Features of synthesis and structure of ethyl (2Z)-3-hydroxy-(2,3,4,5- tetrafluorophenyl)-propyl-2-enoate

Article abstract of DOI:10.1134/S1070363212010197

The structure of key intermediates in the synthesis of fluoroquinolone antibiotics: diethyl (2,3,4,5-tetrafluorobenzoyl)malonate and ethyl (2Z)-3-hydroxy-(2,3,4,5-tetrafluorophenyl)prop-2-enoate was for first time studied using X-ray diffraction (XRD) and

Full text of DOI:10.1134/S1070363212010197

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 1, pp. 116–121. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © D.N. Bazhin, E.V. Shchegol’kov, Yu.S. Kudyakova, K.V. Scherbakov, Ya.V. Burgart, V.I. Saloutin, 2012, published in Zhurnal
Obshchei Khimii, 2012, Vol. 82, No. 1, pp. 120–125.
Features of Synthesis and Structure
of Ethyl (2Z)-3-Hydroxy-(2,3,4,5-tetrafluorophenyl)-
propyl-2-enoate
D. N. Bazhin, E. V. Shchegol’kov, Yu. S. Kudyakova,
K. V. Scherbakov, Ya. V. Burgart, and V. I. Saloutin
Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences,
ul. S. Kovalevskoi 22, Yekaterinburg, 620990, Russia
e-mail: bazhin@ios.uran.ru
Received November 8, 2010
Abstract—The structure of key intermediates in the synthesis of fluoroquinolone antibiotics: diethyl (2,3,4,5-
tetrafluorobenzoyl)malonate and ethyl (2Z)-3-hydroxy-(2,3,4,5-tetrafluorophenyl)prop-2-enoate was for first
1
time studied using X-ray diffraction (XRD) and H, 19F NMR spectroscopy. In solution both the esters were
shown to exist as a mixture of enol and ketone tautomeric forms with predominance of the latter. According to
the XRD analysis, ethyl (2Z)-3-hydroxy-(2,3,4,5-tetrafluorophenyl)prop-2-enoate in the solid state exists
entirely in the enol form.
DOI: 10.1134/S1070363212010197
Ethyl 3-(2,3,4,5-tetrafluorophenyl)-3-oxopropio-
nate (I) is a key intermediate in the organic synthesis
of a wide range of polyfluorinated quinolone deriva-
tives [1–5] and benzotiazines [6] exhibiting antiviral
[7], antibacterial [8], and antitumor [9] activity. It
should be noted in particular that a series of quinolones
represents a specific group of modern antibiotics used
in medicine, such as ciprofloxacin, ofloxacin, levo-
floxacin, and others.
[13, 14], or with the monoethyl potassium malonate
under the action of magnesium chloride and
triethylamine [15]. However, the proposed technique
requires an additional step of the synthesis of malonic
acid monoethyl ester, and implementing specific
conditions in the process of the synthesis (low
temperature, inert atmosphere). An alternative method
for obtaining 3-oxoester I is the reaction of tetrafluoro-
benzonitrile with BrZnCH2COOEt [16, 17].
The necessity to find an effective method of syn-
thesis of the 3-oxoester I is due to the fact that the
polyfluoroaromatic fragment easily undergoes nucleo-
philic substitution, which limits the use of strong bases
[10]. The action of acetoacetic ester on pentafluoro-
benzoyl chloride or ethyl pentafluorobenzoate leads to
transformations with the replacement of fluorine atoms
in the ortho- and para-positions of the aromatic ring
[11]. The classic method of obtaining ester I is the
acylation of malonic ester with 2,3,4,5-tetrafluoro-
benzoyl chloride (II) in the presence of magnesium
followed by hydrolysis and decarboxylation of the
intermediate tricarbonyl derivative III [12]. To
increase the yield of 3-oxo ester I, the acylation with
polyfluorobenzoyl chloride II was carried out with the
monoethyl malonate in the presence of n-butyllithium
As seen, the method using organomagnesium
intermediate is the most convenient for the preparative
synthesis of 3-oxoester I. Analysis of published data
showed the absence of detailed information about the
effect of the process conditions on the possible forma-
tion of by-products, as well as about the structure of
tricarbonyl derivative III and the oxo ester I.
