Mono-and bis(5-O-nitro-1,4:3,6-dianhydro-D-sorbit-2-yl) phosphates: Synthesis and reactions with hydroxy-and amino-containing compounds

Article abstract of DOI:10.1007/s11172-007-0327-2

The reaction of 1,4:3,6-dianhydro-D-sorbitol 5-nitrate with POCl ₃ afforded mono-and bis(5-O-nitro-1,4:3,6-dianhydro-D-sorbit-2-yl) phosphorochloridates, whose hydrolysis resulted in phosphoric acid mono-and diesters. The subsequent treatment of these compounds with bases gave sodium and cyclohexylammonium salts. The reactions of phosphorochloridates with phenol, pentaerythritol dibromohydrin, and ethylenimine in the presence of organic bases afford mixed phosphates and phosphoramidates.

Full text of DOI:10.1007/s11172-007-0327-2

Russian Chemical Bulletin, International Edition, Vol. 56, No. 10, pp. 2097—2104, October, 2007
2097
Monoꢀ and bis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphates:
synthesis and reactions with hydroxyꢀ and aminoꢀcontaining compounds
b
b
L. T. Eremenko,a G. V. Oreshko,a G. V. Lagodzinskaya,a G. G. Aleksandrov, and I. L. Eremenko
ꢀ
aInstitute of Problems of Chemical Physics, Russian Academy of Sciences,
1 prosp. Akad. Semenova, 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 515 5420. Eꢀmail: lago@icp.ac.ru
bN. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
31 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 954 1279. Eꢀmail: ilerem@igic.ras.ru
The reaction of 1,4:3,6ꢀdianhydroꢀDꢀsorbitol 5ꢀnitrate with POCl3 afforded monoꢀ and
bis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphorochloridates, whose hydrolysis resulted
in phosphoric acid monoꢀ and diesters. The subsequent treatment of these compounds with
bases gave sodium and cyclohexylammonium salts. The reactions of phosphorochloridates with
phenol, pentaerythritol dibromohydrin, and ethylenimine in the presence of organic bases
afford mixed phosphates and phosphoramidates.
Key words: phosphorylation, 1,4:3,6ꢀdianhydroꢀDꢀsorbitol 5ꢀnitrate, monoꢀ and bis(5ꢀOꢀ
nitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphates, bis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ
1
2ꢀyl) phosphoramidate, H, 31P, and 13C NMR spectroscopy, Xꢀray diffraction study.
Primary and secondary phosphates play an important
role in the chemistry of living cells. For example, adenoꢀ
sine 5´ꢀmonophosphate1 is a component of certain coenꢀ
zymes regulating redox processes and is involved in the
exchange of amino acids, lipids, and carbohydrates.
Nitroxyalkyl phosphates were described2 as donors of niꢀ
tric oxide, which serves as a neuromediator and reacts in
organisms with various compounds, such as thiols, proꢀ
teins, sugars, protein hemes, etc.
The pharmacological activity of 1,4:3,6ꢀdianhydroꢀDꢀ
sorbitol 5ꢀnitrate (1) (isosorbide mononitrate), which has
found use in the medical practice, is attributed to its abilꢀ
ity to in vivo release nitric oxide.
Earlier,3 we have demonstrated that the phosphorylaꢀ
tion of 1 with POCl3 in the presence of organic bases
affords tris(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl)
phosphate (2). In the present study, we examined the
possibility of the synthesis of monoꢀ (3) and bis(5ꢀOꢀ
nitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphates (4) as
precursors of hybrid drugs4 combining fragments of phosꢀ
phoric acid, 1,4:3,6ꢀdianhydroꢀDꢀsorbitol 5ꢀnitrate, and
other compounds in one molecule.
Several approaches to the synthesis of monoꢀ and
diphosphates were developed5—8 based on the use of phosꢀ
phorus oxyhalides, dialkyl phosphorochloridates, alkyl
chlorophosphoramidates, etc.
The reaction of 1 with POCl3 in a molar ratio of 2 : 1 in
dioxane in the presence of 2 equiv. of pyridine afforded
monochloride 4 in 52% yield. Phosphorochloridates 3
and 4 are highly reactive compounds and are hydrolyzed
to monoꢀ and bis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ
2ꢀyl) phosphates 5 and 6, respectively, even under condiꢀ
tions of spectroscopic analysis.
The IR spectra of phosphates 5 and 6 show a broad
diffuse band at 2250—3000 cm–1 corresponding to hydroxy
groups involved in hydrogen bonding. The absorption from
1205 to 1235 cm–1 is assigned to vibrations of phosphoryl
groups.
The structures of phosphates 5 and 6 were established
by 1H, 31P, and 13C NMR spectroscopy. Table 1 gives the
1H and 31P NMR spectroscopic parameters for compounds
5 and 6 in comparison with the data for phosphate 2
synthesized earlier.3
1
The H NMR spectra of compounds 2, 5, and 6 in
solution show multiplets for eight nonequivalent coupled
protons of the isosorbide moiety, whose parameters are
analogous to those observed for isosorbide mononitrate
derivatives devoid of phosphoryl groups.9 The multiplets
for H(2) and Ha(1) are characterized by an additional
splitting with the spinꢀspin coupling constants of 7.0 and
1.5 Hz, respectively, due to coupling with 31P. In the
protonꢀcoupled 31P NMR spectra, the multiplets are
broadened due to longꢀrange interactions (in compounds 5
and 6, due apparently also to the insufficiently fast proton
exchange in P(O)OH); however, the predominant couꢀ
The reaction of compound 1 with an equimolar
amount of POCl3 in dioxane in the absence of hydrogen
chloride acceptors yields 80% of dichloride 3 (Scheme 1).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2026—2032, October, 2007.
1066ꢀ5285/07/5610ꢀ2097 © 2007 Springer Science+Business Media, Inc.

2098
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 10, October, 2007
Eremenko et al.
