Bisphosphonate prodrugs: Synthesis of new aromatic and aliphatic 1-hydroxy-1,1-bisphosphonate partial esters

Article abstract of DOI:10.1016/j.tet.2005.05.053

Methods for the preparation of various 1-hydroxy-1,1-bisphosphonate partial esters were developed. They were obtained from (alkyl or phenyl) bis(trimethylsilyl) phosphite and aromatic or aliphatic acid chlorides, followed by methanolysis.

Full text of DOI:10.1016/j.tet.2005.05.053

Tetrahedron 61 (2005) 7528–7537
Bisphosphonate prodrugs: synthesis of new aromatic and aliphatic
1-hydroxy-1,1-bisphosphonate partial esters
Maelle Monteil,a Erwann Guenin,a Evelyne Migianu,a Didier Lutomskib and Marc Lecouveya,
*
a
´ ´
Laboratoire de Chimie Structurale Biomoleculaire BIOMOCETI (UMR 7033-CNRS), UFR S.M.B.H. Universite Paris 13. 74,
Rue Marcel Cachin, F-93017 Bobigny Cedex, France
´ ´
Laboratoire de Biochimie des Proteines et Proteomique EA 3408, UFR S.M.B.H. Universite Paris 13. 74, Rue Marcel Cachin,
b
´
F-93017 Bobigny Cedex, France
Received 8 March 2005; revised 16 May 2005; accepted 18 May 2005
Available online 15 June 2005
Abstract—Methods for the preparation of various 1-hydroxy-1,1-bisphosphonate partial esters were developed. They were obtained from
(alkyl or phenyl) bis(trimethylsilyl) phosphite and aromatic or aliphatic acid chlorides, followed by methanolysis.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Masking groups for the negative charge, introduced as
phosphonoester, could be an interesting approach for a
prodrug strategy. Few studies about the design of bispho-
sphonate prodrugs have been reported in the literature.12–14
Only a few reports with phosphonoesters prodrugs15,16 but such
a modification is widely used in phosphate chemistry.17,18
1-Hydroxymethylene-1,1-bisphosphonic acids (HMBP) are
an important class of drugs used clinically in the treatment
of bone diseases involving excessive bone destruction or
resorption such as Paget’s disease, osteoporosis and bone
metastases.1,2 They are also routinely used as 99Tc
complexes in skeletal scintigraphy. They are structural
analogues of natural pyrophosphates containing a P–C–P
backbone and so are stable to enzymatic hydrolysis. More
recently, bisphosphonates have been used for treatment of
metastatic cancer. It has been shown that these compounds
were able to inhibit bone metastases proliferation in prostate
or breast cancer.3–5 They also inhibit experimental
angiogenesis in vitro and in vivo.2,6–8 In addition, HMBP
have also activity against several trypanosomatid and
apicomplexan parasites.9,10
Synthesis of 1-hydroxymethylene-1,1-bisphosphonate is
usually achieved from condensation of a trialkylphosphite
on an acid chloride leading to an a-ketophosphonate which
then reacts with a dialkyl phosphite.19–21 Different
improvements of this method were proposed. Burgada et
al.22–24 described a one pot reaction between acid halides
and a mixture of trialkyl and dialkyl phosphites and Ruel et
al.25 used anions of dialkyl phosphites to obtain directly the
bisphosphonate tetraesters, at low temperature. The main
drawback of these techniques are the thermal and basic
instability of bisphosphonate tetraesters that promote their
phosphonate–phosphate isomerisation.26 Moreover the
regioselective dealkylation to obtain partial esters is difficult
and does not occur in good yield. Our group recently
proposed a very mild and one-pot synthesis to obtain
bisphosphonate methyl esters from bis(trimethylsilyl)-
methyl phosphite and acyl chloride.27
Unfortunately, the bio-availability of HBMP’s is very poor
because of their strong hydrophilicity and their negative
charges due to their high ionization at physiological pH
values. These properties characterize poor cell membrane
permeability. Moreover, they also have powerful complexa-
tion properties towards calcium and other divalent metal
cations decreasing their gastro-intestinal absorption. As
such, only 3–7% of the drug is metabolized.11 As the side
chain of HMBP is responsible for most of the activity, the
modification of some of the phosphonic acid functions
should be a satisfying way to increase lipophilicity.
Herein, we will present the extension of this synthesis to
various 1-hydroxymethylene-1,1-bisphosphonate diesters
using several alkyl or aryl substituents.
2. Results and discussion
Keywords: Bisphosphonate; Arbusov reaction.
*
Corresponding author. Tel.: C33 0 148387709; fax: C33 0 0148387625;
e-mail: m.lecouvey@smbh.univ-paris13.fr
Alkyl or arylbis(trimethylsilyl) phosphites 2 were obtained
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.053

M. Monteil et al. / Tetrahedron 61 (2005) 7528–7537
7529
Table 1. Preparation of alkyl bis(trimethylsilyl) phosphites or aryl
bis(trimethylsilyl) phosphites
from corresponding dialkyl phosphite first by dealkylation
with ammonia and then by silylation of the ammonium
monoalkyl or aryl phosphite 1. The silylphosphites were
then reacted with acid chlorides to yield after hydrolysis, the
corresponding HMBP symmetrical diesters 3 (Scheme 1).
Compound
R
Reaction
conditions
31P{1H}
NMR (D2O)
ppm
Yield %
1a
1b
1c
1d
1e
2a
CH3
6 h, rt
6 h, rt
12 h, rt
2 h, rt
24 h, rt
6 h, reflux,
HMDS
8 h, reflux,
HMDS
24 h, reflux, 118.2
HMDS
2 h, 90 8C,
HMDS
24 h, reflux, 115.0
HMDS
9.2
6.9
4.9
4.5
6.2
115.8
95
87
50
95
85
58
CH3CH2
(CH3)2CH
C6H5
C14H29
CH3
Mono alkyl or aryl phosphites were synthesized as
described by Hammond28 from the dialkyl (or diphenyl)
phosphites by reaction with a 30% ammonia solution.
Reactions were exothermic and addition of the ammonia
solution was carefully done at 0 8C. The course of the
reactions were followed by 31P {1H} NMR and depending
on the nature of the alkyl or aryl substituent the reaction
time varied from one hour starting from dimethyl phosphite
to one day for the less reactive ditetradecyl phosphite
(Table 1). For all compounds 1a-e, co-evaporation with dry
pyridine and benzene was necessary to get rid of water at the
end of the reaction. In the case of ammonium phenyl 1d, or
tetradecyl phosphites 1e, products were further precipitated
in dry ether and washed several times to remove phenol or
tetradecanol formed. All the obtained compounds gave in
31P {1H} NMR a large doublet centred around 4–10 ppm
2b
2c
2d
2e
CH3CH2
(CH3)2CH
C6H5
116.1
55
60
45
80
121.5
C14H29
without further purification. To avoid the formation of
tris(trimethylsilyl) phosphite when synthesizing phenyl
bis(trimethylsilyl) phosphite, BSA could be used as
silylating agent. In this case, the reaction was performed
at K10 8C, in 1 h, using 5 equiv of BSA.
1
with a characteristic coupling constant JP–Hz640 Hz
(Table 1).
As previously described for reaction between tris(trimethyl-
silyl) phosphite with acid chlorides the procedure for (alkyl
or phenyl) bis(trimethylsilyl) phosphites was still efficient in
aromatic or aliphatic series. Various aliphatic acid
chlorides, differently substituted aromatics acid chlorides
and heterocyclic acid chlorides have been used, all giving
good yields of HMBP (Table 2). The key features of this
synthetic pathway were the use of silylated phosphites 2
which reacted readily with acid chlorides. A first equivalent
reacted following an Arbuzov mechanism yielding a
silylated a-ketophosphonate intermediate (Scheme 2). A
second addition of the (alkyl or aryl) bis(trimethylsilyl)
phosphite led to the fully silylated symmetrical bisphos-
phonate diester. This product was then hydrolyzed with
methanol to the corresponding symmetrical bisphosphonate
diester.
Numerous silylating reagents were described to silylate
mono(alkyl or aryl) phosphites. Voronkov and Orlov29,30
initially used trimethylsilyl chloride in pyridine and Sekine
described use of HMDS, BSA, BSTFA.31,32 In our case with
alkyl phosphites, the use of hexamethyldisilazane gave good
results. Reactions were conducted by heating the
ammonium mono(alkyl or phenyl) phosphite in freshly
distilled HMDS, under nitrogen and using dry vessels.
Reaction evolution was followed by 31P {1H} NMR. We
first observed the formation of the monosilylated phosphite
giving a signal at approximately 13 ppm and then the
formation of the alkyl or arylbis(trimethylsilyl) phosphite
giving a characteristic signal between 115–125 ppm
(Table 1). Once again we observed a difference in reactivity
depending on the ammonium mono(alkyl or aryl) phosphite.
Reaction time needed to achieve completion increased from
methyl bis(trimethylsilyl) phosphite 2a to tetradecyl
(trimethylsilyl) phosphite 2e. Moreover, in the case of the
reaction of ammonium phenyl phosphite 1d with HMDS,
yield was lower than with ammonium alkyl phosphite. If
heated to more than 90 8C a new signal was observed in 31P
{1H} NMR at 114 ppm corresponding to the formation of
tris(trimethylsilyl) phosphite. The same phenomenon was
observed with tetradecyl phosphite but in a less extent. All
(alkyl or phenyl) bis(trimethylsilyl) phosphite were distilled
prior use except for the tetradecyl bis(trimethylsilyl)
phosphite 2e which was used, after HMDS evaporation,
For each addition of the aryl or alkyl bis(trimethylsilyl)
phosphite 2 the reaction always evolved towards the leaving
of a silyl group rather than the alkyl or the aryl group. In
fact, alkyl or aryl esters of phosphite were less reactive than
silyl esters towards nucleophiles. Typically alkyl and aryl
bis(trimethylsilyl) phosphites 2 and acid chloride were
reacted for 2 h at room temperature under nitrogen without
solvent or in a minimum of dry THF for solid acid chlorides.
