
17
7 2
C, 26.00; H, 6.18; N, 5.05. Found: C, 26.24; H, 6.06; N, 5.15.
ACKNOWLEDGMENT
The authors thank the management of Aurobindo Pharma Ltd., Research and
Development Department, for supporting this work. The authors also thank

1-Hydroxy-1,1-bisphosphonic Acids
4365
members of the Analytical Research Department for their valuable contri-
bution to this work.
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1