Scheme 1
pling with H(2) is pronounced in all cases. As a result, the
protonꢀcoupled 31P NMR spectra unambiguously showed
that compounds 2, 5, and 6 have three, one, and two
isosorbide fragments, respectively. The similarity of the
chemical shifts and the coupling constants for the isoꢀ
sorbide fragments in all three compounds indicates
that their conformations remain unchanged in spite of the
use of different solvents. A substantial change in the
31P chemical shift is observed only for monophosphate 5.10
The observed chemical shifts are typical of phosphates.
For compounds 2 and 6, the chemical shifts and coupling
constants given in Table 1 were calculated with the use of
the gNMRdemo program by varying the calculated specꢀ
tra until the coincidence with the experimental data was
achieved. The calculations for 1H were carried out for the
nineꢀspin system consisting of eight nonequivalent proꢀ
tons of one of the equivalent substituents (1,4:3,6ꢀdiꢀ
anhydroꢀDꢀsorbitol 5ꢀnitrate) and the phosphorus nucleus.
The 31P multiplet was simulated by the spin system conꢀ
taining, in addition to the phosphorus nucleus, the phosꢀ
phorusꢀcoupled H(1) and H(3) protons of these three and
two substituents, respectively. For compound 5, the calꢀ
culations were not performed; however, taking into acꢀ
count the form of the multiplets, the coupling constants
for compounds 2, 5, and 6 are the same within 0.2—0.3 Hz.
The 13C NMR spectra of compounds 2 and 6 are
also similar and show signals for six nonequivalent carꢀ
bon atoms (two CH2 groups and four CH groups,
13C{1H}DEPT135 data). Taking into account that the
structure of trisꢀphosphate 2 was established by Xꢀray
diffraction, the NMR spectroscopic data completely conꢀ
firm the structures of compounds 5 and 6.
Reagents and conditions: i. POCl3 : 1 = 1 :1, 75 °C;
ii. POCl3 : 1 : Py = 1 : 2 : 2, ~20 °C.
Compound 6 was found to undergo disproportionꢀ
ation in the course of NMR experiments in DMSO. Heatꢀ
ing of compound 6 in MeOH in the presence of Et3N
Note. The atomic numbering scheme presented for compound 1
is used in the description of the NMR spectra.
Table 1. 1H and 31P NMR spectroscopic data (δ, J/Hz) for phosphates 2, 6 (calculations with the use of the gNMRdemo proꢀ
gram), and 5
Comꢀ
pound
Ha(1)
Hb(1)
H(2)
H(3)
H(4)
H(5)
Ha(6)
Hb(6)
31P
2
3.75 (ddd,
4.03 (m,
4.84 (dd,
4.53 (d,
JH(3),H(4) JH(4),H(5)
= 5.0,
5.00 (t,
5.50 (dt,
JH(5),H(4)
JH(5),H (6)
5.0a,
3.87 (dd,
3.93 (dd,
–3.08 (dd,
JH(2),P
≈ 7.0,
|JH (1),H (1)
|
|JH (1),H (1)
|
|
JH(2),H (1)
≈
≈
≈
≈
|JH (6),H (6)
|
|
|JH (6),H (6)
|
a
b
a
b
a
a
b
a
b
= 10.4,
= 10.4,
= 2.0,
JH(4),H(3)
= 11.7,
= 11.7,
JH (1),H(2)
=
JH (1),H(2)
JH(2),P ≈ 7.0, JH(3),H(2)
5.0)
JH (6),H(5)
JH (6),H(5)
JH (1),Р
a
b
a
b
2.0, JH (1),Р
≈ 0)
JH(2),H (1) ≈ 0,
≈ 0)
JH(5),H (6)
=
= 5.0)
≈ 2.2)
≈ a1.5)
a
b
b
≈ 1.5)
3.85 (m)
JH(2),H(3) ≈ 0)
4.79 (m)
2.2)
5.41 (m)
5
6
4.10 (m)
4.61 (m)
5.02 (m)
4.99 (t,
3.85 (m)
3.95 (m)
0.03 (br.d,
JP,H(2) ≈ 7.0)
–2.05 (dd,
JP,H(2)
3.74 (ddd,
4.00 (d,
4.68 (dd,
4.52 (d,
JH(3),H(4) JH(4),H(5)
= 5.0,
5.50 (dt,
3.87 (dd,
3.97 (dd,
|JH (1),H (1)
|
|JH (1),H (1)
JH(2),H (1)
=
=
JH(5),H(4)
=
=
|JH (6),H (6)
|JH (6),H (6)
|
a
b
b
a
a
a
b
a
b
= 10.4,
= 10.4,
= 2.4,
JH(4),H(3)
JH(5),H (6)
= 11.7,
= 11.7,
= 7.1,
a
JH (1),H(2)
≈
JH (1),H(2)
JH(2),P = 7.1, JH(3),H(2)
5.0)
5.0,
JH (6),H(5)
JH (6),H(5)
JР,H (1)
a
b
a
b
a
2.4, JH (1),Р
≈ 0)
JH(2),H (1) ≈ 0,
≈ 0)
JH(5),H (6)
=
= 5.0)
= 2.0)
= 1.5)
a
b
b
= 1.5)
JH(2),H(3) ≈ 0)
2.0)

(5ꢀOꢀNitrodianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphates
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 10, October, 2007
2099
Scheme 3
afforded compounds 2 and 5, which is consistent with the
published data.11
Sodium salts 7 and 8 were synthesized by the reactions
of acids 5 and 6 with MeONa in MeOH (Scheme 2).
Scheme 2
Scheme 4
The structures of salts 7 and 8 were determined based
on the 1H and 31P NMR spectra. The form and the chemiꢀ
cal shifts of the multiplets for eight nonequivalent protons
of the isosorbide fragments in compounds 7 and 8 are
similar to those of 5 and 6, except for the fact that the
multiplet for H(2) in compounds 7 and 8 is shifted upfield
by ~0.2 ppm due to the presence of a negative charge on
this proton, which is indicative of the replacement of the
OH groups by ONa. This is also evident from narrowing
of the lines of the multiplets in the 31P NMR spectra (the
absence of exchange broadening caused by OH groups)
showing a distinct doublet and triplet with J ≈ 8 Hz due to
the presence of one and two isosorbide fragments, respecꢀ
tively.
