A new and improved process for C-aryl glucoside SGLT2 inhibitors

Article abstract of DOI:10.1007/s00706-015-1458-z

A practical and scalable synthesis of C-glycosides identified as highly potent sodium-dependent glucose transporter 2 (SGLT2) inhibitors is described. Highlights of the synthetic process are a concise, ten-step synthesis of a structurally complex active pharmaceutical ingredient from a known intermediate via a selective and quantitative addition of an aryl species to the Weinreb amide, and the isomers of undesired ortho-products were avoided during the preparation. The chemistry developed has been applied to prepare SGLT2 inhibitors without recourse to chromatography.

Full text of DOI:10.1007/s00706-015-1458-z

Monatsh Chem
DOI 10.1007/s00706-015-1458-z
ORIGINAL PAPER
A new and improved process for C-aryl glucoside SGLT2
inhibitors
Yonghai Liu1 Tingming Fu2 Zhidong Chen3 Chunyan Ou1
•
•
•
Received: 14 October 2014 / Accepted: 13 March 2015
ꢀ Springer-Verlag Wien 2015
Abstract A practical and scalable synthesis of C-glyco-
sides identified as highly potent sodium-dependent glucose
transporter 2 (SGLT2) inhibitors is described. Highlights of
the synthetic process are a concise, ten-step synthesis of a
structurally complex active pharmaceutical ingredient from
a known intermediate via a selective and quantitative ad-
dition of an aryl species to the Weinreb amide, and the
isomers of undesired ortho-products were avoided during
the preparation. The chemistry developed has been applied
to prepare SGLT2 inhibitors without recourse to
chromatography.
between the glucose and aglycone is a carbon–carbon bond
[5, 6]. It was reported that (1S,30R,40R,50S,60R)-5-chloro-6-
[(4-ethylphenyl)methyl]-30,40,50,60-tetrahydro-60-(hydroxy-
methyl)-spiro[isobenzofuran-1(3H),20-[2H]pyran]-30,40,50-
triol (12) may be advancing to clinical development to
directly increase glucose excretion and to safely nor-
malize plasma glucose in the treatment of type 2 diabetes
[7–16]. We were recently required to execute several
hundred grams scale delivery of this active pharmaceu-
tical ingredient (API). In this paper we report the
development of a safe and scalable synthetic route that
enabled the production of the required quantity of the
target molecule.
Keywords Glycosides ꢀ Halogenation ꢀ Heterocycles
Two synthetic routes have been used to synthesize 12.
One method is shown in Scheme 1. The key intermediate 7
was prepared by a Friedel–Crafts reaction, but the selec-
tivity for the para-position over the ortho-position was
low. In addition, compound 11 was synthesized by a cou-
pling reaction between 10 and 13 in an unsatisfactory yield
and the synthetic route required eleven steps, which was
unsuitable for a large scale production [7–12]. For the other
reported procedure, the target compound was synthesized
from 1-bromo-4-chloro-2,5-dimethylbenzene with an un-
satisfactory overall yield of 6 %. The synthetic sequence
needed 12 steps and was not feasible for industrial scale-
ups [13–16].
Introduction
Sodium glucose co-transporter 2 (SGLT2) plays a key role
in maintaining glucose equilibrium in the human body [1,
2]. Much attention has been given to SGLT2 as a molecular
target to directly enhance glucose excretion and to safely
normalize plasma glucose in the treatment of type 2 dia-
betes [3, 4]. A promising subset of SGLT2 inhibitors
explored was the carbon glycosides in which the bond
& Yonghai Liu
Recently, we have reported a new synthetic route to 12
on a very small scale via a Suzuki cross-coupling reaction
between a benzylic halide and 4-ethylphenylboronic acid
[17]. A set of experiments were performed in order to
optimize the reaction conditions for this heterogeneous
reaction. Nevertheless, the complexity of the product
mixture obtained and the difficulty in purification of the
product, which required chromatography and took long
times for the reaction to reach completion, and 3500 ppm
dreamlyh@sohu.com
1
School of Pharmacy, Nanjing University of Chinese
Medicine, Nanjing 210046, China
2
Jiangsu Collaborative Innovation Center of Chinese
Medicinal Resources Industrialization, Nanjing 210046,
China
3
Shanghai Oasis Fine Chemicals Co., Ltd., Shanghai 200127,
China
123

