Synthesis of a Benvitimod impurity: (Z)-3,5-dihydroxy-4-isopropylstilbene

Article abstract of DOI:10.3184/174751915X14241928341993

(E)-3,5-dihydroxy-4-isopropylstilbene (Benvitimod), a new medicine for the treatment of psoriasis and eczema, belongs to the hydroxystilbene family. The synthesis leads to the E-isomer, (Z)-3,5-dihydroxy-4-isopropylstilbene being present as a major impuri

Full text of DOI:10.3184/174751915X14241928341993

154 RESEARCH PAPER
VOL. 39 MARCH, 154–158
JOURNAL OF CHEMICAL RESEARCH 2015
Synthesis of a Benvitimod impurity: (Z)-3,5-dihydroxy-4-isopropylstilbene
a
a,b,c
a
d
a
a
Yue Zhang *, Man Du , Hong-wei Xie , Hai-wen Song , Yong-xing Song , Hong-ying Qu
and Ji-xia Yang
a
aSchool of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, P.R. China
bHebei Research Center of Pharmaceutical and Chemical Engineering, Shijiazhuang 050018, P.R. China
cState Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Shijiazhuang 050018, P.R. China
dHebei Normal University of Science and Technology, Chemical College, Qinhuangdao 066004, P.R. China
(
E)-3,5-dihydroxy-4-isopropylstilbene (Benvitimod), a new medicine for the treatment of psoriasis and eczema, belongs to
the hydroxystilbene family. The synthesis leads to the E-isomer, (Z)-3,5-dihydroxy-4-isopropylstilbene being present as a
major impurity in the preparation of Benvitimod. We describe a synthesis of the Benvitimod impurity: (Z)-3,5-dihydroxy-
4
-isopropylstilbene starting from 3,5-dihydroxybenzoic acid, through an isopropyl reaction, esterification and
etherification, reduction, oxidation, Perkin condensation, decarboxylation and demethylation. The optimal reaction
conditions were also determined.
Keywords: Benvitimod, (Z)-3,5-dihydroxy-4-isopropylstilbene, Perkin condensation, optimal reaction conditions
9
–11
Benvitimod [(E)-3,5-dihydroxy-4-isopropylstilbene], is
a
have been proposed for the E-isomers.
Although the
new generation of anti-inflammatory drug which was first
developed by Welichem Biotech. Inc. to treat a variety of major
autoimmune diseases, such as psoriasis, eczema and allergic
Z-isomer is an inevitable by-product in the preparation of
the E-isomer, it is difficult to easily separate it from the
12
synthetic mixture due to the minor amount and its serious
1–3
13–15
disease. It has finished the Clinical Phase II trials in China.
instability.
We now describe a synthesis of (Z)-3,5-
Since it belongs to the hydroxystilbene family, Benvitimod
is inevitably associated with its Z-isomer. Hence, (Z)-3,5-
dihydroxy-4-isopropylstilbene, must be a main impurity in
Benvitimod whether it is made by extraction or synthesis and
consequently it has a great influence on the quality and efficacy
dihydroxy-4-isopropylstilbene 1 (Scheme 1). Starting from the
readily available 3,5-dihydroxybenzoic acid 2, 3,5-dihydroxy-
4-isopropylbenzoic acid
3
can be prepared through
isopropanylation reaction. Esterification and etherification
of 3 was carried out by using CH I/K CO to obtain methyl
3
2
3
4
of Benvitimod. Pharmaceutical quality control ensures the safe
3,5-dimethoxy-4-isopropylbenzoate 4, which was reduced by
use of drugs. The toxicity of impurities and the formulation of
NaBH /CH OH to afford 3,5-dimethoxy-4-isopropylbenzyl
4
3
5,6
a drug are important influencing factors on drug safety. In
addition to the pharmacological activities of the drug itself,
many of the adverse reactions to a drug in clinical application
alcohol 5. By using DMSO/Ac O as an oxidising agent, 5 was
2
oxidised to 3,5-dimethoxy-4-isopropylbenzaldehyde 6. Perkin
condensation between 6 and phenylacetic acid generates the
stilbene skeleton to afford (E)-3-(3,5-dimethoxy-4-isopropyl)-
2-phenylacrylic acid 7. Decarboxylation with Cu/quinoline
gave (Z)-3,5-dimethoxy-4-isopropylstilbene 8. Finally, 1 is
obtained through demethylation by using AlCl3 and N,N-
dimethyl aniline. This method for synthesis of 1 had not been
reported previously and the optimal reaction condition of each
step was developed in detail.