The treatment of compounds 5 and 6 with cyclohexylꢀ
amine yields salts 9 and 10, respectively (Scheme 3).
The structures of salts 9 and 10 were established based
on the 1H and 31P NMR spectra. The chemical shifts and
the coupling constants for the multiplets for the protons
of the isosorbide fragments in compounds 9 and 10 are
similar to those observed for 5 and 6. In the spectra of 9
and 10, the multiplet for H(2) is also shifted upfield
by ~0.2 ppm, analogously to that observed in the spectra
of salts 7 and 8. The chemical shifts and the multiplicities
of the signals in the 31P NMR spectra correspond to phosꢀ
phates and the numbers of the isosorbide substituents in
compounds 9 (doublet) and 10 (triplet).
Scheme 5
The reactivities of phosphorochloridates 3 and 4 in
the reactions with nucleophiles were studied using pheꢀ
nol, pentaerythritol dibromohydrin, and ethylenimine
(Schemes 4 and 5).

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 10, October, 2007
Eremenko et al.
O(8)
O(6)
C(8A)
O(6A)
O(4A)
C(4A)
C(8)
O(4)
N(2)
O(7)
N(2A)
C(7A)
O(7A)
C(5A)
C(7)
C(5)
O(8A)
C(3A)
C(6)
C(4)
O(5A)
O(2A)
O(5)
C(6A)
C(2A)
C(3)
C(1)
P(1A)
O(2)
O(1)
O(1A)
C(1A)
N(1A)
N(1)
O(3A)
P(1)
C(9A)
C(10A)
O(3)
C(12)
O(9)
C(2)
C(12A)
C(9)
O(10A)
C(14A)
C(10)
O(9A)
O(12)
N(3)
C(11A)
O(11A)
C(11)
O(10)
C(14)
C(13A)
O(12A)
N(3A)
O(13A)
O(11)
C(13)
O(13)
A
B
Fig. 1. Structures of two independent molecules in the crystal structure of 14.
The compositions and structures of compounds 11—14
were confirmed by elemental analysis and 1H and
31P NMR spectroscopy. The structure of phosphoramidate
14 was established by Xꢀray diffraction (Fig. 1, Table 2).
grated intensities of the signals for the protons of the Ph
groups and the isosorbide fragments is 10 : 8 and 5 : 16 in
11 and 13, respectively. The 31P NMR spectra show the
3
coupling constants JP,H(2) ≈ 7 Hz characteristic of
The H and 31P NMR spectra of compounds 11 and
isosorbide derivatives. It is known10 that the 31P signal of
each Ph residue in phenyl phosphates is shifted upfield
by ~5 ppm. This is observed in the spectra under considꢀ
eration: 11, δ –11.54 (br.d, 3JP,H(2) ≈ 6.9 Hz); 13, δ –7.32
1
13 unambiguously confirm their structures. These spectra
contain all multiplets for eight nonequivalent protons
characteristic of isosorbide; the ratio between the inteꢀ
Table 2. Selected bond lengths (d) and bond angles (ω) in compound 14
Bond
d/Å
Bond
d/Å
Angle
ω/deg
Angle
ω/deg
P(1)—O(1)
P(1)—O(3)
O(6)—N(2)
O(8)—N(2)
O(12)—N(3)
1.466(6) P(1)—O(2)
1.552(6) P(1)—N(1)
1.581(6) O(1)—P(1)—O(2)
1.620(8) O(1)—P(1)—N(1)
115.3(4) O(1)—P(1)—O(3)
117.6(4) O(2)—P(1)—O(3)
103.6(4) O(3)—P(1)—N(1)
111.7(4)
102.6(3)
104.4(4)
110(1)
111.3(9)
128(1)
110.2(3)
104.8(3)
105.9(4)
114.4(9)
1.41(1)
1.23(2)
1.21(1)
O(7)—N(2)
O(11)—N(3)
O(13)—N(3)
1.19(1)
1.38(1)
1.20(1)
O(2)—P(1)—N(1)
O(6)—N(2)—O(7)
O(7)—N(2)—O(8)
118(1)
132(1)
O(6)—N(2)—O(8)
O(11)—N(3)—O(12)
P(1A)—O(1A) 1.465(6) P(1A)—O(2A) 1.581(6) O(11)—N(3)—O(13)
P(1A)—O(3A) 1.575(6) P(1A)—N(1A) 1.619(8) O(1A)—P(1A)—O(2A)
O(6A)—N(2A) 1.40(1)
O(8A)—N(2A) 1.20(1)
O(12A)—N(3A) 1.19(1)
121.1(9) O(12)—N(3)—O(13)
115.2(4) O(1A)—P(1A)—O(3A)
113.8(4) O(2A)—P(1A)—O(3A)
106.1(4) O(3A)—P(1A)—N(1A)
O(7A)—N(2A) 1.20(1)
O(11A)—N(3A) 1.38(1)
O(13A)—N(3A) 1.22(1)
O(1A)—P(1A)—N(1A)
O(2A)—P(1A)—N(1A)
O(6A)—N(2A)—O(7A) 117.3(9) O(6A)—N(2A)—O(8A)
O(7A)—N(2A)—O(8A) 128(1)
O(11A)—N(3A)—O(13A) 116.9(8) O(12A)—N(3A)—O(13A) 127(1)
O(11A)—N(3A)—O(12A) 115.6(9)

(5ꢀOꢀNitrodianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphates
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 10, October, 2007
2101
(br.t, 3JP,H(2) ≈ 6.5 Hz) compared to δ –2.05 (m, 3JH(2),P
7.1 Hz) for diester 6. It is of note that the shifts characterꢀ
istic (and informative) of the presence of the phenyl subꢀ
≈
1
stituents are observed in the H NMR spectrum as well;
this shift is most substantial for the multiplet of the H(2)
proton, which is shifted downfield to δ 5.16 in the specꢀ
trum of 11 compared to δ 4.7—4.8 in the spectra of the
acids.