The aim of this work was to study the features of
preparation of diethyl (2,3,4,5-tetrafluorobenzoyl)
malonate III and ethyl 3-(2,3,4,5-tetrafluorophenyl)-3-
oxopropionate I and their structures.
The first step in the synthesis of compound I is
obtaining the benzoylmalonate derivative III by the
reaction of 2,3,4,5-tetrafluorobenzoyl chloride II with
malonic ester under the action of magnesium ethoxide
116

FEATURES OF SYNTHESIS AND STRUCTURE
117
Scheme 1.
OEt
Mg
EtO
OEt
EtO
OEt
F
i
Mg + EtOH +
O
O
O
O
IV
F
F
F
F
F
F
F
F
iii
ii
O
O
O
F
F
Mg/2
O
Cl
EtO
OEt
EtO
F
O
O
O
OEt
II
III, 89%
i, CCl4 (cat.), toluene; ii, IV, toluene, 0°С; iii, H2SO4, H2O.
(Scheme 1). According to [11, 18], the formation of
the malonic ester magnesium derivative IV occurs in
ethyl alcohol being initiated by CCl4 at the subsequent
addition of ether as the reaction medium. We found
that replacing the ether by toluene has no effect on the
formation of the benzoylmalonate derivative III. In
this case, the gradual addition of alcohol and malonic
ester to magnesium in toluene allows controlling the
reaction mixture temperature. As a result ethoxy-
magnesiummalonic ester IV formed (Scheme 1). An
excess of alcohol can then react with 2,3,4,5-
tetrafluorobenzoyl chloride II. To avoid the formation
of ethyl 2,3,4,5-tetrafluorobenzoate, the homogeneous
solution formed after dissolution of magnesium was
evacuated and the residual alcohol was removed as a
mixture with toluene.
formation of by-products. For a more complete decom-
position the best is to use 15% sulfuric acid. The benzoyl-
malonate derivative III is a liquid substance, which
was purified by distillation under a reduced pressure.
The isolation of pure malonate derivative III
allowed us for the first time to study its structure. The
individuality of the diester III was confirmed by TLC,
its quantitative composition was established by
elemental analysis, and structural characteristics were
1
19
studied using IR and H, F NMR spectroscopy. The
benzoylmalonate derivative III is a prototropic system
and can exist in the tautomeric forms of a triketone (A)
and a diketoenol (B) (Scheme 2) called further ketone
1
(A) and enol (B) for simplicity. According to H and
19F NMR spectra, the diester III is as a mixture of
ketone (A) and enol (B) tautomers. The presence of the
enol form is indicated by the presence of proton signal
of the hydroxy group at 13.82 ppm (in CDCl3
solution). In the spectrum a doublet signal of methine
proton in the ketone form A at 5.10 ppm (5JHF 2.6 Hz)
and the signals of the tetrafluorophenyl group protons
of enol and ketone forms at 7.16 and 7.80 ppm
respectively can be easily identified. The signals of
ethyl groups of the enol form B are not equivalent due
to the formation of intramolecular hydrogen bond
between the hydroxy proton and the oxygen atom of
one of the ester groups. Basing on the assignment of
the proton signals to the two forms and the comparison
of their integral intensities we conclude that the ketone
form predominates (67%) over the enol (33%). The
resulting percentage is confirmed by the data of the 19F
Further 2,3,4,5-tetrafluorobenzoyl chloride II was
added to the obtained in situ malonic ester magnesium
derivative IV in anhydrous toluene at cooling to 0°C.
We performed similar process also without cooling.
This led to heating and raising the reaction temperature
to 100°C, but the formation of by-products did not
occur and the yield of product III was 82–89%, the
same as with cooling. Hence, the nucleophilic
substitution of fluorine atoms in the aromatic ring of
the initial substrate in toluene medium does not occur
under the influence of ethoxymagnesiummalonic ester
in a wide temperature range (0ºC to 100ºC).
We found that for the successful decomposition of
the formed magnesium salt the most suitable was a
low-temperature regime (5–10°C), which prevents the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 1 2012

118
BAZHIN et al.
Scheme 2.