Y. Liu et al.
Scheme 1
(a) NBS, DMF, 5 °C; (b) SOCl2, MeOH, reflux; (c) NaNO2, HCl, CuCl2,
1,4-dioxane, H2O, 0 °C; (d) KMnO4, t-BuOH, 18-crown-6, H2O, reflux; (e)
(COCl)2, DMF, DCM, r.t.; (f) AlCl3, ethylbenzene, DCM, -5 °C; (g)
Et3SiH, CF3SO3H, TFA, reflux; (h) NaBH4, MeOH, THF, reflux; (i)
MOMCl, DIPEA, DCM, r.t.; (j) n-BuLi, THF, toluene, (3R,4S,5R,6R)-
3,4,5-tris(trimethylsilyloxy)-6-[(trimethylsilyloxy)methyl]-
tetrahydropyran-2-one (13), -78 °C; (k) CH3SO3H, MeOH, r.t..
of Pd, 400 ppm of iron impurities were also found, re-
quiring that this liability to be addressed before larger scale
production could be attempted. Moreover, the more high
cost meant that this route would not be viable to
manufacture kilogram quantities of API in a short time
frame.
Et3SiH in trifluoroacetic acid to afford 19, which was
treated with NaOH in MeOH to give 9. The treatment
of 9 with trimethylsilyl chloride in THF gave silyl
ether 20, which was transformed to the glucopyra-
noside 22 in an excellent yield. Compound 22 was
hydrogenated under 0.1 MPa of hydrogen in the pres-
ence of Pd/C at room temperature to produce 12 in
about 31 % overall yield.
A screen of several solvents was carried out in the
synthesis of 18. For the coupling step diethyl ether re-
mained the best solvent, with 2-methyltetrahydrofuran and
THF as good alternatives. Since diethyl ether is not ap-
propriate for scale-up, THF was selected as the most
favorable solvent for both steps because it gave reasonably
high yields and is commercially available in large
quantities.
Results and discussion
As shown in Scheme 2, a practical and commercial
process of preparing 12 was designed and studied by
us. Compound 15 was readily prepared by reacting
N-bromosuccimide (NBS) with the benzoic acid 14 in
DMF. The treatment of 15 with NBS in the presence of
azodiisobutyronitrile (AIBN) in CCl4 gave 16. Then 18
was prepared by the reactions of Weinreb amide 17 and
Grignard reagent which the isomers of undesired ortho-
products were avoided. Compound 18 was treated with
Moreover, the formation of the Grignard reagent 23 in
THF with magnesium was straightforward with the aid of
1,2-dibromoethane as an initiator and it was used directly
in the next step. This freshly prepared Grignard reagent
123

A new and improved process for…
Scheme 2
(a) DMF, NBS, 25 °C (94%); (b) CCl4, NBS, AIBN, reflux (76%); (c)
DMF / CDI / Et3N / N-methoxymethanamine hydrochloride, 25 °C (98%);
(d) THF / (4-ethylphenyl)magnesium bromide (23), 25 °C (91%); (e)
Et3SiH / TFA / CF3SO3H, reflux (85%); (f) MeOH, NaOH, 25 °C (86%);
(g) THF, trimethylchlorosilane, r.t. (95%); (h) THF/toluene,
(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-
tetrahydropyran-2-one (24), -78 °C; (i) THF/toluene, MeSO3H, r.t. (79%,
two steps); (j) 10% Pd-C, MeOH, H2 (0.1 MPa), 25 °C, 88%.
was added to a THF solution of 17 at 25 ꢁC, and after
quench and workup, a quantitative crude ketone 18 was
obtained in a satisfactory yield.