O(2)
N(1)
P(1)
O(1)
Compounds 12 and 14 were characterized also by
NMR spectra, which convincingly confirmed their strucꢀ
tures. For example, the 1H NMR spectrum of compound
12 shows, along with multiplets of the isosorbide fragꢀ
ment, a complex multiplet for the protons of the 1,3,2ꢀdiꢀ
oxaphosphinane ring. The geminal protons in the OCH2
groups are nonequivalent and their coupling constants
with 31P are strongly different. One of these constants
O(3)
(apparently, J1 eq) is ~20 Hz (due to the trans arrangeꢀ
P,H
ment of the P and H atoms in the chair conformation),
and it is this constant that is clearly observed in the
31P NMR spectrum showing a triplet splitting. Another
Fig. 2. Projection of two molecules in the structure of 14 (the P,
O(1), O(2), O(3), and N(1) atoms are superimposed; the second
molecule (labeled by B) is shown by dashed lines).
coupling constant, J2 ax, being a few Hertz (due to the
P,H
gauche arrangement), together with JP,H(2), which is apꢀ
proximately equal to J2 ax, is responsible for the fact
P,H
Table 3. Selected torsion angles (ϕ) in two independent molꢀ
ecules of compound 14
that each line of this triplet appears as a broadened quartet
with the splitting of ~5—7 Hz. The chemical shift δP –8.21
suggests the involvement of the phosphorus atom in the
ring.10 Compared to the spectra of 12, the spectra of
compound 14 are much more simple. Thus, the 1H specꢀ
trum shows, in addition to the multiplets typical of
isosorbide, a doublet for the equivalent protons of ethylenꢀ
imine with JH,P = 16 Hz, which confirms the presence of
the P—N covalent bond. This is also evidenced by a large
positive 31P chemical shift (δP 15.46).
Angle
ϕ/deg
A
B
C(3)—O(2)—P(1)—O(1)
C(9)—O(2)—P(1)—O(1)
C(3)—O(2)—P(1)—N(1)
C(9)—O(2)—P(1)—N(1)
–43.8
–169.0
85.9
10.8
–173.3
137.4
63.4
63.3
It should be noted that the isosorbide fragments are
equivalent in the NMR spectra of compounds 2, 6, 8,
and 10, whereas these fragments in the spectra of comꢀ
pounds 13 and 14 are nonequivalent. Their diastereoꢀ
topicity12 associated with the asymmetry of the molꢀ
ecule is manifested at 200 MHz as a pronounced douꢀ
bling of the multiplet for H(2) adjacent to the center of
asymmetry and a broadening of the lines of the other
multiplets.
The structure of compound 14 was established by Xꢀray
diffraction. There are two independent molecules per
asymmetric unit (see Fig. 1). In both independent molꢀ
ecules, the phosphorus atom is bound to the phosphoryl
oxygen atom, the ethylenimine nitrogen atom, and two
O atoms of two 5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitol
fragments. The absolute configurations of all asymmetric
C atoms correspond to the D configuration. Both indeꢀ
pendent molecules are not diastereomers. They are, in
fact, rotational isomers characterized by different angles
of rotation of the isosorbide fragments about the P—O
and O—C bonds and of the ethylenimine ring about the
P—N bond (Fig. 2). The torsion angles describing the
orientation of the dianhydrosorbitol fragments in molꢀ
ecules A and B are given in Table 3.
A substantial difference in the orientation of these
groups is apparently associated with the crystal packing
effects. As in the tris(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀ
sorbitꢀ2ꢀyl) phosphate molecule studied earlier,3 the
cisꢀfused oxolane rings adopt conformations intermediate
between an envelope and a twist form. The bond lengths
and bond angles in compound 14 (see Table 2) are similar
to those in the dinitro derivative of 1,4:3,6ꢀdianhydroꢀDꢀ
sorbitol studied earlier.13
To conclude, we synthesized monoꢀ and bis(5ꢀOꢀniꢀ
troꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphates and
studied their transformations. The vasodilator activity of
compound 6* is of the same order of magnitude as the
efficiency of the drug nicorandil.
* The vasodilator activity was determined from the relaxation of
isolated rat aorta contracted with noradrenaline; the investigaꢀ
tion was carried out in the Laboratory of Receptor and Bioꢀ
chemical Pharmacology at the AllꢀRussian Research Center for
Safety of Biologically Active Compounds.

2102
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Eremenko et al.
was obtained in a yield of 1.2 g (52%) as a colorless oil, nD20 1.571.
Found (%): C, 31.20; H, 3.65; Cl, 7.42; N, 6.18; P, 6.44.
C12H16ClN2O13P. Calculated (%): C, 31.15; H, 3.48; Cl, 7.66;
N, 6.05; P, 6.69. The identification of the IR and NMR spectra
was accompanied by hydrolysis of phosphorochloridate.
Experimental
The H (200.13 MHz), 31P (81 MHz), and 13C (50.3 MHz)
NMR spectra were recorded on a Bruker DPXꢀ200 spectroꢀ
meter relative to Me4Si as the internal standard for H and 13C
1
1
Compound 4 (1.2 g, 2.6 mmol) was dissolved in dichloroꢀ
methane (10 mL). The reaction mixture was washed with water
(3×5 mL), the solvent was removed in vacuo, and the residue
was recrystallized from acetone. Compound 6 was obtained as
hydrate in a yield of 1.0 g (83%), m.p. 93—94 °C. Found (%):
C, 31.46; H, 4.28; N, 6.31; P, 6.47. C12H17N2O14P•H2O. Calꢀ
and relative to 85% aqueous H3PO4 as the external standard
for 31P. Different NMR experiments were carried out for the
same freshly prepared samples using a DMSOꢀd6—25 vol.%
CCl4—0.1 vol.% Me4Si mixture as the solvent. The assignment
of the signals was made based on a comparative analysis of our
results3 and the data published in the literature9 for the related
compounds, the forms of multiplets, integrated intensities, and
13C{1H}DEPT experiments.
