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Synthesis and Structure-Activity Relationship of 4-Substituted Benzoic Acids and their Inhibitory Effect on the Biosynthesis of Fatty Acids and Sterols.

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Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
DOI 10.1002/ardp.200400920
Synthesis and Structure-Activity Relationship of
4-Substituted Benzoic Acids and their Inhibitory
Effect on the Biosynthesis of Fatty Acids and
Sterols
Tomoyasu Ohno, Kazuo Ogawa, Shingo Yano, Masakazu Fukushima,
Norihiko Suzuki, Tetsuji Asao
Hanno Research Center, Taiho Pharmaceutical Co. Ltd., Hanno, Japan
The synthesis of 4-[3-(substituted phenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acids and their inhibitory effects on the biosynthesis of fatty acids and sterols is described. IC50 values in vitro were 10⫺6
and 10⫺5 M, respectively. Though the in vitro inhibitory activity of all these compounds toward sterol
biosynthesis was inferior to that of pravastatin, several compounds had a stronger reducing effect in
Sprague-Dawley (SD) rat on both, cholesterol (TC) and triglyceride (TG), than pravastatin and bezafibrate. The potent compounds were present at high concentrations in rat liver. The enantiomers of the
potent racemic compounds (4-[3-(4-bromo-2-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid)
were prepared and their activity was examined in vivo and in vitro. In vivo, each enantiomer possessed
more activity than the racemic compound. Further, in Watanabe hereditable hyperlipidemic (WHHL)
rabbit, optically active (R)-4-[3-(4-bromo-2-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid
also potently reduced the effect of both TC and TG on serum levels, compared with pravastatin
and bezafibrate.
Keywords: Fatty Acids; Sterols; HMG-CoA
Received: July 12, 2004; Accepted: February 10, 2004 [FP920]
Introduction
The serum level of cholesterol is an important factor in
atherosclerotic vascular diseases involving coronary heart
diseases (CHD) [1]. In practice, HMG-CoA reductase inhibitors (Pravastatin, Figure 1) which lower the total cholesterol (TC) level in serum, help to prevent CHD [2]. Recently,
the serum level of triglyceride (TG) has been clarified as a
risk factor for CHD by an epidemiological study [3]. Consequently, a simultaneous reduction in TC and TG is expected
to be beneficial in preventing CHD. We have found the oxopyrrolidine compounds for anti-hypercholesterolemia, and
reported S-2E as a potent compound [4]. This compound
has a chiral center on the oxopyrrolidine ring and the enantiomeric isomer showed a different behavior and an effect
in vivo. The preparation of S-2E was not efficient because it
was prepared from racemic compounds by silicagel column
separation method. We selected 2-oxo-5-oxazolidine as an
Correspondence: Tomoyasu Ohno, Taiho Pharmaceutical Co.
Ltd., Chemical Technology Laboratory, 200-22, Toyohara
Motohara, Kamikawa-Machi, Kodama-Gun, Saitama, 367-0241,
Japan. Phone: ⫹81 495 77-1580, Fax: ⫹81 495 77-3799, e-mail:
tom-ohno@taiho.co.jp
alternative structure that mimicked the oxopyrrolidine and
these enantiomers were easy to synthesize.
In this paper, we report the synthesis and the inhibitory
activites against both sterol and fatty-acid biosynthesis in
vitro of 2-oxo-5-oxazolidinyl derivatives (4, 7, and 10). Furthermore, representive compounds were examined for their
lowering effect on TC and TG levels in vivo (administered
p.o., male SD rat), and the relationships between these lowering effects and the concentration of the compounds in
serum and liver was investigated. In addition, optically active compounds ((R-)-4j, (S)-4j) were prepared and examined as to determine the relationship between the stereoisomers and activities of each enanitiomer. Decreasing effects
on TC and TG in WHHL rabbit are also described.
Chemistry
The racemic compounds were prepared according to
Scheme 1 and 2.
