Highly efficient synthesis of monodisperse poly(ethylene glycols) and derivatives through macrocyclization of oligo(ethylene glycols)

Article abstract of DOI:10.1002/anie.201410309

A macrocyclic sulfate (MCS)-based approach to monodisperse poly(ethylene glycols) (M-PEGs) and their monofunctionalized derivatives has been developed. Macrocyclization of oligo(ethylene glycols) (OEGs) provides MCS (up to a 62-membered macrocycle) as versatile precursors for a range of monofunctionalized M-PEGs. Through iterative nucleophilic ring-opening reactions of MCS without performing group protection and activation, a series of M-PEGs, including the unprecedented 64-mer (2850Da), can be readily prepared. Synthetic simplicity coupled with versatility of this new strategy may pave the way for broader applications of M-PEGs. Macrocycles make synthesis easier: Convenient macrocyclization of the OEGs provides versatile macrocyclic sulfates. These compounds are cornerstones for both monofunctionalization of OEGs and highly efficient synthesis of monodisperse PEGs and derivatives, including an unprecedented 64-mer.

Full text of DOI:10.1002/anie.201410309

Angewandte
Chemie
DOI: 10.1002/anie.201410309
Macrocyclic Sulfates
Highly Efficient Synthesis of Monodisperse Poly(ethylene glycols) and
Derivatives through Macrocyclization of Oligo(ethylene glycols)**
Hua Zhang, Xuefei Li, Qiuyan Shi, Yu Li, Guiquan Xia, Long Chen, Zhigang Yang, and Zhong-
Xing Jiang*
Abstract: A macrocyclic sulfate (MCS)-based approach to
monodisperse poly(ethylene glycols) (M-PEGs) and their
monofunctionalized derivatives has been developed. Macro-
cyclization of oligo(ethylene glycols) (OEGs) provides MCS
(up to a 62-membered macrocycle) as versatile precursors for
a range of monofunctionalized M-PEGs. Through iterative
nucleophilic ring-opening reactions of MCS without perform-
ing group protection and activation, a series of M-PEGs,
including the unprecedented 64-mer (2850 Da), can be readily
prepared. Synthetic simplicity coupled with versatility of this
new strategy may pave the way for broader applications of M-
PEGs.
P
EGs are biocompatible polymers with diverse applications.
Regular PEGs even with an excellent polydispersity index
(PDI) are still complex mixtures of different length oligo-
mers[1] (Figure 3, PEG1500), which brings a range of prob-
lems in their applications.[2] Therefore, M-PEGs are much
more desirable than regular PEGs.[3] However, efficient
synthesis of M-PEGs remains a long-standing challenge
even after decades of efforts[1,4] owing to the following
issues (Scheme 1, chain tripling method was illustrated as an
example): 1) Long synthesis, low yield, and tedious purifica-
tion dramatically deteriorate the synthetic efficacy. 2) No
synthesis on M-PEGs above 2500 Da has ever been reported.
The longest M-PEGs reported so far is a 56-mer (2484 Da)
which was recently synthesized by Livingstonꢀs group.[4j] It is
noteworthy that 4000 Da is regarded as a minimum require-
ment for PEGs to achieve the so-called stealth effect in
biopharmaceuticals.[5] 3) PEG monofunctionalization is a dif-
ficult task because it requires large excess amount of PEGs
(up to 10 equiv), expensive reagents, and tedious manipula-
tion of protecting and activating group(s).[4g,6] Therefore, new
synthetic strategies to address these issues are of great
importance.
Scheme 1. Strategies for M-PEGs and synthesis of derivatives.
Transforming 1,2- or 1,3-diols into the corresponding
cyclic sulfates, where the sulfate group acts as both a protect-
ing group and an activating group during nucleophilic ring-
opening reaction, has been widely used in the monofunction-
alization of these diols.[7,8] We envisioned that this strategy
could be applied in the synthesis of M-PEGs and derivatives
to improve the synthetic efficacy by avoiding hydroxy group
protection and activation as well as undesired difunctional-
ization (Scheme 1).
