Synthesis and antinociceptive activity of capsinoid derivatives

Article abstract of DOI:10.1016/j.ejmech.2009.02.017

According to the data of structural identification, six capsinoids or their derivatives were successfully synthesized to test for their analgesic activity. Three of them were capsinoids with different acyl chain compared with capsaicin after substitution

Full text of DOI:10.1016/j.ejmech.2009.02.017

European Journal of Medicinal Chemistry 44 (2009) 3345–3349
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Synthesis and antinociceptive activity of capsinoid derivatives
,
,
G.-J. He a b, X.-L. Ye c, X. Mou a, Z. Chen a, X.-G. Li a
*
a Chemistry Institute of Pharmaceutical Resources, School of Pharmaceutical Science, Southwest University, Chongqing 400716, China
b Department of Biology and Environment Engineering, Guiyang School, Guizhou 550005, China
c School of Life Sciences, Southwest University, Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history:
According to the data of structural identification, six capsinoids or their derivatives were successfully
synthesized to test for their analgesic activity. Three of them were capsinoids with different acyl chain
compared with capsaicin after substitution of ester for amide at C1 position. The other three could be
described as capsinoid derivatives with different alkoxy chain, compared with capsaicin after substitu-
tion of ester for amide at C1 position and alkoxy for hydroxy at C4 position and synthesis of them was
reported first. Compared with capsaicin, experiment results about pungency showed that capsinoids and
their derivatives synthesized were all no or only slight pungent; that is, capsinoid derivates synthesized
still have the same advantage of nonpungency with capsinoid. Relation between analgesic activity and
molecular structure of compounds synthesized was also reported first, which would facilitate finding
capsinoid derivatives owning excellent analgesic activity. The experiment results about analgesic activity
showed that capsinoids displayed moderate analgesia effect and their antinociceptive activity decreased
with the elongation of acyl chain at C1 position; that antinociceptive activities of capsinoid derivatives
synthesized were much stronger not only than those of indomethacin but also than those of their
precursor (vanillyl decanoate), which increased with elongation of alkoxyl chain at C4 position. Especially
4-hexyloxyl-3-methoxybenzyl decanoate showed the best antinociceptive activity in synthesized
compounds, which was 9-fold higher than its precursor (vanillyl decanoate) and 6-fold higher than that
of indomethacin.
Received 26 October 2008
Received in revised form
1 February 2009
Accepted 7 February 2009
Available online 20 February 2009
Keywords:
Capsaicin
Capsinoid
Capsinoid derivatives
Nonpungency
Antinociceptive activity
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
harmful stimulation [6]. Capsinoids own physiological functions
similar to those of capsaicinoids. Ohnuki [7] have reported that the
Capsaicinoid (CAP) is a pungent principal of capsicum plants
[1,2] and it has various physiological activities [3,4], such as anal-
gesia, weight loss and detoxification, etc. However, its strong
pungency and nociceptive activity limit its application in food or
medicine fields. A novel group of compounds, capsinoids including
capsiate, dihydrocapsiate, and nordihydrocapsiate, have been iso-
lated from the fruits of a sweet cultivar of pepper, CH-19 Sweet
(Capsicum annuum L.) [5,6]. The fundamental chemical structure of
capsinoids is an aliphatic hydroxyl group in vanillyl alcohol with
a fatty acid. Capsinoids bear a marked structural resemblance to
capsaicinoids, except for the central linkage; that is, an amide
moiety is found in capsaicinoids, and ester moiety is in capsinoids.
Despite the structural similarity between capsinoid and cap-
saicinoid, the former has no or only slight pungency and less
intake of a nonpungent pepper containing natural capsinoids raised
human skin temperature and promoted human energy metabo-
lism, and suppressed fat accumulation without marked perspira-
tion or languidness. Such characteristics make it potential to be
widely used in food or medicine [8]. The yield of CH-19 Sweet and
the content of capsinoid in it are too low to meet with the market
need, so chemical synthesis becomes a main way to obtain mate-
rials owning function similar to capsinoids.