The reaction was strongly exothermic and the addition must
be done in an ice bath. Reactions were followed by 31P {1H}
Scheme 1.

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M. Monteil et al. / Tetrahedron 61 (2005) 7528–7537
Table 2. Synthesis of HMBP partial esters 3 to 10 produced via Scheme 1
NMR. After evaporation of the volatile fractions and
methanolysis, crude products were purified by precipitation.
Products presented a unique signal in 31P {1H} NMR as
expected for symmetric bisphosphonates. Observed chemi-
cal shifts were slightly lower than what was described for
corresponding 1-hydroxymethylene-1,1-bisphosphonic
acids. This decrease in the 31P {1H} NMR chemical shift
value was more pronounced in the alkyl family from methyl
to isopropyl and even more pronounced for phenyl esters.
All compounds also presented in 13C {1H} NMR a triplet for
the carbon bearing the two phosphonate groups with a
coupling constant of approximately 145–155 Hz. Yields
were usually good whether substrates were aliphatic,
aromatic or heteroaromatic. They were slightly higher
varying from 60 to 95% for alkyl esters compared to phenyl
esters. This fact could be explained by the relative thermal
instability of such diphenyl bisphosphonates. When reacting
phenyl bis(trimethylsilyl) phosphite 2d with acid chlorides,
addition must be carried out carefully to avoid thermal
dealkylation of the diphenyl bisphosphonate formed. For
example, when reacting phenyl bis(trimethylsilyl) phosphite
with palmitoyl chloride, if the addition was not done in an
ice bath, new signals appeared in 31P {1H} NMR. After
methanolysis, together with the signal at 15.7 ppm for the
symmetrical bisphosphonate diphenyl ester 5d, we observed
two doublets centred on 16.2 and 20.1 ppm corresponding to
the bisphosphonate monophenyl ester. This compound
which was not symmetric possessed two different phos-
phorus atoms which coupled together with a 42 Hz coupling
constant.
HMBP
partial
esters
R
31P{1H}
NMR (D2O)
ppm
Yield %
R0
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
9a
CH3
CH3
CH3
CH3
CH3
23.9
19.9
18.8
17.4
19.4
24.2
20.8
20.4
17.4
20.9
24.1
20.2
18.5
16.2
20.6
20.8
19.7
18.0
15.9
15.4
18.2
16.9
16.4
11.6
15.3
17.3
16.4
15.6
12.8
14.6
16.3
90
95
90
65
88
85
86
92
49
81
85
95
93
37
69
90
95
55
90
63
90
85
95
78
77
90
72
80
70
80
92
CH3CH2
(CH3)2CH
C6H5
C14H29
CH3
CH3CH2
(CH3)2CH
C6H5
C14H29
CH3
CH3CH2
(CH3)2CH
C6H5
C14H29
CH3
CH3CH2
(CH3)2CH
C6H5
C14H29
CH3
CH3CH2
(CH3)2CH
C6H5
C14H29
CH3
CH3CH2
(CH3)2CH
C6H5
C14H29
CH3
CH3
(CH3)2CH
(CH3)2CH
(CH3)2CH
(CH3)2CH
(CH3)2CH
C15H31
C15H31
C15H31
C15H31
C15H31
–
–
C6H5–CH2
C6H5–CH2
C6H5–CH2
C6H5–CH2
C6H5–CH2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H4–Br
C6H4–Br
C6H4–Br
C6H4–Br
C6H4–Br
C6H4–
OCH3
C6H4–
OCH3
C6H4–
OCH3
C6H4–
OCH3
C6H4–
OCH3
9b
9c
9d
9e
CH3CH2
(CH3)2CH
C6H5
17.3
16.6
13.5
15.4
60
77
81
69
3. Conclusion
We have described a convenient route to a new class of
bisphosphonate partial ester derivatives. This procedure offers
many possibilities for combining together different aromatic
and aliphatic phosphonic ester groups and aromatic and
aliphatic substituents on 1-hydroxymethylene-1,1-bisphos-
phonic side chain group. It allows access to an extremely
varied library of bisphosphonate partial esters with potent
biological applications. Recently, we have shown that these
compounds have anti-angiogenic and anti-tumor effects in
breast carcinoma models.33
C14H29
10a
10b
10c
10d
10e
CH3
C5H4N
C5H4N
C5H4N
C5H4N
C5H4N
14.8
14.8
13.0
18.3
12.5
75
90
90
73
50
CH3CH2
(CH3)2CH
C6H5
C14H29
Scheme 2.

M. Monteil et al. / Tetrahedron 61 (2005) 7528–7537
7531
4. Experimental
4.1. General methods
4.2.3. Ammonium isopropyl H-phosphonate (1c). Yield:
50%. Mp 132 8C. 31P NMR {1H} (80.9 MHz, D2O) d 4.9. 1H
3
NMR (200 MHz, D2O) d 1.08 (d, 3H, JH–HZ7 Hz,
3
OCH(CH3)2), 1.18 (d, 3H, JH–HZ7 Hz, OCH(CH3)2),
4.15–4.43 (m, 1H, OCH(CH3)2). 13C NMR {1H}
Unless otherwise noted, all solvents and reagents were high-
purity-grade materials and used without further purification.
THF was distilled from benzophenone sodium. Diethyl-
ether, benzene and hexane were distilled from sodium.
Pyridine was distilled from potassium hydroxide. Hexa-
methyldisilazane was distilled prior use. Solid acyl
chlorides were used directly and liquid acid chlorides
were distilled under reduced pressure. Ditetradecyl phos-
phite was obtained from transesterification of diphenyl
phosphite as described by G Le Bolc’h.34
(125.9 MHz, D2O)
(OCH(CH3)2).
d
26.6 (OCH(CH3)2), 72.3
4.2.4. Ammonium phenyl H-phosphonate (1d). Yield:
95%. Mp 133 8C. 31P NMR {1H} (80.9 MHz, D2O) d 4.5. 1H
NMR (200 MHz, D2O) d 6.94–7.07 (m, 3H, C6H5), 7.20–
7.23 (m, 2H, C6H5). 13C NMR {1H} (125.9 MHz, D2O) d
124.1 (o-C6H5), 127.9 (p-C6H5), 133.2 (m-C6H5), 153.9
(OC6H5).
4.2.5. Ammonium tetradecyl H-phosphonate (1e). Yield:
85%. Mp 52 8C. 31P NMR {1H} (80.9 MHz, D2O) d 6.2. 1H
NMR (200 MHz, D2O) d 0.85 (t, 3H, JH–HZ6.5 Hz,
OCH2CH2(CH2)11CH3), 1.23–1.27 (m, 22H, OCH2CH2
(CH2)11CH3), 1.30–1.33 (m, 2H, OCH2CH2(CH2)11CH3),
4.10–4.11 (m, 2H, OCH2CH2(CH2)11CH3). 13C NMR {1H}
(125.9 MHz, D2O) d 17.1 (OCH2CH2(CH2)11CH3), 26.0
(OCH2CH2(CH2)10CH2CH3), 29.2, 33.2, 33.7 (OCH2CH2
(CH2)10–CH2CH3), 35.5 (OCH2CH2(CH2)11CH3), 67.5
(OCH2CH2(CH2)10–CH2CH3).
Boiling points are given in Torr (Bpvalue). NMR spectra
were recorded with a VARIAN Unity Inova 500 MHz (13C:
125.9 MHz, 1H: 500.6 MHz, 31P: 200.7 MHz) or a
VARIAN Gemini 200 MHz (13C: 50.3 MHz, 1H:
200 MHz, 31P: 80.9 MHz) spectrometer in D2O, CDCl3, or
3
DMSO-d6. Chemical shifts (d) are given in ppm. 31P and 13
C
NMR spectra were recorded with phosphoric acid and
methanol as external references, respectively. 1H NMR
spectra were recorded using HOD or trimethylsilane as
internal standard in D2O or CDCl3. Attribution of aromatic
carbons and protons is given in the text by adding o for
ortho, m for meta and p for para.
4.3. General procedure for synthesis of alkyl or aryl
bis(trimethylsilyl) phosphite 2
Mass spectra were recorded in positive reflectron mode with
DHB as a matrix on a MALDI-TOF-MS (Bruker).
Microanalyses were performed by the Service Central
d’Analyse, CNRS, F-69390, Vernaison, France.
In a 100 mL round-bottom three-neck flask equipped with a
condenser and a thermometer, ammonium alkyl (or phenyl)
phosphite 1 (20 mmol) was mixed, under nitrogen, with
freshly distilled hexamethyldisilazane (95 mmol, 20 mL).
Except in the case of synthesis of 2d which was heated at
90 8C for 2 h, all the other products were obtained by
refluxing the ammonium salts in hexamethyldisilazane,
respectively, 6 h for 2a, 8 h for 2b and 24 h for 2c and 2e.
For each compound, reaction evolution was monitored by
31P {1H} NMR. Hexamethyldisilazane was then evaporated
in vacuo (0.1 Torr). Tetradecylbis(trimethylsilyl) phosphite
2e was used without further purification. All the other silyl
phosphites 2a to 2d were distilled under vacuum.
4.2. General procedure for synthesis of ammonium alkyl
phosphites 1a to 1e
In a 250 mL round bottom three neck flask, equipped with a
thermometer and a condenser, 20 mL of concentrated
ammonia solution (33%) were added carefully over
30 min, to dialkylplhosphite (1, 75 mmol). An exothermic
reaction took place for 1d and 1e and the solution was
therefore kept at room temperature using an ice bath. When
the addition was completed, the mixture was set aside at
room temperature for 2 h for 1d, 6 h for 1a and 1b, 12 h for
1c and 24 h for 1e. Except for 1d, which gave an emulsion
the other compounds gave clear solutions. Then solutions
were concentrated in vacuo. The resulting solid was dried by
repeated co-evaporation with dry benzene (3!20 mL), and
then dry pyridine (3!20 mL) and finally, precipitated in
diethylether for 1d and 1e.