To our knowledge, there is no report on MCS, but three
reports of formation of macrocyclic sulfites (17-membered
and below).[9] After unsuccessful attempts on the macro-
cyclization of commercially available tetra(ethylene glycol)
1a through transesterification[10] with diisopropyl sulfite,
macrocyclization of 1a with SOCl2 in the presence of Et3N
was carried out (Supporting Information, Table S1). Fortu-
nately, the 14-membered macrocyclic sulfite 3a was obtained
in a 51% yield (Table S1, entry 1). It was found that excess
amount of reagents is required to promote the reaction
(Table S1, entries 2–5). Elevated temperature and high con-
centration of 1a both lowered the yield of 3a (Table S1,
entries 4,6,7) while the latter is a common phenomenon in
macrocyclization. It was also found that slow addition of
SOCl2 over 1 hour and stirring at 08C for an additional hour
provided a high yield of 3a (Table S1, entries 8–10). Monitor-
ing the reaction with 1H NMR indicated that slow addition of
SOCl2 is crucial for the macrocyclization process (Supporting
Information, Figure S1). As for the base, DIPEA, DMAP or
their combination gave much better yields of 3a than K2CO3
or pyridine (Table S1, entries 11–14). Solvent screening
[*] H. Zhang,[+] X. Li,[+] Q. Shi, Y. Li, G. Xia, L. Chen, Prof. Z. Yang,
Prof. Z.-X. Jiang
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery
(Wuhan University), Ministry of Education, and Wuhan University
School of Pharmaceutical Sciences
Wuhan 430071 (China)
E-mail: zxjiang@whu.edu.cn
[+] These authors contributed equally to this work.
[**] The research was financially supported by the National Natural
Science Foundation of China (No. 21372181). We thank Dr. Yihua
Bruce Yu, Dr. Wei Zhang, Dr. Xingang Zhang, and Dr. Xiuhua Xu for
their help with the manuscript preparation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410309.
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Table 1: Macrocyclization of oligo(ethylene glycols).[a]
ated in situ afforded the corresponding MCS 4a–4l in good to
excellent yields. It was also found that direct oxidation of the
crude macrocyclic sulfite 3a without chromatographic purifi-
cation conveniently provided MCS 4a with comparable
yields.
It is noteworthy that these macrocyclic sulfites are prone
to decompose, but corresponding MCS are much more stable.
For example, no change was detected by 1H NMR after MCS
4a had been placed in open air at room temperature for
2 months. For the convenience of downstream M-PEG syn-
thesis, 290 g of MCS 4a were prepared in a 55% yield
(Scheme 2). It is notable that 4a was conveniently purified by
Entry
1
n
Conc.
T
[8C]
t[b]
[h]
Yield [%]
[molLÀ1
]
3
4
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
4
2
3
5
6
7
8
9
10
12
16
20
0.041
0.041
0.041
0.041
0.041
0.041
0.021
0.021
0.021
0.005
0.005
0.003
0
0
0
0
0
10
10
10
10
10
10
25
1
1
1
1
1
84(3a)
76(3b)
71(3c)
81(3d)
79(3e)
72(3 f)
82[c](3g)
71(3h)
57(3i)
87(4a)
96(4b)
98(4c)
86(4d)
94(4e)
96(4 f)
75(4g)
89(4h)
84(4i)
1
1
12
12
72
40
24
9
10
11
12
1j
1k
1l
63[d](3j)
51(3k)
49(3l)
83(4j)
69(4k)
62(4l)
Scheme 2. Large-scale preparation of macrocyclic sulfate 4a.
[a] Reactions were performed on 1–5 g scales. [b] Reaction time after
dropwise addition of SOCl2. [c] A yield of 53% was obtained at
0.041 molLÀ1 of 1g. [d] A yield of 59% was obtained at 0.010 molLÀ1 of
1j.
recrystallization instead of flash chromatography, and CH2Cl2
was recovered during large-scale preparation.
The structures of MCS were confirmed by NMR and MS
(see the Supporting Information). Furthermore, a single
crystal of the 26-membered MCS 4g was obtained.[13] X-ray
structure indicates that 4g adopts a twisted conformation like
a partially folded Arabic number 8 (Figure 2). It is interesting
indicated that CH2Cl2 is the solvent of choice (Table S1,
entries 15–18).