The final API exists as an amorphous foam that was
inappropriate for isolation and purification by recrystal-
lization. Herein, a simple and industrial feasible method for
the isolation and purification of compound 12 was devel-
oped (Scheme 3). The solution of crude 12 (Scheme 1) was
dissolved in CH2Cl2 and treated with Ac2O followed by
cooling and drying to provide 25, then treatment of 25 in
turn with LiOH and methanesulfonic acid in THF gave the
target compound 12 in an excellent yield, and the purity of
12 was increased from 86.2 to 99.1 % according to the
tested result of HPLC. Furthermore, we were also pleased
to find that the residual palladium levels were reduced
to \10 ppm in the isolated material.
In order to study the solvent effect in the deprotection
reaction of the benzyl groups in 22, a series of solvents
were screened and the results are shown in Table 1. A
mixture of 12 and 12a were found when benzene, toluene,
chlorobenzene, and 1,2-dichlorobenzene were used as sol-
vents in the deprotection reaction. However, when 20
equiv. Of 1,2-dichlorobenzene was added in the reaction
mixture, by-product 12a could not be detected by LC–MS
(Table 1, entry 4). It was also obtained in an excellent
yield.
123

Y. Liu et al.
Table 1 Synthesis of compound 12 by deprotection of benzyl group
Cl
Cl
O
O
O
O
O
O
HO
BnO
BnO
H2/Pd
HO
+
h
EtOAc/MeOH,12
HO
OH
OBn
HO
OH
12a
12
22
OH
OBn
OH
Entry
1
Solvent
Equimolar amounts
Compound 12 yield/%a
By-product 12a yield/%a
Benzene
Toluene
10
20
10
20
10
20
10
20
48
47
49
48
71
80
91
99
51
52
50
50
27
19
7
2
3
4
a
Chlorobenzene
1,2-Dichlorobenzene
0
Determined by HPLC analysis of crude products before purification
Scheme 3
(a) CH2Cl2, Ac2O, r.t.; (b) THF/MeOH/H2O, LiOH, MeSO3H, r.t..
0.94 kg NBS (5.3 mol) to maintain the temperature below
86 ꢁC, and the reaction mixture was stirred for 16 h at
80 ꢁC, and solvents were removed by rotaevaporation,
cooled to room temperature, then de-ionized water was
added, and then the resultant mixture was extracted with
EtOAc, washed with de-ionized water and brine, dried with
anhydrous sodium sulfate, and concentrated in vacuo.
Subsequently it was recrystallized from 3 dm3 MeOH to
give colorless crystals (1.03 kg, 94 %). M.p.: 205–207 ꢁC;
Conclusion
In conclusion, a more efficient synthetic route for the
synthesis of 12 was developed. The overall yield of the
sequence was about 31 % and the undesired ortho-products
in the coupling reaction between the two aryl pieces in the
previous reports were avoided using the current method.
Experimental
1
IR (KBr): m = 3878, 2951, 1749, 1482 cm-1; H NMR
(300 MHz, CDCl3): d = 8.23 (s, 1H), 7.52 (s, 1H), 2.38 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): d = 165.8, 145.6,
135.2, 133.9, 131.2, 130.6, 122.6, 25.3 ppm; MS:
m/z = 248 (M?), 271 ([M ? Na]?).
All the reagents were obtained from suppliers and were not
purified. Elemental analysis (C, H, N) was determined with
a Perkin-Elmer 240c instrument, their results were found to
be in good agreement ( 0.3 %) with the calculated values.
1H NMR and 13C NMR were measured on a Bruker AM
300 MHz spectrometer. EI mass spectral measurement was
carried out on a Waters alliance 2695 with acetonitrile and
water as a mobile phase.
