Synthesis and antihypertensive activity evaluation in spontaneously hypertensive rats of nitrendipine analogues

Article abstract of DOI:10.1007/s00044-010-9477-0

The antihypertensive activity of nitrendipine analogues can be improved by properly lengthening its alkyl chain in 3- or 5-position. Nitrendipine and its seven analogues were synthesized, and their antihypertensive activities in spontaneously hypertensive rats (SHR) were evaluated by ig administration. It was found that 5-n-heptyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine- 3,5-dicarboxylate [(±)-5] exhibited the strongest antihypertensive effect amongst eight compounds. (?)-5-nheptyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine- 3,5-dicarboxylate [(+)-5] was also prepared. Antihypertensive activities of (±)-5 and (?)-5 in SHR were compared. The results showed that (±)-5 and (?)-5 had a higher potency than nitrendipine, and (+)-isomer was 1.79-fold the raceme at a dose of 2 mg/kg. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9477-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1325–1330
DOI 10.1007/s00044-010-9477-0
ORIGINAL RESEARCH
Synthesis and antihypertensive activity evaluation
in spontaneously hypertensive rats of nitrendipine analogues
•
Kai Zhou Xiao-meng Wang Yi-zhi Zhao
•
•
•
Yong-xiao Cao Qiang Fu San-qi Zhang
•
Received: 1 July 2010 / Accepted: 14 October 2010 / Published online: 28 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The antihypertensive activity of nitrendipine
analogues can be improved by properly lengthening its
alkyl chain in 3- or 5-position. Nitrendipine and its seven
analogues were synthesized, and their antihypertensive
activities in spontaneously hypertensive rats (SHR) were
evaluated by ig administration. It was found that 5-n-heptyl
3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate [( )-5] exhibited the strongest
antihypertensive effect amongst eight compounds. (?)-5-n-
heptyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihy-
dropyridine-3,5-dicarboxylate [(?)-5] was also prepared.
Antihypertensive activities of ( )-5 and (?)-5 in SHR
were compared. The results showed that ( )-5 and (?)-5
had a higher potency than nitrendipine, and (?)-isomer was
1.79-fold the raceme at a dose of 2 mg/kg.
Levine et al., 2003), lacidipine (Raju et al., 2009;
Motomura et al., 1993), felodipine (Trachtman et al.,
2003), etc. are long-acting and high active DHPs calcium
antagonists. Though effective as antihypertensive drugs,
they are relatively complicated in producing and high in
manufacturing cost, and some intermediates are harmful to
environment. Therefore, it is necessary to develop new
DHPs calcium antagonists with simple structure, facile
synthesis and effective antihypertensive.
Nitrendipine is a DHPs calcium antagonist with a simple
structure, but its effectiveness is not high. Studies indicate
that the antihypertensive activity of nitrendipine analogues
can be improved by lengthening its alkyl chain in 3- or
5-position (Baindur et al., 1993; Peri et al., 2000). For this
reason, we synthesized nitrendipine and its seven ana-
logues [3-methyl 5-straight alkyl 2,6-dimethyl-4-(3-nitro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate] (Fig. 1).
Antihypertensive activity of compounds 1–8 in spontane-
ously hypertensive rats (SHR) was compared. It was
found that 5-n-heptyl 3-methyl 2,6-dimethyl-4-(3-nitro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (compound
5) exhibited the strongest antihypertensive effect amongst
all synthesized compounds. The substituted groups in
3- and 5-position in compound 5 are different, so there
are a couple of enantiomers. Studies showed that calcium
antagonistic activity of the S-enantiomer and R-enantiomer
is different. For example, S-enantiomer of nilvadipine is
about 100 times more potent than the R-enantiomer in its
antihypertensive action (Fu et al., 2003; Tokuma and
Noguchi, 1995). In the case of amlodipine, S/R is 1000
(Park et al., 2006). Meanwhile it was elucidated that
(S)-(?)-enantiomer is the active isomer in the nitrendi-
pine analogues (Zhang et al., 2010). So (?)-5-n-heptyl
3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (Fig. 1) was also prepared. The
Keywords Antihypertensive activity ꢀ
1,4-Dihydropyridines ꢀ Nitrendipine analogues ꢀ
Enantiomer ꢀ SHR
Introduction
1,4-Dihydropyridines (DHPs), a class of calcium antago-
nist, is widely used in clinic for the treatment of cardio-
vascular diseases, such as hypertension, etc. (Sabitha et al.,
2003; Zolfigol et al., 2006). Amlodipine (Liu et al., 2010;
K. Zhou ꢀ X. Wang ꢀ Q. Fu ꢀ S. Zhang (&)
Department of Pharmacy, Xi’an Jiaotong University College of
Medicine, Xi’an 710061, Shaanxi, People’s Republic of China
e-mail: sqzhang@xjtu.edu.cn
Y. Zhao ꢀ Y. Cao
Department of Pharmacology, Xi’an Jiaotong University College
of Medicine, Xi’an 710061, Shaanxi, People’s Republic of China
123

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Med Chem Res (2011) 20:1325–1330
Fig. 1 The structures of
synthesized compounds
antihypertensive activity of ( )-5 and (?)-5 in SHR was
compared. Here, we report the synthesis and antihyper-
tensive activity of nitrendipine and its seven analogues.
