Synthesis of 2-deoxy ribose related disaccharide nucleoside and its phosphoramidite

Article abstract of DOI:10.1016/j.tet.2017.05.052

Synthesis of impurity reference compound of anti-tumor drug ISIS 183750 was achieved. In this process, a general method for synthesis of 2-deoxy ribosyl disaccharide nucleosides was established for the first time.

Full text of DOI:10.1016/j.tet.2017.05.052

Accepted Manuscript
Synthesis of 2-deoxy ribose related disaccharide nucleoside and its phosphoramidite
Yili Ding, Rilie Deng, Bingyun Wang
PII:
S0040-4020(17)30539-2
10.1016/j.tet.2017.05.052
TET 28718
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 February 2017
Revised Date: 6 May 2017
Accepted Date: 12 May 2017
Please cite this article as: Ding Y, Deng R, Wang B, Synthesis of 2-deoxy ribose related disaccharide
nucleoside and its phosphoramidite, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.052.
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ACCEPTED MANUSCRIPT
Graphical Abstract
.
Synthesis of 2-Deoxy Ribose Related
Disaccharide Nucleoside and Its
Phosphoramidite
Leave this area blank for abstract info.
Yili Ding*, Rilie Deng and Bingyun Wang
Life Science Department, Foshan University, Foshan, P. R. China, 528000

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of 2-Deoxy Ribose Related Disaccharide Nucleoside and its
Phosphoramidite
Yili Ding*, Rilie Deng and Bingyun Wang
Life Science Department, Foshan University, Foshan, Guangdong, P. R. China, 528000.
E-mail: Yiding93@yahoo.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Synthesis of impurity reference compound of anti-tumor drug ISIS 183750 was achieved. In this
process, a general method for synthesis of 2-deoxy ribosyl disaccharide nucleosides was
established for the first time.
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
Disaccharide nucleoside, phosphoramidite,
synthesis, 2-deoxy ribose, glycosylation
More than hundred disaccharide nucleosides have been
isolated from various natural sources.1 They display
Compound 1 is an impurity found in the production of
ISIS183750, which is a synthetic oligomer of 20 nucleotides
that are connected sequentially by phosphorothioate linkages
and a second-generation antisense oligonucleotide drug for
advanced lung cancer,8 and it is needed as a reference
compound. In this paper, we would like to report its
synthesis while establishing a strategy for synthesizing the
2-deoxy ribose related disaccharide nucleosides and their
phosphoramidites.
antibacterial,
anti-mycotic,
herbicidal,
insecticidal,
antitumor, and antiviral properties,2 are structural elements
of biopolymers, such as tRNA and poly(ADP-ribose),3 and
can be formed during nucleoside metabolism.4 Recent
studies indicated some disaccharide analogues of thymidine
were potential inhibitors of PARPs, which are considered to
be promising targets in designing drugs for the treatment of
stroke, ischemia, diabetes, arthritis, colitis, cancer, viruses
and other inflammatory disorders.5 Most antiviral drugs are
derivatives of nucleosides or nucleotides, anchoring one or
two carbohydrate moieties on their sugar portion may
increase the activity in comparison with the original drugs.6
Therefore, disaccharide nucleoside synthesis methods are
expected to have wide-spread applications in drug
discovery.
The central portion of the oligonucleotide ISIS 183750 is
composed of ten 2′-deoxynucleotides, and synthesized by
introducing DNA or MOE monomers sequentially on solid
support, the disaccharide nucleoside phosphoramidite
1 was
likely formed during the glycosylation and phosphorylation
stages of the monomer synthesis.
Many strategies were developed for the synthesis of
disaccharides nucleosides by using aldohexoses and
pentose.7 As
a component of DNA, 2-deoxyribose
derivatives have an important role in biology. The DNA
(deoxyribonucleic acid) molecule, which is the main
repository of genetic information in life, consists of a long
chain of deoxyribose-containing units called nucleotides,
linked via phosphate groups. However, 2-deoxy ribose
related disaccharide nucleosides have not reported yet.