5-Bromo-4-(bromomethyl)-2-chlorobenzoic
C8H5Br2ClO2)
acid
(16,
To a solution of 1.03 kg 15 (4.15 mol) in 12 dm3 CCl4 was
added 0.89 kg NBS (5 mol) under argon, then 70 g AIBN
(0.42 mol) was added under argon, and the mixture was
stirred at reflux for 15 h, then the mixture was cooled to
room temperature and filtered, and the filtrate was washed
5-Bromo-2-chloro-4-methylbenzoic acid (15, C8H6BrClO2)
To a solution of 0.75 kg 2-chloro-4-methylbenzoic acid
(4.41 mol) in 7 dm3 DMF at 80 ꢁC was slowly added
123

A new and improved process for…
with de-ionized water and brine, concentrated in vacuo to
with ethyl acetate (EtOAc), washed with de-ionized water,
then the organic layer was dried over sodium sulfate, and drying
agent was filtered. The residue was distilled under reduced
pressure, and the fraction boiling at 196–202 ꢁC/2 mm Hg
was collected to give 18 (1.17 kg, 91 %) as a colorless oil.
give a yellow oil (1.03 kg, 76 %). IR (KBr): m = 3894,
2962, 1758, 1498 cm-1 1H NMR (300 MHz, CDCl3):
;
d = 8.32 (s, 1H), 7.48 (s, 1H), 4.62 (s, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d = 165.7, 144.8, 135.6, 134.9, 134.7,
130.8, 122.5, 33.4 ppm; MS: m/z = 326 (M?), 349
([M ? Na]?).
1
IR (KBr): m = 2916, 2863, 1701, 1459 cm-1; H NMR
(300 MHz, CDCl3): d = 7.86 (s, 1H), 7.72 (d, J = 8.0 Hz,
2H), 7.50 (s, 1H), 7.01 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H),
2.58 (q, J = 7.8 Hz, 2H), 1.23 (t, J = 7.8 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): d = 197.1, 148.1, 142.6,
138.9, 135.7, 135.4, 134.8, 130.8, 130.1, 128.1, 121.8,
33.4, 28.8, 14.9 ppm; MS: m/z = 414 (M?), 437
([M ? Na]?).
5-Bromo-4-(bromomethyl)-2-chloro-N-methoxy-N-methyl-
benzamide (17, C10H10Br2ClNO2)
To a solution of 1.03 kg 16 (3.2 mol) in 8 dm3 anhydrous
DMF, 0.67 kg N,N0-carbonyldiimidazole (CDI, 4.1 mol)
was added in portions. After all of the CDI was added,
0.42 kg Et3N (4.1 mol) was added to the mixture, stirred at
25 ꢁC for 1 h, then 0.4 kg N-methoxymethanamine hy-
drochloride (4.1 mol) was added, the reaction mixture was
stirred at 25 ꢁC for 10 h. The product solution was distilled
under vacuum, then the residual was poured into ice water
and extracted with EtOAc, the organic phase was separated
and washed with de-ionized water, concentrated in vacuo.