7,8
are associated with the impurities in the drug. Therefore,
research of the impurity also plays a critical role on assuring
the effectiveness and reducing adverse reactions of drugs.
Hence, the synthesis of (Z)-3,5-dihydroxy-4-isopropylstilbene
is important both for the preparation and the evaluation of the
quality and effectiveness of Benvitimod.
Amongst stilbenes when the E-isomers show the significant
physiological activities the opposite Z-isomers display
nothing. The reported syntheses of stilbenes include Wittig
Control of the reaction temperature was important
in
the
isopropanylation
because
more
isopropyl
(–Horner), Heck, Perkin, Knoevenagel, Grignard, reactions
3,5-dihydroxybenzoate and isopropyl 3,5-dihydroxy-4-
Scheme 1 Synthesis route of (Z)-3,5-dihydroxy-4-isopropylstilbene.
*
Correspondent. E-mail: yuezhang@hebust.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 155
Table 1 Influence of oxidation reagents on 5
are troublesome and highly toxic both to the experimentalist
Entry
Reagent
PCC
CrO /CH Cl
2
Temperature/oC
Time/h
Yield/%
and in the environment. When using CrO /H SO , we almost
3 2 4
failed to obtain 6 but obtained a high yield of 3,5-dimethoxy-
-isopropylbenzoic acid because of over oxidation. When
K Cr O was used, the yield of 6 was low because most of 5
1
2
3
4
5
6
R.t.
R.t.
R.t.
R.t.
68±2
R.t.
2
2
2
3
3
3
95
93
–a
4
3
2
2
2
7
CrO /H SO
3
2
4
was also oxidised to 3,5-dimethoxy-4-isopropylbenzoic acid.
K CrO /H SO
4
38
80
2
7
2
Compound 6 was obtained in high yield by using MnO with
b
2
MnO /THF
2
a little amount of 5 remaining, but the filtration separation
DMSO/Ac O
91
2
was difficult due to the very fine particles of MnO . Oxidation
2
a6 was not obtained and 5 was over oxidised to 3,5-dimethoxy-4-
isopropylbenzoic acid.
There was 5 (15%) remaining.
with DMSO provides an acceptable yield with mild operating
condition and convenient work-up procedure.
b
As the critical step in the whole synthesis, the Perkin
condensation determined the configuration of the target
product. The E-isomer was the desired product of this step
and it was important to select the optimal reaction condition to
improve the yield of E-isomer. In the condensation process, we
found that there was a main impurity appearing along with 7 in
a high yield. The appearance of the impurity interfered with the
yield of 7 and resulted in a difficult separation in the workup
period. Hence, it was necessary to separate and characterise
the impurity in order to look for a method to reduce the
formation of this impurity. After chromatographic separation
R.t., room temperature.
isopropylbenzoate were obtained at a higher temperature,
resulting in a low yield of 3. The sulfuric acid concentration also
had an obvious influence on the yield of isopropyl reaction. In
general, a concentration up to 80% always gave a satisfactory
yield. In the isopropanylation of 2, we used 80% sulfuric acid
to give 3 with a yield of 82%.
Esterification and etherification of phenol compounds by
1
6–19
CH I/K CO had been reported many times with high yields.
3
2
3
1
In our experiment, the esterification and etherification of 3 was
found to proceed rapidly with a yield of 93% for 4.
Esters can be effectively reduced by LiAlH a high yield.
However, the use of NaBH complexed with AlCl or CH OH
as an ester reducing agent had been developed recently.
Reduction of 4 by using NaBH /CH OH in our hands provided
a mild method giving a yield of 96% for 5.