Isocyanates (1) were obtained commercially or prepared
from corresponding aniline and trichloromethyl chloroformate [5].
Oxirane derivatives (2a, 5, and 8) were prepared from epibromohydrin and 4-substituted phenol. Compound 2b was
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
147
148
Ohno et al.
Figure 1. Reference compounds.
Scheme 1. Synthesis routes to compounds 4a⫺4z, 6, and 7.
Scheme 2. Synthesis routes to compounds 9 and 10.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
Table 1. Physical and chemical data of compounds 3, and 6.
Compound
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
3y
3z
6
†
R
m n
H
2-F
3-F
4F
4-Cl
4-Br
2-F,4-F
2-Cl,4-Cl
3-Cl,4-Cl
2-F,4-Br
4-Me
4-Et
4-i-Pr
4-n-Bu
4-i-Bu
4-t-Bu
4-CF3
3-MeO
4-MeO
4-EtO
4-i-PrO
4-CF3O
2-MeO,4-MeO
4-NO2
4-Cl
4-Cl
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
1
Yield
[%]
Mp.
[°C]
79
83
90
91
89
90
88
93
83
68
92
96
94
93
89
95
93
95
93
83
92
93
83
90
75
61
85
158⫺159
116⫺118
145⫺146
126⫺127
146⫺148
150⫺151
104⫺106
135⫺138
142⫺143
154⫺155
140⫺142
139⫺141
145⫺147
126⫺127
144⫺146
175⫺177
152⫺154
124⫺126
133⫺134
oil
152⫺153
142⫺143
137⫺138
200⫺201
139⫺141
67⫺70
133⫺134
Formula†
C18H17NO5
C18H16FNO5
C18H16FNO5
C18H16FNO5
C18H16ClNO5
C18H16BrNO5
C18H15F2NO5
C18H15Cl2NO5
C18H15Cl2NO5
C18H15BrFNO5
C19H19NO5
C20H21NO5
C21H23NO5
C22H25NO5
C22H25NO5
C22H25NO5
C19H16F3NO5
C19H19NO6
C19H19NO6
C21H23NO6
C19H16F3NO6
C20H21NO7
C18H16N2O7
C19H18ClNO5
C19H18ClNO5
C20H20ClNO5
Confirmed by CHN analysis to within ± 0.4% of the theoretical
values.
prepared from methyl 4-(2,2-dimethyl-1,3-dioxolane-4-ylethoxy)benzoate by the most convenient procedure [6]. 2Oxo-oxazolidine derivatives (3, 6, and 9) were prepared by
dropwise addition of a xylene solution of isocyanate and
oxirane derivatives (2, 5, and 8) into a mixture of tri-n-butylphosphine oxide and lithium bromide under reflux, according to Herweh’s method [7]. Physical and chemical data of
compounds 3 and 6 is shown in Table 1.
Unless otherwise noted, the target carboxylic acid derivatives (4) were obtained by the hydrolysis of esters using a
solution of acetic acid and conc. HCl. Isopropoxy-substituted compound (4u) was obtained by hydrolysis of 3u in a
solution of ethanol and 0.5 N potassium hydroxide to avoid
the cleavage of the alkoxy group. Phenylpropionic acid derivative 7 was prepared from p-chlorophenyl isocyanate (1e)
and methyl 4-(oxiranylmethoxy)phenylpropionate (5) following hydrolysis in the same way.
Compound 10 was prepared from aldehyde 9 and malonic
acid heated in pyridine followed by decarboxylation with
10 % sulfuric acid. Each enantiomer of the compounds of
4j was prepared from (R)- and (S)-glycidyl nosylates (11)
according to Scheme 3, respectively.
Synthesis and Activity of 4-Substituted Benzoic Acid
Results and discussion
The inhibitory activity toward fatty-acid and sterol biosynthesis in vitro was examined. The effect of substitution
at the phenyl ring of the compounds is shown in Table 2.
