Synthesis and in-vivo hypolipidemic activity of some novel substituted phenyl isoxazol phenoxy acetic acid derivatives

Article abstract of DOI:10.1016/j.bmcl.2014.03.030

The present study was undertaken to evaluate in-vivo hypolipidemic activity of a novel series of 2-methyl-2-(substituted phenyl isoxazol)phenoxyacetic acid derivatives by triton induced hyperlipidemia in rats. The newly synthesized compounds 5a, 5d and 5g showed significant decrease in the serum TCH, TG, LDL and VLDL along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index and increase in % protective activity compared to control group.

Full text of DOI:10.1016/j.bmcl.2014.03.030

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2155–2158
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and in-vivo hypolipidemic activity of some novel
substituted phenyl isoxazol phenoxy acetic acid derivatives
⇑
Santosh N. Mokale , Manjusha C. Nevase, Nikhil S. Sakle, Pritam N. Dube, Vishakha R. Shelke,
Swati A. Bhavale, Afreen Begum
Dr. Rafiq Zakaria Campus, Department of Pharmaceutical Chemistry, Y. B. Chavan College of Pharmacy, Aurangabad 431001, M.S., India
a r t i c l e i n f o
a b s t r a c t
Article history:
The present study was undertaken to evaluate in-vivo hypolipidemic activity of a novel series of
2-methyl-2-(substituted phenyl isoxazol)phenoxyacetic acid derivatives by triton induced hyperlipid-
emia in rats. The newly synthesized compounds 5a, 5d and 5g showed significant decrease in the serum
TCH, TG, LDL and VLDL along with an increase in serum HDL levels as compared to standard drug
Fenofibrate. The treated groups also showed significant decrease in the atherogenic index and increase
in % protective activity compared to control group.
Received 4 January 2014
Revised 8 March 2014
Accepted 12 March 2014
Available online 21 March 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Hyperlipidemia
Anti-atherosclerotic
Phenoxy acetic acid
Isoxazol
Hyperlipidemia is a heterogeneous group of disorders charac-
terized by an excess of lipids in the bloodstream which includes
cholesterol, cholesterol esters, phospholipids, and triglycerides.
Lipids are transported in the blood as large ‘lipoproteins’. Lipopro-
teins are divided into five classes, based on density: chylomicrons,
very low-density lipoproteins (VLDL), intermediate-density lipopro-
teins (IDL), low-density lipoproteins (LDL), and high-density lipo-
proteins (HDL). Most triglyceride is transported in chylomicrons
or VLDL, and most cholesterol is carried in LDL and HDL.
Hyperlipidemia is a major, modifiable risk factor for atherosclero-
sis and cardiovascular disease, including coronary heart disease.1,2
Fibrates affect lipid metabolism as agonists of enzyme peroxi-
The target compounds 2-methyl-2-(4-(5-(substituted phenyl)
isoxazol-3-yl)phenoxy)acetic acid and 2-methyl-2-(4-(3-(substi-
tuted phenyl)isoxazol-5-yl)phenoxy)acetic acids (5a–j) were
synthesized using substituted acetophenones and 4-hydroxyl
benzaldehyde or substituted benzaldehydes and 4-hydroxyl aceto-
phenone starting material as outlined in Scheme 1. The substituted
hydroxy chalcones (3a–j, Table 1) were synthesized using substi-
tuted benzaldehydes and 4-hydroxyl acetophenone or substituted
acetophenones and 4-hydroxyl benzaldehyde in presence of aq
alkali. The substituted isoxazol phenols (4a–j, Table 2) were
synthesized by cyclization of substituted hydroxy chalcones with
hydroxylamine HCl. In this reaction cyclisation takes place due to
removal of water molecule to form substituted isoxazol phenols.
The final derivatives were obtained by condensing chloro acetic
acid with substituted isoxazol phenols (5a–j, Table 3). The
proposed derivatives were verified by IR, 1H NMR, 13C NMR and
LC–MS spectroscopy.
some proliferator activated receptor alpha (PPAR-
a) by lowering
TG, LDL and by increasing HDL cholesterol level.3–5
The phenoxy acetic acid pharmacophore has been frequently
used in synthesis of potent hypolipidemic agent. Phenoxy acetic
acid was frequently couple with many heterocyclic nucleus such
as pyrimidine, isoxazol, thiazole, morpholine, oxadiazole, indole,
benzisoxazol and piperidine6,7 to have more potent hyperlipidemic
activity.