Subsequently it was dried and recrystallized from 2.5 dm3
MeOH to get a white solid (1.15 kg, 98 %). M.p.: 161–
163 ꢁC; IR (KBr): m = 2956, 1782, 1640, 1488,
1-Bromo-2-(bromomethyl)-4-chloro-5-(4-ethylbenzyl)ben-
zene (19, C16H15Br2Cl)
To a stirred solution of 1.17 kg 18 (2.8 mol) and 0.69 kg
Et3SiH (5.9 mol) in 7 dm3 TFA, 2.6 g CF3SO3H
(0.017 mol) was added dropwise slowly to the reactor
below 45 ꢁC. Within minutes the temperature increased
causing the solution to reflux. After 1 h at reflux, 40 g
Et3SiH was added, and the solution was stirred at reflux for
12 h. The product solution was distilled under vacuum, and
the mixture was poured into water and extracted with
hexane, washed with de-ionized water and concentrated in
vacuo to give an oil (0.96 kg, 85 %). IR (KBr): m = 2921,
2869, 1452 cm-1; 1H NMR (300 MHz, CD3OD): d = 7.96
(s, 1H), 7.54 (s, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.11 (d,
J = 7.8 Hz, 2H), 4.53 (s, 2H), 4.11 (s, 2H), 2.62 (q,
J = 7.8 Hz, 2H), 1.26 (t, J = 7.8 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): d = 146.6, 142.6, 139.1, 135.9, 135.1,
133.4, 131.8, 130.1, 129.2, 122.1, 36.5, 33.2, 28.5,
14.6 ppm; MS: m/z = 400 (M?), 423 ([M ? Na]?).
1193 cm-1 1H NMR (300 MHz, CDCl3): d = 8.10 (s,
;
1H), 7.55 (s, 1H), 4.42 (s, 2H), 3.67 (s, 3H) 3.12 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): d = 168.8, 142.2,
134.6, 132.9, 131.7, 131.4, 68.6, 64.1, 35.6, 32.4 ppm; MS:
m/z = 369 (M?), 392 ([M ? Na]?).
[5-Bromo-4-(bromomethyl)-2-chlorophenyl](4-ethylphe-
nyl)methanone (18, C16H13Br2ClO)
To a stirred suspension of 88.51 g magnesium (3.6 mol) in
2.8 dm3 anhydrous THF was added a solution of 2.6 cm3
1,2-dibromoethane (0.03 mol) and 629 g 1-bromo-4-ethyl-
benzene (3.4 mol) in 0.8 dm3 THF dropwise over 20 min
at 20 ꢁC. When the temperature was 26 ꢁC, the reaction
was placed in a cold-water bath, and the temperature
continued to increase to 32 ꢁC; ice was added to the water
bath to maintain the temperature between 40 and 48 ꢁC
with vigorous stirring (CAUTION: this experimental is
designed to avoid a runaway reaction, but a delay in
initiation may cause the solvent to boil). After the reaction
temperature declined to 20 ꢁC, the water bath was
removed, and the mixture was stirred at 20 ꢁC for an
additional 20 min to give the Grignard reagent, which was
immediately used in the next step.
To a solution of 1.15 kg 17 (3.1 mol) in 10 dm3
anhydrous THF, the air of the reactor was removed by
argon, and above freshly prepared Grignard reagent (4-
ethylphenyl)magnesium bromide (1 M in THF, 3.4 dm3)
was added dropwise slowly to the reactor below 30 ꢁC. The
reaction mixture was stirred at 25 ꢁC for 2 h, and the
reaction was quenched with saturated NH4Cl, extracted
[2-Bromo-5-chloro-4-(4-ethylbenzyl)phenyl]methanol (9,
C16H16BrClO)
To a solution of 0.96 kg 19 (2.39 mol) in 10 dm3 MeOH,
2.63 dm3 1 M NaOH (2.63 mol) was added slowly, and the
mixture was stirring for 5 h at 25 ꢁC, and the product
solution was distilled under vacuum, and the isolated oil
was pouring into water. The resultant mixture was
extracted with EtOAc, washed with de-ionized water and
brine, dried over anhydrous sodium sulfate and concen-
trated in vacuo. Subsequently it was recrystallized from
3 dm3 EtOH/hexane (v:v = 1:2) to get a white solid
(0.7 kg, 86 %). M.p.: 44–46 ꢁC; IR (KBr): m = 3679,
2913, 2871, 1458 cm-1 1H NMR (300 MHz, CDCl3):
;
d = 7.85 (s, 1H), 7.44 (s, 1H), 7.15 (d, J = 7.8 Hz, 2H),
7.09 (d, J = 7.8 Hz, 2H), 4.53 (s, 2H), 4.05 (s, 2H), 2.63
(q, J = 7.8 Hz, 2H), 1.24 (t, J = 7.8 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3): d = 142.5, 141.6, 136.6, 135.8,
134.2, 132.9, 130.8, 129.6, 128.4, 121.2, 64.6, 38.6, 29.6,
16.8 ppm; MS: m/z = 338 (M?), 361 ([M ? Na]?).