4.3.1. Methyl bis(trimethylsilyl) phosphite (2a). Yield:
58%. Bp0.1 42 8C. 31P NMR {1H} (80.9 MHz, CDCl3) d
115.8. 1H NMR (200 MHz, CDCl3) d 0.28 (s, 18H,
3
Si(CH3)3), 3.4 (d, 3H, JP–HZ12.1 Hz, OCH3).
4.3.2. Ethyl bis(trimethylsilyl) phosphite (2b). Yield:
55%. Bp0.1 50 8C. 31P NMR {1H} (80.9 MHz, CDCl3) d
116.1. 1H NMR (200 MHz, CDCl3) d 0.21 (s, 18H,
3
Si(CH3)3), 1.23 (t, 3H, JH–HZ7 Hz, OCH2CH3), 3.75–
3.89 (m, 2H, OCH2CH3).
4.2.1. Ammonium methyl H-phosphonate (1a). Yield:
95%. Mp 108 8C. 31P NMR {1H} (80.9 MHz, D2O) d 9.2. 1H
3
NMR (200 MHz, D2O) d 3.39 (d, 3H, JP–HZ12.4 Hz,
4.3.3. Isopropyl bis(trimethylsilyl) phosphite (2c). Yield:
60%. Bp0.1 54 8C. 31P NMR {1H} (80.9 MHz, CDCl3) d
118.2. 1H NMR (200 MHz, CDCl3) d 0.20 (s, 18H,
OCH3). 13C NMR {1H} (125.9 MHz, D2O) d 53.9 (OCH3).
3
Si(CH3)3), 1.20 (d, 3H, JH–HZ7 Hz, OCH(CH3)2), 1.34
4.2.2. Ammonium ethyl H-phosphonate (1b). Yield: 87%.
Mp 93 8C. 31P NMR {1H} (80.9 MHz, D2O) d 6.9. 1H NMR
3
(d, 3H, JH–HZ7 Hz, OCH(CH3)2), 4.40–450 (m, 1H,
OCH(CH3)2).
3
(200 MHz, D2O) d 1.09 (t, 3H, JH–HZ7 Hz, OCH2CH3)
3
3
3.75 (dt, 2H, JH–HZ7 Hz; JP–HZ7 Hz, OCH2CH3). 13C
NMR {1H} (125.9 MHz, D2O) d 18.4 (OCH2CH3), 63.1
(OCH2CH3).
4.3.4. Phenyl bis(trimethylsilyl) phosphite (2d). Yield:
45%. Bp0.1 83 8C. 31P NMR {1H} (80.9 MHz, CDCl3) d

7532
M. Monteil et al. / Tetrahedron 61 (2005) 7528–7537
3
121.5. 1H NMR (200 MHz, CDCl3) d 0.22 (s, 18H,
Si(CH3)3), 7.00–7.08 (m, 2H, C6H5), 7.24–7.31 (m, 3H,
C6H5).
NMR (500 MHz, D2O) d 1.78 (t, 3H, JP–HZ16.0 Hz,
CH3C(OH)), 7.19 (t, 1H, 3JH–HZ7 Hz, p-C6H5), 7.26–7.29
(m, 2H, o-C6H5), 7.28–7.41 (m, 2H, m-C6H5). 13C NMR
{1H} (125.9 MHz, D2O) d 23.7 (CH3C(OH)), 75.5 (t,
1JP–CZ149.2 Hz, P–C(OH)–P), 124.2 (o-C6H5), 127.1
(p-C6H5), 132.7 (m-C6H5), 155.2 (OC6H5). Anal. Calcd
for C14H14Na2O7P2: C, 41.81; H, 3.51; P, 15.40; Found: C,
41.88; H, 3.53; P, 15.47.
4.3.5. Tetradecyl bis(trimethylsilyl) phosphite (2e).
Yield: 80%. 31P NMR {1H} (80.9 MHz, CDCl3) d 115.0.
1H NMR (200 MHz, CDCl3) d 0.33 (s, 18H, Si(CH3)3), 0.88
(t, 3H, 3JH–HZ7 Hz, OCH2CH2(CH2)11CH3), 1.16–1.41 (m,
22H, OCH2CH2(CH2)11CH3), 1.60–1.80 (m, 2H, OCH2CH2
(CH2)11CH3), 3.96–4.07 (m, 2H, OCH2CH2(CH2)11CH3).
4.4.5.
[1-Hydroxy-1-(hydroxy-tetradecyloxy-phos-
phoryl)-ethyl]-phosphonic acid monotetra decyl ester
(3e). Precipitation in diethylether. Yield: 88%. Mp!50 8C.
31P NMR {1H} (200.7 MHz, CDCl3) d 19.4. 1H NMR
4.4. General procedure for synthesis of bisphosphonate
dialkyl or diaryl esters 3-10
3
(500 MHz, CDCl3) d 0.85 (t, 6H, JH–HZ6.5 Hz, OCH2
CH2(CH2)11CH3), 1.19–1.33 (m, 44H, OCH2CH2(CH2)11
CH3), 1.30–1.37 (m, 4H, OCH2CH2(CH2)11CH3), 1.63 (t,
In a 50 mL round-bottom three-neck flask equipped with a
thermometer, acid chloride (2.5 mmol) was added dropwise,
under argon, at K5 8C, to dialkyl or diaryl phosphite
(5 mmol). When addition was completed, reaction mixture
was allowed to stand at room temperature for 2 h. The
evolution of the reaction was monitored by 31P {1H} NMR.
Then, volatile fractions were evaporated under reduced
pressure (0.1 Torr) before being hydrolyzed with methanol.
After evaporation, crude products were precipitated in an
appropriate mixture of solvent.
3
3H, JP–HZ16 Hz, CH3–COH), 4.08–4.14 (m, 4H, OCH2-
CH2(CH2)11CH3). 13C NMR {1H} (125.9 MHz, CDCl3) d
14.3 (OCH2CH2(CH2)11CH3), 22.9 (OCH2CH2(CH2)10CH2
CH3), 25.9 (s, CH3–COH), 29.9–30.7 (OCH2CH2(CH2)10
CH2CH3), 32.2 (OCH2CH2(CH2)10CH2CH3), 67.8 (OCH2
CH2(CH2)10CH2CH3), 71.6 (t, 1JP–CZ152.7 Hz, P–C(OH)–
P). MS (C30H64O7P2): m/z 621.3 [MCNaCH]C, 599.3
[MCH]C. Anal. Calcd for C30H64O7P2: C, 60.18; H, 10.77;
P, 10.35; Found: C, 60.13; H, 10.75; P, 10.31.
4.4.1. [1-Hydroxy-1-(hydroxy-methoxy-phosphoryl)-
ethyl]-phosphonic acid monomethyl ester (3a). Precipi-
tation in diethylether. Yield: 90%. Mp 76 8C. 31P NMR
{1H} (200.7 MHz, D2O) d 23.9. 1H NMR (500 MHz, D2O)
4.4.6. [1-Hydroxy-1-(hydroxy-methoxy-phosphoryl)-2-
methyl-propyl]-phosphonic acid mono methyl ester
(4a). Precipitation in diethylether. Yield: 85%. Mp
3
1
d 1.04 (t, 3H, JP–HZ16 Hz, CH3–C(OH)), 3.14–3.22 (m,
125 8C. 31P NMR {1H} (200.7 MHz, CDCl3) d 24.2. H
6H, OCH3). 13C NMR {1H} (50.3 MHz, D2O) d 17.7 (CH3–
C(OH)), 51.6 (OCH3), 69.1 (t, 1JP–CZ152.6 Hz, P–C(OH)–
P). Anal. Calcd for C4H12O7P2: C, 20.52; H, 5.17; P, 26.46;
Found: C, 20.57; H, 5.19; P, 26.51.
NMR (500 MHz, CDCl3) d 1.09 (d, 3H, JH–HZ7 Hz,
3
3
(CH3)2CH), 1.10 (d, 3H, JH–HZ7 Hz, (CH3)2CH), 2.16–
2.28 (m, 1H, (CH3)2CH), 3.64–3.66 (m, 6H, OCH3). 13C
NMR {1H} (125.9 MHz, D2O) d 17.1 (CH3)2CH), 39.4
1
((CH3)2CH), 57.4 (OCH3), 78.1 (t, JP–CZ152.2 Hz, P–
C(OH)–P). Anal. Calcd for C6H16O7P2: C, 27.49; H, 6.15;
P, 23.63; Found: C, 27.43; H, 6.13; P, 23.60.
4.4.2. [1-Hydroxy-1-(hydroxy-ethoxy-phosphoryl)-
ethyl]-phosphonic acid monoethyl ester (3b). Precipi-
tation in diethylether. Yield: 95%. MpO260 8C. 31P NMR
{1H} (200.7 MHz, D2O) d 19.9. 1H NMR (500 MHz, D2O)
4.4.7. [1-Hydroxy-1-(hydroxy-ethoxy-phosphoryl)-2-
methyl-propyl]-phosphonic acid mono ethyl ester (4b).
Precipitation in diethylether. Yield: 86%. Mp 216 8C. 31P
NMR {1H} (200.7 MHz, D2O) d 20.8. 1H NMR (500 MHz,
d 1.26 (t, 6H, 3JH–HZ7 Hz, OCH2CH3), 1.52 (t, 3H, 3JP–H
Z
15 Hz, C(OH)CH3), 3.98–4.10 (m, 4H, OCH2CH3). 13C
NMR {1H} (125.9 MHz, D2O) d 19.7 (OCH2CH3), 23.7
(CH3C(OH)), 65.2 (s, OCH2CH3), 75.5 (t, 1JP–CZ146.0 Hz,
P–C(OH)–P). Anal. Calcd for C6H16O7P2: C, 27.49; H,
6.15; P, 23.63; Found: C, 27.43; H, 6.13; P, 23.58.