Under the optimal macrocyclization conditions (Table S1,
entry 14), the scope of this reaction on OEGs was then
investigated (Table 1). Reactions with commercially available
di(ethylene glycol) 1b and tri(ethylene glycol) 1c gave the
corresponding medium-sized cyclic sulfites 3b and 3c in good
yields (Table 1, entries 2,3). Macrocyclization of OEGs 1d–
1l, which were synthesized from 1a–1c and their MCS 4a–4c
(see Supporting Information), also provided the correspond-
ing macrocyclic sulfites 3d–3l with good yields (Table 1,
entries 4–12). Increased reaction time and/or elevated reac-
tion temperature for OEGs above 7-mer are necessary to
drive the reaction to completion (Table 1, entries 6–12). To
avoid the formation of polymers and catenane-like side
products, the reaction was further diluted which resulted in
improved macrocyclization yields (Table 1, entries 7–12). It is
noteworthy that the macrocyclization concentrations are
much higher than conventional concentrations for similar-
sized lactonization (usually < 0.001 molLÀ1), which facilitates
large-scale preparation of MCS. It is interesting to point out
that a 62-membered macrocyclic sulfite 3l was obtained with
a 49% yield (Table 1, entry 12 and Figure 1). From a synthetic
chemistry point of view, formation of macrocycles such as 3l
in high yield without template is very rare. Oxidation of the
macrocyclic sulfites 3a–3l with ruthenium tetraoxide gener-
Figure 2. Single-crystal X-ray structure of macrocyclic sulfate 4g.[13]
to observe that the bond length and bond angle between the
wrapped part and the exposed part are very different
(Figure 2 and Supporting Information). Such structural fea-
ture indicates that the exposed part of the sulfate is less
sterically hindered and would be more reactive toward
nucleophiles.
Successful macrocyclization of OEGs encouraged us to
expand the reaction scope to non-OEG diols. Results shown
in Scheme 3 indicate that non-OEG diols can form macro-
cyclized products in decent yields under the same conditions
for OEGs. Interestingly, it was found that incorporation of
heteroatom(s) into diols could dramatically improve the yield
of macrocyclic sulfites. For example, macrocyclic sulfite 3m
was obtained in a poor yield, but equally sized macrocyclic
sulfites 3a, 3o, 3p, and 3q, each with O or S in the backbone,
were obtained with good yields. Among them, OEG-derived
3a (Table 1, entry 1) gave the highest yield. The conformation
changes resulted from the heteroatom(s) may account for the
Figure 1. Structure of macrocyclic sulfite 3l.
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Table 2: Nucleophilic ring-opening of macrocyclic sulfate 4a.[a]
Scheme 3. Macrocyclization of non-OEG diols.
improved yields. It was also found that formation of 11-
membered macrocyclic sulfite 3n is much easier than 14-
membered 3m and 13-membered 3t. Introducing double or
triple bond may facilitate the macrocyclization as well (3r–
3s). Our results indicate that OEGs are actually ideal
substrates for this macrocyclization.
Monofunctionalization of OEGs through one-pot nucle-
ophilic ring-opening reaction of MCS was then explored
(Table 2). Readily available 4a was used for the treatment
with a range of O-, S-, C-, N- and F-containing nucleophiles
and a variety of monofunctionalized tetra(ethylene glycols)
5a–5s were conveniently prepared. From O-containing
nucleophiles, including alcohols, phenols, and sodium carbox-
ylates, many useful ether and ester derivatives of tetra(-
ethylene glycols) 5a–5m were obtained in good yields
(Table 2, entries 1–13). Monobenzylated tetra(ethylene
glycol) 5a and octa(ethylene glycol) 5b, which were widely
used in M-PEG synthesis,[4] were obtained through sequential
reactions of benzyl alcohol with 4a. Two useful surfactants 5c
and 5d in material sciences were conveniently prepared in
one step.[11] A clickable OEG 5e was also prepared in a 94%
yield. MeONa is also a good nucleophile for this reaction to
afford methoxy-OEG 5 f. Even KOtBu, which is a preferred
base in M-PEG synthesis,[4f,i] is able to nucleophilic attack 4a
to give tert-butyl-OEG 5g as a result of the high reactivity of
MCS. It is notable that tert-butyl-OEGs such as 5g are
important building blocks that are very difficult to prepare
through other means.[4f] A precursor of 19F magnetic reso-
nance imaging agents 5h was also conveniently prepared in
a quantitative yield.[12] 7-Hydroxy-4-methylcoumarin, which
is a bioactive probe with good fluorescence properties,
reacted with 4a to afford a fluorescent OEG 5k. Besides
OEG ethers, OEG esters 5l and 5m were obtained with
quantitative yields. From S-containing nucleophiles, such as
potassium thioacetate and triphenylmethanethiol, sulfur can
be efficiently introduced into OEGs (Table 2, entries 14,15).