A capsinoid was synthesized by the lipase-catalyzed esterifica-
tion of vanillyl alcohol with fatty acid derivatives in an organic
solvent [9]. However, there was no report about the alkoxyl
modification for capsinoid and the relationship between the
structure and analgesic activity of capsinoid or capsinoid deriva-
tives at present.
In the following study, several homologues of capsinoid or their
derivates having various acyl chain length at C1 position or alkoxyl
chain length at C4 position were synthesized chemically to evaluate
the effect of substituted group on the pungency and the analgesic
activity.
Abbreviations: C.L., confidence limits; MPP, the concentrations having
a moderate pain-producing potency; RPP, relative pain-producing potency.
* Corresponding author. Tel./fax: þ86 23 68250728.
E-mail addresses: xuegangli2000@yahoo.com.cn, heguoju78@163.com (X.-G. Li).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.02.017

3346
G.-J. He et al. / European Journal of Medicinal Chemistry 44 (2009) 3345–3349
2. Chemistry
dilutions. Each dilution was dropped into the right eye (vehicle
being administered to the left eye as negative control) of KM rats,
and the total number of protective movements (scratching, wiping
of the eye with the foreleg) was counted for 30 min. Each
concentration was applied to a total of 6 rats (half male and half
female), and a dose–response curve was obtained from the mean
value of each group. MPP (the concentrations having a moderate
pain-producing potency) were calculated from the dose–response
curve; that is, the concentration inducing equal reactions of 32
scratches (the median response induced by CAP) was recorded. On
the basis of the MPP values obtained, RPP (relative pain-producing
potency) values were determined with respect to the pain-
producing potency of CAP, which was taken as 1000.
With vanillyl alcohol as lead compound, caprylyl chloride, dec-
anoyl chloride or lauroyl chloride as acylating agent, under strict
control of reaction conditions, capsinoid compared with capsaicin
after substitution of ester for amide at C1 position, i.e. vanillyl
caprylate (A in Fig. 1), vanillyl decanoate (B in Fig. 1), vanillyl laurate
(C in Fig. 1), were synthesized according to Fig. 1. In addition, the
chemistry reaction between vanillyl alcohol and corresponding
alkyl bromide took place and their product was intermediate of
4-alkoxy-3-methoxybenzyl alcohol, then capsinoid derivatives
compared with capsaicin after substitution of ester for amide at C1
position and alkoxy for hydroxy at C4 position were obtained by
acylation reaction of intermediate with decanoyl chloride, i.e.
4-ethoxy-3-methoxybenzyl decanoate (D in Fig. 1), 4-butoxy-3-
methoxybenzyl decanoate (E in Fig. 1), 4-hexyloxy-3-methox-
ybenzyl decanoate (F in Fig. 1) according to Fig. 1. Synthesis of D–F
was reported first.
3.2. Evaluation of antinociceptive effects
According to the method [11], antinociceptive tests were carried
out in half male and half female mice. Capsaicin and six compounds
synthesized were dissolved by 10% Tween-80 aqueous solution in
successive twofold dilutions. Each group included eight mice fed
with food and water randomly. The test solution was administered
by subcutaneous injection with single dose of 0.2 mL (indometh-
acin and vehicle administered as control). After 20 min, 0.2 mL of
0.7% acetic acid was injected intraperitoneally to induce writhing.
Then the mice were placed in separate clear glass cages and the
number of writhes was counted for 30 min after acetic acid injec-
tion, a writhe being defined as a sequence of arching of the back,
followed by pelvic rotation and hind limb extension. According to
the experiment results, ED50 values were obtained at last.
3. Pharmacology
Healthy Kunming mice of both genders (20 ꢀ 2 g, 7 weeks old)
were purchased from Laboratory Animal Centre of Chongqing
Medical University. Animal certificate No. was 0001802, and license
No. was scxk (Yu) 20020004. Mice were housed in stainless cages in
a room with controlled temperature (23 ꢀ 2 ꢁC) and humidity
(40–60%) and a 12 h light/dark cycle. The protocol complied with
the guidelines of Chongqing City Laboratory Animal Administration
Committee of China for the care and use of laboratory animals. Then
animals were kept under observation for 7 days to detect the effect
of capsinoids and their derivatives on analgesic activity and
pungent potency.