Many of the commonly used oxidation reagents
examined for the preparation of 6 from 5 in order to find suitable
conditions (Table 1). A series of chromium oxidation reagents
and characterisation by H NMR and HRMS, the impurity was
finally shown to be (E)-3-(3,5-dimethoxy-4-isopropylphenyl)-
acrylic acid (9) (Fig. 1). Clearly, the formation of 9 was caused
by Perkin condensation between acetic acid and 6. In order to
obtain the optimal condition with reducing the formation of this
2
0
4
4
3
3
19
25–27
4
3
impurity, various basic catalysts reported in the literature
such as triethylamine, anhydrous K CO , KF, NaAc and KAc
2
3
21–24
were
were tried for this step. The yield was poor when triethylamine
was used as a base. Anhydrous K CO or KF as bases, led to a
2
3
difficult work-up and emulsion formation was serious and the
reaction mixture was a black glue. The yield was higher and
the work-up was simple when NaAc or KAc is employed. The
catalytic effect of NaAc and KAc was investigated in detail and
the results are summarised in Table 2. This shows that the yield
of 7 using NaAc was found to be higher than that with KAc. As
the reaction time increased, the yield of the product decreased
due to the generation of by-products. The content of 7 using
NaAc was higher than KAc and decreased with the time
because of the formation of the impurity. Excess basic catalyst
did not promote the yield of 7. The results indicate that NaAc
was superior to KAc as the catalyst and the optimal reaction
condition of Perkin condensation was with 2.5/1 of molar ratio
of NaAc/6 and 16 h of reaction time.
such as PCC, PDC and CrO /CH Cl gave a high yield of 6 but
some had tedious work-up procedures because of the serious
phenomenon of emulsions. Chromium residues in the product
3
2
2
Fig. 1 Structures of compounds 9 and 10.
Table 2 Conditions for the Perkin condensationa
NaAc
KAc
Entry
nb
Time/hc
Yield/%d
7/9e
Yield/%d
7/9e
1
2
3
4
5
6
7
8
9
2.0:1
2.5:1
3.0:1
2.0:1
2.5:1
3.0:1
2.0:1
2.5:1
3.0:1
2.0:1
2.5:1
3.0:1
8
8
8
42
34
39
34
43
35
53
57
47
43
44
40
0.96
0.86
1.10
1.17
1.46
1.66
1.65
1.96
1.54
1.47
1.23
1.04
35
44
34
25
25
32
23
39
27
30
38
34
0.89
0.56
0.76
0.80
0.93
1.02
1.71
1.45
0.71
0.61
0.76
0.74
12
12
12
16
16
16
20
20
20
10
1
1
12
a
Reaction temperature was 138 °C.
Molar ratio of n (NaAc or KAc)/n (6).
b
c
Timed from reflux.
d
Yield of 7 and 9.
Ratio of 7/9.
e

156 JOURNAL OF CHEMICAL RESEARCH 2015
Itwasimportanttocontrolsomefactorsinthedecarboxylation
step such as temperature and time to prevent the Z-isomer
rearranging to an E-isomer. In a conventional decarboxylation,
the high reaction temperature which was up to 200–210 °C
easily increased the configuration inversion of the Z-isomer,
Experimental
,5-Dihydroxybenzoic acid (>98%) was purchased from Jiangsu
3
Tianjiayi Chemical Co. Ltd. Other solvents and reagents used in the
present study were commercially available and are of analytical grade
without further purification. Isopropanol, sulfuric acid, Na CO ,
2
3
2
8–29
eventually giving priority to the E-isomer,
with a lower
Mg SO , K CO , DMF, tetrahydrofuran (THF), methyl tertiary butyl
2 4 2 3
ether (MTBE), NaBH , CH Cl , HCl, pyridine, CrO , acetic anhydride,
yield of the of Z-isomer. In this work, we strictly controlled
the reaction temperature and time on the basis of using Cu/
quinoline as the decarboxylation reagent. Based on these results
shown in Table 3, the effect of various reaction temperature and
time was carefully investigated to find the optimal condition for
decarboxylation to synthesise 8. We found that the temperature
played an important role in controlling the formation of
Z-isomer. Compound 7 could not be decarboxylated thoroughly
below 180 °C. The content of Z-isomer did not increase with
time as the temperature increased to 180 °C, while the content
of 8 was higher when the reaction temperature reached 190 °C
but decreased as the time lengthened because more (E)-3,5-
dimethoxy-4-isopropylstilbene (10, Fig. 1) was obtained. When
the temperature exceeded 200 °C, the inversion of the Z-isomer
to the E-isomer occurred. The results indicate that the optimal
condition for decarboxylation was with a temperature of 190 °C
and a reaction time of 4 h.