The reaction with potassium thioacetate was carried out in
water and 4a was consumed in several minutes. The result
indicates that MCS may be promising aqueous PEGylation
agents for cysteine-containing peptides and proteins. With C-
containing nucleophile diethyl malonate, a carbon–carbon
single bond was constructed in 5p (Table 2, entry 16). When
[a] All reactions were performed on 1 g scales. [b] DMF was used as
solvent. [c] The reaction was run at 1208C.
amine or azide was used as the nucleophile, nitrogen could be
conveniently
incorporated
into
OEGs
(Table 2,
entries 17,18). In the case of benzylamine, an one-pot dual
nucleophilic ring-opening reaction afforded a tertiary amine
5q in an 80% yield. Another clickable OEG 5r was obtained
in an excellent yield when NaN3 was employed. Finally, the
weak nucleophilic reagent NaF successfully attacked 4a to
give a monofluorinated OEG 5s in an 88% yield (Table 2,
entry 19). Since the ring-opening reaction is completed at
1208C in a few minutes, it may provide a useful way for the
radiochemical synthesis of 18F labelled PEGs. These ring-
opening reactions indicate that MCS are highly reactive
toward a broad range of nucleophiles. Therefore, this MCS-
based OEG monofunctionalization provides an efficient and
alternative method for many important OEG derivatives,
especially for those hard to synthesize with other methods.
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Scheme 4. Synthesis of M-PEGs 7 and monomethoxy M-PEGs 15.
The nucleophilic ring-opening reaction of MCS was then
employed to the synthesis of M-PEGs and derivatives
(Scheme 1). To illustrate the generality and efficacy of this
strategy, 36-mer 7 and monomethoxy 64-mer 15 were chosen
as the target molecules (Scheme 4). Firstly, from tetra(ethy-
lene glycol) 1a and its MCS 4a, 36-mer 7 was successfully
prepared in four steps with an overall yield of 51%. During
the four cycles of one-pot dual chain extension reaction, the
bis(sodium sulfate) intermediates are insoluble in THF and
DMF was used instead. After the ring-opening reaction, DMF
was removed and the intermediate was directly hydrolyzed in
THF. Secondly, from MeONa and MCS 4g, a series of
monomethoxy M-PEGs 8–15, which are the most used forms
in PEGylation, were conveniently prepared. The longest
monomethoxy M-PEG 15, a 64-mer, was prepared in eight
steps with an overall yield of 15%. Monomethoxy M-PEG 15
is eight units more than the longest M-PEG reported so far.[4j]
Apart from monomethoxy M-PEGs, other monofunctional-
ized M-PEGs such as N3-, F-, TrtS-, and Bn-substituted M-
PEGs (Table 2) can also be prepared with this MCS-based
strategy.
Figure 3. MALDI-TOF-MS of M-PEGs 6 and 7, monomethoxy M-PEGs
14 and 15, and regular PEG1500.
28-mer 6 and 36-mer 7 together with monomethoxy M-PEGs
56-mer 14 and 64-mer 15 synthesized through this method
exhibit high monodispersity. Based on the MALDI-TOF-MS,
PDIs of these M-PEGs were calculated as 1.00057 (6), 1.00007
(7), 1.00005 (14), and 1.00003 (15). Negligible impurities,
derived from starting materials[4j] and depolymerization, can
be detected by MALDI-TOF-MS. As a comparison, MALDI-
TOF-MS of the commercially available regular PEG1500
contains more than 26 pairs of peaks corresponding to
different length oligomers (each pair containing a [M+Na]+
peak and a [M+K]+ peak).