3
D2O) d 1.07 (d, 6H, JH–HZ7 Hz, (CH3)2CH), 1.19 (t, 6H,
3JH–HZ7 Hz, OCH2CH3), 2.14–2.26 (m, 1H, (CH3)2CH),
4.02–4.08 (m, 4H, OCH2CH3). 13C NMR {1H} (125.9 MHz,
D2O) d 19.1 (OCH2CH3), 20.8 ((CH3)2CH), 37.0
1
4.4.3. [1-Hydroxy-1-(hydroxy-isoproxy-phosphoryl)-
ethyl]-phosphonic acid monoisopropyl ester (3c). Pre-
cipitation in diethylether/hexane: 80/20. Yield: 90%. Mp
((CH3)2CH), 66.6 (OCH2CH3), 80.6 (t, JP–CZ146.5 Hz,
P–C(OH)–P). Anal. Calcd for C8H20O7P2: C, 33.11; H,
6.95; P, 21.35; Found: C, 33.07; H, 6.86; P, 21.28.
1
128 8C. 31P NMR {1H} (200.7 MHz, CDCl3) d 18.8. H
3
NMR (500 MHz, CDCl3) d 1.30 (d, 6H, JH–HZ6.0 Hz,
4.4.8. [1-Hydroxy-1-(hydroxy-isopropoxy-phosphoryl)-
2-methyl-propyl]-phosphonic acid mono isopropyl ester
(4c). Precipitation in diethylether.Yield: 92%. Mp 200 8C.
31P NMR {1H} (200.7 MHz, CDCl3) d 20.4. 1H NMR
3
OCH(CH3)2), 1.33 (d, 6H, JH–HZ6.0 Hz, OCH(CH3)2),
3
1.62 (t, 3H, JP–HZ16.0 Hz, CH3C(OH)), 4.77–4.86 (m,
2H, OCH(CH3)2). 13C NMR {1H} (125.9 MHz, CDCl3) d
18.4 (CH3C(OH)), 23.9 (OCH(CH3)2), 24.3 (OCH(CH3)2),
71.4 (t, 1JP–CZ154.4 Hz, P–C(OH)–P), 73.1 (OCH(CH3)2).
Anal. Calcd for C8H20O7P2: C, 33.11; H, 6.95; P, 21.35;
Found: C, 33.15; H, 6.96; P, 21.44.
3
(500 MHz, CDCl3) d 1.19 (d, 6H, JH–HZ6.8 Hz, (CH3)2
CHCOH), 1.32 (d, 6H, 3JH–HZ6 Hz, OCH(CH3)2), 1.34 (d,
3
6H, JH–HZ6 Hz, OCH(CH3)2), 2.30–2.42 (m, 1H, (CH3)2
CHCOH), 4.76–4.86 (m, 2H, OCH(CH3)2). 13C NMR {1H}
(125.9 MHz, CDCl3) d 18.3 ((CH3)2CHCOH), 24.0
(OCH(CH3)2), 24.4 (OCH(CH3)2), 32.9 ((CH3)2CHCOH),
72.5 (OCH(CH3)2), 77.4 (t, 1JP–CZ147.1 Hz, P–C(OH)–P).
Anal. Calcd for C10H24O7P2: C, 37.74; H, 7.60; P, 19.47;
Found: C, 37.82; H, 7.61; P, 19.51.
4.4.4. Disodium salt of [1-hydroxy-1-(hydroxy-phenoxy-
phosphoryl)-ethyl]-phosphonic acid monophenyl ester
(3d). Precipitation in diethylether/hexane: 95/5. Yield: 65%.
MpO260 8C. 31P NMR {1H} (200.7 MHz, D2O) d 17.4. 1H

M. Monteil et al. / Tetrahedron 61 (2005) 7528–7537
7533
4.4.9. Disodium salt of [1-hydroxy-1-(hydroxy-phenoxy-
phosphoryl)-2-methyl-propyl]-phosphonic acid mono-
phenyl ester (4d). Precipitation in water as diacid form.
Yield: 49%. Mp 122 8C. 31P NMR {1H} (200.7 MHz, D2O)
hexadecyl]-phosphonic acid mono isopropyl ester (5c).
Precipitation in diethylether. Yield: 93%. Mp!50 8C. 31P
NMR {1H} (200.7 MHz, CDCl3) d 18.5. 1H NMR (500 MHz,
CDCl3) d 0.85 (t, 3H, 3JH–HZ7 Hz, CH3(CH2)14COH), 1.23–
1.34 (m, 36H, CH3(CH2)12CH2CH2COH; OCH(CH3)2),
1.53–1.62 (m, 2H, CH3(CH2)12CH2CH2COH), 1.99–2.12
(m, 2H, CH3(CH2)12CH2CH2COH), 4.79–4.83 (m, 2H,
OCH(CH3)2). 13C NMR {1H} (125.9 MHz, CDCl3) d 14.3
(CH3(CH2)14COH), 22.9 (CH3CH2(CH2)13COH), 24.0
((CH3)2CH), 24.3 ((CH3)2CH), 29.8 ((CH3)2CH), 32.1 (CH3
CH2(CH2)11CH2CH2COH), 33.4 (CH3CH2(CH2)11CH2CH2-
1
3
d 17.4. H NMR (500 MHz, D2O) d 1.34 (d, 6H, JH–HZ
6.8 Hz, (CH3)2CH), 2.50–2.59 (m, 1H, (CH3)2CH), 7.20–
3
7.26 (m, 6H, C6H5), 7.39 (t, 4H, JH–HZ7.5 Hz, m–C6H5).
13C NMR {1H} (125.9 MHz, D2O) d 21.2 ((CH3)2CH), 37.5
1
((CH3)2CH), 82.1 (t, JP–CZ143.9 Hz, P–C(OH)–P), 124.2
(o-C6H5), 127.8 (p-C6H5), 132.9 (o-C6H5), 153.9 (OC6H5).
Anal. Calcd for C16H18Na2O7P2: C 44.67; H, 4.22; P, 14.40;
Found: C, 44.72; H, 4.23; P, 14.48.
1
COH), 72.7 (OCH(CH3)2), 74.3 (t, JP–CZ151.2 Hz, P–
C(OH)–P). Anal. Calcd for C21H45O7P2: C, 53.49; H, 9.62; P,
13.14; Found: C, 53.54; H, 9.64; P, 13.20.
4.4.10. [1-Hydroxy-1-(hydroxy-tetradecyloxy-phos-
phoryl)-ethyl]-phosphonic acid mono tetradecyl ester
(4e). Yellow oil. Yield: 81%. 31P NMR {1H} (200.7 MHz,
4.4.14. [1-Hydroxy-1-(hydroxy-phenoxy-phosphoryl)-
hexadecyl]-phosphonic acid mono phenylester (5d).
Yellow oil. Yield: 37%. 31P NMR {1H} (200.7 MHz,
1
CDCl3) d 20.9. H NMR (500 MHz, CDCl3) d 0.85 (t, 6H,
3JH–HZ6.5 Hz, OCH2CH2(CH2)11CH3), 1.13–1.27 (m,
50H, OCH2CH2(CH2)11CH3; (CH3)2CH), 1.32–1.33 (m,
4H, OCH2CH2(CH2)11CH3), 2.46–2.53 (m, 1H, (CH3)2CH),
3.96–4.10 (m, 4H, OCH2CH2(CH2)11CH3). 13C NMR {1H}
(125.9 MHz, CDCl3) d 14.3 (OCH2CH2(CH2)11CH3), 18.3
((CH3)2CH), 22.9 (OCH2CH2(CH2)10CH2CH3), 25.7–30.7
(OCH2CH2(CH2)10CH2CH3), 32.1 (OCH2CH2(CH2)10CH2
CH3), 32.8 ((CH3)2CH), 67.6 (OCH2CH2(CH2)10CH2CH3),
1
CDCl3) d 16.2. H NMR (500 MHz, CDCl3) d 0.86 (t, 3H,
3JH–HZ7 Hz, CH3(CH2)14COH), 1.15–1.29 (m, 24H, CH3
(CH2)12CH2CH2COH), 1.54–1.65 (m, 2H, CH3 (CH2)12
3
CH2CH2COH), 2.30 (t, 2H, JH–HZ8 Hz, CH3 (CH2)12
CH2CH2COH), 6.99–7.24 (m, 10H, C6H5). 13C NMR {1H}
(125.9 MHz, CDCl3) d 14.3 (CH3(CH2)14COH), 22.9 (CH3
CH2(CH2)13COH), 24.9–30.1 (CH3CH2(CH2)11 CH2CH2
COH), 32.2 (CH3CH2(CH2)11CH2CH2COH), 34.2 (CH3
71.8
(t,
1JP–CZ152.7 Hz,
P–C(OH)–P).
MS
(C32H66O7P2Na2): m/z 670.8 [MCH]C. Anal. Calcd for
C32H68O7P2: C, 61.32; H, 10.93; P, 9.88; Found: C, 61.39;
H, 10.95; P, 9.96.
CH2(CH2)11CH2CH2COH), 75.0 (t, JP–CZ152.9 Hz, P–
1
C(OH)–P), 121.0 (o-C6H5), 124.9 (p-C6H5), 129.7
(m-C6H5), 150.7 (OC6H5). Anal. Calcd for C28H44O7P2: C
60.64; H, 8.00; P, 11.17; Found: C, 60.59; H, 7.99; P, 11.12.
4.4.11. [1-Hydroxy-1-(hydroxy-methoxy-phosphoryl)-
hexadecyl]-phosphonic acid mono methyl ester (5a).
