A facile and selective high yield synthesis of symmetric dialkyl-substituted methylenebisphosphonic acids

Article abstract of DOI:10.1081/SCC-120006033

Symmetric P,P′-dialkyl partial esters of methylenebisphosphonic acid were prepared in high yield and high selectivity from the corresponding acid chloride via a facile two-step, one-pot process. The newly developed synthesis, which does not require chromatographic or acid-base extractive purification, offers substantial advantages over previously used procedures.

Full text of DOI:10.1081/SCC-120006033

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A FACILE AND SELECTIVE HIGH YIELD SYNTHESIS
OF SYMMETRIC DIALKYL-SUBSTITUTED
METHYLENEBISPHOSPHONIC ACIDS
Dominique C. Stepinski a & Albert W. Herlinger b
a Department of Chemistry , Loyola University Chicago , Chicago, IL, 60626, U.S.A.
b Department of Chemistry , Loyola University Chicago , Chicago, IL, 60626, U.S.A.
Published online: 20 Aug 2006.
To cite this article: Dominique C. Stepinski & Albert W. Herlinger (2002) A FACILE AND SELECTIVE HIGH YIELD SYNTHESIS OF
SYMMETRIC DIALKYL-SUBSTITUTED METHYLENEBISPHOSPHONIC ACIDS, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:17, 2683-2690, DOI: 10.1081/SCC-120006033
To link to this article: http://dx.doi.org/10.1081/SCC-120006033
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 17, pp. 2683–2690, 2002
A FACILE AND SELECTIVE HIGH
YIELD SYNTHESIS OF SYMMETRIC
DIALKYL-SUBSTITUTED
METHYLENEBISPHOSPHONIC ACIDS
*
Dominique C. Stepinski and Albert W. Herlinger
Department of Chemistry, Loyola University Chicago,
Chicago, IL 60626, USA
ABSTRACT
Symmetric P,P0-dialkyl partial esters of methylene-
bisphosphonic acid were prepared in high yield and high
selectivity from the corresponding acid chloride via a facile
two-step, one-pot process. The newly developed synthesis,
which does not require chromatographic or acid–base extrac-
tive purification, offers substantial advantages over previously
used procedures.
Key Words: Phosphonic acids and derivatives; Esterifica-
tion; Tetrazoles
INTRODUCTION
Bisphosphonic acids are among the most important of the organo-
phosphorus compounds.[1,2] Ligands based on these acids form very
stable complexes with a wide variety of metal ions,[3] and many practical
*Corresponding author. E-mail: aherlin@luc.edu
2683
DOI: 10.1081/SCC-120006033
Copyright & 2002 by Marcel Dekker, Inc.
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2684
STEPINSKI AND HERLINGER
applications rely on the strong metal complexing ability of these molecules.
For example, chelation of a cation by a bisphosphonate ligand increases its
toxicological acceptability, facilitates its transport and ensures its selective
concentration in target organs.[2] Bisphosphonic acids, their salts and
tetraesters are widely used for treatment of diseases of the skeletal system
as well as bone formation and resorption disorders.[4] Our interest in bis-
phosphonic acids is derived from their ability to strongly chelate actinides
under highly acidic conditions and their potential for use in transuranic and
mixed waste treatment.[5,6] The chelating ability of alkylenebisphosphonic
acids has been utilized in metal ion separations in aqueous solution and on
ion exchange and extraction chromatographic resins.[6,7,8] Partial functiona-
lization of an alkylenebisphosphonic acid with an organic moiety enhances
its solubility in non-aqueous solvents, while leaving the remaining acidic
hydrogens available for exchange with the metal for charge neutralization.[8]
Further, the lower acidity of the dialkyl partial esters is expected make them
good candidates as drugs for treatment of bone diseases since this should
lead to better binding to bone, improved bio-availability and superior thera-
peutic behavior.[9]
Utilization of partial esters of methylenebisphosphonic acid has
been limited by the difficulty in obtaining pure compounds having exactly
the desired number of ester substituents. A selective preparative method
that has been used successfully to prepare P,P0-dialkyl and P,P0-disilyl
partial esters is the dicyclohexylcarbodiimide-promoted coupling
of methylenebisphosphonic acid with an alcohol of choice.[8,10] This
procedure, which may not be applicable for some silicon-containing
alcohols,[11] requires long reaction times at elevated temperature and a
series of tedious acid–base extractions that generate large volumes of
waste. Selective synthetic procedures have also been developed for pre-
paring partial esters of dichloromethylenebisphosphonic acid from tetra-
esters using tertiary and secondary amines as dealkylating reagents.[12,13]
Partial deprotection of the bisphosphonate, however, reportedly requires
the presence of an activating group at the bridging methylene to instigate
dealkylation.[12]
We report here a highly efficient two-step, one-pot method for selec-
tively forming P,P0-dialkyl partial esters of methylenebisphosphonic acid
from the acid chloride using 1H-tetrazole to control the regio-selectivity of
the reaction. Our methodology draws upon workrecently reported by
Zhao and Laundry for the formation of mixed dialkyl monophospho-
nates.[14] In the first step of the synthesis, a catalytic amount of 1H-
tetrazole is used to promote the condensation of methylenebis(phosphonic
dichloride) with two equivalents of alcohol under mild, anhydrous con-
ditions in the presence of a hindered base. In the second step, the partial