2
Tetrahedron
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Current reports for the synthesis of disaccharide nucleosides
may be classified into two methods. In the first method, N-
glycosylation of properly protected disaccharide with
thymidine, after sequentially treating it with TMSCl/Et3N,
triazol/POCl3, NH3/H2O and DMT-Cl. Protection of the 5-
OH of methyl 2-deoxyribofuranoside with DMT group,
followed by acetylation, gave the monosaccharide
a
heterocyclic base is employed and this method is not high
yielding as disaccharide glycosylation donors are not very
stable.9 The second method involves coupling reaction between a
nucleoside and a properly protected monosaccharide donor.10 As
our target compound 1 contains a natural nucleoside, direct
glycosylation of the properly protected thymidine 2 with a p-
dimethoxytrityl (DMT) protected monosaccharide donor 3 under
classic glycosylation conditions was considered first as shown in
the Scheme 1.
glycosylation donor
compound and was attempted under standard conditions
which resulted in a complicate mixture of products. After
work up and careful purification, no desired disaccharide
nucleoside was isolated. Similarly
monosaccharide donors
3.
The glycosylation between
2
3
，
or
we also tried other
under different
4
,
5
,
6
7
glycosylation conditions, the results were same. This may be
due to the DMT protecting groups in compounds and
2
3
which are not stable under the attempted glycosylation
conditions, and based on the LCMS analysis, only trace
amount of disaccharide without DMT protecting group was
detected. Hence
groups stable under acidic conditions, such as
butyldiphenylsilyl ether (TBDPS).
， it’s felt we should employ protecting
t-
Accordingly
5’-OH position to provide the compound
steps, thymidine derivative was transferred to the cytidine
derivative , which was coupled with per- -acetyl 2-deoxy
methyl-ribofuranoside in the presence of SnCl4. After
，
thymidine was protected with TBDPS at
8, and in three
8
9
O
5
work up, and careful purification, an unstable coupling
product mixture was isolated. Based on their NMR and MS
data, the compounds were not the desired products instead
they were found to be compounds 10
glycosylated products instead of the 3’-OH in the nucleoside
acceptor . (Scheme 2
α and 10β which are N-
9
)
SCHEME 1
. Regents and Conditions: a) 1: DMTCl, DMF,
DMAP (2 eq.), room temperature, 3 h; 2: TMSCl/Et3N,
triazol/POCl3, NH3/H2O; 3: Bz2O, DMF, 85%; 4: K2CO3,
THF/MeOH, room temperature, 3 h, 90% b) for compound
1: methyl 2-deoxyribofuranoside, DMTCl, DMF, DMAP (2
eq.), room temperature, 4 h.
2: (Ac)2O, pyridine, 0oC, 4 h,
85% for two steps; for compound : methyl 2-deoxyfuranoside,
Ac2O, pyridine, 90%; for compound methyl 2-
deoxyribofuranoside, H2SO4, Ac2O, 0oC, 63%; for compound
compound
in HBr/AcOH, 0oC, 30 min., 95%; for compound
, CH2Cl2 (HCl), 0oC, 2 h, 85%; c) for compounds
: compound , compound , or
CH2Cl2, 0oC, SnCl4,
or : compound , compounds or 7,
3,
；
4
5
:
6
:
5
7
3
: compound
or
5
,
4
5
2
3
,
4
5
2 h; for compounds
6
7
2
6
CH2Cl2, 0oC, Ag2CO3, dark, 3 h.
The desired cytidine acceptor
2
was synthesized in
standard fashion starting from commercially available

3
SCHEME 2. Reagents and Conditions: a) TBDPSCl, pyridine,
90%; b) TMSCl/Et3N, triazol/POCl3, NH3/H2O; 85%; c)
CH2Cl2, 0oC, SnCl4, 2 h.
The mixture of compounds 13α and 13β was then treated
ACCEPTED MANUSCRIPT
with TBAF in THF to give the unprotected disaccharide
nucleosides 14α and 14β, which also could not be separated.
Then DMT-ethers (15α and 15β) of 14α and 14β were prepared
by treating them with DMTCl in DMF in the presence of DMAP.
Among all the methods studied for their separation, only the
supercritical fluid chromatography method was found to be
suitable.
In order to avoid the N-glycosylation products, the NH2 group
in 9 was protected with Bz group to give the nucleoside acceptor
11. Under SnCl4 conditions, compound 11 was coupled with the
glycosylation donor 4 in dry dichloromethane to give a mixture
(1:1) of disaccharide nucleosides 12α and 12β in more than 70%
yield. We also tried the coupling reactions between 11 and other
monosaccharide donors 5, 6 or 7 under different glycosylation
conditions and the results were similar based on the TLC
(Scheme 3).