F
F
F
F
F
F
F
R
H
R
OEt
O
F
O
O
O
OEt
B
A
R = COOEt (III), H (I).
NMR spectrum of compound III. The tautomerization
ester groups at 1739 cm–1 and 1703 cm–1. The first one
is close to the unperturbed absorption of the ester
group due to vibrations of the two ethoxycarbonyl
groups in ketone A. The band at 1703 cm–1
corresponds to vibrations of the free ester group in
enol B, the observed frequency shift is due to the
conjugation of this group with the C=C bond. The
band at 1632 cm–1 appears in the region of the
absorption of chelated 3-oxoesters and is related to the
enol form. The absorption bands of C=C and OH
groups of the enol form are at 1526 and 2910 cm–1,
respectively.
1
is markedly accelerated in the acidic medium. The H
NMR spectrum of solution of III in CD3COOD shows
an increase in the content of the enol form B, the
tautomers A and B are formed in approximately equal
amounts, 51% and 49%, respectively. In addition to
deuteration of the proton of the enol form a slight
decrease in the integrated intensity of the methine
proton of keto form is observed, apparently due to
partial deuteration that indicates its mobility.
Polyfluoroalkyl-substituted benzoylmalonates also
exist as a mixture of ketone and enol tautomers, but
with a slight predominance of the enol form (54–57%)
regardless of polyfluoroalkyl residue [19]. The higher
trend to enolization of polyfluoroalkyl analogs com-
pared with 2-tetrafluorobenzoylmalonate III probably
originates from their high acidity due to the strong
electron-withdrawing polyfluoroalkyl substituent.
For the synthesis of 3-oxoester I one of the ester
groups of benzoylmalonate III was hydrolyzed under
the action of 10% aqueous solution of sulfuric acid
followed by decarboxylation (Scheme 3). For complete
conversion of starting diester III its boiling in the
acidic solution was required. Increasing the percentage
of acid in solution to 20% leads to the formation of
2,3,4,5-tetrafluorophenyl methyl ketone V as an
The IR spectrum of benzoylmalonate III taken
from a thin layer contains two absorption bands of
Scheme 3.
F
F
F
F
i
OEt
OH
O
I, 88%
III
F
F
F
ii
I
+
Me
78_80%
F
O
V, 2_3%
i, H2SO4 (10%), 100°C; ii, H2SO4 (20%), 100°С.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 1 2012

FEATURES OF SYNTHESIS AND STRUCTURE
impurity (2–3%, according to GC-MS). According to
119
the literature, in contrast to ester I, its pentafluoro-
phenyl analog undergoes the ketone cleavage under
more rigid conditions, under the action of a mixture of
sulfuric and acetic acids [18].
Structure of 3-oxoester I in solid state was studied
by XRD and IR spectroscopy and in solution by the
method of 1H and 19F NMR spectroscopy.
Fig. 1. The general view of the molecule I.
The X-ray diffraction analysis of compound I
(Fig. 1) showed that in the crystal this substance
existed as the enol (B), ethyl 2-(Z)-3-hydroxy-3-(2,3,4,5-
tetrafluorophenyl)prop-2-enoate. The oxygen atom O1
of the ester moiety is involved in an intramolecular
hydrogen bond with the hydrogen atom H3 of the
hydroxy group. Thus, the intramolecular distance
O1–H3 is 1.70(3) Å, and angles O1H3O3 and C3O3H3
are 105(2)° and 97(1)°, respectively.
2940, 1646 and 1525 cm–1 correspond to vibrations of
OH, C=C, and C = O fragments, respectively, forming
the chelate node.
However, at the dissolution the 3-oxoester I
1
undergoes tautomeric transformation. Its H and 19F
NMR spectra taken from the CDCl3 solution contain a
double set of signals corresponding to the enol (B) and
ketone (A) forms (Scheme 2), the ketone form
predominating (62%). In other solvents [CD3OD,
CD3CN, (CD3)2SO, (CD3)2CO] the ratio of tautomers
remained approximately the same.
The molecules are packed in the crystal at the
angles of 39 and 54 degrees to the axes a and b,
respectively, and form the anti-directed parallel layers.