then dried to give compound 1. Yield 74.2%; mp
194.0–195.5°C [lit. mp 188.0–191.0°C (Ghorbani-Chog-
hamarani et al., 2008)]; MS (m/z): 347.1 (M?1); 1H NMR
(CDCl3) d:2.36 (s, 6H, 29–CH3), 3.65 (s, 6H, 29–OCH3),
5.10 (s, 1H, CH), 5.86 (s, 1H, –NH–), 7.37 (t, 1H, 50-Ph-H),
7.62 (d, 1H, 60-Ph-H), 8.00 (d, 1H, 40-Ph-H), 8.09 (s, 1H,
20-Ph-H).
Materials and methods
Quinidine was obtained from J&K Chemical Ltd. 3-nitro-
benzaldehyde, methyl acetoacetate, glacial acetic acid,
piperidine and solvent were purchased from SCRC, China.
Straight alkyl 3-aminocrotonate[methyl ester–dodecyl
ester] was prepared by ourselves.
Synthesis of straight alkyl methyl 2,6-dimethyl-4-(3-
nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
(2–8)
All melting points were determined on a Beijing micro
melting-point apparatus and thermometer was uncorrected.
1H NMR spectra were recorded in CDCl3 at 300 MHz,
with an internal reference tetramethylsilane (TMS), Bruker
NMR spectrometer. All chemical shifts are reported in
parts per million (ppm). Mass spectra were performed on a
Shimadzu GC-MS-QP2010 instrument. The measurement
of e.e was performed in a Shimadzu LC-10AT HPLC
instrument. Optical rotation was measured on a full circle
manual polarimeter (WXG-4). The blood pressure of SHR
was measured by a BP-6 animal non-invasive tail-cuff
plethysmography, Chengdu Thai Union Technology Co.,
Ltd. China. Spontaneously hypertensive rats (SHR) were
purchased from Beijing Vital River Laboratory Animal
Technology Co., Ltd, China. The experimental protocol
was approved by Ethic’s Committee of Xi’an Jiaotong
University.
Methyl 2-(3-nitrobenzylidene)-3-oxobutanoate was syn-
thesized according to reported procedure (Wu et al., 2003),
mp 151–154°C [lit. mp 156–158°C].
A mixture of methyl 2-(3-nitrobenzylidene)-3-oxobut-
anoate (23.42 g, 90 mmol) and a straight alkyl 3-amino-
crotonate (ethyl ester–dodecyl ester, 90 mmol) in anhydrous
ethanol (120 ml) was heated to reflux for 6 h under stirring.
Solvent (about 50 ml) was removed under reduced pressure
and the mixture was kept at ambient temperature. When a
crystal was formed, the mixture was kept in a refrigerator
overnight. The crystals were collected by filtration and re-
crystallized from ethanol (40 ml) to give the corresponding
compounds 2–8.
5-Ethyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (2, nitrendipine): Yield
86.0%; mp 157.0–159.0°C [lit. mp 157.0–158.0°C (Pala-
cios et al., 2007)]; MS (m/z): 361.1 (M?1); 1H NMR
(CDCl3) d:1.33 (t, 3H, –CH3), 2.36 (s, 3H, –CH3), 2.37 (s,
3H, –CH3), 3.65 (s, 3H, –OCH3), 4.03 (m, 2H, –OCH2–),
5.10 (s, 1H, CH), 5.75 (s,1H, –NH–), 7.37 (t, 1H, 50-Ph-H),
7.63 (d, 1H, 60-Ph-H), 7.99 (d, 1H, 40-Ph-H), 8.11 (s, 1H,
20-Ph-H).