123

Y. Liu et al.
[4-(4-Ethylbenzyl)-2-bromo-5-chlorobenzyloxy]trimethyl-
silane (20, C18H22BrClOSi)
To a solution of 1.17 kg 22 (1.49 mol) in 13 dm3 EtOAc/
MeOH (2:3), 115 g palladium on carbon and 4.5 dm3 1,2-
dichlorobenzene were added in turn. The air of reactor was
removed by argon, then 0.1 MPa H2 was added for 12 h at
25 ꢁC. The solvent was filtrated, filter cake was washed by
EtOAc, and the filtrate was concentrated in vacuo to give a
crude 12 as an yellow oil.
A stirred solution of crude 12 in 2 dm3 CH2Cl2
containing 1.4 kg diisopropylethylamine (10.8 mol) and
1.5 g DMAP (12.3 mol) was cooled to 0 ꢁC. Acetic
anhydride (978 g, 9.57 mol) was slowly added at such a
rate that the temperature did not exceed 5 ꢁC, and then the
solution was warmed to 20 ꢁC and stirred for 10 h, and
quenched with saturated NaHCO3. The mixture was
extracted with EtOAc, washed with water and brine, dried
with anhydrous sodium sulfate and concentrated in vacuo
to give an oil, crystallization from 10 dm3 EtOH yielded
the tetraacetylated C-glucoside 25 as a white solid. 1H
NMR (300 MHz, CDCl3): d = 7.24 (s, 2H), 7.09 (dd, 4H,
J = 8.4, 13.7 Hz), 5.51–5.62 (m, 2H), 5.24 (dd, 1H,
J = 8.8, 9.5 Hz), 5.11 (dd, 2H, J = 12.2, 13.0 Hz),
4.22–4.33 (m, 2H), 4.01–4.12 (m, 3H), 2.61 (q, 2H,
J = 7.6 Hz), 2.04 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.75
(s, 3H), 1.21 (t, 3H, J = 7.6 Hz) ppm.
To a stirred 0 ꢁC solution of 0.7 kg 9 (2.05 mol) and
3.37 kg 4-methylmorpholine (4.1 mol) in 10 dm3 THF was
added slowly 0.55 kg trimethylchlorosilane (5.1 mol), and
reaction mixture was stirred for 12 h at r.t., then it was
poured into ice water, extracted with EtOAc, washed with
de-ionized water, brine and concentrated in vacuo to give a
slightly yellow oil (0.78 kg, 95 %). IR (KBr): m = 2918,
2867, 1451, 1083 cm-1 1H NMR (300 MHz, CDCl3):
;
d = 7.85 (s, 1H), 7.44 (s, 1H), 7.15 (d, J = 7.8 Hz, 2H),
7.09 (d, J = 7.8 Hz, 2H), 4.05 (s, 2H), 2.63 (q, J = 7.8 Hz,
2H), 1.24 (t, J = 7.8 Hz, 3H), 0.27 (s, 9H) ppm; 13C NMR
(100 MHz, CDCl3): d = 4.5, 14.9, 28.5, 36.8, 120.9,
128.4, 129.1, 129.8, 132.9, 134.8, 137.8, 138.6, 142.3,
144.7 ppm; MS: m/z = 396 (M?), 419 ([M ? Na]?).