Precipitation in diethylether. Yield: 85%. Mp 64 8C. 31P
NMR {1H} (200.7 MHz, CDCl3) d 24.1. 1H NMR
4.4.15. [1-Hydroxy-1-(hydroxy-tetradecyloxy-phos-
phoryl)-hexadecyl]-phosphonic acid mono tetradecyles-
ter (5e). Precipitation in hexane. Yield: 69%. Mp!50 8C.
3
31P NMR {1H} (200.7 MHz, CDCl3) d 20.6. 1H NMR
(500 MHz, CDCl3) d 0.85 (t, 3H, JH–HZ7 Hz, CH3
3
(CH2)14COH), 1.23–1.26 (m, 24H, CH3(CH2)12CH2CH2
COH), 1.52–1.64 (m, 2H, CH3(CH2)12CH2CH2COH), 1.96–
1.99 (m, 2H, CH3(CH2)12CH2CH2COH), 3.82–3.84 (m, 6H,
OCH3). 13C NMR {1H} (125.9 MHz, CDCl3) d 14.3
(CH3(CH2)15COH), 22.9 (CH3CH2(CH2)13COH), 23.4–
30.5 (CH3CH2(CH2)11CH2CH2COH), 32.1 (CH3CH2
(CH2)11CH2CH2COH), 33.4 (CH3CH2(CH2)11CH2CH2
(500 MHz, CDCl3)
d
0.85 (t, 9H, JH–HZ7 Hz,
O(CH2)13CH3; CH3(CH2)14COH), 1.23–1.30 (m, 70H,
OCH2CH2(CH2)11CH3; CH3(CH2)13CH2COH), 1.56–1.61
(m, 4H, OCH2CH2(CH2)11CH3), 1.86–2.00 (m, 2H, CH3
(CH2)13CH2COH), 4.01–4.09 (m, 4H, OCH2CH2(CH2)11
CH3). 13C NMR {1H} (125.9 MHz, CDCl3) d 14.3 (CH3
(CH2)14COH; OCH2CH2(CH2)11CH3), 22.9 (OCH2(CH2)11
CH2CH3; CH3CH2(CH2)13COH), 26.0–30.9 (OCH2CH2
(CH2)10CH2CH3; CH3CH2(CH2)11CH2CH2COH), 32.2
(CH3CH2(CH2)11CH2CH2COH; OCH2CH2(CH2)10CH2
CH3), 34.2 (CH3CH2(CH2)11CH2CH2COH), 67.1 (OCH2
CH2(CH2)10CH2CH3), 74.7 (t, 1JP–CZ148.3 Hz, P–C(OH)–
P). MS (C44H90O7P2Na2, pHZ7.5): m/z 817.6 [MCNaC
H]C, 795.6 [MCH]C. Anal. Calcd for C44H92O7P2: C,
66.46; H, 11.66; P, 7.79; Found: C, 66.53; H, 11.68; P, 7.84.
1
COH), 54.1 (CH3O), 75.0 (t, JP–CZ151.0 Hz, P–C(OH)–
P). Anal. Calcd for C17H37O7P2: C 49.15; H, 8.98; P, 14.91;
Found: C, 49.07; H, 8.96; P, 14.82.
4.4.12. [1-Hydroxy-1-(hydroxy-ethoxy-phosphoryl)-hex-
adecyl]-phosphonic acid monoethyl ester (5b). Precipi-
tation in diethylether. Yield: 95%. Mp 66 8C. 31P NMR
{1H} (200.7 MHz, D2O) d 20.2. 1H NMR (500 MHz, D2O)
3
d 0.74 (t, 3H, JH–HZ7 Hz, CH3(CH2)14COH), 1.15 (m,
30H, CH3(CH2)12CH2CH2COH; OCH2CH3), 1.55–1.63 (m,
2H, CH3(CH2)12CH2CH2COH), 1.93–2.07 (m, 2H, CH3
4.4.16. [1-Hydroxy-1-(hydroxy-methoxy-phosphoryl)-2-
phenyl-ethyl]-phosphonic acid mono-methyl ester (6a).
Precipitation in diethylether. Yield: 90%. Mp 130 8C. 31P
NMR {1H} (200.7 MHz, CDCl3) d 20.8. 1H NMR
(CH2)12CH2CH2COH), 4.18–4.28 (m, 4H, OCH2CH3). 13
C
NMR {1H} (125.9 MHz, D2O) d 17.1 (CH3(CH2)14COH),
19.5 (OCH2CH3), 22.9 (CH3CH2(CH2)13COH), 25.9–33.4
(CH3CH2(CH2)11CH2CH2COH), 35.3 (CH3CH2(CH2)11
CH2CH2COH), 37.6 (CH3CH2(CH2)11CH2CH2COH), 65.9
3
(500 MHz, D2O) d 3.16 (t, 2H, JP–HZ13.5 Hz, C6H5CH2-
COH), 3.44–3.49 (m, 6H, OCH3), 7.14–7.20 (m, 3H, C6H5),
3
7.26 (d, 2H, JH–HZ6.5 Hz, C6H5). 13C NMR {1H}
(50.3 MHz, DMSO-d6) d 37.2 (C6H5–CH2–COH), 51.1
1
(OCH2CH3), 75.1 (t, JP–CZ149.2 Hz, P–C(OH)–P). Anal.
Calcd for C20H24O7P2: C, 52.39; H, 9.67; P, 13.51; Found:
C, 52.30; H, 9.65; P, 13.43.
1
(OCH3), 73.4 (t, JP–CZ145.4 Hz, P–C(OH)–P), 125.1 (p-
C6H5–CH2), 126.1 (m-C6H5–CH2), 129.5 (o-C6H5–CH2),
134.1 (C6H5–CH2). Anal. Calcd for C10H16O7P2: C, 38.72;
H, 5.20; P, 19.97; Found: C, 38.65; H, 5.19; P, 19.88.
4.4.13. [1-Hydroxy-1-(hydroxy-isopropoxy-phosphoryl)-

7534
M. Monteil et al. / Tetrahedron 61 (2005) 7528–7537
4.4.17. [1-Hydroxy-1-(hydroxy-ethoxy-phosphoryl)-2-
phenyl-ethyl]-phosphonic acid monoethyl ester (6b).
Precipitation in diethylether. Yield: 95%. Mp 134 8C. 31P
NMR {1H} (200.7 MHz, D2O) d 19.7. 1H NMR (500 MHz,
4.4.21. [1-Hydroxy-(1-hydroxy-methoxy-phosphoryl)-2-
phenyl-methyl]-phosphonic acid monomethyl ester (7a).
Precipitation in diethylether. Yield: 90%. Mp 195 8C. 31P
NMR {1H} (200.7 MHz, D2O) d 18.2. 1H NMR (500 MHz,
D2O) d 3.49–3.52 (m, 6H, OCH3), 7.24–7.29 (m, 1H,
3
D2O) d 1.04 (t, 6H, JH–HZ7 Hz, OCH2CH3), 3.17 (t, 2H,
3JP–HZ13.3 Hz, C6H5CH2COH), 3.84–3.91 (m, 4H,
OCH2CH3), 7.16–7.21 (m, 3H, C6H5), 7.26 (d, 2H,
3JH–HZ6.5 Hz, o-C6H5). 13C NMR {1H} (125.9 MHz,
D2O) d 19.2 (OCH2CH3), 42.0 (C6H5–CH2–COH), 66.4
(OCH2CH3), 74.4 (t, 1JP–CZ143.8 Hz, P–C(OH)–P), 130.2
(p-C6H5–CH2), 131.2 (m-C6H5–CH2), 134.5 (o-C6H5–CH2),
138.8 (C6H5–CH2). Anal. Calcd for C12H20O7P2: C, 42.61;
H, 5.96; P, 18.32; Found: C, 42.70; H, 5.97; P, 18.39.
p-C6H5), 7.33 (t, 2H, JH–HZ7 Hz, m-C6H5), 7.63 (d, 2H,
3
3JH–HZ7 Hz, o-C6H5). 13C NMR {1H} (125.9 MHz, D2O) d
56.9 (OCH3), 79.6 (t, 1JP–CZ148.4 Hz, P–C(OH)–P), 129.1
(o-C6H5), 131.1 (p-C6H5), 131.4 (m-C6H5), 138.5
(C6H5C(OH)). Anal. Calcd for C9H14O7P2: C, 36.50; H,
4.76; P, 20.92; Found: C, 36.43; H, 4.74; P, 20.90.
4.4.22. [1-Hydroxy-1-(hydroxy-ethoxy-phosphoryl)-2-
phenyl-methyl]-phosphonic acid monoethyl ester (7b).
Precipitation in diethylether. Yield: 85%. Mp 168 8C. 31P
NMR {1H} (200.7 MHz, D2O) d 16.9. 1H NMR (500 MHz,
4.4.18. [1-Hydroxy-1-(hydroxy-isopropoxy-phosphoryl)-
2-phenyl-ethyl]-phosphonic acid mono isopropyl ester
(6c). Precipitation in diethylether. Yield: 55%. Mp 130 8C.