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METHYLENEBISPHOSPHONIC ACIDS
2685
Figure 1.
ester is formed directly by quenching the unreacted P-Cl groups with water
(Figure 1).
The procedure, which does not require chromatographic or acid–base
extractive purification, offers substantial advantages over the previously
used carbodiimide-promoted coupling route.[8,10]
EXPERIMENTAL
General Methods
All reagents supplied by Aldrich were used as received without
further purification. Methylenebis(phosphonic dichloride) was handled
under anhydrous conditions. Anhydrous solvents were dispensed from
Aldrich Sure-Seal bottles and all glassware was oven dried at 120ꢀC. The
purity of the compounds was established by 1H and 31P NMR spectroscopy,
potentiometric titration, elemental analysis and infrared spectroscopy. The
1H and 31P NMR spectra were recorded on a VXR 400 MHz spectrometer
using CDCl3 as the solvent. The d values in parts per million (ppm) are
relative to internal CHCl3 and external 85% H3PO4, respectively. The
equivalent weight of the partial esters was determined by titration with
0.1 M NaOH in an isopropanol–toluene mixture using an Orion EA 940
pH meter. Combustion analyses were performed by Galbraith Laboratories,
Inc., Knoxville, TN. Infrared spectra were obtained on a Mattson Genesis
series FTIR spectrometer operating in the 4000–400 cmÀ1 region using a
liquid IR cell with NaCl windows. Spectra were recorded for 0.10 M sol-
utions of the partial esters in CCl4 using 64 scans at 4 cmÀ1 resolution with
solvent as the background. Melting points were a measured using an Arthur
H. Thomas, Hoover capillary melting point apparatus with a calibrated
thermometer.