4
2
2
3
NaHCO , NaAc, KAc, Cu, quinoline, NaCl, toluene, methanol, N,N-
3
dimethylaniline, AlCl and ethyl acetate were obtained from Hebei
3
Yongda Chemical Ltd. Co. The IR spectra were obtained from a FTIR
1
spectrometer (FTS 135) using KBr pellets. The H NMR spectra were
obtained using a Bruker Avance (DRX-500) spectrometer operating
at 500.13 MHz. The melting point of product was determined from a
DSC-TGA (SDT-Q600). The high resolution mass (HRGC-HRMS)
spectra were obtained on a FTICR-MS (Ionspec 7.0T) spectrometer.
The purity of each compound obtained in the synthesis were
determined by using HPLC which was performed by using Agilent
1260 LC system according to the following method. The column
was Elite C18 column (5 µm, 250×4.6 mm), the mobile phase was at
–1
a flow rate of 1.0 mL·min and the injection volume was 10 μL. For
compound 7 and 9, column temperature was 20 °C, the wavelength
was at 297 nm, the mobile phase was a mixture of acetonitrile/water
(
90/10, V/V), the retention time of 7 and 9 was respectively 3.526 min
and 4.104 min. For compound 8 and 10, column temperature was
5 °C, the wavelength was at 317 nm, the mobile phase was a mixture
of acetonitrile/water (75/25, V/V), the retention times of 10 and 8 were
.623 min and 10.347 min respectively. For compound 1, the column
2
Pyridine hydrochloride is a favoured demethylation reagent
owing to its low cost, convenience and the fact that no solvent
8
3
0
is required . We tried it in our experiment but the high
temperature of 180–190 °C easily caused the inversion of the
configuration of the Z-isomer to the E-isomer. In addition to
the high cost and toxic of BBr , the volatility of BBr meant
temperature was 30 °C, the wavelength was at 318 nm, the mobile
phase was a mixture of acetonitrile/water/MTBE (38/57/5, V/V/V),
the retention time of E-isomer (Benvitimod) and 1 was respectively
1
0.419 min and 12.163 min, good linearity and precision were obtained
3
3
–1
that this reaction must be conducted at –70 to –80 °C, making
for 1 and the linear concentration of 1 ranged from 1.05 mg·L to
157 mg·L (r=0.99991).
31
–1
the operation difficult. By using AlCl /N,N-dimethylaniline,
3
the reaction temperature was 110 °C and Z-isomer was
obtained with a high yield. Moreover, the conditions were
Synthesis of 3,5‑dihydroxy‑4‑isopropylbenzoic acid (3)
Compound 2 (1.54 g, 0.01 mol) was dissolved in 80% H SO (5 mL)
2
4
mild and the work-up was convenient. We adopted AlCl /N,N-
3
and warmed to 6–65 °C. Isopropanol (1 mL) was added dropwise to
the above solution. When the addition of isopropanol was completed,
the mixture was stirred for 3 h at the same temperature and then
cooled to room temperature. The mixture was carefully poured into
ice-water (10 mL) and pH was adjusted to 7 with saturated Na CO
dimethylaniline as demethylation reagent and the yield of 1
was 58%.
Table 3 The conditions for the decarboxylic reactiona
Entry Temperature/oC Time/hb Content of 10/% Content of 8/%
2
3
–
1
solution. After filtration, the filtrate was acidified with HCl (6 mol·L )
and extracted with ethyl acetate (3×20 mL). The combined extract
was dried over anhydrous Mg SO for 2 h and concentrated to obtain 3
1
2
3
4
5
6
7
8
9
170
170
180
180
180
190
190
190
190
200
200
210
210
5
6
4
5
6
3
4
5
6
2
3
2
3
23
29
32
43
39
31
22
45
61
59
77
74
85
28
33
41
53
55
64
73
49
32
36
13
19
7
2
4
–1
as a yellowish solid with a yield of 82%. M.p. 182 °C. IR (KBr, ν, cm )
1
3
465, 3369, 2970, 1667, 1584, 1438, 1260, 1004. H NMR (DMSO,
ppm, δ) 12.48(s, 1H), 9.34(s, 2H), 6.90(s, 2H), 3.51–3.45(hept, 1H),
+
1.26–1.24(d, J=7.0 Hz, 6H). HRMS calcd for C H NaO [M+Na ]
10
12
4
219.0628, found 219.0627.