4. Results and discussion
4.1. Synthesis of compounds
3.1. Evaluation of the potency of pungency
The spectral data and other characteristic parameters of
compounds A–F are shown in Section 6.2. From the IR data, we
could see that diagnostic IR absorbance of phenolic hydroxyl bond,
ester bond emerged in the IR spectra of compounds A–C and only
The wiping test [10] was performed to evaluate the pungency
potency. Briefly, capsaicin and six compounds synthesized were
dissolved by 10% Tween-80 aqueous solution in successive twofold
O
H2C
OH
H2C
OH
H2C
O
C
R2
1
4
acyl chloride / THF
CeCl3, r.t
OCH3
Cs2CO3/DMSO
R1Br, K2CO3, r.t
3
OCH3
OCH3
OH
OR1
OR1
R1
R2
7
6~3
2
1
A
B
Vanillyl caprylate
Vanillyl decanoate
Vanillyl laurate
H
H
H
-CH2(CH2)4CH2CH3
8~3
-CH2(CH2)6CH2CH3
11 10~3
9
2
1
2
1
-CH2(CH2)8CH2CH3
8~3
-CH2(CH2)6CH2CH3
8~3
-CH2(CH2)6CH2CH3
8~3
-CH2(CH2)6CH2CH3
C
D
2' 1'
-CH2CH3
9
2
1
4-ethoxy-3-methoxybenzyl decanoate
4-butoxy-3-methoxybenzyl decanoate
4'~2' 1'
-(CH2)3CH3
9
2
1
E
F
6'~2' 1'
-(CH2)5CH3
9
2
1
4-hexyloxy-3-methoxybenzyl decanoate
Fig. 1. Synthesis of capsinoid derivatives.

G.-J. He et al. / European Journal of Medicinal Chemistry 44 (2009) 3345–3349
3347
Table 2
ester bond in the IR spectra of compounds D–F. Compared with
compounds A–C’s 1H NMR data, the peak data of Ph-OH dis-
appeared and the peak data of alkoxy hydrogen emerged in the 1H
NMR data of compounds D–F. All spectral data could be analyzed
reasonably by their molecular structures. So, we concluded that
compounds A–F were synthesized successfully.
Antinociceptive effects of synthesized compounds on acetic acid-induced writhing
in mice.
Compound
ED50 (95% C.L.)a (mg/kg)
Potency ratio
Indomethacin
10.08 ꢀ 0.86
12.61 ꢀ 1.24
15.60 ꢀ 1.40
19.42 ꢀ 1.08
3.92 ꢀ 0.25
3.16 ꢀ 0.18
1.84 ꢀ 0.11
1.00
0.80
0.65
0.52
2.57
3.19
5.89
A
B
C
D
E
F
4.2. Evaluation of the pungency for compounds synthesized
Relative pungent potency of compounds synthesized was listed
in Table 1. According to evaluation method of pungency potency,
those concentrations inducing equal reactions of 32 scratchings
must be found, before MPP values were obtained during the
experiment. The MPP value of capsaicin was 0.099 mg/mL, and its
RPP value was defined as 1000; that is, 0.099 mg/mL of capsaicin
could make mice scratch 32 times in 30 min. During the experi-
ment, six compounds synthesized were undiluted by solvent and
dropped directly into rats’ eyes, the total number of protective
movements of rats for six compounds could not reach 32 times.
According to the results of Table 1, the MPP value of compounds
synthesized was 10 000-fold higher than that of capsaicin. It indi-
cated that compounds synthesized were no or only slight pungent
compared with capsaicin after substitution of ester for amide at C1
position.
a
ED50 and 95% confidence limits were calculated by means of SPSS 10.0 statistical
software.
While ED50 values of compounds D-CF were much lower than
not only their precursor (compound B) but also that of indometh-
acin; that is, their antinociceptive effect is better than not only their
precursor but also indomethacin, so they showed excellent anti-
nociceptive activity. With the alkoxyl chain of derivates prolonging,
the ED50 would be declined. Especially, the ED50 of 4-hexyloxyl-3-
methoxybenzyl decanoate was one sixth of that of indomethacin
and one ninth of that of compound B. It indicated that the anti-
nociceptive activity of capsinoid derivates increased with the
elongation of alkoxyl chain at C4 position, which was stronger than
that of indomethacin and that of their precursor.