Synthesis of dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (1,m-nifedipine)
Trichloroacetic acid (16.86 g, 100 mmol) and methyl
3-aminocrotonate (12.08 g, 110 mmol) were added in
sequence to a solution of 3-nitrobenzaldehyde (6.02 g,
40 mmol) in ethanol (40 ml) cooled with ice water under
stirring. After the addition was completed, the mixture was
stirred for 1 h at the same temperature. The precipitated
solid was collected by filtration, rinsed with ethanol and
3-Methyl 5-n-propyl 2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (3): Yield 60.2%;
mp 145.0–146.5°C; MS (m/z): 375.1 (M?1); 1H NMR
(CDCl3) d:0.86 (t, 3H, –CH3), 1.61 (m, 2H, –CH2–), 2.36
(s, 3H, –CH3), 2.37 (s, 3H, –CH3), 3.65 (s, 3H, –OCH3),
4.03 (m, 2H, –OCH2–), 5.10 (s, 1H, CH), 5.75 (s, 1H,
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Med Chem Res (2011) 20:1325–1330
1327
–NH–), 7.37 (t, 1H, 50-Ph-H), 7.63 (d, 1H, 60-Ph-H), 7.99
(d, 1H, 40-Ph-H), 8.11 (s, 1H, 20-Ph-H) [Ar–H].
according to reported procedure (Ashimori et al., 1991).
mp 168–172°C, [a]D = -16.258 (c = 0.04 g/ml, THF).
lit. (Shibanuma et al., 1980). mp 169–170°C, [a]D = -19.68
(c = 0.542 g/ml, acetone). A solution of SOCl2 (0.8 ml,
9.61 mmol) in CH2Cl2 (10 ml) was added dropwise to a
suspension of (-)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-
nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid (2.66 g,
8.01 mmol) in CH2Cl2 (10 ml) and DMF (4.5 ml) at -1°C
to 2°C under N2 atmosphere. After the addition was com-
pleted, the mixture was stirred for 2.5 h at the same tem-
perature, added a solution of n-heptanol (2.1 ml, 14.42
mmol) in CH2Cl2 (6 ml), and stirred for another 3.5 h below
3°C, diluted with CH2Cl2 (20 ml), then washed with water, a
solution of K2CO3 (0.5 M) and brine. The organic phase was
dried over sodium sulphate and the volatile was removed
under reduced pressure. Flash chromatograph of the residue
over silica gel, using petroleum ether–ethyl acetate (8:1),
gave (?)-5 as pale yellow solid. The solid was recrystallized
in ethanol to produce (?)-5 (2.30 g). Yield 67.6%; mp
103.0–105.0°C; [a]D = ?16.258 (c = 0.04 g/ml, acetone);
3-Methyl 5-n-pentyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (4): Yield 64.2%; mp
1
90.0–91.5°C; MS (m/z): 403.2 (M?1); H NMR (CDCl3)
d:0.88 (t, 3H, –CH3), 1.26 (m, 4H, 29–CH2–), 1.58 (m, 2H,
–CH2–), 2.36 (s, 3H, –CH3), 2.37 (s, 3H, –CH3), 3.65 (s, 3H,
–OCH3), 4.02 (m, 2H, –OCH2–), 5.09 (s, 1H, CH), 5.74
(s, 1H, –NH–), 7.37 (t, 1H, 50-Ph-H), 7.63 (d, 1H, 60-Ph-H),
8.00 (d, 1H, 40-Ph-H), 8.10 (s, 1H, 20-Ph-H).
5-n-Heptyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (5): Yield 85.0%;
mp 112.5–114.0°C; MS (m/z): 431.4 (M?1); 1H NMR
(CDCl3) d:0.88 (t, 3H, –CH3), 1.25 (m, 8H, 49–CH2–),
1.59 (m, 2H, –CH2–), 2.37 (s, 6H, 29–CH3), 3.66 (s, 3H,
–OCH3), 4.03 (t, 2H, –OCH2–), 5.10 (s, 1H, CH), 5.82
(s, 1H, –NH–), 7.37–8.12 (m, 4H, Ph-H).
3-Methyl 5-n-octyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (6): Yield 70.2%; mp
99.0–100.5°C [lit. mp 100.0°C (Wehinger et al., 1983)];
1
1
MS (m/z): 445.2 (M?1); H NMR (CDCl3) d:0.88 (t, 3H,
MS (m/z): 431.4 (M?1); H NMR (CDCl3) d:0.88 (t, 3H,
–CH3), 1.23 (s, 10H, 59–CH2–), 1.57 (m, 2H, –CH2–),
2.36 (s, 3H, –CH3), 2.37 (s, 3H, –CH3), 3.65 (s, 3H,
–OCH3), 4.02 (m, 2H, –OCH2–), 5.09 (s, 1H, CH), 5.82
(s, 1H, –NH–), 7.37 (t, 1H, 50-Ph-H), 7.64 (d, 1H, 60-Ph-H),
7.99 (d, 1H, 40-Ph-H), 8.11 (s, 1H, 20-Ph-H).
