SHORT PAPER
Preparation of (1-Acetyloxyethylidene)-1,1-bisphosphonic Acid Derivatives
993
thesis of (1-acetyloxyethylidene)-1,1-bisphosphonic acid
trimethyl ester (2) in 83% yield is reported for the first
time. The selective synthesis of (1-acetyloxyethylidene)-
1,1-bisphosphonic acid (4) in 84% yield from the etidron-
ic acid tetramethyl ester (6) is also described. The acety-
lated derivatives 1–4 are used as starting materials and
model compounds in our ongoing study of the preparation
of new BP prodrugs.
Solvents were HPLC grade and dried before use. Tubes filled with
anhydrous CaCl2 were used to protect reactions from humidity un-
less otherwise stated. 1H,31Pand 13C NMR spectra were recorded on
a Bruker Avance 500 spectrometer operating at 500.1, 202.5 and
125.8 MHz, respectively. TMS or TSP (for D2O solutions) was used
1
as an internal standard for H and 13C measurements, and 85%
H3PO4 was used as an external standard for 31P measurements. The
nJHP coupling constants were calculated from proton spectra and all
J values are given in Hz. The number of protons on each carbon
were detected from DEPT-135 experiments and marked after each
carbon by the letters d (doublet), t (triplet), q (quartet) or qt (quin-
tet). The nJCP coupling constants were calculated from carbon spec-
tra with the coupling constants given in Hz. In the case of symmetric
structure only the sums of the JCP couplings (SJCP, the width of the
virtual triplet) are given, since the satellite lines were unambiguous
to detect from the background. The purity of products was deter-
mined from 1H and 31P NMR spectra and was 95%.
Scheme 2 Reaction conditions: a) 2 equiv NaI in acetone, 94%; b)
1 equiv KI in acetone, 88%; c) 5 equiv AcCl in Ac2O, 100% or AcCl,
46%; d) concd HCl, 100%; e) Ac2O, 84%; f) Ac2O–HOAc (1:1),
83%; g) Ac2O, 81%; h) ca. 4 equiv (CH3)3SiCl/NaI in CH3CN, then
MeOH, 100%; i) 2 equiv NaI in acetone, 98%
(1-Acetyloxyethylidene)-1,1-bisphosphonic Acid Tetramethyl
Ester (1)
Compound 6 (212 mg, 0.81 mmol) was dissolved in Ac2O (2 mL)
and AcCl (300 mL, 4.22 mmol) was added. The mixture was stirred
at 55 °C for 26 h and evaporated in vacuo to give 1 (247 mg, 100%)
as a colorless syrup.
dealkylation of tetraesters.4d Selective acetylation of 7 to
target compound 2 was observed in excess Ac2O.
Acetylated etidronic acid 4 has been reported to be one of
the products described by Prentice et al.5 in their experi-
ments, but its synthesis and separation required several
steps and two recrystallizations for purification. Our strat-
egy to obtain 4 was more straightforward. The synthesis
started from tetramethyl ester 6, which was first hydro-
lyzed by concentrated HCl and crystallized from acetic
acid to give a solid etidronic acid (5) in quantitative yield.
Compound 5 was then stirred in excess Ac2O at 60 °C for
46 hours to give 4 in 84% yield after isolation. (1-Acety-
loxyethylidene)-1,1-bisphosphonic acid (4) can also be
prepared by a silylation method from 1 as described earli-
er.4b
1H NMR (CDCl3): d = 3.91–3.86 (m, 12 H), 2.14 (s, 3 H), 1.91 (t, 3
H, 3JHP = 15.7 Hz).
3
13C NMR (CDCl3): d = 168.75 (t; JCP = 7.9 Hz), 79.13 (t;
1JCP = 155.4 Hz), 54.73 (qt; JCP = 6.6 Hz), 54.33 (qt; JCP = 6.9 Hz),
21.28 (q), 18.57 (qt;2JCP = 2.5 Hz).
31P NMR (CDCl3): d = 20.15.
[1-(Dimethoxyphosphoryl)-1-acetyloxyethyl]-1-phosphonic
Acid Monomethyl Ester Monopotassium Salt (2)
Compound 7 (305 mg, 1.07 mmol) and Ac2O (5 mL) were stirred at
60 °C for 5 h and evaporated to dryness in vacuo. The residue was
dissolved in CH2Cl2 (2 mL), Et2O (5 mL) and hexanes (10 mL) was
added with vigorous stirring. The solution was removed and the re-
maining syrup was washed with hexanes and Et2O. The residue was
dried for 6 h in vacuo to give 2 (283 mg, 81%) as a white solid.
Formation of the acetylated products 1–4 during the reac-
1
tions was easily detected from H and 31P NMR spectra.
For example, the methyl protons on the P–C–P backbone
for compound 8 give rise to a characteristic triplet at 1.53
ppm, which shifts to a higher ppm value after acetylation
(1.73 ppm for 3), like for the other acetylated derivatives.
In the 31P NMR spectra the signal shifts to a lower ppm
value after acetylation [e.g. for 6 from 22.85 ppm to 20.15
ppm (1)]. Another characteristic finding was the lower
2JPP coupling constant obtained for the new compound 2
(23.6 Hz as compared to 34.4 Hz for the starting material
7).
1H NMR (CDCl3): d = 3.83 (d, 3 H, 3JHP = 10.6 Hz), 3.79 (d, 3 H,
3
3JHP = 10.7 Hz), 3.68 (d, 3 H, JHP = 10.0 Hz), 2.09 (s, 3 H), 1.81
(dd, 3 H, 3JHP = 13.1 Hz, 3JHP¢ = 16.4 Hz).
3
3
13C NMR (CDCl3): d = 169.66 (dd; JCP = 6.7 Hz, JCP¢ = 6.4 Hz),
81.43 (dd; 1JCP = 135.7 Hz, 1JCP¢ = 135.7 Hz), 53.97 (qd; 2JCP = 7.2
Hz), 53.92 (qd; 2JCP = 7.3 Hz), 53.62 (qd; 2JCP = 6.4 Hz), 21.68 (q),
20.03 (q).
31P NMR (CDCl3): d = 24.70 (d, 2JPP = 23.6 Hz), 11.15 (d).
(1-Acetyloxyethylidene)-1,1-bisphosphonic Acid P,P¢-Dimethyl
Ester (3)
Compound 8 (800 mg, 2.88 mmol), AcOH (3 mL) and Ac2O (3 mL)
were stirred at 55 °C for 19 h and evaporated to dryness in vacuo.
The residue was dissolved in MeOH (5 mL), then i-PrOH (5 mL)
was added and the mixture was heated to reflux. After the addition
In conclusion, an alternative route for the selective prepa-
ration of (1-acetyloxyethylidene)-1,1-bisphosphonic acid
P,P¢-dimethyl ester (3) was found. Improvement in the
yield from 46% to 100% in the preparation of the acetylat-
ed tetramethyl ester of etidronate (1) was observed. Syn-
Synthesis 2004, No. 7, 992–994 © Thieme Stuttgart · New York