Comparing to known M-PEG synthesis, our method
reduces half of the synthetic steps by omitting the hydroxy
group protection and activation. Furthermore, one-pot dual
chain extension reaction further minimized the synthetic steps
by introducing two OEG fragments at a time. As for the
purification, all the intermediates were purified by flash
chromatography on silica gel with methanol and CH2Cl2 as
eluents. It was found that most impurities can be removed by
selectively extracting sodium sulfate intermediates into water
and leaving most impurities in the organic phase. The rest
impurities can be easily removed by flash chromatography
after hydrolysis of the intermediates. In this way, excess MCS
in this reaction were also recovered. With this strategy, many
biopharmaceutically useful M-PEGs and derivatives which
are difficult to synthesize with established methods can be
conveniently prepared within minimal synthetic steps from
the corresponding OEGs and MCS. Finally, we want to point
out that the selection of OEG and MCS is very flexible which
depends on the target M-PEG and the availability of starting
materials.
In conclusion, we have prepared a class of novel MCS and
successfully applied them into OEG monofunctionalization,
M-PEGs and derivatives synthesis. Although the chemistry 5-
and 6-membered small cyclic sulfates have been well-estab-
lished, it is the first report on synthesis and application of
MCS up to a 62-membered macrocycle. From these stable and
easily available MCS, various highly valuable M-PEGs and
related compounds in a broad range of applications can be
conveniently prepared with high efficacy and purity. More-
over, such MCS are promising in the branched M-PEG
synthesis, 18F radiolabeling of PEGs, and aqueous PEGylation
of therapeutic peptides and proteins. Those works are
currently in progress and will be reported in due course.
Received: October 21, 2014
Revised: December 8, 2014
Published online: && &&, &&&&
The monodispersity of M-PEGs was measured by
Keywords: cyclization · macrocycles · macrocyclic sulfates ·
poly(ethylene glycol) · synthetic methods
.
MALDI-TOF-MS (Figure 3).[4f,i] It was found that M-PEGs
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[5] K. Knop, R. Hoogenboom, D. Fischer, U. S. Schubert, Angew.
[1] D. Niculescu-Duvaz, J. Getaz, C. J. Springer, Bioconjugate
Chem. 2008, 19, 973 – 981.
Chem. Int. Ed. 2010, 49, 6288 – 6308; Angew. Chem. 2010, 122,
6430 – 6452.
[2] a) M. J. Vicent, L. Dieudonnꢁ, R. J. Carbajo, A. Pineda-Lucena,
Expert Opin. Drug Delivery 2008, 5, 593 – 614; b) V. Gaberc-
Porekar, I. Zore, B. Podobnik, V. Menart, Curr. Opin. Drug
Discovery Dev. 2008, 11, 242 – 250.
[6] a) T. Gibson, J. Org. Chem. 1980, 45, 1095 – 1098; b) N. N. Reed,
K. D. Janda, J. Org. Chem. 2000, 65, 5843 – 5845.
[7] a) Z.-X. Jiang, Y.-Y. Qin, F.-L. Qing, J. Org. Chem. 2003, 68,
7544 – 7547; b) Z.-X. Jiang, Y. B. Yu, J. Org. Chem. 2007, 72,
1464 – 1467.
[3] a) M. Berna, D. Dalzoppo, G. Pasut, M. Manunta, L. Izzo, A. T.
Jones, R. Duncan, F. M. Veronese, Biomacromolecules 2006, 7,
146 – 153; b) A. Bach, C. N. Chi, G.-F. Pang, L. Olsen, A. S.
Kristensen, P. Jemth, K. Strømgaard, Angew. Chem. Int. Ed.
2009, 48, 9685 – 9689; Angew. Chem. 2009, 121, 9865 – 9869; c) T.
Muraoka, K. Adachi, M. Ui, S. Kawasaki, N. Sadhukhan, H.