The IR spectra were recorded on a Specord Mꢀ82 spectroꢀ
meter. The melting points were determined on a Boetius
RWMKꢀ05 instrument. Isosorbide 5ꢀmononitrate (Acros),
POCl3 (99%, Aldrich), Py, Et3N, solvents, and inorganic reꢀ
agents of reagent grade were used. Pyridine, Et3N, and the solꢀ
vents were dried according to standard procedures.14
(5ꢀOꢀNitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphoroꢀ
dichloridate (3) and (5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl)
phosphate (5). Phosphorus oxychloride (0.88 g, 5.74 mmol) was
added with stirring to a solution of compound 1 (1 g, 5.23 mmol)
in anhydrous dioxane (15 mL) at ~20 °C. The reaction mixture
was stirred at ~20 °C for 30 min. Then the temperature was
gradually raised to 75 °C for 1 h. After cooling of the mixture
to ~20 °C, volatile components were removed in vacuo. The
residue was dissolved in anhydrous acetone (10 mL) and poured
into anhydrous diethyl ether (15 mL). The oil that formed was
separated and dried in vacuo. Compound 3 was obtained in a
culated (%): C, 31.28; H, 4.14; N, 6.06; P, 6.70. IR, ν/cm–1
:
1638, 1280, 965, 855 (ONO2); 1026 (POC); 1256 (P=O).
1H NMR (DMSOꢀd6—CCl4), δ: 3.74 (m, Ha(1), |2JH (1),H (1)| =
a
b
3
4
10.4 Hz, JH (1),H(2) = 2.4 Hz, JH (1),P ≈ 1.5 Hz); 3.87 (m,
a
a
Ha(6), |2JH (6),H (6)| = 11.7 Hz, JH (6),H(5) = 5.0 Hz); 3.97 (m,
3
a
b
a
Hb(6), |2JH (6),H (6)| = 11.7 Hz, JH (6),H(5) ≈ 2.0 Hz); 4.00 (m,
3
a
b
b
Hb(1), |2JH (1),H (1)| = 10.4 Hz, JH (1),H(2) ≈ 0 Hz); 4.38 (s,
3
a
b
b
P(O)OH + H2O); 4.52 (d, H(3), 3JH(3),H(4) = 5.0 Hz, 3JH(3),H(2)
≈
3
3
0 Hz); 4.68 (m, H(2), JH(2),H (1) = 2.4 Hz, JH(2),H(3) ≈ 0 Hz,
a
3JH(2),P ≈ 7.1 Hz); 4.99 (m, H(4), JH(4),H(5)
5.0 Hz); 5.50 (m, H(5), JH(5),H(4)
=
3JH(4),H(3)
≈
3
3
≈
3JH(5),H (6) ≈ 5.0 Hz,
a
3JH(5),H (6) = 2.0 Hz). 31P NMR (DMSOꢀd6—CCl4), δ: –2.05
b
(m, P(O), JH(2),P ≈ 7.1 Hz, JH (1),P ≈ 1.5 Hz). 31P{1H} NMR:
3
4
a
singlet. 13C{1H} and 13C{1H}DEPT135(+,–) NMR
3
(DMSOꢀd6—CCl4), δ: 87.48 (+) (d, C(3), JC(3),P = 6.0 Hz);
83.18 (+) (s, C(4) or C(5)); 82.11 (+) (s, C(5) or C(4)); 79.90 (+)
(d, C(2), 2JC(2),P = 5.0 Hz); 74.35 (–) (d, C(1), 3JC(1),P = 5.0 Hz);
69.81 (–) (s, C(6)).
Sodium monoꢀ and bis(5ꢀOꢀnitroꢀ1,4;3,6ꢀdianhydroꢀDꢀsorbitꢀ
2ꢀyl) phosphates (7 and 8). A methanolic solution of compound
5 or 6 was added with stirring to a methanolic solution of
MeONa. The reaction mixture was stirred at ~20 °C for 15 min
and kept in a refrigerator at 5—10 °C for 12 h. The salt was
filtered off, washed with diethyl ether, and dried in a vacuum
desiccator over P2O5. Diethyl ether (1 : 4) was added to the
filtrate, and an additional amount of the sodium salt was obꢀ
tained.
20
yield of 1.3 g (81%) as a colorless oil, nD 1.587. Found (%):
C, 23.61; H, 2.88; Cl, 22.87; N, 4.72; P, 10.21. C6H8Cl2NO7P.
Calculated (%): C, 23.40; H, 2.62; Cl, 23.02; N, 4.55; P, 10.06.
The recording of the IR and NMR spectra was accompanied by
hydrolysis of phosphorodichloridate 3.
Compound 3 (1.3 g, 4.2 mmol) was dissolved in aqueous
acetone (10 mL). The reaction mixture was stirred for 3 h and
kept for 20 h. Then anhydrous MgSO4 was added, the mixture
was filtered, the solvent was removed in vacuo, and the residue
was additionally dried in a vacuum desiccator over P2O5. Comꢀ
pound 5 was obtained in a yield of 1.1 g (96%), nD 1.5045.
Found (%): C, 26.65; H, 3.91; N, 5.26; P, 11.24. C6H10NO9P.
Calculated (%): C, 26.65; H, 3.72; N, 5.17; P, 11.42. IR, ν/cm–1
1650, 1280, 958, 855 (ONO2); 1005 (POC); 1205 (P=O).
1H NMR (CDCl3—CD3CN), δ: 3.70—4.08 (m, 4 H, Ha(1),
Hb(1), Ha(6), Hb(6)); 4.61 (m, 1 H, H(3)); 4.79 (m, 1 H, H(2));
Disodium (5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl) phosꢀ
phate (7). The reaction of compound 5 (2.71 g, 10 mmol) in
MeOH (5 mL) and sodium methoxide (prepared from Na (0.46 g,
20 mmol)) in MeOH (10 mL) afforded compound 7 in a yield of
2.60 g (82.5%), t.decomp. 203—205 °C. Found (%): C, 21.41;
H, 3.22; N, 4.40. C6H8Na2NO9P•H2O. Calculated (%):
20
:
C, 21.63; H, 3.03; N, 4.21. IR, ν/cm–1
: 1632, 1280,
988, 872 (ONO2); 1056 (POC); 1164 (P=O). 1H NMR
(DMSOꢀd6—CCl4—(CD3)2C=O), δ: 3.60—4.40 (m, 4 H,
Ha(1), Hb(1), Ha(6), Hb(6), H2O); 4.51 (m, 2 H, H(3),
5.02 (m, 1 H, H(4)); 5.41 (m, 1 H, H(5)); 7.34 (br.s, 2 H, OH).