31P NMR {1H} (200.7 MHz, CDCl3) d 18.0. 1H NMR
3
D2O) d 1.14 (t, 6H, JH–HZ6.5 Hz, OCH2CH3) 3.89–3.98
(m, 4H, OCH2CH3), 7.33–7.38 (m, 1H, p-C6H5), 7.41 (t, 2H,
3
3JH–HZ7.0 Hz, m-C6H5), 7.73 (d, 2H, JH–HZ7.0 Hz,
3
(500 MHz, CDCl3) d 1.15 (d, JH–HZ6.5 Hz, 6H,
o-C6H5). 13C NMR {1H} (125.9 MHz, D2O) d 19.1
3
(OCH(CH3)2), 1.22 (d, 6H, JH–HZ6.5 Hz, (OCH(CH3)2),
1
3.46 (t, 2H, 3JP–HZ13.5 Hz, C6H5CH2COH), 4.72–4.81 (m,
2H, OCH(CH3)2), 7.26–7.29 (m, 3H, C6H5), 7.36 (d, 2H,
3JH–HZ6.5 Hz, o-C6H5). 13C NMR {1H} (125.9 MHz,
(OCH2CH3), 67.2 (OCH2CH3), 79.5 (t, JP–CZ148.9 Hz,
P–C(OH)–P), 129.2 (o-C6H5), 131.1 (p-C6H5), 131.4 (m-
C6H5), 138.6 (C6H5C(OH)). Anal. Calcd for C11H18O7P2:
C, 40.75; H, 5.60; P, 19.11; Found: C, 40.84; H, 5.62; P,
19.20.
CDCl3) d 26.9 (OCH(CH3)2), 27.2 (OCH(CH3)2), 42.4
Z
1
(C6H5–CH2–COH), 72.7 (OCH(CH3)2), 78.9 (t, JP–C
140.8 Hz, P–C(OH)–P), 129.6 (p-C6H5–CH2), 130.9 (m-
C6H5–CH2), 134.9 (o-C6H5–CH2), 140.7 (C6H5–CH2).
Anal. Calcd for C14H24O7P2: C, 45.91; H, 6.60; P, 16.91;
Found: C, 45.82; H, 6.58; P, 16.83.
4.4.23. [1-Hydroxy-(1-hydroxy-isopropoxy-phosphoryl)-
2-phenyl-methyl]-phosphonic acid mono isopropyl ester
(7c). Precipitation in diethylether. Yield: 95%. Mp 174 8C.
31P NMR {1H} (200.7 MHz, D2O) d 16.4. 1H NMR
3
(500 MHz, D2O)
d
1.09 (d, 6H, JH–HZ6.5 Hz,
3
4.4.19. Disodium salt of [1-hydroxy-1-(hydroxy-phe-
noxy-phosphoryl)-2-phenyl-ethyl]-phosphonic acid
monophenyl ester (6d). Yellow oil in the acidic form.
(OCH(CH3)2), 1.20 (d, 6H, JH–HZ6.5 Hz, OCH(CH3)2),
4.45–4.53 (m, 2H, (OCH(CH3)2), 7.35–7.40 (m, 1H,
3
p-C63H5), 7.43 (t, 2H, JH–HZ7.0 Hz, m-C6H5), 7.76 (d,
1
Yield: 90%. 31P NMR {1H} (200.7 MHz, D2O) d 15.9. H
2H, JH–HZ7.0 Hz, o-C6H5). 13C NMR{1H} (125.9 MHz,
D2O) d 26.2 (OCH(CH3)2), 26.6 (OCH(CH3)2), 76.3
3
NMR (500 MHz, D2O) d 3.56 (t, 2H, JP–HZ13.0 Hz,
C6H5CH2COH), 6.99–7.55 (m, 15H, C6H5). 13C NMR {1H}
(50.3 MHz, D2O) d 38.2 (C6H5–CH2–COH), 74.6 (t,
1JP–CZ146.1 Hz, P–C(OH)–P), 119.8 (o–C6H5), 125.2
(p–C6H5), 126.5 (m-C6H5), 128.2 (p-C6H5–CH2), 130.4
(m-C6H5–CH2), 135.7 (o-C6H5–CH2), 137.6 (C6H5–CH2),
150.7 (C6H5O). Anal. Calcd for C20H18Na2O7P2: C, 50.27;
H, 3.79; P, 12.95; Found: C, 50.35; H, 3.80; P, 12.99.
1
(OCH(CH3)2), 79.3 (t, JP–CZ143.1 Hz, P–C(OH)–P),
129.4 (o-C6H5), 131.0 (p-C6H5), 131.3 (m-C6H5), 138.6
(C6H5C(OH)). Anal. Calcd for C13H22O7P2: C, 44.33; H,
6.30; P, 17.59; Found: C, 44.25; H, 6.29; P, 17.48.
4.4.24. Disodium salt of [1-hydroxy-(1-hydroxy-phe-
noxy-phosphoryl)-2-phenyl-methyl]-phosphonic acid
monophenyl ester (7d). Precipitation in diethylether.
Yield: 78%. Mp!50 8C. 31P NMR {1H} (200.7 MHz,
CDCl3) d 11.6. 1H NMR (500 MHz, CDCl3) d 6.75–7.89 (m,
15H, C6H5). 13C NMR {1H} (50.3 MHz, D2O) d 76.9 (t,
1JP–CZ143.1 Hz, P–C(OH)–P), 119.9–128.6 (C6H5;
C6H5C(OH)), 136.8 (C6H5C(OH)), 150.7 (C6H5O). Anal.
Calcd for C19H16Na2O7P2: C, 49.15; H, 3.47; P, 13.34;
Found: C, 49.22; H, 3.48; P, 13.39.
4.4.20. [1-Hydroxy-1-(hydroxy-tetradecyloxy-phos-
phoryl)-2-phenyl-ethyl]-phosphonic acid mono tetrade-
cyl ester (6e). Precipitation in diethylether. Yield: 63%.
Mp!50 8C. 31P NMR {1H} (200.7 MHz, CDCl3) d 15.4. 1H
3
NMR (500 MHz, CDCl3) d 0.85 (t, 6H, JH–HZ6.5 Hz,
O(CH2)13CH3), 1.15–1.32 (m, 44H, OCH2CH2(CH2)11
CH3), 1.39–1.47 (m, 4H, OCH2CH2(CH2)11CH3), 3.39 (t,
3
2H, JP–HZ13.5 Hz, C6H5CH2COH), 3.84–4.01 (m, 4H,
OCH2CH2(CH2)11CH3), 7.20–7.25 (m, 3H, C6H5), 7.37 (d,
4.4.25. [1-Hydroxy-(1-hydroxy-tetradecyloxy-phos-
phoryl)-2-phenyl-methyl]-phosphonic acid mono tetra-
decyl ester (7e). Precipitation in diethylether. Yield: 77%.
Mp!50 8C. 31P NMR {1H} (200.7 MHz, CDCl3) d 15.3. 1H
3
2H, JH–HZ6.5 Hz, o-C6H5). 13C NMR {1H} (125.9 MHz,
CDCl3) d 14.3 (OCH2CH2(CH2)11CH3), 22.9 (OCH2
(CH2)11CH2CH3), 29.9–30.4 (OCH2CH2(CH2)10CH2CH3)
30.4 (OCH2CH2(CH2)10CH2CH3), 41.0 (C6H5–CH21–COH),
3
NMR (500 MHz, CDCl3) d 0.86 (t, 6H, JH–HZ6.5 Hz,
67.8 (OCH2CH2(CH2)10CH2CH3), 76.8 (t, JP–C
Z
O(CH2)13CH3), 1.04–1.29 (m, 44H, OCH2CH2(CH2)11
CH3), 1.30–1.36 (m, 4H, OCH2CH2(CH2)11CH3), 3.59–
3.69 (m, 2H, OCH2CH2(CH2)11CH3), 3.80–3.88 (m, 2H,
OCH2CH2(CH2)11CH3), 7.23–7.29 (m, 1H, p-C6H5), 7.33
145.6 Hz, P–C(OH)–P), 123.5 (p-C6H5–CH2), 133.9 (m-
C6H5–CH2), 136.2 (o-C6H5–CH2), 137.7 (C6H5–CH2). MS
(C36H66O7P2Na2, pHZ7.5): m/z 697.5 [MCNaCH]C,
675.4 [MCH]C. Anal. Calcd for C36H68O7P2: C, 64.07;
H, 10.16; P, 9.18; Found: C, 64.08; H, 10.15; P, 9.10.
3
3
(t, 2H, JH–HZ8 Hz, m-C6H5), 7.82 (d, 2H, JH–HZ8 Hz,
o-C6H5). 13C NMR {1H} (125.9 MHz, CDCl3) d 14.2

M. Monteil et al. / Tetrahedron 61 (2005) 7528–7537
7535
(OCH2CH2(CH2)11CH3), 22.8 (OCH2(CH2)11CH2CH3),
29.2–30.3 (OCH2CH2(CH2)10CH2CH3), 30.3 (OCH2CH2
(CH2)10CH2CH3), 32.1 (OCH2CH2(CH2)10CH2CH3), 76.5
4.4.30. (4-Bromo-phenyl)-hydroxy-(hydroxy-tetradecy-
loxy-phosphoryl)-methyl]-phosphonic acid monotetra-
decyl ester (8e). Precipitation in diethylether/hexane: 50/
50. Yield: 80%. Mp 54 8C. 31P NMR {1H} (200.7 MHz,
1
(t, JP–CZ153.7 Hz, P–C(OH)–P), 126.2 (o-C6H5), 127.8
1
(p-C6H5), 128.0 (m-C6H5), 133.6 (C6H5C(OH)). MS
(C35H64O7P2Na2, pH Z7.5): m/z 684.4 [MCNaCH]C,
661.4 [MCH]C. Anal. Calcd for C35H66O7P2: C, 63.61; H,
10.07; P, 9.37; Found: C, 63.70; H, 10.09; P, 9.45.
