Synthesis of adamantylalkyl tosyloxymethylphosphonates

Full text of DOI:10.1134/S1070363209080313

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 8, pp. 1755–1757. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.N. Reznikov, M.V. Leonova, A.K. Shiryaev, Yu.N. Klimochkin, 2009, published in Zhurnal Obshchei Khimii, 2009, Vol. 79, No. 8,
pp. 1397–1399.
LETTERS
TO THE EDITOR
Synthesis of Adamantylalkyl Tosyloxymethylphosphonates
A. N. Reznikov, M. V. Leonova, A. K. Shiryaev, and Yu. N. Klimochkin
Samara State Technical University,
ul. Molodogvardeyskaya, 244, Samara, 420088 Russia
e-mail: orgchem@samgtu.ru
Received February 16, 2009
DOI: 10.1134/S1070363209080313
Tosyloxymethylphosphonates are key compounds
in the synthesis of nucleoside phosphonates, the
promising antiviral drugs of a new generation [1–3].
Low bioavailability caused by the presence of polar
phosphoryl group in the molecule is an essential
drawback of the known drugs of this class (adefovir,
cidofovir, tenofovir). At the same time phosphoryl
group is one of the fragments conditioning high
activity. Drugs development on the matrix of
nucleoside phosphonates modified with lipophilic
substutuents offers a solution of this problem. Some
of the synthesis method of phosphonic acids Na-salts
involving alkoxyalkyl substituents have been
described [4]. We carried out synthesis of tosyl-
methylphosphonates on the base of adamantane series
alcohols.
Reaction of diethyl tosyloxymethylphosphonate I
[5] with bromotrimethylsilane yields bistrimethylsilyl
ester II, which reacts with oxalyl chloride in the
presence of catalytic amounts of N,N-dimethyl-
formamide (DMF) to form dichlorophosphonate III:
O
O
O
O
Cl
O
O
Me3SiBr
(COCl)2
Et
Et
Me3Si
Me3Si
P
P
P
O
Cl
OTs
OTs
OTs
I
III
II
Reaction of compound III with adamantane
derivatives IVa–IVd in the presence of a base
(pyridine, triethylamine) followed by monochloro-
derivatives Va–Vd hydrolysis with the saturated
aqueous solution of sodium hydrogen carbonate
produces Na-salts of the corresponding adamantly-
alkyl and adamantyloxyalkyl phosphonates VIa–VId.
form (100 ml). Extract was washed with water
(3×100 ml) and dried with calcium chloride. Then
the solvent was removed. Yield 5.79 g (72%).
Charac-teristics of the compound obtained corres-
ponded to literary data [8].
Sodium 1-adamantylmethyl tosyloxymethyl-
phosphonate (VIa). To a solution of 4.61 g of I in
76 ml of dichloromethane was added 16.2 g of
bromotrimethylsilane under stirring. The reaction
mixture was kept for 16 h. Dichloromethame and
bromomethylsilane excess were removed in a
vacuum. To the residue dissolved in 60 ml of di-
chloromethane was added 0.20 ml of dry DMF at 0°С
under stirring and a solution of 5.45 g of
oxalylchloride in 15 ml of dichloromethane within
45 min. This mixture was stirred for 6 h, rising
slowly temperature to ambient. Dichloromethane and
2-(1-Adamantyl)ethanol IVb and 3-(1-adaman-
tyloxy)propanol IVd were prepared by procedures [6]
and [7] respectively.
2-(1-Adamantyloxy)ethanol (IVc). A mixture
of 50 ml of ethylene glycol, 8.81 g of 1-bromo-
adamantane, 18 ml of triethylamine and 0.62 g of 1,8-
diazabicyclo[5.4.0]undec-7-ene was stirred at 110°С
for 5 h. The reaction mixture was poured into water
(250 ml). Organic layer was extracted with chloro-
1755