Synthesis of methyl 3,5‑dimethoxy‑4‑isopropylbenzoate (4)
A stirred solution of 3 (1.96 g, 0.01 mol) in DMF (50 mL), was
1
11
0
treated with anhydrous K CO (4.15 g, 0.03 mol) at 0±2 °C. CH I
2
3
3
1
2
(4.26 g, 0.03 mol) was introduced into the mixture with stirring.
The temperature of the mixture was gradually increased to room
temperature and maintained for 2 h. The mixture was added to
water with stirring and extracted with ethyl acetate (3×20 mL). The
combined organic layer was washed with water until it was neutral
and then concentrated under vacuum to obtain faint yellow solid 4 in
13
a
Molar ratio of n (Cu)/n (7) is 6:1.
Time from reaching the specified temperature.
b
Conclusions
–1
a yield of 93%. M.p. 108 °C. IR (KBr, ν, cm ): 2990, 2962, 1717, 1585,
1
We have successfully developed a new efficient route for the
synthesis of 1 from 2 by isopropanylation, esterification and
etherification, reduction, oxidation, Perkin condensation,
decarboxylation and demethylation. Furthermore, the optimal
condition for each step was determined in detail. This novel
method is convenient since it uses commercial available
reagents and provides a new approach in the synthesis of these
Z‑hydroxystilbene compounds.
1416, 1237, 1142, 1006. H NMR (CDCl
3
, ppm, δ) 7.22(s, 2H), 3.91(s,
3
H), 3.85(s, 6H), 3.66–3.60(hept, 1H), 1.28–1.27(d, J=7.0 Hz, 6H).
+
HRMS calcd for C H O [M+H ] 239.1278, found 239.1279.
13 19
4
Synthesis of 3,5‑dimethoxy‑4‑isopropylbenzyl alcohol (5)
Compound 4 (2.4 g, 0.01 mol), THF (30 mL) and NaBH4 (1.51 g,
0.04 mol) were placed into a 100 mL round-bottom flask. The mixture
was stirred and heated to reflux. Methanol (4 mL) was added dropwise
to the mixture which was kept under reflux for 4 h. Then the mixture

JOURNAL OF CHEMICAL RESEARCH 2015 157
was poured into water (30 mL) with stirring and extracted with ethyl
acetate (3×20 mL). The combined organic layer was washed with
water until it was neutral and then concentrated to remove the solvent.
The residue was recrystallised from ethanol/water (75/25, V/V) to
yield white needle crystal 5 with a yield of 96%. M.p. 100 °C. IR (KBr,
Synthesis of (Z)‑3,5‑dihydroxy‑4‑isopropylstilbene (1)
A mixture of 8 (2.82 g, 0.01 mol) and toluene (40 mL) was cooled to
0
±2 °C. N,N-Dimethyl aniline (6.06 g, 0.05 mol) was introduced into
the mixture with stirring; 10 min later, AlCl (0.06 mol) was added to
3
the above mixture by three batches at 10 min interval. After stirring
for 15 min, the ice-bath was removed and the mixture was heated to
–1
1
ν, cm ) 3240, 2953, 2869, 1583, 1421, 1139. H NMR (CDCl , ppm, δ)
3
6
.56(s, 2H), 4.64(s, 2H), 3.80(s, 6H), 3.62–3.53(hept, 1H), 1.27–1.26(d,
110 °C for 3 h. The mixture was cooled to room temperature, acidified
+
J=7.5 Hz, 6H). HRMS calcd for C H NaO [M+Na ] 233.1148, found
12
18
3
with HCl (10%, 15 mL) and extracted with ethyl acetate (3×20 mL).
The combined organic layer was washed with water until it was
neutral and was then evaporated to remove the solvent under vacuum.
The residue was purified by column chromatography using petroleum
ether/ethyl acetate (30/1, V/V) as eluent to afford 1 as a pale-green,
fluffy solid with a yield of 58% and purity of 99%.
