An efficient strategy for the synthesis of 1-chloroethyl phosphates and phosphoramidates

Article abstract of DOI:10.1021/jo0513562

A versatile, efficient, and simple method for the preparation of various 1-chloroethyl phosphates and phosphoramidates is described. The protected chlorophosphates or phosphoramidates are synthesized to the vinyl derivative under mild conditions, followed

Full text of DOI:10.1021/jo0513562

in the body.12,13 To overcome this drawback, we were
interested in developing ethylidene-linked prodrugs,
which are metabolized to the less toxic acetaldehyde.
Previously, an ethylidene spacer group was used in
(acyloxy)alkyl prodrugs,14,15 but no descriptions of eth-
ylidene-linked phosphate prodrugs as ways to increase
the water solubility of a drug molecule have been
published. The compounds described in the present study
are excellent starting materials for the preparation of
ethylidene-linked phosphate prodrugs.
An Efficient Strategy for the Synthesis of
1-Chloroethyl Phosphates and
Phosphoramidates
Hanna Kumpulainen,*,† Tomi Ja¨rvinen,† Raimo Saari,†
Marko Lehtonen,† and Jouko Vepsa¨la¨inen‡
Department of Pharmaceutical Chemistry and
Department of Chemistry, University of Kuopio,
P.O. Box 1627, FI-70211 Kuopio, Finland
The ethylidene phosphate prodrugs could be prepared
via addition of 1-chloroethyl phosphates or phosphora-
midates to an appropriate functional group (e.g., hydroxyl
or amine group) of the drug molecule. However, there is
no efficient and practical method to synthesize 1-chloro-
ethyl phosphates or phosphoramidates. The 1-chloroethyl
derivatives of carboxylic acids are traditionally prepared
from the acetaldehyde and the corresponding acid chlo-
ride using ZnCl2 as the catalyst.16 However, this method
was not successful for the synthesis of 1-chloroethyl
phosphates. The only reported approach to synthesize
1-chloroethyl phosphates is a method in which diethyl
1-chloroethyl phosphate is synthesized from ethyl phos-
phorodichloridate using hazardous chemicals and meth-
ods (chlorine gas, mercury vapor lamp).17 In the present
study, we report an efficient and practical synthetic
approach for the preparation of 1-chloroethyl phosphates
and phosphoramidates, in which the protected chloro-
phosphates or phosphoramidates are synthesized to the
vinyl derivative under mild conditions, followed by the
conversion to the 1-chloroethyl phosphate or phosphor-
amidate by dry HCl gas.
Hanna.Kumpulainen@uku.fi
Received June 30, 2005
A versatile, efficient, and simple method for the preparation
of various 1-chloroethyl phosphates and phosphoramidates
is described. The protected chlorophosphates or phosphora-
midates are synthesized to the vinyl derivative under mild
conditions, followed by conversion to the chloroethylidene
phosphate or phosphoramidate by dry HCl gas, resulting in
good to excellent yields. 1-Chloroethyl phosphates and
phosphoramidates are excellent building blocks for the
synthesis of novel ethylidene-linked phosphate prodrugs.
Phosphates and phosphoramidates are widely used as
prodrug moieties to enhance water solubility1 or thera-
peutic potential of a parent drug.2-4 The phosphorami-
dates are also used to synthesize phosphate esters with
different protecting groups by the replacement of amide
with an ester group.5,6 In addition, they can be used to
synthesize a monoester phosphate prodrug by hydrolyz-
ing the phosphoramide bond7 to yield limited enhance-
ment of the water solubility of the parent compound.
Phosphate promoieties are often attached to the parent
drug via an oxymethyl spacer group,8-10 which is a
problem due to highly toxic formaldehyde11 released
systemically during metabolism of the oxymethyl group
The desired vinyl intermediates were prepared from
the corresponding chlorophosphates 1, which are com-
mercially available (1b,c,e,g) or prepared by the known
method from phosphorus trichloride18,19 (1a,d,f,h) or from
diethyl phosphorodichloridate20 (1i). Nine different vinyl
phosphates or phosphoramidates were prepared by treat-
(10) Ueda, Y.; Matiskella, J. D.; Golik, J.; Connolly, T. P.; Hudyma,
T. W.; Venkatesh, S.; Dali, M.; Kang, S. H.; Barbour, N.; Tejwani, R.;
Varia, S.; Knipe, J.; Zheng, M.; Mathew, M.; Mosure, K.; Clark, J.;
Lamb, L.; Medin, I.; Gao, Q.; Huang, S.; Chen, C. P.; Bronson, J. J.
Bioorg. Med. Chem. Lett. 2003, 13, 3669-3672.
(11) Slikker, W., Jr.; Andersen, M. E.; Bogdanffy, M. S.; Bus, J. S.;
Cohen, S. D.; Conolly, R. B.; David, R. M.; Doerrer, N. G.; Dorman, D.
C.; Gaylor, D. W.; Hattis, D.; Rogers, J. M.; Woodrow Setzer, R.;
Swenberg, J. A.; Wallace, K. Toxicol. Appl. Pharmacol. 2004, 201, 203-
225.
† Department of Pharmaceutical Chemistry.
‡ Department of Chemistry.
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Med. Chem. 2001, 44, 223-231.
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Rephaeli, A. J. Med. Chem. 2005, 48, 1042-1054.
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C. J. Med. Chem. 2003, 46, 4564-4571.
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M.; Zhuk, R.; Sampson, S. R.; Langzam, L.; Fibach, E.; Prus, E.;
Pugach, V.; Rephaeli, A. Eur. J. Med. Chem. 2001, 36, 63-74.
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P. A. J. Am. Chem. Soc. 1992, 114, 3535-3546.
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10.1021/jo0513562 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/27/2005
9056
J. Org. Chem. 2005, 70, 9056-9058