The fluoroaromatic fragments of the 3-oxoester I in the
same layer are directed outwards, while ester groups to
each other, providing shortened intermolecular
contacts between the hydrogen atom of the OH group
and fluorine atom F4, the methyl group hydrogen atom
and fluorine atom F4, and the hydrogen atom of
tetrafluorophenyl ring and the oxygen of the OH
group. Some of the distances are shorter than the sum
of the van der Waals radii (Fig. 2).
Comparing the degree of enolization in the series of
3-oxoesters unsubstituted in 2 position, we conclude
that ester I occupies an intermediate position between
the nonfluorinated acetoacetic (6–8%) and benzoyl-
acetic (20%) esters and the polyfluoroalkyl-containing
derivatives (89–100%), like the difluoro-substituted
acetoacetic ester (53%) [20]. This distribution agrees
well with the data on the acidity of 3-oxoesters, which
has a decisive influence on the degree of enolization of
carbonyl compounds.
IR spectrum of the ester I in solid state also points
to its enol structure, since the absorption bands at
b
a
c
Fig. 2. Packing of molecules I in the crystal.
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120
BAZHIN et al.
However, the existence of 3-oxoester I in solid state
turnings (4.6 g, 0.20 mol) was added 1 ml of
anhydrous CCl4, 7 ml of anhydrous ethanol (99.9%),
and then a mixture of diethyl malonate (32 g, 0.20 mol)
with 100 ml of anhydrous toluene. After the magne-
sium dissolution, the resulting homogeneous solution
was evacuated until the formation of a viscous residue,
to which was added 150 ml of anhydrous toluene. The
reaction mixture was cooled to 0°C and a solution of
2,3,4,5-tetrafluorobenzoyl chloride II (40 g, 0.20 mol)
in 70 ml of anhydrous toluene was added and the
mixture was kept for 3 h. Then 250 ml of 10% solution
of H2SO4 was added to it. Organic layer was separated
and washed with water. The solvent was evaporated
under a reduced pressure, the residue was distilled in a
vacuum. 59.81 g of product III was isolated, yield
89%, bp 140–143°C (3 Torr). IR spectrum (from a
layer between the KBr plates, ν, cm–1): 3079, 2987,
2942, 2910 (O–H, CH); 1739 (C=O-ketone) 1703
(C=O-enol) 1632 (C=O-enol ) 1526 (C=C) 1485, 1448,
as the enol form is due, apparently, only to greater
thermodynamic stability of the enol compared to
ketone tautomer.
Thus, for the first time was isolated and
characterized diethyl (2,3,4,5-tetrafluorobenzoyl)malo-
nate (III), the parent compound for the synthesis of 3-
oxoester I. Esters I and III in solutions are mixtures of
ketone and enol tautomers with a predominance of the
former. However, solid 3-oxoester I exists exclusively
as the enol form, as confirmed by the XRD data.
EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer
1
Spectrum One B spectrophotometer. The H and 19F
NMR spectra were recorded on a Bruker DRX 400
spectrometer from solutions in CDCl3, the working
frequencies 400.1 MHz (1H) and 376.5 MHz (19F),
internal references Me4Si and C6F6, respectively.
Elemental analysis was performed using an automatic
Perkin-Elmer CHN PE 2400 analyzer. The mass
spectra were obtained on a gas chromatograph Agilent
7890A with a mass spectrometer 5975 inert XL. The
melting points were determined on a Stuart SMP3
device.
1
1407, 1365 (Ar); 1277, 1236 (CF). H NMR spectrum
(δ, ppm, J, Hz): A, 1.30 t (3H, Me, J = 7.1); 4.30 q
(2H, CH2, J = 7.1); 5.10 d (1H, CH, J = 2.6); d.d.d.d
7.67 (1H, C6F4H, J = 10.4, 8.4, 6.1, 2.5); B, 1.15 and
1.38 two t (3H, Me, J = 7.1); 4.12 and 4.37 two q ( 2H,
CH2, J = 7.1); 7.67 m (1H, C6F4H), 13.83 s (1H, OH).