It was observed from literature survey that isoxazol scaffold has
never used previously for the development of antihyperlipidemic
agent. In view of this, we have attempted the synthesis of isoxazol
derivative containing phenoxy acetic acid pharmacophore to have
potent hyperlipidemic activity (Fig. 1).
Heterocyclic linker
Pharmacophore
O
N
R
Lipophilic tail
R
O
O
OH
⇑
Corresponding author. Tel.: +91 2402381307.
E-mail address: santoshmokale@rediffmail.com (S.N. Mokale).
Figure 1. Designed scaffold.
http://dx.doi.org/10.1016/j.bmcl.2014.03.030
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

2156
S. N. Mokale et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2155–2158
O
O
2
R
CH3
OH
H
R
1
HO
N
OH
a
HO
O
O
H
/
E
O
t
H
O
O
H
O
O
NaOH/EtOH
NaOH/EtOH
NaOH/EtOH
H3C
O
R
O
OH
O
R
O
R
HO
R
OH
O
3c
3b
OH
3d-j
3a
HONH2·HCl/
KOH
HONH2·HCl/
KOH
HONH2·HCl/
KOH
HONH2·HCl/
KOH
R
R
R
O
N
R
O
N
N
O
O
N
OH
O
HO
4a
HO
4c
HO
4b
4d-j
O
O
NaOH
Cl
O
NaOH
O
Cl
OH
NaOH
OH
Cl
NaOH
Cl
OH
OH
R
R
R
R
N
O
O
O
N
N
O
N
O
O
O
O
O
O
O
O
OH
OH
HO
5d-j
O
OH
5c
5a
5b
Scheme 1. Synthesis of designed compounds (5a–j).
Albino Wistar rats of either sex (200–250 g) were kept in a
room with controlled temperature (25–26 °C), humidity (60–80%)
and 12/12 h light/dark cycle under hygienic conditions. Animals
were acclimatized for one week before starting the experiment
with free access to the normal diet and water.
Table 1
Characterization data for substituted hydroxy chalcone
Compd
R
% Yield
Melting point
Rf value**
3a
68.12
130
0.54
The hypolipidemic activity of the synthesized compounds was
studied in the triton induced hyperlipidemic rats for 7 days by oral
administration of the drug and compounds. Hyperlipidemia was
developed by intra-peritoneal administration of triton WR-1339
(Sigma Aldrich, USA) at a dose of 400 mg/kg to all animals except
the control. The compounds were suspended in Tween 80 and
administered orally at a dose 250 mg/kg for 7 days. Animals of con-
trol and triton group without treatment with compounds were gi-
ven vehicle only. Fenofibrate (250 mg/kg) was used as standard for
the hypolipidemic activity.8,9
The serum was analysed for total cholesterol (TC), triglycerides
(TG), high-density lipoprotein (HDL). The LDL and VLDL were
calculated using Friedwald formula (Table 4). The atherogenic
index (AI) was calculated as (TC-HDL/HDL, Table 4).10 Data
obtained in the test were compared against the control group using
3b
3c
71.42
69.20
123
127
0.49
0.62
F
OCH3
3d
3e
66.32
65.90
126
125
0.51
0.48
OCH3
OCH3
OCH3

S. N. Mokale et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2155–2158
2157
Table 3
Table 1 (continued)
Characterization data for of substituted phenyl isoxazol phenoxy acetic acid
Compd
R
% Yield
71.24
Melting point
120
Rf value**
Compd
ID
R
Molecular
formula
Molecular %
weight
Melting Rf
Yield point* value**
Cl
Cl
3f
0.60
5a
5b
5c
C18H15NO5
C17H13NO4
325.10
76.63 180
71.65 165
70.36 145
0.56
0.52
0.52
295.08
3g
3h
67.49
65.20
128
131
0.52
0.61
F
Cl
C17H12FNO4 313.08
O
OCH3
5d
5e
C18H15NO5
325.10
385.12
65.12 150
65.78 163
0.45
0.51
3i
3j
66.10
68.20
130
124
0.53
0.56
Cl
OCH3
OCH3
OCH3
C20H19NO7
**
Solvent system chosen for Rf value determination is chloroform/methanol (4:1).