SCHEME 1. Synthesis of Vinyl (2a-i) and
1-Chloroethyl Phosphates and Phosphoramidates
(3a-i)
but some of the products partially decomposed during the
purification procedure. Since the crude products from the
synthesis of 3 did not contain any major impurities
according to 1H, 13C, and 31P NMR, these building blocks
should be used without further purification. Thus the
yields of 3a-i presented in Table 1 are reported without
purification and are estimated from the actual chemical
1
yields according to purity of H and 31P NMR spectra,
but the NMR data, GC-MS analyses, and elemental
analyses (CHNS) were obtained from the purified prod-
ucts.
In conclusion, the first method for the synthesis of
1-chloroethyl phosphates and phosphoramidates was
developed. The synthetic route was started with vinyla-
tion of chlorophosphate or phosphoramidate as the start-
ing material, followed by addition of hydrogen chloride
to the vinyl double bond to yield 1-chloroethyl phosphate
or phosphoramidate. This method was found to be
versatile and a simple way to synthesize phosphates and
phosphoramidates with various protecting groups and is
thus applicable for a wide range of molecules. 1-Chloro-
ethyl phosphates and phosphoramidates are excellent
building blocks for the synthesis of ethylidene-linked
prodrugs.
TABLE 1. Synthesis of Vinyl and Chloroethylidene
Phosphates and Phosphoramidates
2: yield 3: yield
(%)
(%)a
timeb
(h)
entry
R
R′
1a Me
1b Et
OMe
OEt
OCl3Et
OPh
2a: 52 3a: 86 29 (12)c
2b: 64 3b: 91 24 (7)c
2c: 68 3c: 66 912 (195)c
2d: 54 3d: 87 500 (50)c
1c
Cl3Et
1d Me
1e (2,6-Me2)Ph O-(2,6-Me2)Ph 2e: 35 3e: 92 480 (90)c
1f
-CH2CH2CH2O-
2f: 76
3f: 98 30 (12)c
d
1g Ph
1h Bz
OPh
OBz
NEt2
2g: 70 3g: -
-
2h: 30 3h: 68 48e
2i: 88 3i: 91 21e
1i
Me
a Yield without purification. b The reaction times are the total
reaction times of step 2, with the times of HCl bubbling in
parentheses. c Reaction conditions: HCl bubbling, room temper-
ature. d Did not react under any kind of conditions. e Reaction
conditions: EtOAc saturated with HCl, 4 °C.
Experimental Section
A General Method for the Preparation of Vinyl Phos-
phates 2. To a 100-mL round-bottom flask was added dry THF
(50 mL) under argon and cooled to 0 °C, followed by adding 1.6
M n-butyllithium (15 mL, 24 mmol) in hexane at 0 °C. The
reaction mixture was stirred for 0.5 h at 0 °C and then overnight
at 25 °C. After 18 h without cooling, this enolate of acetaldehyde
was added dropwise to the chlorophosphate or phosphoramidate
1 (25.2 mmol, 1.05 equiv) in THF (5 mL) during 15 min at -78
°C. After the addition was complete, the reaction mixture was
allowed to reach room temperature over 45 min and the solvents
were evaporated. The residue was dissolved in CH2Cl2 (50 mL),
washed with 10% sodium phosphate buffer (pH 7.0, 5 × 15 mL),
dried with Na2SO4, and evaporated to dryness. The residue was
purified by column chromatography to yield vinyl derivative 2.
The chromatography purification conditions are described in
detail along with each molecule description.
SCHEME 2. Electrophilic Addition Reaction of
HCl to Vinyl Phosphate
ing 1 with the enolate of acetaldehyde21 with reasonable
good yields (Scheme 1, Table 1). The vinylation occurred
under mild conditions, which makes it a suitable method
for different kinds of molecules.
Phosphoric Acid Dimethyl Ester Vinyl Ester 2a: 52%,
The electrophilic addition reaction of HCl to the vinyl
double bond was obtained by bubbling dry HCl gas
through a solution of 2 in dry ethyl acetate. The reaction
occurs via the attack of H+ to yield an intermediate
carbocation, which quickly undergoes a reaction with a
negative halide ion to yield an alkyl halide (Scheme 2).
The results listed in Table 1 show that there are
remarkable differences in the reaction times and condi-
tions depending on the chemical nature of the phosphate
substituents. The compounds 3h and 3i were readily
obtained under mild conditions, but on the other hand,
the diphenyl derivative 2g did not react at all, even
though several common catalysts and overpressure (5
atm) were tested.
colorless oil. Chromatography eluent EtOAc/petrol ether, 2:3. 1H
3
NMR (CDCl3) δ 6.579 (1H, ddd, J ) 13.52 Hz, 5.86 Hz, JHP
)
4
6.52 Hz), 4.933 (1H, ddd, J ) 13.52 Hz, 2.17 Hz, JHP ) 1.19
Hz), 4.601 (1H, ddd, J ) 5.86 Hz, 2.17 Hz, 4JHP ) 2.67 Hz), 3.825
(6H, d, 3JHP ) 11.24 Hz Hz); 13C NMR (CDCl3) δ 142.14 (d, 2JCP
3
2
) 5.7 Hz), 100.11 (d, JCP ) 10.2 Hz), 54.69 (d, JCP ) 6.0 Hz);
31P NMR (CDCl3) δ -2.10. GC-MS m/z 151 (M - 1).
A General Method for the Synthesis of Chloroeth-
ylidene Phosphates 3. To a 10-mL round-bottom flask was
added vinyl phosphate 2 (5.6 mmol) and EtOAc (2 mL) under
argon. Dry gaseous HCl was bubbled through the solution (2a-
f). In the case of 3h,i, the solution on 2 in EtOAc was cooled to
4 °C followed by addition of EtOAc saturated with HCl (2 mL).
The progress of the HCl addition was monitored by measuring
1H and 31P NMR spectra from the reaction mixture. After the
appropriate reaction time, the solvents were evaporated and the
residue was purified by column chromatography. The reaction
time and conditions varied between the reactions and are
illustrated in detail in Table 1.
All 1-chloroethyl products, except 3h,22 could be puri-
fied and isolated with silica gel column chromatography,
(21) Stowell, J. K.; Widlanski, T. S. J. Am. Chem. Soc. 1994, 116,
789-790.
(22) 3h was found to be extremely labile, since it decomposed during
warming, column chromatography, and GC-MS/HPLC-MS analysis.
Phosphoric Acid 1-Chloroethyl Ester Dimethyl Ester
3a: 86% (without purification), colorless viscose oil. Chroma-
tography eluent hexane/EtOAc, 1:1. 1H NMR (CDCl3) δ 6.242
J. Org. Chem, Vol. 70, No. 22, 2005 9057