Though no structure-activity relationship on the substituent
group was observed in vitro, the inhibitory activity was affected by the spacer groups linking substitution and the oxazolidine ring (4y, 4z). All compounds, except 4t and 4z,
exhibited inhibitory activity (IC50 :10⫺6 to 10⫺5 μM order)
against both fatty-acid and sterol biosynthesis, in analogy
with oxopyrrolidine type compounds (I). In a series of active compounds, the inhibitory activities for fatty-acid and
sterol biosynthesis were superior to those of bezafibrate.
Though the inhibition of sterol biosynthesis was weak, relative to pravastatin, both IC50 values were of the same order.
It is to be expected that these compounds reduce both TG
and TC simultaneously in vivo.
In order to examine the lowering effect on both TG and
TC in vivo (administered p.o., male SD rat), we selected as
representive compounds, halogen (4e, 4h, and 4j), alkyl (4k,
4l, and 4q), and alkoxy (4s, 4u, and 4v) substituted compounds. Among those tested, dihalogen-substituted compounds (4h, 4j) and trifluoromethoxy-substituted compound (4v) showed potent dose-dependent activity in vivo.
Other compounds had a weak or no effect (Table 3). As
reported, pravastatin, which is a HMG-CoA reductase inhibitor, does not exhibit a lowering effect on cholesterol in
rat [8], the mechanism of decrease of TC in serum induced
by the active compounds (4h, 4j, and 4v) may be different
from that of pravastatin.
These in vivo effects led us to examine the relationship between the lowering effect on TG and TC, and the concentration of the compounds in serum and liver (Table 4). The
AUC (area under the concentration-time curve) values for
serum and liver differed for individual compounds. The
AUC values in serum of 4e and 4u were almost equal to
those of 4j, but AUC values in liver of 4j were twice those
of 4e and 4u. In particular, dihalogen-substituted compound
(4h, 4j) and trifluoromethoxy-substituted compound (4v)
showed much higher AUC values in liver than alkyl-, alkoxy-substituted type (4k⫺4u) and monohalogen-substituted
compound (4e). The compounds 4h, 4j, and 4v had remarkable lowering effects on both TG and TC in vivo (Table 3).
These results suggest that the AUC value in liver is an important factor in the lowering effect on TG and TC in vivo.
For efficiency and safety reasons, we selected 4j and investigated the relationship between the stereoisomers and the
activities against the optically active compounds (R)-4j and
(S)-4j (Table 5). In terms of inhibitory activity for sterol and
fatty-acid biosynthesis in vitro, the (S)-form was superior to
the (R)-form. In vitro, the (S)-form was compared to the
(R)-form the better inhibitor of the sterol biosynthesis, but
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
149
150
Ohno et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
Scheme 3. Synthesis of stereochemically defined compounds.
there was no different to the (R)-form in the inhibitory activity for fatty-acid biosynthesis.
In vivo, (R)-4j was more effective than (S)-4j in decreasing
the serum TG level, but less active against the serum TC
level.
Next, we selected (R)-4j under the safety aspect and compared it with pravastatin using WHHL rabbit, an animal
model for studying the TC lowering effect of pravastatin [9]
(Table 6). Though (R)-4j had less of a decreasing effect on
serum TC, it was more active than pravastatin at reducing
the level of TG in serum. On the other hand, bezafibrate
showed no effect on serum TG in this animal model. Recently, mechanism about anti-hyperlipidemic action of S-2E
is reported [10]. S-2E itself at a concentration of up to 100
μM did not inhibit the activity of HMG-CoA reductase in
sterol synthesis, S-2E-CoA was identified as the major
metabolite in liver homogenates from rats that had been
administered S-2E, and this metabolite inhibited the activity
of this enzyme in a noncompetitive manner. Competitive
inhibitor of HMG-CoA reductase, Pravastatin induces the
enzyme transcription in rat. On the other hand, as competitive inhibitor of HMG-CoA reductase, pravastatin induces
the enzyme transcription and reduces the lowering effect of
cholesterol on rat. The lowering effect of choresterol on rat
treated with S-2E may be explained by this difference in
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
inhibition mechanism. It was verified that thiazolidine derivatives reported here are converted to CoA metabolite and
inhibit the enzyme (data not shown). Further studies concerning the accumulation of the compound in the liver and
the inhibition activity of these metabolites are required to
clear the anti-hyperlipidemic effect.