31P NMR (CDCl3—CD3CN), δ: 0.03 (br.d, P(O), JP,H(2)
=
H(2)); 4.90 (m, 1 H, H(4)); 5.46 (m, 1 H, H(5)). 31P NMR
3
3
5.0 Hz). 31P{1H} NMR: singlet.
(DMSOꢀd6—CCl4—(CD3)2CO), δ: 1.11 (br.d, P(O), JP,H(2)
≈
Bis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphoroꢀ
chloridate (4) and bis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl)
phosphate (6). A solution of POCl3 (0.77 g, 5.0 mmol) in anhyꢀ
drous dioxane (5 mL) was added to a solution of compound 1
(1.9 g, 10 mmol) and Py (0.8 g, 10.1 mmol) in anhydrous diꢀ
oxane (10 mL) at 8—10 °C. The reaction mixture was stirred at
8—10 °C for 1 h and then at 18—20 °C for 2 h. The precipitate
that formed was filtered off, and the solvent was removed
in vacuo. The residue was treated with a 1 : 1 acetone—diethyl
ether mixture (2×5 mL), the solvent was removed, and the resiꢀ
due was dried in a vacuum desiccator over P2O5. Compound 4
7.9 Hz). 31P{1H} NMR: singlet.
Sodium bis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl) phosꢀ
phate (8). The reaction of compound 6 (2.31 g, 5 mmol) in
MeOH (5 mL) and sodium methoxide (prepared from Na (0.12 g,
5 mmol) in MeOH (10 mL)) afforded compound 8 in a yield of
2.05 g (84.5%), t.decomp. 186—188 °C. Found (%): C, 29.53;
H, 3.26; N, 5.57. C12H16NaN2O14P•H2O. Calculated (%):
C, 29.76; H, 3.75; N, 5.78. IR, ν/cm–1: 1636, 1281, 966,
854 (ONO2); 1090 (POC); 1241 (P=O). 1H NMR
(DMSOꢀd6—CCl4), δ: 3.55—4.00 (m, 8 H, Ha(1), Hb(1), Ha(6),
Hb(6)); 4.34—4.54 (m, 4 H, H(2), H(3)); 4.89 (t, 2 H, H(4));

(5ꢀOꢀNitrodianhydroꢀDꢀsorbitꢀ2ꢀyl) phosphates
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 10, October, 2007
2103
3
5.44 (m, 2 H, H(5)). 31P NMR (DMSOꢀd6—CCl4), δ: –1.41
(br.t, P(O), JP,H(2) ≈ 7.6 Hz).
31P NMR (DMSOꢀd6—CCl4), δ: –11.54 (br.d, P(O), JP,H(2)
≈
3
6.9 Hz). 31P{1H} NMR: singlet.
Cyclohexylammonium (5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀ
sorbitꢀ2ꢀyl) phosphate (9). A solution of compound 5 (2.7 g,
10 mmol) in MeOH (10 mL) was added with stirring to a soluꢀ
tion of cyclohexylamine (2.0 g, 20 mmol) in MeOH (15 mL) at
5—10 °C. The reaction mixture was stirred for 2 h, the temperaꢀ
ture being gradually raised to ~20 °C. Diethyl ether (25 mL) was
added, and the salt was filtered off, washed with diethyl ether,
and dried in a vacuum desiccator over P2O5. Compound 9 was
obtained as hydrate in a yield of 2.9 g (85.3%), t.decomp.
171—173 °C. Found (%): C, 37.30; H, 6.63; N, 6.94; P, 7.71.
5,5ꢀBis(bromomethyl)ꢀ2ꢀ(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀ
sorbitꢀ2ꢀyloxy)ꢀ2ꢀoxoꢀ1,3,2ꢀλ ꢀdioxaphosphinane (12). A soluꢀ
5
tion of compound 3 (3.08 g, 10 mmol) in anhydrous dioxane
(10 mL) was added with stirring to a solution of pentaerythritol
dibromohydrin (2.62 g, 10 mmol) and Py (1.6 g, 20.2 mmol) in
anhydrous dioxane (15 mL) at 25—30 °C. The reaction mixture
was stirred for 3 h and kept at ~20 °C for 20 h. The precipitate
that formed was filtered off, the solvent was distilled off in vacuo,
and the residue was treated with water. The reaction product
was filtered off, washed with water, dried in air, and recrystalꢀ
lized from aqueous acetone. Compound 12 was obtained in a
yield of 3.3 g (64%), m.p. 148—150 °C. Found (%): C, 25.86;
H, 3.81; Br, 31.18; N, 2.65; P, 5.86. C11H16Br2NO9P•H2O.
Calculated (%): C, 25.65; H, 3.52; Br, 31.03; N, 2.72; P, 6.01.