Cl
Cl
5f
C17H12ClNO4 329.08
67.20 168
68.25 120
0.48
0.50
Table 2
5g
C17H11Cl2NO4 363.01
Characterization data for substituted isoxazol phenols
Compd
R
% Yield
Melting point*
Rf value**
Cl
4a
70.23
156
0.57
O
5h
5i
C15H11NO5
C17H13NO4
285.25
295.08
72.89 190
66.14 168
70.52 156
0.46
0.56
0.53
4b
4c
62.61
63.45
158
161
0.60
0.50
F
Cl
OCH3
5j
C17H12ClNO4 329.05
4d
4e
69.50
59.36
169
165
0.59
0.63
**
Solvent system chosen for Rf value determination is ethyl acetate/n-hexane (1:1).
*Melting points are uncorrected.
OCH3
OCH3
OCH3
the one-way analysis of variance method and followed by a post-hoc
Dunnett test. For all statistical analysis, alpha was set to 0.05.
Statistical analysis was performed using the SPSS 16 stat software.
Results were presented as mean standard error mean (mean SEM).
In SAR, isoxazol was used as heterocyclic spacer in between
phenoxy acetic acid pharmacophore and lipophilic tail. All the
synthesized derivatives have ability to lower the elevated lipid lev-
els. The substitution on phenoxy acetic acid ring has influence on
the hypolipidemic activity. The substitution with OCH3 (5a) on
phenoxy acetic acid ring showed highest activity in comparison
with unsubstituted derivatives. The substitution lipophilic tail also
has influence on the hypolipidemic activity. The 2-OCH3 showed
highest activity on lipophilic tail (5d) followed by 2,6 dichloro
derivative (5g).
In conclusion, a new series of substituted phenyl isoxazol phen-
oxy acetic acid was synthesized and evaluated for hypolipidemic
activity. Most of these compounds showed better potency,
amongst which 5a, 5d and 5g were found to be the most active
agents as compared to standard. The pharmacological screening
of synthesized molecules indicates that isoxazol ring is important
for hypolipidemic activity.
Cl
Cl
4f
63.15
64.00
160
154
0.60
0.58
4g
Cl
O
4h
4i
60.85
68.52
62.34
153
158
146
0.61
0.56
0.60
Cl
4j
*
Melting points are uncorrected.
Solvent system chosen for Rf value determination is ethyl acetate/n-hexane (1:1).
**

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S. N. Mokale et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2155–2158
Table 4
Interpretation of pathological investigation (mg/dl) after 7 days and atherogenic index for target compounds
Groups
CH
TG
HDL
LDL
VLDL
Atherogenic index
% Protection
Normal
Untreated
126 1.57
116.5 0.79
190 1.98#
119 0.86a
115 1.01a
123.5 0.99a
105.5 1.62a
117.5 1.06a
125 0.91a
110 1.99a
113.5 1.10a
113 1.13a
132 0.81a
131.5 0.87a
33 1.42
58.6 1.58
154 1.82#
48.2 1.24a
25 1.11a
23.3 0.58
38 1.80#
2.53
10.18
1.67
1.5
1.91
1.43
1.64
2.09
1.75
1.55
1.69
2.26
2.21
—
—
83.6
209 1.45#
116.5 1.41a
94 1.22a
17 1.70#
44.5 1.51a
46 1.60a
Std
5a
5b
5c
5d
5e
5f
5g
5h
5i
23.8 0.91a
23 1.01a
85.27
81.24
85.95
83.89
79.47
82.81
84.77
83.4
91 2.22a
42.5 1.20a
43.5 1.70a
44.5 2.10a
40.5 1.10a
40 2.20a
23.3 0.78a
16.4 1.01a
10.5 1.04a
29 0.81a
25.2 1.60a
21.1 1.51a
23.5 1.88a
25.5 1.84a
22 1.07a
81 2.10a
77.5 0.67a
82.5 2.18a
148.5 1.87a
90 1.91a
86.5 0.98a
22.8 0.88a
22.4 0.94a
11.1 1.52a
16.2 1.13a
44.5 1.80a
42 1.90a
22.7 1.22a
22.6 1.95a
26.4 1.00a
26.3 1.80a
87 1.00a
88 1.29a
40.5 1.69a
41 1.53a
77.8
78.29
5j
83.5 1.41a
Values are in mean SEM; number of animals in each group = 6.
a
p < 0.001 versus untreated.
p < 0.001 versus normal.