The desired isomer 15β was characterized by different 2D
NMR studies such as 2D H-H COSY and C-H COSY apart from
assigning each proton in its H-NMR spectrum. The triplet at
1
5.15 ppm was assigned for H-1 in the monosaccharide part while
the multiplet at 6.04 ppm was assigned for H-1’ in the nucleoside
part. The multiplet at 4.05 ppm was assigned for H-4 in
monosaccharide, and the multiplet at 4.07 ppm was assigned for
H-4’ in the nucleoside part. In its 2D NOESY spectrum, the H-1
triplet at 6.04 ppm was found to have interaction with the H-4 at
4.05 ppm, and the H-1’ multiplet at 5.15 ppm was found to
interact with that of H-4’ at 4.07 ppm, indicating that both sugars
have the β configurations and indeed this compound is 15β as
desired. By using the similar studies, the structure of compound
15α was also confirmed.
The separation of anomeric diastereomers 12α and 12β
was found to be very difficult. All attempted methods, silica
gel column chromatography, preparative TLC, HPLC and
reverse phase C-18 column chromatography and SCF
separation, didn’t give satisfactory separation. Even the
corresponding hydroxyl derivatives 13α and 13β, which
were obtained by subjecting compounds 12α and 12β to
weak basic conditions, also couldn’t be purified
satisfactorily.
SCHEME 4. a) 1: Bz2O, DMF, room temperature, 12 h; 2:
K2CO3, TFH/MeOH, room temperature, 56% for two steps; b)
tetra
isopropyl
phosphorodiamidite,
tetrazole,
N-
methylimidazole, DMF/CH3CN, room temperature, 12 h., 63%.
Finally, the isomer 15β was transformed into the target
compound 1 as shown in the Scheme 4. Thus, the NH2 at
heterocyclic part in compound 15β was protected with Bz group
in a two-step sequence to give the compound 16β. The compound
16β was then treated with tetraisopropylphosphorodiamidite,
tetrazole and N-methylimidazole in dry DMF, to give the
phosphorylated product. After HPLC purification, the desired
phosphoramidite 1, with more than 92% purity was obtained in
1
62% yield. Its structure was confirmed by H NMR, 13C NMR,
31P NMR and mass spectra.
In conclusion,
nucleoside phosphoramidite
a
partially protected disaccharide
was successfully synthesized
1
as the impurity reference compound for the antisense anti-
tumor drug ISIS183750. We believe this method allows
synthesis of compound
1 in sufficient quantities and it’s also
believed that the synthetic strategy permits synthesis of 2-
deoxy ribose related disaccharide nucleosides and the
corresponding phosphoramidites in an expedient fashion.
SCHEME 3. Regents and conditions: a) Bz2O, DMF, room
temperature, 12 h., 83%; b) CH2Cl2, SnCl4, 0oC, 2 h., 72%; c)
K2CO3, THF/MeOH (1:1), 78%; d) TBAF, THF, room
temperature, 12 h, 80%; e): DMTCl, DMAP (3 eq.), DMF,
65%.
Experiments
NMR spectra were obtained with a Bruker AV-400 (400
1
MHz), the H NMR chemical shifts were measured relative to
tetramethylsilane, CDCl3 or DMSO-d6 as the internal reference,
while the 13C NMR chemical shifts were recorded with CDCl3 or

4
Tetrahedron
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DMSO-d6 as the internal standard. Mass spectra were obtained on
Agilent LCMS instrument. Unless otherwise noted, all reagents
were obtained from commercial suppliers and used without
further purification. Anhydrous solvents were dried by heating at
reflux for at least 24 h over CaH2, dichloromethane, DMF,
tetrahydrofuran, toluene, and diethyl ether were freshly distilled
prior to use. Unless otherwise indicated, all syntheses and
manipulations were carried out under dry nitrogen atmosphere.
was stirred at 0℃ for 2h, quenched with saturated sodium
bicarbonate solution, extracted with dichloromethane (500 mL).