For compounds A–C, the scratching times in 30 min decreased
with the elongation of the acyl chain lengths at C1 position. It
indicated that the pungency was weakened correspondingly.
For compounds D–F, the scratching times were only 4, 8 and 11,
respectively, while those of their precursor (compound B) were 25
times. Therefore, the pungency of D–F would be weaker than that of
compound B. It suggested the substitution of alkoxy for hydroxy at
C4 position make the scratching times decrease greatly. As a result,
4-alkoxyl-3-methoxybenzyl decanoates had no pungency,
compared with capsaicin; that is, capsinoid derivates synthesized
still remain with the same nonpungent property with capsinoid.
Yet there was an increasing trend in pungency relatively for
compounds D–F with elongation of alkoxyl chain at C4 position.
5. Conclusion
According to the data of structural identification, capsinoids and
their derivates were synthesized successfully. Pungent results
showed that capsinoid and its derivatives were no or only slight
pungent compared with capsaicin after substitution of ester for
amide at C1 position. Antinociceptive experiment suggested that
capsinoid derivatives had a stronger antinociceptive activity after
the substitution of alkoxy for hydroxy at C4 position compared with
capsinoid, which increased with elongation of alkoxyl chain.
4-Hexyloxyl-3-methoxybenzyl decanoate showed the best
antinociceptive activity in synthesized compounds and its anti-
nociceptive activity was 6-fold higher than that of indomethacin
and 9-fold higher than its precursor (vanillyl decanoate).
4.3. Experiment result of antinociceptive effect for
synthesized compounds
6. Materials and methods
Using indomethacin as
a reference compound, the anti-
6.1. Chemicals and apparatus
nociceptive effects of compounds synthesized are listed in Table 2.
All mice treated with these compounds showed a dose-related
decrease in writhing counts induced by acetic acid. Writhing was
most pronounced for 30 min following the administration of acetic
acid, gradually subsiding after having reached a peak in the first
10–15 min.
In general, ED50 values of compounds A–C were slightly higher
than those of indomethacin, and displayed moderate analgesia
effect. And their antinociceptive activity decreased with the elon-
gation of acyl chain at C1 position.
Capsaicin (purity of more than 99%) was provided by Chemistry
Institute of Pharmaceutical Resources of Southwest University in
China (Chongqing, China); vanillyl alcohol was purchased from
Sigma–Aldrich Japan K.K. (Japan). Other reagents were of A.R.
grade, purchased from Chongqing Chemical Reagent Company
(Chongqing, China).
UV, IR, 1H NMR and TLC were used to identify the structures of
compounds A–F. 1H NMR was recorded on a Bruker DPX400 spec-
trometer with TMS as internal standard. IR data were obtained
through Model Perkin Elmer IR spectrometer and UV data through
Model Hitachi U-1800 UV spectrometer. Elemental analysis was
performed on Model Perkin Elmer 240 element analyzer within
ꢀ0.4% of the theoretical values. TLC with mixtures of petroleum
(60–90 ꢁC) and ethyl acetate as developer was used to identify the
compounds synthesized, performed on silica gel-GF254 thin layer
with separated compounds visualized at 254 nm under a UV lamp.
Table 1
The relative pungent potency of substances synthesized.
Compound
Scratching times in 30 min (x ꢀ s)
MPP (mg/mL)
RPP
Capsaicin
32 ꢀ 4.8**
28 ꢀ 2.5**
25 ꢀ 1.9**
22 ꢀ 1.2**
4 ꢀ 0.4**
8 ꢀ 0.8**
11 ꢀ 1.2**
0.099
1000
a
A
B
C
D
E
F
–
–
–
–
–
–
a
a
a
a
a
6.2. Synthesis of capsinoids and capsinoid derivates
a
The synthesis route of capsinoids and capsinoid derivatives is
shown in Fig. 1.
Treatment with pure compounds (purity of more than 97%); **p < 0.01
compared with capsaicin; –: relative nonpungency compared with capsaicin.