19F NMR spectrum (δ, ppm): A, 8.83 m (1F); 17.00 m
(1F); 25.82 m (1F); 26.40 m (1F); B, 7.46 m (1F);
10.73 m (1F); 23.81 d.d.d.d (1F, J = 21.1, 12.7, 9.9,
3.2); 24.68 t.d.d (1F, J = 18.4, 12.0, 5.9). Found, %: C
49.87, H 3.47; F 22.49. C14H12F4O5. Calculated, %: C
50.01, H 3.60; F 22.60.
Single crystals of 3-oxoester I were obtained by
crystallization from ethanol. The XRD experiment was
carried out on a Xcalibur 3 diffractometer with a CCD
detector [graphite monochromator, λMoKα 0.71073 Å,
temperature 145(2) K, ω-scanning]. The structure was
solved by the direct method and difference Fourier
syntheses with the SHELXS-97 program [21].
Positions and temperature parameters of the non-
hydrogen atoms were refined in the anisotropic full-
matrix least-squares approximation with the SHELXL-
97 program [21].
Synthesis of ethyl (2Z)-3-hydroxy-(2,3,4,5-tetra-
fluorophenyl)prop-2-enoate (I). To 50 g (0.15 mol)
of compound III was added 200 ml of 10% solution of
sulfuric acid. The reaction mixture was refluxed for 3–
4 h, then organic layer was separated and washed with
sodium hydrogen carbonate solution until neutral
reaction. The solvent was evaporated, the residue was
distilled at a reduced pressure. 33.4 g (85%) of
compound I was obtained as white transparent crystals,
mp 40–41°C (mp 41–42°C [22]). bp 117–119°C
(3 Torr). IR spectrum, ν, cm–1: 3080 (C–H), 2940
(OH), 1646 (C=O-enol) 1525 (C=C-enol) 1485, 1450,
1407, 1365 (Ar); 1277 , 1236 (CF). 1H NMR spectrum
(δ, ppm, J, Hz): A, 1.28 t (3H, Me, J = 7.1); 3.97 d
(2H, CH2, J = 3.7); 4.23 q (2H, CH2, J = 7.1); 7.62
d.d.d.d (1H, C6F4H, J = 10.4, 8.4, 6.1, 2.5); (B): 1.35 t
(3H, Me, J = 7.1); 4.29 q ( 2H, CH2, J = 7.1); 5.83 s
Crystallographic data of compound I: C11H8F4O3,
M 364.17, space group P-1, the crystals are triclinic, a
= 5.2722(5), b = 7.9390(7), c = 12.7631(15) Å, α =
99.488(8), β = 93.344(8 ), γ = 90.083(7)°, V = 525.97
(9) Å3, Z = 2, dcalc = 1,668 g cm–3 , μ = 0.165 mm–1.
The total number of reflections 2996, independent
reflections 2058, R-factor 0.039, the number of refined
parameters 167. Complete crystallographic parameters
of compound I are available at www.ccdc.cam.ac.uk/
conts/retrieving.html (CCDC 797287).
19
Synthesis of diethyl (2,3,4,5-tetrafluorobenzoyl)
malonate (III). To the iodine-activated magnesium
(1H, CH), 7.54 m (1H, C6F4H), 12.72 s (1H, OH). F
NMR spectrum, δ, ppm: (A): 8.64 t.t (1F, J = 19.8,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 1 2012

FEATURES OF SYNTHESIS AND STRUCTURE
121
7. DE Patent no. 4425648, 1996, C. A., 1996, vol. 124,
2.7); 16.13 t.d.d (1F, J = 21.3, 19.1, 8.6); 25.33 m
(1F); 26.09 m (1F); (B): 7.27 t.t (1F , J = 19.8, 2.7);
10.86 m (1F); 23.69 m (1F); 24.85 t.d.d (1F, J = 19.9,
13.3, 6.8). Found, %: C 49.64, H 3.17; F 28.67.
C11H8F4O3. Calculated, %: C 50.01, H 3.05; F 28.77.
Retention time 14.91 min. Mass spectrum, m/z (I, %):
264 (11) [M]+•, 218 (9) [M – EtOH]+•, 177 (100)
[HC6F4C (O)]+•, 149 (15) [HC6F4]+•.
289570.