#
3066, 2908, 1592, 744 cmÀ1 1H NMR (400 MHz, DMSO): d = 10.9 (s, 1H, –OH),
;
References and notes
8.1–7.5 (m, 5H, Ar-H), 6.9–7.3 (m, 3H, Ar-H), 6.7 (s, 1H, isoxazole), 4.7 (s, 2H, –
CH2), 3.8 (s, 3H, –OCH3); 13C NMR (100 MHz, DMSO): d = 174.2, 170.1, 161.2,
151.3, 148.7, 129.9, 128.4, 127.6, 125.4, 123.2, 115.2, 98.1, 65.3, 55.9; MS: m/
z = 326.1 [M+1].
1. Mokale, S. N.; Elgire, R. D.; Sakle, N.; Shinde, D. B. Bioorg. Med. Chem. Lett. 2011,
21, 682.
2. Shrivastava, A.; Chaturvedi, U.; Singh, S. V.; Saxena, J. K.; Bhatia, G. Lipids 2013,
48, 597.
3. Howland, R. D.; Mycek, M. J. Antihyperlipidemic Drug. In Lippincott’s Illustrated
Review Pharmacology, 3rd ed.; Lippincott Williams and Willkins: India, 2006;
pp 245–255.
4. Mokale, S. N.; Shete, M. T.; Shaikh, S. I.; Shinde, D. B. Chem. Biol. Drug Des. 2012,
79, 548.
5. Bitzur, R.; Cohen, H.; Kamari, Y.; Shaish, A.; Harats, D. Diab. Care 2009, 32, S373.
6. Mokale, S. N.; Elgire, R. D.; Sakle, N. S.; Shinde, D. B. Arch. Pharm. 2012, 345, 22.
7. Vogel, G. H. Drug Discovery and Evaluation-Pharmacological Assays, 3rd ed.;
Spinger: Berlin, Heidelberg, New York, 2008. p 1676.
8. Mokale, S. N.; Sanap, P. T.; Shinde, D. B. Eur. J. Med. Chem. 2010, 45, 3096.
9. Sashidhara, K. V.; Palnati, G. R.; Sonkar, R.; Avula, S. R.; Awasthi, C.; Bhatia, G.
Eur. J. Med. Chem. 2013, 64, 422.
10. Hamauzu, Y.; Nosaka, T.; Ito, F.; Suzuki, T.; Torisu, S.; Hashida, M.; Fukuzawa,
A.; Ohguchi, M.; Yamanaka, S. Food Chem. 2011, 129, 810.
11. Jeong, T. S.; Kim, K. S.; An, S.; Cho, K. H.; Lee, S.; Lee, W. S. Bioorg. Med. Chem.
Lett. 2004, 14, 2715.
12. Weidner-Wells, M. A.; Henninger, T. C.; Fraga-Spano, S. A.; Boggs, C. M. Bioorg.
Med. Chem. Lett. 2004, 14, 4307.
2-(2-(5-Phenylisoxazol-3-yl)phenoxy)acetic acid (5b): IR (KBr): 3019, 3066, 2908,
1592, 744 cmÀ1 1H NMR (400 MHz, DMSO): d = 10.9 (s, 1H, –OH), 7.8–7.4 (m,
;
5H, Ar-H), 7.0–7.3 (m, 4H, Ar-H), 6.6 (s, 1H, isoxazole), 4.7 (s, 2H, –CH2); 13C
NMR (100 MHz, DMSO): d = 173.7, 169.3, 160.7, 158.3, 132.7, 129.3, 128.4,
128.1, 127.5, 125.4, 116.7, 114.8, 98.4, 64.8; MS: m/z = 296.1 [M+1].