3348
G.-J. He et al. / European Journal of Medicinal Chemistry 44 (2009) 3345–3349
6.2.1. Vanillyl caprylate (A in Fig. 1)
(m, 3H, 3ArH); Anal. Calcd for C10O3H14: C 65.91, H 7.74; found: C
65.96, H 7.71. And those data proved the intermediate product was
synthesized successfully to a great extent.
The synthesis method made reference to literature [12]. Under
a nitrogen atmosphere, to a solution of vanillyl alcohol (1.62 mM) in
dry THF (8 mL), caprylyl chloride (1.62 mM) and CeCl3 (0.081 mM)
were added. After stirring at room temperature for 12 h, the reac-
tion was worked up by removal of the solvent, and the residue was
partitioned between EtOAc and saturated NaHCO3 (ca. 50 mL each).
The organic phase was washed with anhydrous Na2SO4 and evap-
orated. Then the residue was purified by gravity column chroma-
tography on silica gel (petroleum ether–ethyl acetate, 7:2, V/V) to
give 350 mg (77%) of vanillyl caprylate as a colourless oil. UV
Then under a nitrogen atmosphere, to a solution of 4-ethoxy-3-
methoxybenzyl alcohol (1.62 mM) in dry THF (8 mL), caprylyl
chloride (1.62 mM) and CeCl3 (0.081 mM) were added. After stir-
ring at room temperature for 12 h, the reaction was worked up by
removal of the solvent. The residue was partitioned between EtOAc
and saturated NaHCO3 (ca. 50 mL each). The organic phase was
washed with anhydrous Na2SO4 and evaporated, and the residue
was purified by gravity column chromatography on silica gel
(petroleum ether–ethyl acetate, 3:1) to give 446 mg (82%) of
compound D as a colourless oil. Spectral data of D were as follows:
(CH3OH) lmax (log 3 d:
): 281 (2.22), 238 (2.77) nm; 1H NMR (CDCl3)
0.87 (t, J ¼ 7 Hz, 3H, 1-CH3), 1.22–1.33 (m, 8H, 3–6-(CH2)4), 1.63 (m,
2H, 2-CH2), 2.33 (t, J ¼ 7.6 Hz, 2H, 7-CH2), 3.90 (s, 3H, ArOCH3), 5.03
(s, 2H, ArCH2O), 5.70 (s, 1H, ArOH), 6.86–6.90 (m, 3H, 3ArH). IR
UV (CH3CH2OH) lmax (log
(CDCl3)
3
): 255 (3.86), 292 (3.33) nm; 1H NMR
: 0.87 (t, J ¼ 6.8 Hz, 3H, 1-CH3), 1.27 (t, J ¼ 8 Hz, 12H, 3–8-
d
(primary absorption apex, KBr pellet, cmꢂ1
)
n
: 3445, 2925, 2857,
(CH2)6), 1.46 (t, J ¼ 7 Hz, 3H, 10-CH3), 1.62 (m, 2H, 2-CH2), 2.34 (t,
J ¼ 7.8 Hz, 2H, 9-CH2), 3.88 (s, 3H, OCH3), 4.10 (q, J ¼ 6.9 Hz, 2H, 20-
CH2), 5.04 (s, 2H, ArCH2O), 6.83–6.91 (m, 3H, 3ArH); IR (primary
absorption peak, KBr pellet, cmꢂ1) v: 2925, 1736, 1592, 1516, 1265,
1162, 803; Anal. Calcd for C20H32O4: C 71.41, H 9.59; found C 71.33,
H 9.62.
1733, 1614, 1520, 1464, 1434, 1382, 1275, 1234, 1036, 853, 819, 743,
724; Anal. Calcd for C16H24O4: C 68.54, H 8.63; found C 68.46, H
8.61.