–CH3), 1.24 (m, 8H, 49–CH2–), 1.58 (m, 2H, –CH2–), 2.36
(s, 3H, –CH3), 2.38 (s, 3H, –CH3), 3.65 (s, 3H, –OCH3), 4.03
(t, 2H, –OCH2–), 5.10 (s, 1H, CH), 5.76 (s, 1H, –NH–), 7.34
(t, 1H, 50-Ph-H), 7.63 (d, 1H, 60-Ph-H), 8.01 (d, 1H, 40-Ph-H),
8.11 (s, 1H, 20-Ph-H).
5-n-Decyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (7): Yield 74.2%; mp
88.0–90.0°C [lit. mp 90.0°C (Wehinger et al., 1983)]; MS
(m/z): 473.3 (M?1); 1H NMR (CDCl3) d:0.88 (t, 3H,
–CH3), 1.23 (s, 14H, 79–CH2–), 1.57 (m, 2H, –CH2–),
2.36 (s, 3H, –CH3), 2.37 (s, 3H, –CH3), 3.65 (s, 3H,
–OCH3), 4.02 (m, 2H, –OCH2–), 5.09 (s, 1H, CH), 5.82
(s, 1H, –NH–), 7.37 (t, 1H, 50-Ph-H), 7.64 (d, 1H, 60-Ph-H),
7.99 (d, 1H, 40-Ph-H), 8.11 (s, 1H, 20-Ph-H).
Determination of enantiomeric excess of (?)-5
The enantiomeric excess of (?)-5 was determined by high
performance liquid chromatography (HPLC) analyses using
chiral stationary phase columns, Chiral-AGP (150 mm 9
4.0 mm, 5 lm) [column temperature, 25°C; maintained by a
HT-230Acomlum heater, mobile phase, 2-propanol-ammo-
nium acetate (pH 6.87, 5:95, v/v); flow rate, 0.5 ml/min;
sample load volume, 10 lL; detection, ultraviolet (UV) at
240 nm].
5-n-Dodecyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate(8): Yield 78.0%;
mp 91.0–92.5°C [lit. mp 94.0°C (Wehinger et al., 1983)];
1
MS (m/z): 501.3 (M?1); H NMR (CDCl3) d:0.88 (t, 3H,
Antihypertensive activity
–CH3), 1.23 (s, 18H, 99–CH2–), 1.58 (m, 2H, –CH2–),
2.36 (s, 3H, –CH3), 2.37 (s, 3H, –CH3), 3.65 (s, 3H,
–OCH3), 4.03 (m, 2H, –OCH2–), 5.09 (s, 1H, CH), 5.77
(s, 1H, –NH–), 7.37 (t, 1H, 50-Ph-H), 7.64 (d, 1H, 60-Ph-H),
7.99 (d, 1H, 40-Ph-H), 8.11 (s, 1H, 20-Ph-H).
Male SHR weighing 250–300 g was trained for 5 days.
The blood pressure was measured via a non-invasive tail-
cuff plethysmography method. The rats were loaded in a
cage and set into test box in which the temperature was
37°C. The tail was passed through the pulse detector and a
cuff balloon and stabilized for 10 to 15 minutes so that the
tail artery was fully expanded. When the test signal was
stable, the blood pressure was measured and systolic blood
pressure was read. The measurement was repeated two
times, and an averaging value was recorded as the blood
pressure of an individual animal. The values of blood
pressure were measured before and 1, 2 4 h after ig
administration of drugs.
Synthesis of (?)-5-n-heptyl 3-methyl 2,6-dimethyl-4-
(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
[(?)-5]
(-)-5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydro-3-pyridine- carboxylic acid was prepared
by resolution of ( )-5-(methoxycarbonyl)-2,6-dimethyl-
4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid
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Med Chem Res (2011) 20:1325–1330
Results and discussion
Organic synthesis
(-)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydro-3-pyridine- carboxylic acid since the compound
was not dissolved in acetone.
3-Methyl 5-straight alkyl 2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate were synthesized
following the routes in Scheme 1.