In conclusion, we identified (R)-4j as a potent compound
possessing activity to decrease both TG and TC levels in
serum in SD rat and WHHL rabbit.
Experimental
General
Melting points were obtained on a Yanagimoto micromelting apparatus (Yanagimoto Company) and are uncorrected. 1H-NMR
spectra were recorded on a JEOL JNM EX-270 spectrometer (Jeol,
Tokyo, Japan) using tetramethylsilane (TMS) as an internal standard. Chemical shifts are expressed as δ values (ppm). Elemental
analysis was carried out with a Yanagimoto C,H,N Corder MT-2.
Mass spectra (MS) were measured using JEOL JMS 102 mass spectrometer.
Isocyanates (1a⫺x) were obtained commercially (Sigma-Aldrich
and Tokyo Kasei Kogyo Co, Ltd), or otherwise prepared from corresponding aniline and trichloromethyl chloroformate [5].
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
Synthesis and Activity of 4-Substituted Benzoic Acid
Table 2. Physical and chemical data and inhibitory activity of compounds 4, 7 and 10 for fatty-acid and sterol biosyntheses
in vitro.
Compound
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4y
4z
7
10
R
m
n
H
2-F
3-F
4-F
4-Cl
4-Br
2-F,4-F
2-Cl,4-Cl
3-Cl,4-Cl
2-F,4-Br
4-Me
2-Et
4-i-Pr
4-n-Bu
4-i-Bu
4-t-Bu
4-CF3
3-MeO
4-MeO
4-EtO
4-i-PrO
4-CF3O
2-MeO,4-MeO
4-NO2
4-Cl
4-Cl
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
1
Yield
[%]
Mp.
[°C]
93
81
85
82
89
97
67
61
94
87
93
93
95
92
83
85
79
87
84
84
89
91
89
85
86
75
79
84
247⫺249
164⫺166
229⫺230
229⫺231
240⫺242
260⫺261
200⫺202
218⫺220
250⫺252
204⫺205
252⫺253
233⫺234
254⫺255
213⫺214
220⫺221
270⫺271
236⫺238
218⫺220
211⫺213
166⫺167
231⫺232
208⫺209
209⫺211
236⫺238
206⫺207
197⫺199
162⫺163
223⫺224
Formula†
Inhibition (in vitro)
IC50 [μ M]‡
Sterols
FA
C17H15NO5
C17H14FNO5
C17H14FNO5
C17H14FNO5
C17H14ClNO5
C17H13BrNO5
C17H13F2NO5
C17H13Cl2NO5
C17H13Cl2NO5
C17H13BrFNO5
C18H17NO5
C19H19NO5
C20H21NO5
C21H23NO5
C21H23NO5
C21H23NO5
C18H14F3NO5
C18H17NO6
C18H17NO6
C19H19NO6
C20H21NO6
C18H14F3NO6
C19H19NO7
C17H14N2O7
C18H16ClNO5
C18H16ClNO5
C19H18ClNO5
C19H16ClNO5
13.9
11.0
15.7
9.1
3.0
3.2
13.1
7.9
6.6
7.7
5.7
5.6
5.1
4.4
12.0
17.5
4.8
9.0
5.7
⬎50
12.6
12.5
19.7
3.8
25.8
⬎50
16.3
17.4
6.9
7.6
8.0
5.3
2.0
1.6
5.1
4.7
4.0
3.0
2.9
2.8
1.5
2.8
4.3
5.8
3.2
5.3
2.6
26.3
5.2
5.9
4.9
1.3
8.1
37.4
3.7
5.7
11.7
⬎500
0.2
4.8
⬎500
⬎500
S-2E
Bezafibrate
Pravastatin
†
‡
Confirmed by CHN analysis to within ± 0.4% of the theoretical values.