The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by flash
column (CH2Cl2 : CH3OH = 20:1) to give the compounds
12α and 12β as a solid (6.43 g, yield: 71.52%), 1H NMR
(CDCl3): δ8.30 (m, 2H), 7.70-7.60 (m, 5H), 7.50-7.30 (m, 10H),
6.30-6.50 (m, 1H), 5.30-5.00 (m, 2H), 4.50 (m, 1H), 4.30-3.90
(m, 5H), 2.55-2.35 (m, 2H), 2.20-2.10 (m, 2H), 2.10 (s, 3H), 2.00
(s, 3H), 1.70 (s, 3H), 1.10 (s, 9H); ESIMS: m/z 785 [M+H]+.
2-Deoxy 3 ， 5-di-O-acetyl methyl ribofuranoside (4) was
prepared according to the procedures reported by Iglesias.11
2’-Deoxy 3’-O-(2”-deoxy ribofuranosyl) 5’-O-TBDPS 5-
methyl cytidine (13α, 13β): To a solution of the compounds
12α, 12β (25.5 g, 32.57 mmol) in the mixture of THF (150 mL)
and methanol (150 mL) was added anhydrous potassium
carbonate (6.75 g, 48.85 mmol). The mixture was stirred at room
temperature under N2 overnight, the solvent was removed, and
the residue was purified by flash silica column (CH2Cl2: CH3OH
= 10:1) to give compounds 13α, 13β as a solid (15.23 g, yield:
2’-Deoxy 5’-O-TBDPS 5-methyl uridine (8): To a solution of
2’-deoxy 5-methyl uridine (14.71 g, 0.061 mol) in dry pyridine
(88 mL) was added imidazole (8.30 g, 0.122 mol), followed by
addition of TBDPSCl (26.83 g, 0.098 mol). The reaction mixture
was stirred at room temperature under N2 overnight, and
quenched by adding water. The solvent was evaporated, and the
residue was purified by flash column (CH2Cl2 : CH3OH = 20:1)
to give the compound 8 as a solid (22 g, yield: 75.21%), 1H NMR
(CDCl3): δ8.50 (s, 1H), 7.50 (m, 5H), 7.20 (m, 7H), 6.20 (m, 1H),
4.40 (d, 1H), 4.00 (d, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 2.40 (m,
1H), 1.90 (m, 1H), 1.60 (s, 3H), 0.80 (s, 9H); ESIMS: m/z 481
[M+H]+.
1
78.59%). H NMR (DMSO-D6): δ7.95 (m, 1H), 7.60 (m, 5H),
7.40 (m, 9H), 6.80 (m, 1H), 6.10 (m, 1H), 5.20 (m, 1H), 5.10 (m,
1H), 4.90 (m, 1H), 4.80-4.30 (m, 3H), 4.10-3.60 (m, 7H), 3.60-
3.20 (m, 10H), 2.4-1.9 (m, 4H), 1.50 (two s, 3H), 1.00 (s, 9H);
ESIMS: m/z 596 [M+H]+.
2’-Deoxy 5’-O-TBDPS 5-methyl cytidine (9): To a solution of
compound 8 (72 g, 0.15mol) in anhydrous acetonitrile (480 mL)
was added Et3N (242.4 g, 2.4 mol) at -15°C under N2. After
stirring for 20 min., TMSCl (48.6 g, 0.45 mol) was added, after
another 1h, triazole (82.8 g, 1.2 mol) and POCl3 (45.6 g, 0.3 mol)
were added at -15°C. This mixture was stirred at this temperature
for 2h, quenched with addition of 240 mL of water at -15°C. The
mixture was extracted with EtOAc, and the aqueous phase was
re-extracted with EtOAc. The solvent was evaporated, and the
residue was dissolved in the mixture of 1,4-dioxane (600 mL)
and aqueous ammonia (30 mL). The mixture was stirred at room
temperature under N2 overnight. After evaporation, the product
was purified by flash column (CH2Cl2 : CH3OH = 10:1) to give
the compound 9 as a solid (63 g, yield: 87.5%), 1H NMR
(CDCl3): δ7.65 (m, 5H), 7.40 (m, 6H), 6.50 (m, 1H), 4.50 (m,
1H), 4.10 (d, 1H), 4.00 (dd, 1H), 3.80 (dd, 1H), 2.65 (m, 1H),
2.10 (m, 1H), 1.60 (s, 3H), 1.09 (s, 9H); ESIMS: m/z 480
[M+H]+.