(30R,40S,50R,60R)-30,40,50-Tris(benzyloxy)-60-(benzy-
loxymethyl)-5-chloro-6-(4-ethylbenzyl)-30,40,50,60-tetrahydro-
3H-spiro[isobenzofuran-1,20-pyran] (22, C50H49ClO6)
To a stirred -78 ꢁC solution of 0.78 kg 20 (1.9 mol) in
15 dm3 anhydrous THF/toluene (1:2) was slowly added
1.9 dm3 1.1 M n-BuLi (2.1 mol) in hexane to maintain the
temperature below -70 ꢁC. After stirring for 10 min at
-78 ꢁC, the reaction mixture was added dropwise a
solution of 1.21 kg (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-
6-(benzyloxymethyl)-tetrahydro-pyran-2-one (2.27 mol) in
8 dm3 of toluene at -78 ꢁC. The solution was stirred for
5 h at the same temperature prior to quenching by addition
of a solution of 405 g methanesulfonic acid (4.16 mol) in
8 dm3 of THF. The reaction was stirred for 24 h as the
temperature rose to 25 ꢁC, and then quenched with
saturated NaHCO3. The mixture was extracted with
EtOAc, washed with water and brine, dried with anhydrous
sodium sulfate, and concentrated in vacuo. Subsequently it
was recrystallized from 10 dm3 EtOH to get light yellow
crystals (1.17 kg, 79 %). M.p.: 81–83 ꢁC; IR (KBr):
To a stirred solution of 25 in 6 dm3 THF/MeOH (2:3)
under N2 at 25 ꢁC was added 58.8 g LiOHꢀH2O (1.47 mol)
in 2 dm3 H2O, then the solution was stirred for 12 h at
25 ꢁC, and 96.1 g methylsulfonic acid (1 mol) was added
slowly and stirred for 1 h at 25 ꢁC, and then quenched with
saturated NaHCO3. The product solution was filtered and
distilled under vacuum, and the isolated oil was pouring
into de-ionized water. The resultant mixture was extracted
with EtOAc, washed with de-ionized water and brine, dried
over anhydrous sodium sulfate and concentrated in vacuo
to get 12 as a glassy off white solid (0.55 kg, 88 %).
[a]2D0 = -26.5ꢁ cm2 g-1 (c = 1, methanol); IR (KBr):
1
m = 3858, 2919, 2842, 1478, 1281 cm-1; H NMR, 13C
1
m = 2912, 2831, 1467, 1291 cm-1; H NMR (300 MHz,
NMR, and mass spectra were identical with those described
CDCl3): d = 7.52 (d, 1H, J = 1.5 Hz), 7.38–7.42 (m, 6H),
7.29–7.32 (m, 9H), 7.17–7.21 (m, 4H), 7.11 (d, 4H,
J = 1.2 Hz), 7.08 (d, 2H, J = 8.4 Hz), 4.88–4.96 (m, 3H),
4.72 (s, 2H), 4.56–4.67 (m, 3H), 4.46 (d, 1H, J = 10.8 Hz),
4.16–4.22 (m, 2H), 3.88 (d, 1H, J = 8.4 Hz), 3.82 (s, 1H),
3.66–3.77 (m, 4H), 3.36 (d, 1H, J = 9.6 Hz), 2.60 (q, 2H,
J = 7.6 Hz), 1.24 (t, 3H, J = 7.6 Hz) ppm; 13C NMR
(100 MHz, CD3OD): d = 139.8, 138.6, 137.6, 130.5,
129.5, 129.1, 129.0, 128.9, 128.8, 128.6, 128.4, 128.3,
128.2, 128.1, 128.0, 127.4, 101.2, 85.6, 84.9, 79.8, 78.9,
78.5, 77.5, 76.4, 75.6, 74.9, 73.6, 70.2, 62.7, 39.4, 28.8,
16.0 ppm; MS: m/z = 780 (M?), 803 ([M ? Na]?).
in Refs. [7–16].
Acknowledgements This work was financially supported by
Jiangsu Province Natural Science Fund (20131414) and by the
National Natural Science Foundation of China (51403104).
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