Enantiomeric excess of (?)-5
Retention time of (?)-5 was 3.4 min. The ( )-5 was also
determined in the same condition. There were two peaks
with retention times: (?)-5, 3.4 min; (-)-5, 8.1 min. Since
the peak of (-)-5 was not detected in chromatogram of
(?)-5, the enantiomeric excess of (?)-5 was concluded to
be almost 100%.
The condensation of 3-nitrobenzaldehyde and methyl
3-aminocrotonate in the presence of trichloroacetic acid
yielded dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihy-
dropyridine-3,5-dicarboxylate (1, Scheme 1). The con-
densation of 3-nitrobenzaldehyde and methyl acetoacetate
in the presence of glacial acetic acid and piperidine at 30°C
produced methyl 2-(3-nitrobenzylidene)-3-oxobutanoate.
The reaction was carried out under solvent-free condition.
The work-up was simple and the yield was satisfied.
Refluxing of methyl 2-(3-nitrobenzylidene)-3-oxobutano-
ate and straight alkyl 3-aminocrotonate in ethanol afforded
methyl straight alkyl 2,6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylate (2–8). The synthesis
of compound 5 was not found in the literature. The struc-
tures of synthesized compounds were characterized by MS
Results of antihypertensive activity
The antihypertensive effects of compounds 1–8 in SHR
were summarized in Table 1.
The results showed that antihypertensive effects of
nitrendipine analogues is closely related to the length of the
alkyl chain in 5-position. Short and long alkyl chain in
5-position of DHP reduced their antihypertensive effects.
The seven saturated carbon is most suitable length in
5-position of DHP and compound 5 is the most effective
drug in the tested compounds.
1
and H NMR.
(?)-5-n-Heptyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate [(?)-5] was synthe-
sized following the routes in Scheme 2.
The antihypertensive effects of nitrendipine, ( )-5 and
(?)-5, in SHR were summarized in Table 2. The data
showed that antihypertensive effects of ( )-5, (?)-5 had a
higher potency than nitrendipine, and (?)-isomer was
1.79-fold the raceme, 2.34-fold nitrendipine at a dose of
2 mg/kg, respectively. The antihypertensive effect of ( )-5
depends mostly on (?)-5, which is consistent with enan-
tiomer activity of nitrendipine analogue. ( )-5 was tested
at 1.0, 2.0 and 4.0 mg/kg; the results showed that the
antihypertensive activity can maintain 8 h at 4.0 mg/kg,
and its activity, as well as lasting time, were dose-
dependent.
(-)-5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydro-3- pyridinecarboxylic acid was prepared by
resolution of ( )-5-(methoxycarbonyl)-2,6-dimethyl-4-
(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid using
quinidine as resolution agent (Ashimori et al., 1991). The
reaction of (-)-acid with thionyl chloride and n-heptanol in
sequence gave (?)-5. (-)-5 was not prepared because it
was elucidated that (?)-enantiomer is the active isomer
in the nitrendipine analogues (Zhang et al., 2010).
THF was used as solvent to measure optical rotation of
Scheme 1 Synthesis of
compounds 1–8
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Med Chem Res (2011) 20:1325–1330
1329
Scheme 2 Synthesis of (?)-5
Table 1 Effects of compounds
Drugs
SBP before
drugs (mmHg)
SBP after drugs administration (mmHg)a
Measured value Reduced value
1–8 on systolic blood pressure
(SBP) in SHR at l h (x s,
n = 6)
l(m-ninifedipine)
209
208
210
211
208
209
210
212
211
8
8
8
8
6
6
6
7
6
183
170
167
167
156
171
179
195
214
4
4
3
3
3
4
3
3
4
26
39
43
44
52
38
31
17
-3
5
6
5
5
5
6
6
4
3
2(nitrendipine)
3
4
5
6
a
All compounds were
administrated by ig at 2 mg/kg
7
8
b
Solventb
30% Tween-80, 20% EtOH,
50% distilled water
Table 2 Effects of ( )-5, (?)-5 on systolic blood pressure in SHR (x s, n = 6)
Drugs
Dose (mg/kg)
SBP before
drugs (mmHg)
Reduced SBP after drugs administration (mmHg)
1 h
2 h
4 h
6 h
8 h
Nitrendipine
2.0
1.0
2.0
4.0
2.0
208
196
208
214
212
211
8
9
6
6
9
6
39
33
6
4
5
8
8
7
4
-2
3
3
0
(
)-5
52
42 15
-4
119
107
9
67 15
45 17
21
8
6
(?)-5
Solvent
a
93 10
-3
47 12
-2
-6
1
5
3
-6
5
-6
5
-6
30% Tween-80, 20% EtOH, 50% distilled water
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