2-(4-(3-(4-Fluorophenyl)isoxazol-5-yl)phenoxy)acetic acid (5c): IR (KBr): 3089,
3016, 1893, 2568, 686, 590 cmÀ1 1H NMR (400 MHz, DMSO): d = 10.8 (s, 1H, –
;
OH), 8.2, 7.4 (m, 4H, Ar-H), 7.4–7.0 (m, 4H, Ar-H), 6.6 (s, 1H, isoxazole), 4.7 (s,
2H, –CH2); 13C NMR (100 MHz, DMSO): d = 173.1, 169.2, 162.4, 158.7, 131.4,
131.2, 128.5, 127.3, 125.4, 123.7, 122.8, 118.9, 114.3, 98.4, 67.6; MS: m/
z = 314.3 [M+1].
2-(4-(3-(2-Methoxyphenyl)isoxazol-5-yl)phenoxy)acetic acid (5d): IR (KBr): 3016,
2480, 1727, 1901, 574 cmÀ1 1H NMR (400 MHz, DMSO): d = 11.1 (s, 1H, –OH),
;
7.6–7.4 (m, 4H, Ar-H), 7.2–7.0 (m 4H, Ar-H), 6.3 (s, 1H, isoxazole), 4.6 (s, 2H, –
CH2), 3.7 (s, 3H, –OCH3); 13C NMR (100 MHz, DMSO): d = 170.2, 161.3, 160.1,
158.9, 132.4, 129.6, 128.5, 127.2, 123.2, 122.6, 117.4, 114.7, 110.2, 65.3, 53.2;
MS: m/z = 326.2 [M+1].
2-(4-(3-(3,4,5-Trimethoxyphenyl)isoxazol-5-yl)phenoxy)acetic acid (5e): IR (KBr):
3016, 2480, 1727, 1901, 574 cmÀ1 1H NMR (400 MHz, DMSO): d = 11.0 (s, 1H,
;
–OH), 7.7–7.1 (m, 4H, Ar-H), 6.8 (m, 2H, Ar-H), 6.4 (s, 1H, isoxazole), 4.5 (s, 2H,
–CH2), 3.8-3.7 (s, 9H, –OCH3); 13C NMR (100 MHz, DMSO): d = 174.4, 163.7,
161.2, 158.5, 153.4, 132.1, 129.7, 127.5, 124.4, 122.1, 115.3, 112.7, 99.9, 64.8,
58.2, 53.3; MS: m/z = 386.2 [M+1].
13. Nagaraj, A.; Reddy, S. C. J. Iran Chem. Soc. 2008, 5, 262.
14. General: Melting points were determined on scientific melting point apparatus
in open capillaries and were uncorrected. FT-IR spectra were recorded on
JASCO FT-IR 4000 using KBr powder. 1H and 13C NMR spectra were recorded on
2-(4-(3-(2-Chlorophenyl)isoxazol-5-yl)phenoxy)acetic acid (5f): IR (KBr): 3016,
a
BRUKER AVANCE II 400 spectrometer (400 MHz) with TMS as internal
2480, 1727, 1901, 574 cmÀ1 1H NMR (400 MHz, DMSO): d = 10.9 (s, 1H, –OH),
;
standard and DMSO as a solvent. Mass spectra were recorded on a Varian Inc.,
410 Prostar Binary LC with 500 MS IT PDA detectors. All the reagents and
solvents used were of analytical grade.
7.7–7.4 (m, 4H, Ar-H), 7.2–7.0 (m, 4H, Ar-H), 6.6 (s, 1H, isoxazole), 4.6 (s, 2H, –
CH2); 13C NMR (100 MHz, DMSO): d = 171.9, 161.2, 159.7, 155.2, 134.5, 131.7,
128.3, 126.4, 124.8, 121.5, 118.6, 115.1, 114.9, 64.5, 52.8; MS: m/z = 331.1
[M+1].
General procedure for the synthesis of substituted hydroxy chalcones:11 In to
250 ml of conical flask placed 0.01 mol of substituted benzaldehyde and
0.01 mol of 4-hydroxyl acetophenone or substituted acetophenone and 4-
hydroxyl benzaldehyde in 40 ml of ethanol containing 15 ml of 40% sodium
hydroxide solution. The resulting solution stir for 2 h and reaction mixture was
kept aside for 48 h. On next day crushed ice was added in reaction mixture and
acidified it by dil.HCL. The crude product obtained was filtered and
recrystallized by ethanol.