IR, ν/cm–1: 1648, 1284, 1004, 868 (ONO2); 1024 (POC); 1241
(P=O); 664 (CBr). 1H NMR (DMSOꢀd6—CCl4), δ: 3.52 (s,
2 H, CH2Br); 3.60—4.50 (m, 8 H, Ha(1), Hb(1), Ha(6),
Hb(6) + 2 OCH2); 3.81 (s, 2 H, CH2Br); 4.61 (m, 1 H, H(3));
4.80 (m, 1 H, H(2)); 5.06 (m, 1 H, H(4)); 5.51 (m, 1 H,
C
12H23N2O9P•H2O. Calculated (%): C, 37.12; H, 6.49; N, 7.21;
P, 7.98. IR, ν/cm–1: 1640, 1280, 960, 855 (ONO2); 1100 (POC);
1250 (P=O). 1H NMR (DMSOꢀd6—CCl4—(CD3)2CO), δ:
1.00—2.00 (m, 10 H, C5H10); 2.83 (unresolved m, 1 H, NCH);
3.10—7.00 (br.s, 3 H, POH + NH2); 3.60—4.00 (m, 4 H,
Ha(1), Hb(1), Ha(6), Hb(6)); 4.51 (m, 2 H, H(2), H(3));
4.89 (m, 1 H, H(4)); 5.48 (m, 1 H, H(5)). 31P NMR
(DMSOꢀd6—CCl4—(CD3)2CO), δ: 0.06 (br.d, 3JP,H(2) ≈ 6.8 Hz).
31P{1H} NMR: singlet.
Cyclohexylammonium bis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀ
sorbitꢀ2ꢀyl) phosphate (10). A solution of compound 6 (2.2 g,
5 mol) in acetone (10 mL) was added with stirring to a solution
of cyclohexylamine (1.0 g, 10 mmol) in acetone (10 mL)
at 0—5 °C. The reaction mixture was stirred for 1 h, the temꢀ
perature being gradually raised to 18—20 °C. Then the mixture
was cooled to 0 °C, and diethyl ether (25 mL) was added. The
salt that precipitated was filtered off, washed with cold methaꢀ
nol and diethyl ether, and dried in a vacuum desiccator. Comꢀ
pound 10 was obtained in a yield of 5 g (90%), t.decomp.
183—184 °C. Found (%): C, 38.73; H, 5.92; N, 7.65; P, 5.30.
C18H30N3O14P•H2O. Calculated (%): C, 38.51; H, 5.74;
N, 7.48; P, 5.52. IR, ν/cm–1: 1647, 1281, 975, 852 (ONO2);
1076 (POC); 1207 (P=O). 1H NMR (DMSOꢀd6—CCl4), δ:
1.00—2.00 (m, 10 H, C5H10); 2.83 (m, 1 H, NCH); 3.10—7.00
(br.s, 3 H, POH + NH2); 3.60—4.00 (m, 8 H, Ha(1), Hb(1),
Ha(6), Hb(6)); 4.42 (m, 4 H, H(2), H(3)); 4.89 (m, 2 H, H(4));
5.46 (m, 2 H, H(5)). 31P NMR (DMSOꢀd6—CCl4), δ: –2.44
(br.t, P(O)). 31P{1H} NMR: singlet.
H(5)). 31P NMR (DMSOꢀd6—CCl4), δ: –8.21 (br.tq, P(O),
3
3J(1)
≈ 20 Hz, 3J(2)
≈ J(3)
≈ 4—6 Hz). 31P{1H} NMR:
P,H
P,H
P,H(2)
singlet.
Bis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl)phenyl phosꢀ
phate (13). A solution of compound 4 (2.31 g, 5 mmol) in anꢀ
hydrous dioxane (10 mL) was added with stirring to a solution of
phenol (0.47 g, 5 mmol) and Et3N (0.61 g, 6 mmol) in anꢀ
hydrous dioxane (10 mL) at 20—25 °C. The reaction mixture
was stirred at 45—50 °C for 3 h and kept at ~20 °C for 20 h. The
precipitate that formed was filtered off, anhydrous diethyl ether
(25 mL) was added to the filtrate, and an additional amount of
the precipitate was filtered off. The organic layer was washed
with ice water, 5% aqueous H2SO4, a 5% aqueous NaHCO3
solution, and water and dried over MgSO4. After removal of the
solvent in vacuo, compound 13 was obtained in a yield of 1.5 g
20
(58%) as a colorless oil, nD 1.5120. Found (%): C, 41.32;
H, 4.31; N, 5.60; P, 5.76. C18H21N2O14P. Calculated (%):
C, 41.55; H, 4.07; N, 5.38; P, 5.95. IR, ν/cm–1: 1639,
1281, 960, 852 (ONO2); 1027 (POC); 1238 (P=O). 1H NMR
(DMSOꢀd6—CCl4), δ: 3.71—4.16 (m, 8 H, Ha(1), Hb(1), Ha(6),
Hb(6)); 4.51 and 4.58 (both m, 1 H each, H(3)); 4.85—5.12 (m,
4 H, H(2), H(4)); 5.48 (m, 2 H, H(5)); 7.10—7.50 (m, 5 H,
C6H5O). 31P NMR (DMSOꢀd6—CCl4), δ: –7.32 (br.t, OP(O),
3JP,H(2) ≈ 6.5 Hz). 31P{1H} NMR: singlet.
(5ꢀOꢀNitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl)diphenyl phosꢀ
phate (11). A solution of compound 3 (3.1 g, 10 mmol) in anꢀ
hydrous dioxane (10 mL) was added with stirring to a solution of
phenol (1.9 g, 20 mmol) and Et3N (2.2 g, 22 mmol) in anꢀ
hydrous dioxane (15 mL) at ~20 °C. The reaction mixture was
stirred for 30 min, the temperature being gradually raised to
50—55 °C. Then the mixture was kept at 50—55 °C for 1 h and
at ~20 °C for 20 h. The precipitate that formed was filtered off,
the solvent was distilled off in vacuo, and the residue was disꢀ
solved in CH2Cl2 (30 mL). The resulting solution was washed
with water, 5% aqueous H2SO4, a 5% aqueous NaHCO3 soluꢀ
tion, and water and dried over MgSO4. After removal of the
solvent in vacuo, compound 11 was obtained in a yield of 2.4 g
Aziridinobis(5ꢀOꢀnitroꢀ1,4:3,6ꢀdianhydroꢀDꢀsorbitꢀ2ꢀyl)
phosphate (14). A solution of compound 4 (4.6 g, 10 mmol) in
anhydrous dioxane (20 mL) was added with stirring to a solution
of ethylenimine (0.5 g, 11.6 mmol) and Et3N (1.2 g, 11.8 mmol)
in anhydrous dioxane (10 mL) at 15—20 °C. The reaction mixꢀ
ture was stirred at ~20 °C for 3 h and kept for 20 h. The precipiꢀ
tate that formed was filtered off, the solvent was distilled off
in vacuo, and the residue was recrystallized from chloroform.