233.1149.
Synthesis of 3,5‑dimethoxy‑4‑isopropylbenzaldehyde (6)
Compound 5 (2.12 g, 0.01 mol), DMSO (8 mL) and acetic anhydride
(
5 mL) were mixed with stirring at room temperature for 2 h. The
mixture was diluted with water and extracted with ethyl acetate
3×20 mL). The combined organic layer was washed with water to
–1
1
: M.p. 114 °C. IR (KBr, ν, cm ) 3278, 2956, 1620, 1578, 1423, 998.
(
1
H NMR (CDCl , ppm, δ) 7.30–7.29(d, J=7.0 Hz, 2H), 7.27–7.24(t,
neutral and evaporated to remove the solvent under vacuum, resulting
in an off-white solid. The solid was recrystallised from petroleum
ether/ethyl acetate (90/10, V/V) to yield 6 as ivory-coloured needles
3
2H), 7.21–7.18(t, 1H), 6.54–6.52(d, J=12.5 Hz, 1H), 6.39–6.36(d,
J=12.0 Hz, 1H), 6.21(s, 2H), 4.52(s, 2H), 3.43–3.37(hept, 1H),
–1
+
with a yield of 90%. M.p. 62 °C. IR (KBr, ν, cm ) 2989, 2961, 2872,
1.34–1.33(d, J=7.0 Hz, 6H). HRMS calcd for C H O [M+H ]
17
19
2
1
2
843, 2812, 2719, 1691, 1585, 1382, 1139. H NMR (CDCl , ppm, δ)
255.1380, found 255.1382.
Benvitimod: M.p. 142 °C (142°C in literature ). H NMR (CDCl ,
3
32
1
9
.89(s, 1H), 7.05(s, 2H), 3.88(s, 6H), 3.70–3.61(hept, 1H), 1.29–1.28(d,
3
+
J=7.0 Hz, 6H). HRMS calcd for C H NaO [M+Na ] 231.0992,
ppm, δ) 7.48–7.46(d, J=7.5 Hz, 2H), 7.36–7.33(t, 2H), 7.27–7.25(t, 1H),
7.00–6.97(d, J=16.5 Hz, 1H), 6.92–6.89(d, J=16.0 Hz, 1H), 6.50(s,
12
16
3
found 231.0992.
2
H), 4.70(s, 2H), 3.46–3.43(hept, 1H), 1.38–1.37(d, J=7.0 Hz, 6H).
Synthesis of (E)‑3‑(3,5‑dimethoxy‑4‑isopropylphenyl)‑2‑phenylacrylic
acid (7)
+
HRMS calcd for C H O [M+H ] 255.1380, found 255.1380.
1
7
19
2
NaAc (2.46 g, 0.03 mol) was added to a solution of 6 (2.09 g, 0.01 mol)
and phenylacetic acid (1.36 g, 0.01 mol) dissolved in acetic anhydride
We express our gratitude to the Hebei Research Center of
Pharmaceutical and Chemical Engineering, Pharmaceutical
Molecular Chemistry Key Laboratory of Ministry Technology
and Hebei Province Key Laboratory of Molecular Chemistry
for Drugs. Support funds from Hebei University of Science and
Technology are also appreciated.
(50 mL) with continuously stirring. The mixture was warmed to
138±2°C and maintained at this temperature for 6 h. The resultant
obtained mixture was cooled to room temperature and adjusted to
pH=2 with 10% HCl. The mixture was extracted with ethyl acetate
(3×20 mL). The combined organic layer was washed with water until
it was neutral and then concentrated. The residue was neutralised to
pH=7 with NaHCO solution and extracted with CH Cl after stirring
for 2 h. The aqueous phase was acidified to pH=2 with 10% HCl
and filtered to give a yellow solid, which was purified using column
chromatography to give 7 (m.p. 202 °C) as a white, fluffy solid with a
yield of 56% and purity of 99%.
Received 13 November 2014; accepted 9 February 2015
Paper 1403023 doi: 10.3184/174751915X14241928341993
Published online: 18 March 2015
3
2
2
–
1
7
: IR (KBr, ν, cm ) 2960, 2838, 1676, 1568, 1267, 1141.