CDCl3) d 14.6. H NMR (500 MHz, CDCl3) d 0.86 (t, 6H,
3JH–HZ7.0 Hz, O(CH2)13CH3), 1.15–1.31 (m, 44H, OCH2
CH2(CH2)11CH3), 1.33–1.39 (m, 4H, OCH2CH2(CH2)11
CH3), 3.72–3.80 (m, 2H, OCH2CH2(CH2)11CH3), 3.86–3.94
3
(m, 2H, OCH2CH2(CH2)11CH3), 7.47 (d, 2H, JH–H
Z
C
8.0 Hz, m-C6H4), 7.70 (d, 2H, 3JH–HZ8.0 Hz, o-C6H4). 13
4.4.26. (4-Bromo-phenyl)-hydroxy-(hydroxy-methoxy-
phosphoryl)-methyl]-phosphonic acid monomethyl
ester (8a). Precipitation in diethylether. Yield: 90%. Mp
165 8C. 31P NMR {1H} (200.7 MHz, D2O) d 17.3. 1H NMR
(500 MHz, D2O) d 3.79 (d, 3H, 3JP–HZ3.0 Hz, OCH3), 3.81
(d, 3H, 3JP–HZ3.0 Hz, OCH3), 7.59 (d, 2H, 3JH–HZ8.0 Hz,
NMR {1H} (125.9 MHz, CDCl3) d 14.3 (O(CH2)13CH3),
22.9 (O(CH2)12CH2CH3), 25.3–30.4 (OCH2CH2(CH2)10
CH2CH3), 32.1 (OCH2CH2(CH2)10CH2CH3), 69.0 (OCH2
CH2(CH2)10CH2CH3), 76.2 (t, 1JP–CZ148.6 Hz, P–C(OH)–
P), 122.4 (p-C6H4), 127.9 (m-C6H4), 131.4 (o-C6H4), 132.6
(C6H4C(OH)). MS (C35H63O7P2Na2, pHZ7.5): m/z 763.3
[MCNaC2H]C739.3 [MCH]C. Anal. Calcd for
C35H65BrO7P2: C, 56.83; H, 8.86; P, 8.37; Found: C,
56.89; H, 8.88; P, 8.43.
3
m-C6H4), 7.66 (d, 2H, JH–HZ8.0 Hz, o-C6H4). 13C NMR
1
{1H} (125.9 MHz, D2O) d 56.8 (OCH3), 74.6 (t, JP–C
Z
146.2 Hz, P–C(OH)–P), 124.4 (p-C6H4), 131.1 (m-C6H4),
134.3 (o-C6H4), 138.9 (C6H4C(OH)). Anal. Calcd for
C9H13BrO7P2: C, 28.82; H, 3.49; P, 16.52; Found: C,
28.92; H, 3.50; P, 16.57.
4.4.31. [Hydroxy-(hydroxy-methoxy-phosphoryl)-(4-
methoxy-phenyl)-methyl]-phosphonic acid monomethyl
ester (9a). Precipitation in diethylether. Yield: 92%. Mp
4.4.27. (4-Bromo-phenyl)-hydroxy-(hydroxy-ethoxy-
phosphoryl)-methyl]-phosphonic acid monoethyl ester
(8b). Precipitation in diethylether.Yield: 72%. Mp 199 8C.
1
225 8C. 31P NMR {1H} (200.7 MHz, CDCl3) d 16.3. H
NMR (500 MHz, CDCl3) d 3.38–3.60 (m, 6H, OCH3), 3.80
3
31P NMR {1H} (200.7 MHz, D2O) d 16.4. 1H NMR
(s, 3H, C6H4OCH3), 6.86 (d, 2H, JH–HZ8.0 Hz,
3
3
m-C6H4OCH3), 7.5 (d, 2H, JH–HZ8.0 Hz, o-C6H4OCH3).
(500 MHz, D2O)
OCH2CH3), 3.89–3.98 (m, 4H, OCH2CH3), 7.60 (d, 2H,
d
1.16 (t, 6H, JH–HZ6.5 Hz,
13C NMR {1H} (50.3 MHz, DMSO-d6) d 53.5 (OCH3), 55.0
(C6H4OCH3), 75.8 (t, 1JP–CZ145.8 Hz, P–C(OH)–P), 112.5
(m-C6H4), 127.8 (o-C6H4), 128.9 (C6H4C(OH)), 158.1
(p-C6H4). Anal.Calcd for C10H16O8P2: C, 36.82; H, 4.94;
P, 18.99; Found: C, 36.76; H, 4.93; P, 18.92.
3
3JH–HZ8.5 Hz, m-C6H4), 7.68 (d, 2H, JH-HZ8.5 Hz,
o-C6H4). 13C NMR {1H} (125.9 MHz, D2O) d 19.2
1
(OCH2CH3), 66.9 (OCH2CH3), 79.1 (t, JP–CZ138.2 Hz,
P–C(OH)–P), 119.5 (p-C6H4), 131.2 (m-C6H4), 134.2 (o-
C6H4), 138.9 (C6H4C(OH)). Anal. Calcd for C11H17BrO7P2:
C, 32.78; H, 4.25; P, 15.37; Found: C, 32.71; H, 4.24; P,
15.30.
4.4.32. [Hydroxy-(hydroxy-ethoxy-phosphoryl)-(4-meth-
oxy-phenyl)-methyl]-phosphonic acid monoethyl ester
(9b). Precipitation in diethylether. Yield: 60%. Mp 172 8C.
31P NMR {1H} (200.7 MHz, D2O) d 17.3. 1H NMR
4.4.28. (4-Bromo-phenyl)-hydroxy-(hydroxy-isopro-
poxy-phosphoryl)-methyl]-phosphonic acid monoisopro-
pyl ester (8c). Precipitation in diethylether. Yield: 80%. Mp
198 8C. 31P NMR {1H} (200.7 MHz, D2O) d 15.6. 1H NMR
(500 MHz, D2O) d 1.09 (d, 3H, 3JH–HZ6 Hz, OCH(CH3)2),
1.20 (d, 6H, 3JH–HZ7 Hz, OCH(CH3)2), 4.41–4.50 (m, 2H,
3
(500 MHz, D2O) d 1.11 (t, 6H, JH–HZ6.5 Hz, OCH2CH3),
3.78 (s, 3H, C6H4OCH3), 3.86–3.95 (m, 4H, OCH2CH3), 6.98
(d, 2H, 3JH–HZ9.0 Hz, m-C6H4OCH3), 7.64 (d, 2H, 3JH–H
Z
9.0 Hz, o-C6H4OCH3). 13C NMR {1H} (125.9 MHz, D2O) d
19.1 (OCH2CH3), 58.6 (C6H4OCH3), 67.3 (OCH2CH3), 79.0
(t, 1JP–CZ145.9 Hz, P–C(OH)–P), 116.8 (m-C6H4), 130.7 (o-
C6H4), 130.8 (C6H4C(OH)), 161.7 (p-C6H4). Anal. Calcd for
C12H20O8P2: C, 40.69; H, 5.69; P, 17.49; Found: C, 40.75;
H, 5.71; P, 17.58.
3
OCH(CH3)2), 7.61 (d, 2H, JH–HZ8.5 Hz, m-C6H4), 7.69
3
(d, 2H, JH–HZ8.5 Hz, o-C6H4). 13C NMR {1H}
(125.9 MHz, D2O)
(OCH(CH3)2), 74.0 (OCH(CH3)2), 76.8 (t, JP–C
d
26.5 (OCH(CH3)2), 27.0
Z
1
143.5 Hz, P–C(OH)–P), 123.1 (p-C6H4), 131.4 (m-C6H4),
133.6 (o-C6H4), 140.9 (C6H4C(OH)). Anal. Calcd for
C13H21BrO7P2: C, 36.21; H, 4.91; P, 14.37; Found: C,
36.28; H, 4.93; P, 14.42.
4.4.33. [Hydroxy-(hydroxy-isopropoxy-phosphoryl)-(4-
methoxy-phenyl)-methyl]-phosphonic acid monoisopro-
pyl ester (9c). Precipitation in diethylether. Yield: 77%. Mp
187 8C. 31P NMR {1H} (200.7 MHz, D2O) d 16.6. 1H NMR
3
4.4.29. (4-Bromo-phenyl)-hydroxy-(hydroxy-phenoxy-
phosphoryl)-methyl]-phosphonic acid monophenyl
ester (8d). Precipitation in diethylether.Yield: 70%. Mp
(500 MHz, D2O)
d
1.09 (d, 6H, JH–HZ6 Hz,
3
(OCH(CH3)2), 1.21 (d, 6H, JH–HZ7 Hz, OCH(CH3)2),
3.85 (s, 3H, C6H4OCH3), 4.45–4.49 (m, 2H, OCH(CH3)2),
1
3
92 8C. 31P NMR {1H} (200.7 MHz, D2O) d 12.8. H NMR
7.04 (d, 2H, JH–HZ9.0 Hz, m-C6H4OCH3), 7.69 (d, 2H,
(500 MHz, D2O) d 6.93–7.80 (m, 14H, C6H4; C6H5). 13C
NMR (50.3 MHz, DMSO-d6) d 77.1 (t, 1JP–CZ145.4 Hz, P–
C(OH)–P), 116.1 (C6H5), 121.5 (C6H5), 124.6 (p-C6H4),
129.9 (C6H5), 130.7 (m-C6H4), 130.8 (o-C6H4), 137.5
(C6H4C(OH)), 152.3 (O–C6H5). Anal. Calcd for
C19H17BrO7P2: C, 45.72; H, 3.43; P, 12.41; Found: C,
45.62; H, 3.42; P, 12.36.
3JH–HZ9.0 Hz, o-C6H4OCH3). 13C NMR {1H}
(125.9 MHz, DMSO-d6) d 26.2 (OCH(CH3)2), 26.6
(OCH(CH3)2), 58.6 (C6H4OCH3), 76.2 (OCH(CH3)2), 76.6
1
(t, JP–CZ144.6 Hz, P–C(OH)–P), 116.7 (m-C6H4), 130.9
(o-C6H4), 131.0 (C6H4C(OH)), 161.7 (p-C6H4). Anal. Calcd
for C14H24O8P2: C, 43.99; H, 6.33; P, 16.20; Found: C,
44.08; H, 6.34; P, 16.25.

