A novel synthetic route for the preparation of alkyl and benzyl chloromethyl phosphates

Article abstract of DOI:10.1016/S0040-4039(02)00707-4

An efficient and simple synthesis is described for the production of various chloromethyl phosphates as useful reagents for the preparation of phosphonooxymethyl prodrugs.

Full text of DOI:10.1016/S0040-4039(02)00707-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3793–3794
A novel synthetic route for the preparation of alkyl and benzyl
chloromethyl phosphates
a,
b
a
a
Antti M a¨ ntyl a¨ , * Jouko Veps a¨ l a¨ inen, Tomi J a¨ rvinen and Tapio Nevalainen
a
Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland
b
Department of Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland
Received 5 March 2002; revised 27 March 2002; accepted 10 April 2002
Abstract—An efficient and simple synthesis is described for the production of various chloromethyl phosphates as useful reagents
for the preparation of phosphonooxymethyl prodrugs. © 2002 Elsevier Science Ltd. All rights reserved.
Modern drug discovery techniques, such as combinato-
rial chemistry and high-throughput pharmacological
screening, often introduce new lead compounds with
aqueous solubility problems. Phosphate prodrugs are
widely used to enhance the aqueous solubility of parent
ever, this method is laborious and gives low yields.
Herein we report a novel, simple method for the prepa-
ration of dibutyl, dibenzyl, diallyl and di-tert-butyl
chloromethyl phosphates, which are superior reagents
for the derivatization of hydroxyl and amino groups
with phosphonooxymethyl moieties (Scheme 1).
1
,2
drugs.
Phosphate promoieties are bound either
directly or via a spacer group to drug molecules, espe-
3
–6
cially those having an hydroxyl functionality. How-
ever, it has been reported that phosphate moieties
directly attached to a hydroxyl group are not always
accessible to enzymatic cleavage, due to steric hin-
A general procedure for the preparation of dialkyl and
dibenzyl (Table 1) chloromethyl phosphates is as fol-
14,15
16
lows: dialkyl
or dibenzyl phosphate (4.76 mmol),
sodium bicarbonate (19.04 mmol) and tetra-n-butylam-
monium hydrogen sulfate (0.476 mmol) were dissolved
in water (40 ml). Dichloromethane (DCM, 25 ml) was
added and the mixture was vigorously stirred at 0°C for
5
,6
drance,
and consequently there has been a great
interest in the development of phosphonooxymethyl
prodrugs, which have been shown to be enzymatically
7
,8
labile. This hydrolysis occurs via a two-step reaction;
enzymatic cleavage of the ester group followed by
spontaneous decomposition of the hydroxymethyl
intermediate. It is important to point out that the
hydroxymethyl intermediate releases the parent drug by
spontaneous chemical hydrolysis, while larger hydroxy-
alkyl groups are not, and thus are not useful interme-
9,10
diates for the design of bioreversible prodrugs.
Scheme 1.
The phosphonooxymethyl moieties are useful interme-
diates in the synthesis of enzymatically stable oligonu-
cleotide analogues containing methylene acetal linkages
Table 1. Synthesis of dialkyl and dibenzyl chloromethyl
phosphates (2a–d) via Scheme 1
1
1
in place of the phosphate diester bond. The widely-
used strategy for their preparation involves the synthe-
Product
R
Yield (%)a
1
2
sis of a methylthiomethyl ether intermediate, which is
converted to phosphonooxymethyl ethers by an N-
iodosuccinimide (NIS) mediated esterification. How-
2
2
2
2
a
b
c
-CH CH CH CH
3
84
90
36
2
2
2
13
-CH C H
2
6
5
-CH CHꢀCH
2
2
b
d
-C(CH3)3
72
a
*
0
Corresponding author. Fax: +358 17 162456; e-mail:
antti.mantyla@uku.fi
Isolated yield.
The more laborious synthetic method gives 35% yield.8
b
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00707-4

3
794
A. M a¨ ntyl a¨ et al. / Tetrahedron Letters 43 (2002) 3793–3794
1
0 min, followed by the addition of chloromethyl
Acknowledgements
1
7
chlorosulfate (5.7 mmol) in DCM (15 ml) with con-
tinuous vigorous stirring overnight at room tempera-
ture. The organic layer was separated, washed with
brine, dried (Na SO ) and evaporated. The residue
was purified by flash silica gel column chromatogra-
phy using ethyl acetate/hexanes (1:3) as eluent to give
compounds 2a–d. The products were identified by H
and C NMR, mass spectral analysis and elemental
analysis. Dibutyl chloromethyl phosphate (2a):
NMR (CDCl ), 500 MHz l 0.94 (t, 6H, J=7 Hz),
This work was supported by the National Technology
Agency of Finland (Tekes), The Academy of Finland,
The Savo Foundation for Advanced Technology and
The Finnish Cultural Foundation. The authors are
grateful to Ms. Miia R a¨ s a¨ nen and Mrs. Maritta
Salminkoski for their skillful technical assistance.
2
4
1
1
3
1
H
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3
1
2
3
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1
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27 (MH ). Anal. (C H ClO P·0.05EtOAc) C, H:
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calcd 38.37, 5.64. Found 38.35, 5.55. (identical to
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(
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1
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3
9
20
4
1.51, 7.87. The results are summarized in Table 1.
1
With the present method, all chloromethyl phosphates
were obtained in good to excellent yields (Table 1)
without formation of any side products, except for
the diallyl chlorophosphate, where the synthetic pro-
cedure was not optimized. Hydroxyl or amine group
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(
1
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1
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1
In conclusion, the reaction described above will be a
highly useful method for the preparation of
chloromethyl phosphates having various substituents.
Using the present methodology, bioreversible pro-
drugs were obtained that enhance the aqueous solu-
bility of poorly water-soluble compounds. It is also
believed that the new method will be useful for the
synthesis of enzymatically stable oligonucleotide ana-
logues.
1
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