3
3
(1H, dq, J ) 5.62 Hz, JHP ) 7.62 Hz), 3.83723 (3H, d, JHP
)
Graduate School of Bioorganic and Medicinal Chemis-
try, the National Technology Agency of Finland, the
Academy of Finland, Research Foundation of Orion
Corporation, and Association of Finnish Chemical
Societies.
11.44 Hz), 3.80223 (3H, d, 3JHP ) 11.31), 1.856 (3H, dd, J ) 5.62
Hz, JHP ) 1.09 Hz); 13C NMR (CDCl3) δ 85.78 (d, JCP ) 6.4
4
2
Hz), 54.8223 (d, 2JCP ) 6.1 Hz), 54.5523 (d, 2JCP ) 6.0 Hz), 27.54
(d, JCP ) 8.4 Hz); 31P NMR (CDCl3) δ -0.76. GC-MS m/z 189
3
(M + 1), 153 (M - Cl). Anal. Calcd for C4H10ClO4P‚0.7 HCl: C,
22.44; H, 5.04. Found: C, 22.53; H, 4.76.
Supporting Information Available: General methods,
NMR, and GC-MS data for compounds 2b-i (except 2g, only
NMR data) and NMR, GC-MS, and CHNS data for 3b-i
(except 3h, only NMR data). This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Mrs. Miia Reponen
and Mrs. Maritta Salminkoski for their skillful technical
assistance. This study was financially supported by the
(23) Due to their chiral center, OMe signals have different chemical
shifts.
JO0513562
9058 J. Org. Chem., Vol. 70, No. 22, 2005