7536
M. Monteil et al. / Tetrahedron 61 (2005) 7528–7537
4.4.34. Disodium salt of [hydroxy-(hydroxy-phenoxy-
phosphoryl)-(4-methoxy-phenyl)-methyl]-phosphonic
acid monophenyl ester (9d). Precipitation in diethylether/
hexane: 80/20 in the acid form. Yield: 81%. Mp 198 8C. 31P
NMR {1H} (200.7 MHz, D2O) d 13.5. 1H NMR (500 MHz,
D2O) d 3.87 (s, 3H, C6H4OCH3), 6.92–7.82 (m, 14H,
C6H4OCH3; C6H5). 13C NMR {1H} (50.3 MHz, D2O) d 55.7
phosphoryl)-pyridin-3-yl-methyl]-phosphonic acid
monoisopropyl ester (10c). Precipitation in diethylether
in the acidic form. Yield: 90%. Mp 197 8C. 31P NMR {1H}
(200.7 MHz, D2O) d 13.0. 1H NMR (500 MHz, D2O) d 1.15
3
3
(d, 6H, JH–HZ6 Hz, OCH(CH3)2), 1.20 (d, 6H, JH–H
7 Hz, OCH(CH3)2), 4.16–4.56 (m, 2H, OCH(CH3)2), 8.07
Z
3
(dd, 1H, JH–HZ5.0, 8.0 Hz, H5–C5H4N), 8.72 (d, 1H,
1
3
(C6H4OCH3), 77.9 (t, JP–CZ144.5 Hz, P–C(OH)–P),
3JH–HZ5.0 Hz, H4–C5H4N), 8.94 (d, 1H, JH–HZ8.0 Hz,
H6–C5H4N), 9.05 (s, 1H, H2–C5H4N).
113.4, 119.0, 121.2, 123.8, 127.8, 129.4, 132.1 (C6H5;
C6H4), 152.2 (OC6H5), 157.8 (p-C6H4). Anal. Calcd for
C20H18Na2O8P2: C, 48.60; H, 3.67; P, 12.53; Found: C
48,.51; H, 3.65; P, 12.49.
C NMR {1H}
13
26.6 (OCH(CH3)2), 75.3
(125.9 MHz, D2O)
d
1
(OCH(CH3)2), 78.6 (t, JP–CZ139.9 Hz, P–C(OH)–P),
129.5 (C5–C5H4N), 141.9 (C3–C5H4N), 142.4 (C4–
C5H4N), 143.5 (C6–C5H4N), 147.6 (C2–C5H4N). Anal.
Calcd for C12H20NNaO7P2: C, 38.41; H, 5.37; N, 3.73; P,
16.51; Found: C, 38.55; H, 5.38; N, 3.74; P, 16.57.
4.4.35. [Hydroxy-(hydroxy-tetradecyloxy-phosphoryl)-
(4-methoxy-phenyl)-methyl]-phosphonic acid monote-
tradecyl ester (9e). Precipitation in diethylether/hexane:
80/20. Yield: 69%. Mp!50 8C. 31P NMR {1H}
4.4.39. Sodium salt of [hydroxy-(hydroxy-phenoxy-
phosphoryl)-pyridin-3-yl-methyl]-phosphonic acid
monophenyl ester (10d). Precipitation in methanol in the
acid form. Yield: 73%. Mp 134 8C. 31P NMR {1H}
1
(200.7 MHz, CDCl3) d 15.4. H NMR (500 MHz, CDCl3)
d 0.85 (t, 6H, 3JH–HZ6.5 Hz, O(CH2)13CH3), 1.02–1.29 (m,
44H, OCH2CH2(CH2)11CH3), 1.32–1.35 (m, 4H, OCH2
CH2(CH2)11CH3), 3.78 (s, 3H, C6H4OCH3), 3.82–3.86 (m,
1
(200.7 MHz, D2O) d 18.3. H NMR (500 MHz, D2O) d
3
4H, OCH2CH2(CH2)11CH3), 6.87 (d, 2H, JH–HZ9.0 Hz,
6.96–7.34 (m, 10H, C6H5), 7.74–7.95 (m, 1H, H5–C5H4N),
8.55–8.82 (m, 2H, H4–C5H4N; H6–C5H4N), 9.04 (s, 1H,
H2–C5H4N). 13C NMR {1H} (125.9 MHz, D2O) d 77.6 (t,
1JP–CZ140.4 Hz, P–C(OH)–P), 117.7 (C6H5), 122.9
(C6H5), 129.8 (C5–C5H4N), 132.2 (C6H5), 141.6 (C6H5),
141.9 (C3–C5H4N), 144.6 (C4–C5H4N), 146.8 (C6–
C5H4N), 149.2 (C2–C5H4N). Anal. Calcd for C18H16
NNaO7P2: C, 48.77; H, 3.64; N, 3.16; P, 13.98; Found: C,
48.85; H, 3.65; N, 3.17; P, 14.04.
m-C6H4OCH3), 7.73 (d, 2H, 3JH–HZ9.0 Hz, p-C6H4OCH3).
13C NMR {1H} (125.9 MHz, CDCl3)
d
14.3
(O(CH2)13CH3), 22.9 (O(CH2)12CH2CH3), 29.5–30.3
(OCH2CH2(CH2)10CH2CH3), 32.8 (OCH2CH2(CH2)11
CH3), 55.4 (C6H4OCH3), 69.0 (OCH2CH2(CH2)11CH3),
1
76.2 (t, JP–CZ145.9 Hz, P–C(OH)–P), 113.6 (m-C6H4),
127.5 (p-C6H4), 132.8 (C6H4C(OH)), 159.5 (p-C6H4). MS
(C35H63O7P2Na2, pHZ7.5) m/z 713.4 [MCNaCH]C,
691.3 [MCH]C. Anal. Calcd for C36H68O8P2: C, 64.07;
H, 10.16; P, 9.18; Found: C, 65.10; H, 10.18; P, 9.24.
4.4.40. Sodium salt of [hydroxy-(hydroxy-tetradecyloxy-
phosphoryl)-pyridin-3-yl-methyl]-phosphonic acid
monotetradecyl ester (10e). Precipitation in methanol in
the acidic form. Yield: 50%. Mp 146 8C. 31P NMR {1H}
4.4.36. Sodium salt of [hydroxy-(hydroxy-methoxy-
phosphoryl)-pyridin-3-yl-methyl]-phosphonic acid
monomethyl ester (10a). Precipitation in diethylether in
the acidic form. Yield: 75%. Mp 220 8C. 13P NMR {1H}
(200.7 MHz, D2O) d 14.8. 1H NMR (500 MHz, D2O) d 3.48
1
(200.7 MHz, CDCl3) d 12.5. H NMR (500 MHz, CDCl3) d
3
0.90 (t, 6H, JH–HZ7.0 Hz, O(CH2)13CH3), 0.98–1.48 (m,
44H, OCH2CH2(CH2)11CH3), 1.51–1.87 (m, 4H, OCH2CH2
(CH2)11CH3), 3.60–4.16 (m, 4H OCH2CH2(CH2)11CH3),
7.50–7.85 (m, 1H, H5–C5H4N), 8.25–8.58 (m, 1H, H4–
C5H4N), 8.65–8.94 (m, 1H, H6–C5H4N), 9.4 (s, 1H, H2–
C5H4N). MS (C34H64NNaO7P2, pHZ7.5) m/z 684.4 [MC
H]C. Anal. Calcd for C34H64NNaO7P2: C, 59.72; H, 9.43; N,
2.05; P, 9.06; Found: C, 59.81; H, 9.45; N, 2.08; P, 9.12.
3
(d, 6H, JP–HZ9.0 Hz, OCH3), 7.82–7.94 (m, 1H, H5–
C5H4N), 8.47–8.55 (m, 1H, H4–C5H4N), 8.70–8.79 (m, 1H,
H6–C5H4N), 8.86 (s, 1H, H2–C5H4N). 13C NMR {1H}
(125.9 MHz, D2O) d 54.9 (OCH3), 78.9 (t, 1JP–CZ142.1 Hz,
P–C(OH)–P), 129.6 (C5–C5H4N), 141.9 (C3–C5H4N), 142.5
(C4–C5H4N), 143.4 (C6–C5H4N), 147.4 (C2–C5H4N). Anal.
Calcd for C8H12NNaO7P2: C, 30.11; H, 3.79; N, 4.39; P,
19.41; Found: C, 30.08; H, 3.78; N, 4.38; P, 19.35.
Acknowledgements
4.4.37. Sodium salt of [hydroxy-(hydroxy-ethoxy-phos-
phoryl)-pyridin-3-yl-methyl]-phosphonic acid mono-
ethyl ester (10b). Precipitation in diethylether in the acid
form. Yield: 90%. MpO260 8C. 31P NMR {1H}
This work was supported by grants from the Association de
Recherche contre le Cancer, the Ligue contre le Cancer and
the Agence Nationale de Valorisation de la Recherche
(ANVAR), France.
1
(200.7 MHz, D2O) d 14.8. H NMR (200 MHz, D2O) d
0.96 (t, 6H, 3JH–HZ7.2 Hz, OCH2CH3), 3.68–3.75 (m, 4H,
OCH2CH3), 7.31–7.42 (m, 1H, H5–C5H4N), 8.06–8.20 (m,
1H, H4–C5H4N), 8.26–8.35 (m, 1H, H6–C5H4N), 8.72 (s,
1H, H2–C5H4N). 13C NMR {1H} (50.3MHz, D2O) d 14.3
(OCH2CH3), 60.8 (OCH2CH3), 74.8 (t, 1JP–CZ140.1 Hz, P–
C(OH)–P), 121.8 (C5–C5H4N), 134.7 (C3–C5H4N), 143.3
(C4–C5H4N), 143.5 (C6–C5H4N), 147.2 (C2–C5H4N).
Anal. Calcd for C10H16NNaO7P2: C, 34.60; H, 4.65; N,
4.05; P, 17.84; Found: C, 34.54; H, 4.64, N, 4.04; P, 17.80.
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