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REZNIKOV et al.
O
O
O
O
O
Py
Cl
Cl
O
H2O
R
R
Na
P
P
+ ROH
P
NaHCO3
−HCl
Cl
OTs
OTs
OTs
IVа−IVd
Vа−Vd
III
VIа−VId
(IVа−VIа);
(IVc−VIc);
R =
(IVb−VIb);
(IVd−VId).
O
O
oxalyl chloride excess were removed in a vacuum.
The residue was mixed with 25 ml of unhydrous
diethyl ether. To the decanted ether solution was
added a mixture of 1.19 g of 1-adamantylmethanol
IVa [9] and 1.23 g of pyridine in 25 ml of unhydrous
diethyl ether. The reaction mixture was stirred for 2 h
and hydrolyzed with 150 ml of saturated solution of
NaHCO3. Then ether layer was separated. The oily
layer and water phase were extracted with chloro-
form. The obtained extract was dried with anhydrous
MgSO4. The solvent was removed. The product was
chromatographically isolated (silica gel 0.063–0.200 mm,
eluent chloroform–methanol (10%). Yield 2.38 g
(38.2%). Found, %: С 51.93; Н 6.10. Calculated, %:
10 Hz), 7.47, 7.51, 7.73, 7.77 (4Н, Ar, АВ-system).
13C NMR spectrum, δC, ppm: 20.99 (СН3, p-Tol),
29.78 (3CH, Ad), 35.82 (3CH2, Ad), 41.00 (3CH2,
Ad), 58.50 (СН2ОAd), 64.17 (СН2ОP), 71.24
(PСН2О), 127.54 (m-СН, p-Tol), 130.00 (о-СН, p-
Tol), 144.74 (p-С, p-Tol). 31P NMR spectrum, δP,
ppm: 7.06.
Sodium 1-(1-adamantyloxy)prop-3-yl tosyloxy-
methylphosphonate (VId) was prepared similarly.
Yield 23.8%. Found, %: С 52.48; Н 6.31. Calculated,
1
%: С 52.49; Н 6.29. Н NMR spectrum, δ, ppm: 0.85
s, 1.15 m, 1.30 m, 1.55 s, 1.65 s, 2.10 s (15H, Ad),
2.40 (3Н, СН3), 3.00 m, 3.65 d (2Н, СН2О, 3JHP 10 Hz),
3
3.80 d (2Н, СН2О, JHP 10 Hz), 7.47, 7.51, 7.73, 7.77
1
С 52.29; Н 6.00. Н NMR spectrum, δ, ppm: 1.34 s
(4Н, Ar, АВ-system). 13C NMR spectrum, δC, ppm:
21.02 (СН3, p-Tol), 29.75 (3CH, Ad), 31.63
(ОСН2СН2СН2О), 35.87 (3CH2, Ad), 41.01 (3CH2,
Ad), 55.86 (СН2ОAd), 61.48 (СН2ОP), 70.94
(PСН2О), 79.10 (С, Ad), 127.66 (m-СН, p-Tol),
(4Н, 2СН2, Ad), 1.61 m (8Н, СН2, Ad), 1.90 s (2Н,
3
2СН, Ad), 2.42 s (3Н, СН3), 3.9 d (2Н, СН2О, JHP
11 Hz), 7.47, 7.51, 7.73, 7.77 (4Н, Ar, АВ-system).
31P NMR spectrum, δP, ppm: 6.85.
31
Sodium 2-(1-adamantyl)ethyl tosyloxymethyl]
phosphonate (VIb) was prepared similarly. Yield
37.7%, dp 253–255°С . Found, %: С 53.29; Н 6.31.
Calculated, %: С 53.33; Н 6.27. 1Н NMR spectrum,
δ, ppm: 1.2 t (2Н, Ad), 1.4 s (6Н, Ad), 1.6 m (6Н,
Ad), 1.8 (1Н, CH, Аd, 2H, Ad–CH2–), 2.4 (3Н, СН3),
130.00 (о-СН, p-Tol), 144.76 (р-С, p-Tol). P NMR
spectrum, δP, ppm: 7.82.
The NMR spectra were registered on a Brucker
AC200 and a Brucker AM300 devices using DMSO-
d6 as a solvent [200.13, 300.13 (1H), 50.32, 75.47
(13С) and 121.49 MHz (31Р)]. Measurements were
carried out without use of additional references with
frequency connection to deuterated solution signal.
3
3.8 (2Н, СН2О, JHP 10 Hz), 7.47, 7.51, 7.73, 7.77
(4Н, Ar, АВ-system). 13C NMR spectrum, δC, ppm:
20.99 (СН3, p-Tol), 27.91 (3CH, Ad), 36.48 (3CH2,
Ad), 41.96 (3CH2, Ad), 127.54 (m-СН=, p-Tol),
129.99 (о-СН, p-Tol). 31P NMR spectrum, δP, ppm:
6.70.
ACKNOWLEDGMENTS
This work was carried out as a part of Federal
Program “Studies and developments of priority
directions of development of Russian complex of
science and technology in the years 2007–
2012,” (State contract no. 02.11.512.2248) and
supported by Russian Foundation for Basic Research
(grant no. 08-03-99038-R-OFI).
Sodium 2-(1-adamantyloxy)ethyl tosyloxyme-
thylphosphonate (VIc) was prepared similarly. Yield
7.2%, mp 198–202°С. Found, %: С 51.47; Н 6.09.
Calculated, %: С 51.50; Н 6.05. 1Н NMR spectrum,
δ, ppm: 1.58 s, 1.62 s (12Н, 6CH2, Ad), 2.05 s (3Н,
3
3CH, Ad), 2.40 (3Н, СН3), 3.85 (2Н, СН2О, JHP
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 8 2009

1757
SYNTHESIS OF ADAMANTYLALKYL TOSYLOXYMETHYLPHOSPHONATES
5. Barral, K., Priet, S., Sire, J., et al., J. Med. Chem.,
2006, vol. 49, no. 26, p. 7799.
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