2’-Deoxy 3’-O-(2”-deoxy ribofuranosyl) 5-methyl cytidine
(14α, 14β): To a solution of the compounds 13α, 13β (15.23 g,
25.60 mmol) in THF (200 mL) was added TBAF (33.28 g, 12.8
mmol). The mixture was stirred at room temperature under N2
overnight. The solvent was removed, and the residue was purified
by flash column (CH2Cl2 : CH3OH = 10:1) to give compounds
14α, 14β as a white solid (7.36 g, yield: 80.61%), 1H NMR
(CDCl3): δ7.60 (m, 1H), 7.35 (m, 1H), 6.80 (m, 1H), 6.20 (m,
1H), 5.20 (m, 1H), 5.00 (m, 1H), 5.85 (m, 1H), 4.35 (m, 1H),
4.10 (m, 1H), 3.90 (m, 1H), 3.80 (m, 1H), 3.70 (m, 1H), 3.40-
3.60 (m, 3H), 2.30-1.90 (m, 4H), 1.70 (s, 3H); ESIMS: m/z 358
[M+H]+.
2’-Deoxy 3’-O-(2”-deoxy 5”-O-DMT α-D-ribofuranosyl) 5’-
O-DMT 5-methyl cytidine (15α) and 2’-deoxy 3’-O-(2”-deoxy
5”-O-DMT β-D-ribofuranosyl) 5’-O-DMT 5-methyl cytidine
(15β): To a solution of the compounds 14α, 14β (2.05 g, 5.74
mmol) in anhydrous DMF (15 mL) was added DMTCl (3.88 g,
11.48 mmol) and DMAP (1.75 g, 14.35 mmol). The mixture was
stirred at room temperature under N2 for four days. The reaction
mixture was purified by supercritical fluid chromatography
separation to give the products 15β (0.9 g, 32.67%) and 15α (0.9
g, 32.67%) as solids. Spectral data for compound 15β, 1H NMR
(DMSO-D6): δ8.09 (d, 0.5H), 7.40-7.10 (m, 22H), 6.75-6.90 (m,
20H), 6.58 (d, 0.5H), 6.04 (t, 1H), 5.15 (d, 1H), 5.10 (d, 1H),
4.49 (m, 1H), 4.10 (m, 1H), 3.90 (m, 1H), 3.85 (m, 1H), 3.72 (s,
3H), 3.71(s, 3H), 3.70 (s, 3H), 3.69 (s, 3H), 3.15 (m, 2H), 3.08
(m, 1H), 2.97-1.80 (m, 4H), 1.50 (s, 3H); 13C NMR (DMSO-D6):
103.5, 102.0, 86.5, 86.0, 85.8, 83.0, 77.5, 71.2, 65.5, 55.5, 37.0,
31.5, 12.9; ESIMS: m/z 962 [M+H]+; spectral data for compound
15α, 1H NMR (DMSO-D6): δ8.10 (d, 0.37H), 7.50 (m, 1H), 7.35-
7.10 (m, 21H), 6.80-6.70 (m, 10H), 6.55 (m, 0.45H), 6.20 (t, 1H),
5.50 (m, 1H), 4.93 (d, 1H), 4.53 (m, 1H), 4.15 (m, 1H), 3.85 (m,
1H), 3.75 (m, 1H), 3.64 (s, 3H), 3.63 (s, 3H), 3.62 (s, 3H), 3.61
(s, 3H), 3.23 (m, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.40-2.10 (m,
3H), 1.65 (m, 1H), 1.35 (s, 3H); 13C NMR (DMSO-D6): 102.0,
87.0, 86.0, 85.2, 84.3, 77.8, 71.2, 64.5, 55.5, 42.0, 39.0, 13.9;
ESIMS: m/z 962 [M+H]+.