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2686
STEPINSKI AND HERLINGER
General Synthetic Procedure for the Preparation of P,P0-Dialkyl
Partial Esters of Methylenebisphosphonic Acid
Methylenebis(phosphonic dichloride) (4.00 mmol) and 1H-tetrazole
(0.6 mmol) were placed in a 100 mL Schlenkflaskand dissolved in 50 mL
of toluene with vigorous stirring under a nitrogen atmosphere. When dis-
solution was complete, a solution of the alcohol (7.92 mmol) and diisopro-
pylethylamine (8.80 mmol) in 20 mL of toluene was added dropwise through
an addition funnel over a 2.0 h period. After stirring overnight at room
temperature under an atmosphere of nitrogen, the reaction mixture was
quenched with 30 mL of water. The mixture was stirred for 15 min, trans-
ferred to a separatory funnel and the organic phase was washed with two
30 mL portions of 0.1 M HCl. The tetrazole and amine partition into the
aqueous phase as their respective salts, while the desired product remains in
the organic phase. The final product was obtained by removing the solvent
and residual water under reduced pressure at 60ꢀC. Typical yields are
85–95%.
P,P0-Di-n-hexyl methylenebisphosphonic acid, H2DH[MBP]: This novel
compound was obtained as a white solid in 89% yield, m.p. 39.5–40.5ꢀC.
1H NMR (CDCl3, d): 10.89 (s, 2 H, OH), 4.06 (dt, 4 H, JP,H ¼ J ¼ 6.8 Hz,
OCH2), 2.42 (t, 2 H, JP,H ¼ 21.6 Hz, P-CH2-P), 1.65 (p, 4 H, J ¼ 6.9 Hz,
OCH2CH2), 1.22–1.38 (m, 12 H, CH2), 0.88 (t, 6 H, J ¼ 6.8 Hz, CH3);
31P NMR (CDCl3, d): 19.4 (s). Equiv. Wt.: calcd 172.2 g/mol, found
174.0 g/mol. Anal. calcd for C13H30O6P2: C, 45.35; H, 8.78, found: C,
45.32; H, 9.19.
P,P0-Dicyclohexyl methylenebisphosphonic acid, H2DcH[MBP]: This
partial ester, reported in the literature to be an oil,[15] was isolated as a
white solid in 94% yield, m.p. 133–135ꢀC. H NMR (CDCl3, d): 10.38 (s,
1
2 H, OH), 4.50 (m, 2 H, CH), 2.43 (t, 2 H, JP,H ¼ 21.6 Hz, P-CH2-P),
1.15–2.02 (m, 20 H, CH2); 31P NMR (CDCl3, d): 18.4 (s). Equiv. Wt.:
calcd 170.1 g/mol, found 179.5 g/mol. Anal. calcd for C13H26O6P2: C,
45.89; H, 7.70, found: C, 46.33; H, 8.01.
P,P0-Di-n-octyl methylenebisphosphonic acid, H2DO[MBP]: This
compound was isolated as a white solid in 94% yield, m.p. 54–56ꢀC
(lit. 55ꢀC).[16] 1H NMR (CDCl3, d): 10.11 (s, 2 H, OH), 4.06 (dt, 4 H,
JP,H ¼ J ¼ 6.9 Hz, OCH2), 2.42 (t, 2 H, JP,H ¼ 21.6 Hz, P-CH2-P), 1.65
(p, 4 H, J ¼ 7.0 Hz, OCH2CH2), 1.20–1.39 (m, 20 H, CH2), 0.88 (t, 6 H,
J ¼ 7.0 Hz, CH3); 31P NMR (CDCl3, d): 19.4 (s). Equiv. Wt.: calcd
200.2 g/mol, found 204.0 g/mol.
P,P0-Di(2-ethylhexyl) methylenebisphosphonic acid, H2DEH[MBP]:
1
This dialkyl ester was isolated as a colorless oil in 92% yield. H NMR
(CDCl3, d): 10.46 (s, 2 H, OH), 3.97 (m, 4 H, OCH2), 2.43 (t, 2 H,

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METHYLENEBISPHOSPHONIC ACIDS
2687
JP,H ¼ 21.8 Hz, P-CH2-P), 1.55 (m, 2 H, CH), 1.22–1.42 (m, 16 H, CH2), 0.87
(m, 12 H, CH3); 31P NMR (CDCl3, d): 19.4 (s). Equiv. Wt.: calcd
200.2 g/mol, found 199.2 g/mol. Anal. calcd for C17H38O6P2: C, 50.99; H,
9.56, found: C, 51.37; H, 9.89.
P,P0-Di(2,4,4-trimethylpentyl) methylenebisphosphonic acid, H2DTMP-
[MBP]: This novel C8 ester of methylenebisphosphonic acid was isolated as
a white solid in 93% yield, m.p. 67–70ꢀC. 1H NMR (CDCl3, d): 10.44 (s, 2H,
OH), 3.72–3.92 (m, 4 H, OCH2), 2.42 (t, 2 H, JP,H ¼ 21.8 Hz, P-CH2-P), 1.83
(m, 2 H, CH), 0.97–1.28 (m, 4 H, CH2), 0.97 (d, 6 H, J ¼ 6.8 Hz, CHCH3),
0.89 (s, 18 H, CCH3); 31P NMR (CDCl3, d): 19.3 (s). Equiv. Wt.: calcd
200.2 g/mol, found 207.4 g/mol. Anal. calcd for C17H38O6P2: C, 50.99; H,
9.56, found: C, 51.14; H, 10.00.
P,P0-Di[3-(trimethylsilyl)propyl]
methylenebisphosphonic
acid,
H2DTMSP[MBP]: This compound was obtained as a white solid in 90%
yield, m.p. 39–41ꢀC (lit. 32–34ꢀC).[10] 1H NMR (CDCl3, d): 10.31 (s, 2 H,
OH), 4.01 (dt, 4 H, JP,H ¼ J ¼ 7.2 Hz, OCH2), 2.43 (t, 2 H, JP,H ¼ 21.6 Hz,
P-CH2-P), 1.65 (m, 4 H, OCH2CH2), 0.48 (m, 4 H, OCH2CH2CH2), 0.01 (s,
18 H, CH3); 31P NMR (CDCl3, d): 19.3 (s). Equiv. Wt.: calcd 202.3 g/mol,
found 203.9 g/mol.
General Purification Procedure for Partial Esters
A product of high purity is obtained upon washing the crude product
with 0.1–0.2 M HCl. This ensures that all unreacted amine and tetrazole
partition into the aqueous phase as salts and obviates the foaming that
can be problematic if the product is washed with water. If necessary,
purification of an alcohol-containing product could be achieved by the
acid–base extraction method described previously for the carbodiimide-
promoted coupling procedure.[8,10]
RESULTS AND DISCUSSION
A highly efficient and facile method for selectively forming P,P0-di-
alkyl partial esters of methylenebisphosphonic acid has been developed. The
reaction sequence, shown in Figure 1, utilizes 1H-tetrazole to catalyze the
coupling of methylenebis(phosphonic dichloride) with two equivalents of
alcohol under mild conditions. The procedure has general synthetic
applicability for the preparation of a variety of water immiscible diesters
of methylenebisphosphonic acid. A number of primary alkyl, cyclic second-
ary alkyl and silicon-containing alcohols were successfully utilized in this