H NMR (DMSO, ppm, δ) 12.64(s, 1H), 7.71(s, 1H), 7.45–7.42(t, 2H),
.37–7.34(t, 1H), 7.22–7.21(d, J=8.0 Hz, 2H), 6.33(s, 2H), 3.42(s, 6H),
.41–3.34(hept, 1H), 1.13–1.11(d, J=7.0 Hz, 6H). HRMS calcd for
References
1
1
V.M. Lopez, M.F. Martinez and R.C. Delvalle, Food. Sci. Nutr., 2003, 43,
33.
7
3
2
2
B.A. Vara, A. Mayasundari, J.C. Tellis, M.W. Danneman, V. Arredondo,
T.A. Davis, J. Min, K. Finch, R.K. Guy and J.N. Johnston, J. Org. Chem.,
2014, 79, 6913.
+
C H NaO [M+Na ] 349.1410, found 349.1417.
: M.p. 171 °C. IR (KBr, ν, cm ) 3000, 2963, 2839, 1680, 1624, 1573,
423, 1143, 980. H NMR (DMSO, ppm, δ) 12.33(s, 1H), 7.57–7.53(d,
J=16.0 Hz, 1H), 6.96(s, 2H), 6.60–6.56(d, J=16.0 Hz, 1H), 3.82(s,
H), 3.56–3.54(hept, 1H), 1.23–1.22(d, J=7.0 Hz, 6H). HRMS calcd
2
0
22
4
–1
9
1
3
4
http://www.chictr.org/en/proj/show.aspx?proj=4621.
C.F. Xiao, Y. Zou, J.L. Du, H.Y. Sun and X.K. Liu, Synth. Commun,, 2012,
1
42, 1243.
6
5
6
7
8
9
U. Holzgrabe, D. Brinz, C. Weber and S. Almeling, Chromatography,
2010, 483.
O.V. Gunar, N.I. Kalamova and N.S. Evtushenko, J. Pharm. Chem., 2003,
+
for C H NaO [M+Na ] 273.1097, found 273.1098.
14
18
4
Synthesis of (Z)‑3,5‑dimethoxy‑4‑isopropylstilbene (8)
37, 44.
Compound 7 (3.26 g, 0.01 mol), Cu powder (3.84 g, 0.06 mol) and
quinoline (50 mL) were mixed and heated to 180±2°C for 3 h. The
mixture was cooled to room temperature and added to ethyl acetate
with stirring. The resultant suspension was filtered and the filtrate was
washed with 10% HCl until the water layer lost its colour. The organic
phase was concentrated under reduced pressure to remove the solvent.
The residue was purified by the column chromatography to give 8
G.P. Jadhav, V.S. Kasture, S.S. Pawar, A.R. Vadgaonkar, A.P. Lodha, S.K.
Tuse, H.R. Kajale and S.A. Borbane, J. Pharm. Res., 2014, 8, 696.
S. Kamboj, N. Kamboj, R.K. Rawal, A. Thakkar and T.R. Bhardwaj, Curr.
Pharm. Anal., 2014, 10, 145.
J.F. Guastavino, M.E. Buden and R.A. Rossi, J. Org. Chem., 2014, 79,
9
104.
A.C. Farina, C.M. Ferranti and M.G.N. Guiso, Nat. Prod. Res., 2007, 21,
64.
R. Rotta, A.C. Neto, D.P. Lima, A. Beatriz and G.V.J. Silva, J. Mol. Struct.,
010, 975, 59.
10
5
(
m.p. 58 °C) with a yield of 73% and the purity of 99%.
11
–1
8: IR (KBr, ν, cm ) 2990, 2955, 2872, 1598, 1447, 1422, 1138.
2
1
HNMR (CDCl , ppm, δ) 7.33–7.32(d, J=7.0 Hz, 2H), 7.28–7.25(t,
3
12 G.H. Chen, J.X. Li, W. Liu and J. Webster, 2004, WO 2004031117 A1
20040415.
13 D.P. Lima, R. Rotta, A. Beatriz, M.R. Marfues, R.C. Montenegro, M.C.
Vasconcellos, C. Pessoa, M.O. Moraes and L.V. Costa-Lotufo, Eur. J. Med.