6.2.2. Vanillyl decanoate (B in Fig. 1)
Compound B was prepared using the similar method as used for
A, yet difference from the latter was that reactant caprylyl chloride
was substituted by decanoyl chloride and the residue containing
vanillyl decanoate was purified by gravity column chromatography
on silica gel (petroleum ether–ethyl acetate, 3:1) to give 357 mg
(71%) of vanillyl caprylate as a colourless oil. UV (CH3OH) lmax
6.2.5. 4-Butoxy-3-methoxybenzyl decanoate (E in Fig. 1)
Compound E was prepared using the similar method as used for
compound D, yet difference from the latter was that reactant of
ethyl bromide was replaced by 1-butyl bromide. Then 4-butoxy-3-
methoxybenzyl alcohol of intermediate product (86%) was
synthesized and its spectral data were as follows: 1H NMR (CDCl3)
(log 3 d: 0.87 (t,
): 281 (2.34), 240 (2.59) nm; 1H NMR (CDCl3)
J ¼ 7.0 Hz, 1-CH3), 1.25–1.27 (m, 12H, 3–8-(CH2)6), 1.63 (q, J ¼ 7.2 Hz,
2H, 2-CH2), 2.32 (t, J ¼ 7.6 Hz, 2H, 9-CH2), 3.88 (s, 3H, OCH3), 5.05 (s,
2H, ArCH2O), 5.70 (s, 1H, ArOH), 6.86–6.91 (m, 3H, 3ArH); IR
d
: 0.88 (t, J ¼ 7.3 Hz, 3H, 10-CH3), 1.39 (m, 2H, 20-CH2), 1.63 (m, 2H,
30-CH2), 2.47 (t, J ¼ 6.8 Hz, 2H, 40-CH2), 3.70 (s, 3H, OCH3), 3.90 (s,
2H, ArCH2O), 4.38 (s, 1H, ArCOH), 6.53–6.88 (m, 3H, 3ArH); Anal.
Calcd for C12O3H18: C 68.54, H 8.63; found: C 68.47, H 8.65.
In the end 466 mg (79%) of Compound E was obtained as a kind
of colourless oil. Its spectra data were as follows: UV (CH3CH2OH)
(primary absorption apex, KBr pellet, cmꢂ1
) n: 3445, 2926, 2856,
1733, 1614, 1560, 1516, 1464, 1435, 1381, 1277, 1230, 1036, 853, 819,
744, 723; Anal. Calcd for C18H28O4: C 70.09, H 9.15; found C 69.97, H
9.16.
lmax (log 3 d: 0.88
): 254 (3.87), 293 (3.34) nm; 1H NMR (CDCl3)
(t, J ¼ 7 Hz, 3H, 1-CH3), 0.97 (t, J ¼ 7.4 Hz, 3H, 10-CH3), 1.25–1.28
(m, 12H, 3–8-(CH2)6), 1.49 (m, 2H, 20-CH2), 1.63 (m, 2H, 2-CH2), 1.83
(m, 2H, 30-CH2), 2.33 (t, J ¼ 7.6 Hz, 2H, 9-CH2), 3.87 (s, 3H, OCH3),
4.02 (t, J ¼ 6.8 Hz, 2H, 40-CH2), 5.04 (s, 2H, ArCH2O), 6.84–6.89 (m,
6.2.3. Vanillyl laurate (C in Fig. 1)
Compound C was also prepared using the similar method as
used for A, yet difference from the latter was that reactant caprylyl
chloride was substituted by lauroyl chloride; that the residue
containing vanillyl laurate was purified by gravity column chro-
matography on silica gel (petroleum ether–ethyl acetate, 2:1) to
give 388 mg (72%) products as a colourless oil. UV (CH3OH) lmax
3H, 3ArH); IR (primary absorption apex, KBr pellet, cmꢂ1 (cmꢂ1):
) n
2927, 2857, 1738, 1608, 1515, 1267, 1163, 803; Anal. Calcd for
C22H36O4: C 72.49, H 9.95; found C 72.45, H 9.91.
(log
3
): 280 (2.39), 239 (2.77) nm; 1H NMR (CDCl3)
d
: 0.87 (t,
6.2.6. 4-Hexyloxy-3-methoxybenzyl decanoate (F in Fig. 1)
J ¼ 7.0 Hz, 3H, 1-CH3), 1.24–1.29 (m, 16H, 3–10-(CH2)8), 1.62 (m, 2H,
2-CH2), 2.33 (t, J ¼ 7.6 Hz, 2H, 11-CH2), 3.88 (s, 3H, ArOCH3), 5.03 (s,
2H, ArCH2), 5.70 (s, 1H, ArOH), 6.86–6.90 (m, 3H, 3ArH); IR
Compound F was also prepared using the similar method as D,
yet the difference from the latter was that reactant of ethyl bromide
was replaced by bromic 1-hexane. Then 4-hexyloxy-3-methox-
ybenzyl alcohol of intermediate product (84%) was synthesized and
(primary absorption apex, KBr pellet, cmꢂ1
) n: 3445, 2926, 2855,
1733, 1615, 1516, 1464, 1434, 1383, 1275, 1233, 1036, 854, 817, 742,
723; Anal. Calcd for C20H32O4: C 71.39, H 9.59; found C 71.33, H
9.61.