8. Asahina, Y., Takei, M., Kimura, T., and Fukuda, Y.,
J. Med. Chem., 2008, vol. 51, no. 11, p. 3238.
9. USA Patent no. 5318965, 1994, C. A., 1995, vol. 122,
160653.
10. Prudchenko, A.T., Shchegoleva, G.S., Barkhash, V.A.,
and Vorozhtsov, N.N., Jr., Zh. Obshch. Khim., 1967,
vol. 37, no. 11, p. 2487.
In the reaction of III with 20% aqueous solution of
sulfuric acid the product I contained 2% of 2,3,4,5-
tetrafluorophenyl methyl ketone IV (determined by
GC-MS). Retention time: 8.20 min. Mass spectrum,
m/z (I, %): 192 (15) [M]+•, 177 (100) [HC6F4C(O)]+•,
149 (15) [HC6F4]+•, 43 (7) [CH3C(O)]+•.
11. Prudchenko, A.T., Barkhash, V.A., and Vorozh-
tsov, N.N., Jr., Izv. Akad. Nauk SSSR, Ser. Khim., 1965.
p. 1798.
12. DE Patent no. 3318145, 1984, C. A., 1985, vol. 102,
78744.
13. Chu, D.T.W., Fernandes, P.B., Claiborn, A.K., Pihuleac, E.,
Nordeen, C.W., Maleczka, R.E., Jr., and Pernet, A.G.,
J. Med. Chem., 1985, vol. 28, no. 11, p. 1558.
ACKNOWLEDGMENTS
14. Chu, D.T.W., Fernandes, P.B., Claiborn, A.K.,
Gracey, E.H., and Pernet, A.G., J. Med. Chem., 1986,
vol. 29, no. 11, p. 2363.
This work was performed along the State Contract
no. 02.522.12.2011.
15. Chu, D.T.W., Fernandes, P.B., Maleczka, R.E., Jr.,
Nordeen, C.W., and Pernet, A.G., J. Med. Chem., 1987,
vol. 30, no. 3, p. 504.
REFERENCES
1. Hayakawa, I., Hiramitsu, T., and Tanaka, Y., Chem.
Pharm. Bull., 1984, vol. 32, no. 12, p. 4907 .
2. Atarashi, S., Yokohama, S., Yamazaki, K., Sakano, K.-I.,
Imamura, M., and Hayakawa, I., Chem. Pharm. Bull.,
1987, vol. 35, no. 5, p. 1896.
3. Langer, O., Mitterhauser, M., Wadsak, W., Brunner, M.,
Müller, U., Kletter, K., and Müller, M., J. Label.
Compd. Radiopharm., 2003, vol. 46, p. 715.
16. Clay, R.J., Collom, T.A., Karrick, G.L., and Wemple, J.,
Synthesis, 1993, p. 290.
17. WO Patent no. 2003033469, 2003, C. A., 2003, vol. 138,
337993.
18. Filler, R., Rao, Y.S., Biezais, A., Miller, F.N., and
Beaucaire, V.D., J. Org. Chem., 1970, vol. 35, no. 4,
p. 930.
19. Krokhalev, V.M., Saloutin, V.I., Romas’, A.D., Er-
shov, B.A., and Pashkevich, K.I., Izv. Akad. Nauk SSSR,
Ser. Khim., 1990, no. 2, p. 376.
4. Na, Y., Bull. Korean Chem. Soc., 2005, vol. 26, no. 12,
p. 2047.
5. Dinakaran, M., Senthilkumar, P., Yogeeswari, P.,
China, A., Nagaraja, V., Sriram, D., Bioorganic &
Medicinal Chemistry Letters, 2008, vol. 18, no. 3,
p. 1229.
6. Cecchetti, V., Fravolini, A., Fringuelli, R., Schiaffella, F.,
Lorenzini, M.C., J. Heterocyclic Chem., 1993, vol. 30,
no. 4, p. 1143.
20. Pashkevich, K.I. and Saloutin, V.I., Usp. Khim., 1985,
vol. 54, no. 12, p. 1997.
21. Scheldrik, G.M., SHELXS 97 and SHELXL 97,
University of Göttingen, Germany, 1997.
22. China Patent no. 101362693, 2009, C. A., 2009, vol. 150,
282562.
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