Obara, H. Tochio, M. Shirakawa, K. Kinbara, Angew. Chem. Int.
Ed. 2013, 52, 2430 – 2434; Angew. Chem. 2013, 125, 2490 – 2494.
[4] a) R. Fordyce, E. L. Lovell, H. Hibbert, J. Am. Chem. Soc. 1939,
61, 1905 – 1910; b) E. M. D. Keegstra, J. W. Zwikker, M. R.
Roest, L. W. Jenneskens, J. Org. Chem. 1992, 57, 6678 – 6680;
c) A. Harada, J. Li, M. Kamachi, J. Am. Chem. Soc. 1994, 116,
3192 – 3196; d) F. A. Loiseau, K. K. Hii, A. M. Hill, J. Org.
Chem. 2004, 69, 639 – 647; e) S. A. Ahmed, M. Tanaka, J. Org.
Chem. 2006, 71, 9884 – 9886; f) A. C. French, A. L. Thompson,
B. G. Davis, Angew. Chem. Int. Ed. 2009, 48, 1248 – 1252; Angew.
Chem. 2009, 121, 1274 – 1278; g) G. Szꢁkely, M. Schaepertoens,
P. R. J. Gaffney, A. G. Livingston, Polym. Chem. 2014, 5, 694 –
697; h) Y. Li, Q. Guo, X. Li, H. Zhang, F. Yu, W. Yu, G. Xia, M.
Fu, Z. Yang, Z.-X. Jiang, Tetrahedron Lett. 2014, 55, 2110 – 2113;
i) K. Maranski, Y. G. Andreev, P. G. Bruce, Angew. Chem. Int.
Ed. 2014, 53, 6411 – 6413; Angew. Chem. 2014, 126, 6529 – 6531;
j) G. Szꢁkely, M. Schaepertoens, P. R. J. Gaffney, A. G. Living-
ston, Chem. Eur. J. 2014, 20, 10038 – 10051.
[8] For reviews, see: a) B. B. Lohray, Synthesis 1992, 1035 – 1052;
b) H.-S. Byun, L. He, R. Bittman, Tetrahedron 2000, 56, 7051 –
7091.
[9] a) H. W. Roesky, H. G. Schmidt, Angew. Chem. Int. Ed. Engl.
´
1985, 24, 695; Angew. Chem. 1985, 97, 711; b) Z. Florjanczyk, D.
Raducha, A. Kozera-Szalkowska, Macromolecules 1996, 29,
826 – 834; c) M. J. Wingstrand, C. M. Madsen, M. H. Clausen,
Tetrahedron Lett. 2009, 50, 693 – 695.
[10] S. A. King, B. Pipik, D. A. Conlon, M. Bhupathy, Synth.
Commun. 1997, 27, 701 – 707.
[11] a) J. Boekhoven, P. van Rijin, A. M. Brizard, M. C. A. Stuart,
J. H. van Esch, Chem. Commun. 2010, 46, 3490 – 3492; b) J. Lai,
V. Molinier, M. Sauthier, L. Moity, Y. Castanet, A. Mortreux, J.-
M. Aubry, Langumuir 2012, 28, 242 – 250.
[12] a) Z.-X. Jiang, Y. Feng, Y. B. Yu, Chem. Commun. 2011, 47,
7223 – 7235; b) X. Yue, Y. Feng, Y. B. Yu, J. Fluorine Chem. 2013,
152, 173 – 181.
[13] CCDC 1027571 (4g) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Communications
Macrocyclic Sulfates
H. Zhang, X. Li, Q. Shi, Y. Li, G. Xia,
L. Chen, Z. Yang,
Z.-X. Jiang*
&&& — &&&
Highly Efficient Synthesis of
Macrocycles make synthesis easier:
Convenient macrocyclization of the OEGs
provides versatile macrocyclic sulfates.
These compounds are cornerstones for
both monofunctionalization of OEGs and
highly efficient synthesis of monodis-
perse PEGs and derivatives, including an
unprecedented 64-mer.
Monodisperse Poly(ethylene glycols) and
Derivatives through Macrocyclization of
Oligo(ethylene glycols)
6
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