its spectral data were as follows: 1H NMR (CDCl3)
d: 0.89 (t,
J ¼ 7.1 Hz, 3H, 10-CH3), 1.31–1.34 (m, 4H, 30–40-(CH2)2), 1.45 (m, 2H,
20-CH2), 1.82 (m, 2H, 50-CH2), 3.80 (s, 3H, OCH3), 3.90 (s, 2H, ArCH2),
4.01 (t, J ¼ 7 Hz, 2H, 60-CH2), 4.38 (s, 1H, ArCOH), 6.63–6.88 (m, 3H,
3ArH); Anal. Calcd for C14O3H22: C 70.56, H 9.30; found: C 70.63, H
9.33.
6.2.4. 4-Ethoxy-3-methoxybenzyl decanoate (D in Fig. 1)
Under a nitrogen atmosphere, the following substances were
added to a round-bottomed flask in the sequence: anhydrous
DMSO (5.0 mL), Cs2CO3 (0.1 mM), K2CO3 (2.0 mM), vanillyl alcohol
(1.0 mM), ethyl bromide (1.5 mM), molecular sieve (200 mg). After
stirring at room temperature for 15 h, isopropyl ether (100 mL) was
added to play a role in dilution. Mixture in flask was filtered and
was washed in water and dehydrated with anhydrous Na2SO4. After
evaporation, the reside was purified by silica gel column chroma-
tography (petroleum ether–ethyl acetate, 5:2) to get a colourless oil
At last 489 mg offspring (78%) of compound F was obtained as
a
colourless oil and its spectra data were as follows: UV
(CH3CH2OH) lmax (log 3
): 255 (3.86), 291 (3.34) nm; 1H NMR
(CDCl3)
d
: 0.86 (t, J ¼ 6.9 Hz, 3H, 1-CH3), 0.90 (t, J ¼ 7.1 Hz, 3H, 10-
CH3), 1.24–1.28 (m, 12H, 3–8-(CH2)6), 1.31–1.35 (m, 4H, 30–40-
(CH2)2), 1.45 (m, 2H, 20-CH2), 1.64 (m, 2H, 2-CH2), 1.84 (m, 2H,
50-CH2), 2.33 (t, J ¼ 7.6 Hz, 2H, 9-CH2), 3.87 (s, 3H, OCH3), 4.00 (t,
J ¼ 7 Hz, 2H, 60-CH2), 5.03 (s, 2H, ArCH2), 6.83–6.90 (m, 3H, 3ArH);
IR (primary absorption apex, KBr pellet, cmꢂ1) v (cmꢂ1): 2927, 2857,
1738, 1608, 1515, 1267, 1163, 804; Anal. Calcd for C24H40O4: C 73.43,
H 10.27; found C 73.37, H 10.24.
(87%) of 4-ethoxy-3-methoxybenzyl alcohol. 1H NMR (CDCl3)
d:
1.36 (t, J ¼ 7 Hz, 3H, 10-CH3), 3.42 (q, J ¼ 6.9 Hz, 2H, 20-CH2), 3.78 (s,
3H, OCH3), 3.91 (s, 2H, ArCH2O), 4.40 (s, 1H, ArCOH), 6.80–6.91

G.-J. He et al. / European Journal of Medicinal Chemistry 44 (2009) 3345–3349
3349
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Acknowledgement
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This work was supported by the National Natural Science
Foundation of China (NO. 20673084), the Natural Science Founda-
tion Project of CQ CSTC (2008BB5257) and the Major Technologies
R&D Program of CQ CSTC (2008AA5021).
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