2’-Deoxy 5’-O-TBDPS N-benzoyl 5-methyl cytidine (11): To
a solution of the compound 9 (63 g, 0.13 mol) in anhydrous DMF
(480 mL) was added Bz2O (32.57 g, 0.14 mol). The mixture was
stirred at room temperature under N2 overnight, the solvent was
removed, and the residue was diluted with EtOAc (200 mL), the
resulting solution was washed with water (100 mL×2), dried with
anhydrous Na2SO4. After filtration and concentration, the residue
was purified by flash silica gel column (EtOAc : PE = 3:1) to
1
give the compound 11 as a solid (63 g, yield: 82.89%), H NMR
(DMSO-D6): δ13.00 (s, 1H), 8.10 (m, 2H), 7.70 (m, 1H), 7.60
(m, 4H), 7.50 (m, 1H), 7.40 (m, 8H), 6.20 (m, 1H), 5.40 (m, 1H),
4.30 (m, 1H), 3.95 (m, 2H), 3.80 (m, 1H), 2.25 (m, 2H), 1.70 (s,
3H), 1.00 (s, 9H); ESIMS: m/z 585 [M+H]+.
2’-Deoxy 5’-O-TBDPS 3’-O-(2”-deoxy 5”,3”-O-diacetyl
ribofuranosyl)-N-benzoyl 5-methyl cytidine (12α, 12β): To a
solution of the compound 4 (2.66 g, 11.49 mmol) in anhydrous
CH2Cl2 (100 mL) was added dropwise SnCl4 (3.53 mL) at 0°C.
The mixture was stirred at 0℃ under nitrogen for 15 min.,
compound 11 (6.7 g, 11.49 mmol) was added, and the reaction

5
2’-Deoxy 3’-O-(2”-deoxy 5”-O-DMT β-D-ribofuranosyl) 5’-
O-DMT N-benzoyl 5-methyl cytidine (16β): To a solution of the
compound 15β (1.4 g, 1.45mmol) in anhydrous DMF (9 mL) was
added Bz2O (0.64 g, 2.9mmol), the mixture was stirred at room
temperature under N2 overnight. After evaporation of the solvent,
the residue was dissolved in the mixture of THF and methanol
(1:1, 100 mL), 80 mL of saturated potassium carbonate solution
was added, and the reaction mixture was stirred at room
temperature and monitored by TLC. When the starting material
was almost consumed, aqueous citric acid solution (pH=6) was
added to neutralize the solution. After the solvent was removed,
the residue was dissolved in EtOAc (10 mL). The solution was
washed with water (5 mL×2), evaporated, and the residue was
purified by preparatory HPLC to give the compound 16β as a
1H), 2.70 (t, J = 5.6 Hz, 1H), 2.61 (t, J = 5.6 Hz, 1H), 2.02~2.30
ACCEPTED MANUSCRIPT
(m, 3H), 1.68 (s, 3H), 1.04 (m, 12H); 31P NMR (CDCl3): 147.85,
147.52; ESIMS: m/z: 1267 [M+H]+.
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white solid (0.71 g), H NMR (DMSO-D6): δ8.15 (m, 2H), 7.60-
7.10 (m, 23H), 6.90-6.80 (m, 8H), 5.97 (t, 1H), 5.20-5.10 (m,
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Glycotechnol. 2013;25(141):13.
followed by the addition of
ditetraisopropylamino-O-
propanenitrile phosphinoamidite (452 mg, 1.5 mmol) and
tetrazole (1.25 mL, 0.45 M in MeCN, 0.56 mmol) at room
temperature under nitrogen. After 5 minutes, 30 ꢀL of N-
methylimidazole was added, and the mixture was stirred at room
temperature overnight. The crude product was purified by HPLC
to give the compound 1 as a white foam (150 mg, yield: 63%)
1
with 95% purity (based on HPLC). H NMR (CDCl3): δ12.86
(11) Gudiño ED, Iribarren AM, Iglesias LE. Tetrahedron:
Asymmetry. 2009; 20(15):1813.
(brs, 1H, ), 8.13 (brs, 2H), 7.79 (brs, 1H), 7.55 (t, J = 7.2 Hz, 1H),
7.46 (t, J = 7.6 Hz, 2H), 7.30~7.42 (m, 4H), 7.10~7.30 (m, 14H),
6.78~6.90 (m, 8H), 5.99 (t, J = 6.4 Hz, 1H), 5.25 (m, 1H),
4.30~4.48 (m, 2H), 3.94~4.10 (m, 2H), 3.60~3.70 (m, 12H),
3.40~3.60 (m, 3H), 3.22 (m, 2H), 3.07~3.18 (m, 1H), 2.99 (m,