Chem., 2009, 44, 701.
2
H), 7.20–7.19(t, J=7.5 Hz, 1H), 6.60–6.58(d, J=12.0 Hz, 1H),
.51–6.49(d, J=12.5 Hz, 1H), 6.42(s, 2H), 3.58(s, 6H), 3.53–3.50(hept,
6
1
2
+
H), 1.25–1.24(d, J=7.0 Hz, 6H). HRMS calcd for C H O [M+H ]
19
23
2
83.1693, found 283.1692.
0: M.p. 77 °C. IR (KBr, ν, cm ) 2989, 2934, 2868, 2838, 1600,
1
15
4
S.C. Zhao, Y.F. Yu and Y. Zhang, Youji Huaxue, 2013, 33, 1851.
Y.J. Shang, Y.P. Qian, X.D. Liu, F. Dai, X.L. Shang, W.Q. Jia, Q. Liu, J.G.
Fang and B. Zhou, J. Org. Chem., 2009, 74, 5025.
–1
1
1
1567, 1141, 957. H NMR (CDCl , ppm, δ) 7.52–7.50(d, J=9.5 Hz,
3
2
3
H), 7.37–7.34(t, 2H), 7.25(t, 1H), 7.05(s, 2H), 6.70(s, 2H), 3.86(s, 6H),
16
K. Nakamura and S. Handa, J. Biochem., 1986, 99, 219.
.60–3.57(hept, 1H), 1.29–1.28(d, J=7.5 Hz, 6H). HRMS calcd for
17 J.U. Chung, M.J. Kim, Y.S. Lee, S.H. Ma, Y.S. Cho, S.H. Lee, Y.J. Na, M.J.
Kang and W.S. Park, 2012, PCT WO 2012050393 A2 20120419.
+
C H O [M+H ] 283.1693, found 283.1695.
19
23
2

158 JOURNAL OF CHEMICAL RESEARCH 2015
1
8
J.C. Mukuria, M. Naiki and S. Kato, Immunol. Lett., 1986, 12, 165.
M. Cavazza and M. Zandomeneghi, Gazz. Chim. Ital., 1993, 123, 723.
0 Y. Suzuki, D. Kaneno, M. Miura and S. Tomoda, Tetrahedron Lett., 2008,
26 Z.X. Wang, X.J. Zhang, Y. Zhou and Y. Zou, J. Chin. Pharm. Sci., 2005,
14, 204.
1
9
27
K. Gukroger, J.A. Hadfied, L.A. Hepworth, N.J. Lawrence and A.T.
McGown, J. Org. Chem., 2001, 66, 8135.
2
4
9, 4223.
2
2
3
8
9
0
Z.Y. Kang, Z.Z. Wu, Z.T. Sun and Z.X. Tang, 2005, PCT/CN2005/001086.
V. Sharma and V.R. Chourey, Int. J. Adv. Res., 2014, 2, 617.
J. Yang, G.Y. Liu, F. Dai, X.Y. Cao, Y.F. Kang, L.M. Hu, J.J. Tang, X.Z. Li,
Y. Li, X.L. Jin and B. Zhou, Bioorg. Med. Chem. Lett., 2011, 21, 6420.
A. Farina, C. Ferranti, C. Marra, M. Guiso and G. Norcia, Nat. Prod. Res.,
2
1
A. Saeed and Z. Ashraf, J. Chem. Sci., 2006, 118, 419.
2
2
2
3
R.A. Fernandes and P. Kumar, Tetrahedron Lett., 2003, 44, 1275.
V.I. Barkovskii, V.V. Pankratov, L.F. Koltanyuk, L.P. MikhaIlik and O.S.
Barkovskaya, Russ. 2006, RU 2273919 C1 20060410.
Y. Zhang and S.C. Zhao, 2010, CN 101830764 A.
A.K. Sinha, V. Kumar, A. Sharma, A. Sharma and R. Kumar, Tetrahedron,
31
2
2
4
5
2
007, 21, 564.
32 J.G. Gao, Y. Zhang, H.T. Zheng, C.F. Wang, H.X. Liu and S.C. Zhao, Adv.
Mater. Res., 2011, 236, 2378.
2
007, 63, 11070.

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