2-(4-(3-(2,6-Dichlorophenyl)isoxazol-5-yl)phenoxy)acetic acid (5g): IR (KBr):
3056, 2488, 1756, 1680, 1940, 650, 764 cmÀ1 1H NMR (400 MHz, DMSO):
;
d = 10.9 (s, 1H, –OH), 7.6–7.4 (m, 3H, Ar-H), 7.1–7.0 (m, 4H, Ar-H), 6.7 (s, 1H,
isoxazole), 4.6 (s, 2H, –CH2); 13C NMR (100 MHz, DMSO): d = 173.2, 170.4,
161.7, 156.4, 136.9, 132.2, 130.4, 129.7, 128.9, 119.3, 115.2, 114.7, 98.7, 66.3;
MS: m/z = 366.1 [M+2].
2-(4-(3-(Furan-2-yl)isoxazol-5-yl)phenoxy)acetic acid (5h): IR (KBr): 3023, 3108,
General procedure for synthesis of substituted isoxazol phenols:12 In 250 ml of
RBF, provide with reflux condenser placed substituted hydroxy chalcone
(0.01 mol) and hydroxylamine HCl (0.01 mol) in a solution of KOH (0.02 mol)
in 50 ml of methanol. The resultant solution was refluxed in water bath for
12 h. The hot solution was acidified with concd HCl. The solid which was
obtained filtered off, washed with water, dried and recrystallized by ethanol.
General procedure for the synthesis substituted phenyl isoxazol phenoxy acetic
acid:13,14 In 500 ml of RBF provided with reflux condenser, placed substituted
isoxazol phenols (0.01 mol), NaOH (0.02 mol) and mono chloro acetic acid
(0.01 mol) in methanol. The resultant solution was refluxed in oil bath. After
1 h, pH of solution had dropped to 7 and further 1 g NaOH was added.
Refluxing was continued for 2 h and 1 g NaOH added and again refluxes for 2 h.
The hot solution was acidified with concd HCl and crystallization take place on
cooling. The solid was filtered off, washed with water, dried and recrystallized
by ethanol.
1727, 1600, 640, 590 cmÀ1 1H NMR (400 MHz, DMSO): d = 10.9 (s, 1H, –OH),
;
7.7, 7.6, 7.0 (m, 3H, furan ring), 7.2–7.1 (m, 4H, Ar-H), 6.6 (s, 1H, isoxazole), 4.6
(s, 2H, –CH2); 13C NMR (100 MHz, DMSO): d = 170.1, 169.3, 160.7, 157.8, 154.9,
144.1, 128.5, 125.4, 116.3, 112.4, 108.8, 98.4, 67.6; MS: m/z = 286.2 [M+1].
2-(4-(3-Phenylisoxazol-5-yl)phenoxy)acetic acid (5i): IR (KBr): 3023, 3108, 1727,
1600, 640, 590 cmÀ1 1H NMR (400 MHz, DMSO): d = 10.8 (s, 1H, –OH), 7.8–7.5
;
(m, 5H, Ar-H), 7.3–7.0 (m, 4H, Ar-H), 6.7 (s, 1H, isoxazole), 4.5 (s, 2H, –CH2); 13
C
NMR (100 MHz, DMSO): d = 171.2, 164.5, 161.5, 145.4, 129.8, 128.5, 127.9,
126.3, 126.2, 115.2, 111.7, 109.9, 98.3, 67.4; MS: m/z = 296.1 [M+1].
2-(4-(3-(4-Chlorophenyl)isoxazol-5-yl)phenoxy)acetic acid (5j): IR (KBr): 3108,
2923, 1689, 2564, 2676, 1920, 763, 628 cmÀ1 1H NMR (400 MHz, DMSO):
;
d = 11.1 (s, 1H, –OH), 7.8–7.6 (m, 4H, Ar-H), 7.4–7.1 (m, 4H, Ar-H), 6.6 (s, 1H,
isoxazole), 4.7 (s, 2H, –CH2); 13C NMR (100 MHz, DMSO): d = 174.2, 168.7,
161.5, 148.9, 136.6, 129.8, 128.3, 127.2, 126.3, 125.8, 117.9, 114.7, 115.1, 97.2,
66.9; MS: m/z = 331.7 [M+2].
2-(2-Methoxy-4-(5-phenylisoxazol-3-yl)phenoxy)acetic acid (5a): IR (KBr): 3019,