Compound 14 was obtained in a yield of 2.2 g (45.8%), m.p.
100—101 °C. Found (%): C, 35.58; H, 4.57; N, 8.72; P, 6.46.
C14H20N3O13P. Calculated (%): C, 35.83; H, 4.30; N, 8.95;
P, 6.60. IR, ν/cm–1: 1636, 1276, 956, 856 (ONO2); 1024 (POC);
1248 (P=O). 1H NMR (DMSOꢀd6—CCl4), δ: 2.15 (d, 4 H,
20
(57%) as a colorless oil, nD 1.5408. Found (%): C, 51.30;
H, 4.42; N, 3.18; P, 7.21. C18H18NO9P. Calculated (%):
C, 51.07; H, 4.20; N, 3.31; P, 7.32. IR, ν/cm–1: 1644,
1281, 957, 852 (ONO2); 1026 (POC); 1261 (P=O). 1H NMR
(DMSOꢀd6—CCl4), δ: 3.78—4.21 (m, 4 H, Ha(1), Hb(1), Ha(6),
Hb(6)); 4.60 (m, 1 H, H(3)); 5.04 (m, 1 H, H(4)); 5.16 (m, 1 H,
H(2)); 5.46 (m, 1 H, H(5)); 7.10—7.50 (m, 10 H, C6H5O).
3
NCH2, JH,NP = 16.0 Hz); 3.70—4.10 (m, 8 H, Ha(1), Hb(1),
Ha(6), Hb(6)); 4.52 (m, 2 H, H(3)); 4.82 (m, 2 H, H(2)); 5.00 (m,

2104
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 10, October, 2007
Eremenko et al.
2 H, H(4)); 5.50 (m, 2 H, H(5)). 31P NMR (DMSOꢀd6—CCl4),
δ: 15.46 (m, P(O)). 31P{1H} NMR: singlet.
Ser. Khim., 2006, 380 [Russ. Chem. Bull., Int. Ed., 2006,
55, 393].
Xꢀray diffraction study. Xꢀray diffraction data were colꢀ
lected on an EnrafꢀNonius CADꢀ4 automated diffractometer
(λ(MoꢀKα), graphite monochromator, ω scanning technique,
4. V. G. Granik and N. B. Grigor´ev, Izv. Akad. Nauk, Ser.
Khim., 2002, 1268 [Russ. Chem. Bull., Int. Ed., 2002,
51, 1375].
T = 293 K, 2θ
= 50.2°, 3497 independent reflections, of
5. E. Fischer, Ber., 1914, 47, 3193.
max
which 1500 reflections were with F 2 > 2σ(I )). The structure was
solved by direct methods and refined by the leastꢀsquares method
using the SHELXS9715 and SHELXL9716 program packages with
anisotropic displacement parameters for nonhydrogen atoms
(isotropic displacement parameters for H atoms) to R = 0.0375
(wR2 = 0.067) based on 1500 reflections with F 2 > 2σ(I ); the
goodnessꢀofꢀfit GOOF = 1.000. Crystals of 14 are triclinic, a =
6.535(2) Å, b = 9.179(2) Å, c = 16.046(3) Å, α = 102.96°,
β = 95.26(2)°, γ = 95.06(2)°, Z = 2, dcalc = 1.586 g cm–3, µ =
0.217 mm–1, V = 982.8(4) Å3, space group P–1. The Flack paꢀ
rameter is –0.00(17).
6. M. Gulland and G. I. Hobday, J. Chem. Soc., 1940, 746.
7. P. T. Gilham and H. G. Khorana, J. Am. Chem. Soc., 1958,
80, 6212.
8. H. A. C. Montgomery and J. H. Turnbull, J. Chem. Soc.,
1958, 1963.
9. H. Hayashi, J. Ikeda, T. Kuroda, K. Kubo, T. Sano, and
F. Suzuki, Chem. Pharm. Bull., 1993, 41, 1091.
10. E. E. Nifant´ev, Khimiya fosfororganicheskikh soedinenii
[Chemistry of Organophosphorus Compounds], Izdꢀvo MGU,
Moscow, 1971, 352 pp. (in Russian).
11. Phosphorusꢀ31 NMR: Principles and Applications, Ed. D. G.
Gorenshtein, Academic Press, New York, 1984, 604 pp.
12. K. Mislow and M. Raban in Topics in Stereochemistry,
Eds N. L. Allinger and E. L. Eliel, Intersci. Publ.—Wiley
and Sons, New York, 1967.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 06ꢀ03ꢀ32482)
and the Presidium of the Russian Academy of Sciences
(Program of Fundamental Research No. 08P).
13. J. A. Kanters, A. Schouten, G. J. Sterk, and M. H. de Jomg,
J. Mol. Struct., 1993, 298, 113.
14. A. J. Gordon and R. A. Ford, The Chemists Companion.
A Handbook of Practical Data, Techniques and References,
J. Wiley and Sons, New York—London, 1972.
15. G. M. Sheldrick, SHELXS97, Program for the Solution of
Crystal Structures, University of Göttingen, Germany, 1997.
16. G. M. Sheldrick, SHELXL97, Program for the Refinement of
Crystal Structures, University of Göttingen, Germany, 1997.
References
1. M. D. Mashkovskii, Lekarstvennye sredstva [Drugs], Novaya
Volna, Moscow, 2005, 1206 pp. (in Russian).
2. V. G. Granik and N. B. Grigor´ev, Vestn. RFFI, 2002, 30,
No. 4, 49 [RFBR Information Bulletin, 2002, 30, No. 4 (Engl.
Transl.)].
3. L. T. Eremenko, G. V. Oreshko, G. V. Lagodzinskaya, G. G.
Aleksandrov, and I. L. Eremenko, Izv. Akad. Nauk,
Received October 2, 2006;
in revised form April 3, 2007