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2688
STEPINSKI AND HERLINGER
procedure. The yield of high purity partial ester achieved using this method
is higher than that previously obtained using carbodiimide-promoted coup-
ling procedures.[8,10] The extraction performance of the product formed by
the 1H-tetrazole catalyzed esterification of methylenebis(phosphonic
dichloride) is as good if not better than the performance of the product
formed by the latter route.[17]
The 31P NMR spectra of the partial esters consist of a single sharp
resonance. The position of this resonance (d ꢁ 19) is not strongly influenced
1
by the nature of the alkyl-substituent. The H NMR spectra of the esters
exhibit resonances of the expected intensity and splitting patterns in the
appropriate spectral regions. There is no evidence of unreacted alcohol
being present in these samples. The infrared spectra of the partial esters
are indicative of a strongly hydrogen-bonded dialkyl alkylenebisphosphonic
acid. These characteristic spectral features are not given here since they
have been previously discussed in detail for H2DEH[MBP][18,19] and
H2DTMSP[MBP].[10] The phosphoryl band position (ꢁ1240 cmÀ1) is not
strongly influenced by the nature of the alkyl-substituent. Small differences
are observed in the 3000–2800 cmÀ1 region due to differences in the alkyl
chains. The most notable difference is the simplified two-band spectrum
exhibited in this region by the dicyclohexyl partial ester H2DcH[MBP].
The 1H-tetrazole catalyzed coupling reaction was investigated in a
variety of aromatic (benzene and toluene) and chlorinated hydrocarbon
(CH2Cl2 and CHCl3) solvents. Aromatic solvents afforded the highest
yields and best purity. Toluene, with its lower vapor pressure and toxicity,
appears to be the solvent of choice. Reactions carried out in halogenated
solvents afforded lower yields, and the purity of the product was lowered by
the presence of hydrocarbon by-products.
The procedure is carried out using a small excess of the acid chloride
to prevent the formation of the triester, which is not easily removed. The
formation of a small amount of the parent acid or the monoester is not a
concern since both are water-soluble and partition into the aqueous phase
when the reaction is quenched. Features of the process which are critical to
successfully obtaining the desired product in high purity are careful control
of reagent stoichiometry, use of anhydrous solvents, and slow simultaneous
addition of alcohol and hindered base to the acid chloride. Advantages of
this method over existing preparative methods include: higher yields, shorter
reaction times, milder conditions, less expensive and less toxic
starting reagents, smaller secondary waste streams and simpler isolation
and purification procedures.
The procedure is not applicable for the preparation of water-soluble
partial esters of methylenebisphosphonic acid, nor does it workwell with
tertiary or highly hindered secondary alcohols. Reaction of phenol or a

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METHYLENEBISPHOSPHONIC ACIDS
2689
fluoroalkyl alcohol with methylenebis(phosphonic dichloride) produces a
mixture of all possible bisphosphonate esters. Workto expand the applic-
ability of the 1H-tetrazole catalyzed esterification of methylene-
bis(phosphonic dichloride) to a wider range of alcohols is currently in
progress in our laboratory.
ACKNOWLEDGMENTS
The authors thankJulie A. Dzielawa and Daniel R. McAlister for
helpful discussions and suggestions. This workwas supported by the PG
Research Foundation, Inc., Darien, IL 60561.
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2690
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Received in the USA September 4, 2001