The numerical value is due to mean value of three times.
Animals
SD and Wistar rats were purchased from Clea Japan, Tokyo, Japan.
WHHL rabbits were purchased from Kitayama Labes, Japan).
AUC Values for serum and liver
Male Sprague-Dawley (SD) rats were used for this study. Compounds were suspended with 0.5 % (w/v) HPMC (hydroxypropylmethylcellulose) solution and administered at a dosage of 25 mg/
10 mL/kg, p.o. AUC values for serum and liver were calculated
based on each value at 1, 2, 4, 8, 12, and 24 h.
Chemistry
residue was distilled to give 1g (47 g, 83 %) as colorless oil; bp.
63⫺65 °C (5 mmHg). 1H-NMR (CDCl3) δ: 6.91⫺7.00 (1H, m),
7.20⫺7.25 (1H, m), 7.26⫺7.37 (1H, m).
4-Isopropoxyphenyl isocyanate (1u)
Trichloromethyl chloroformate (39 g, 0.2 mol) was added slowly to
a solution of 4-isopropoxyaniline (25 g, 0.17 mol) in dioxane
(200 mL) at 0 °C. After being stirred for 1 h at room temperature,
the reaction mixture was refluxed for 3 h. After evaporation, the
residue was distilled to give 1u (15 g, 51 %) as colorless oil; bp. 90 °C
(5 mmHg). 1H-NMR (CDCl3) δ: 1.32 (6H, d, J ⫽ 5.9 Hz),
4.42⫺4.55 (1H, m), 6.81 (2H, d, J ⫽ 8.9 Hz), 6.99 (2H, d, J ⫽
8.9 Hz).
4-Bromo-2-fluorophenyl isocyanate (1g)
Trichloromethyl chloroformate (70 g, 0.34 mol) was added slowly
to a solution of 4-bromo-2-fluoroaniline (50 g, 0.26 mol) in dioxane
(50 mL) at 0 °C. After being stirred for 1 h at room temperature,
the reaction mixture was refluxed for 2 h. After evaporation, the
Methyl 4-oxiranylmethoxybenzoate (2a)
A mixture of methyl 4-hydroxybenzoate (5.0 g, 33 mmol), epibromohydrin (4.5 g, 33 mmol) and K2CO3 (5.45 g, 40 mmol) in DMF
(60 mL) was stirred overnight at 70 °C. The mixture was extracted
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
151
152
Ohno et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
Table 3. Decreasing effect on the serum fatty-acid and
cholesterol level.
Compound
100 mg/kg
TG†
TC†
Table 5. Activities of the optically active compounds and
racemate in vitro and in vivo, and concentrations of compounds in liver of S.D. rat.
300 mg/kg
TC†
TG†
Compound
⫺15.3
⫺14.4
⫺6.6
13.7
⫺12.8
⫺9.3
⫺9.2
⫺8.3
⫺35.9
6.6
⫺68.1
⫺37.1
⫺7.7
20.8
⫺9.4
4.3
9.9
⫺69.0
Pravastatin‡
3.8
⫺43.7
Bezafibrate‡
⫺18.9
⫺71.4
4e
4h
4j
4k
4l
4q
4s
4u
4v
†
‡
⫺11.4
⫺26.8
⫺32.4
⫺3.5
⫺17.1
⫺11.2
⫺10.6
⫺10.9
⫺50.4
23.5
⫺65.5
⫺62.9
⫺1.0
⫺2.7
⫺20.8
3.0
⫺20.0
⫺83.0
9.7
3.5
7.7
(R)-4j
(S)-4j
racemi-4j
†
Inhibition (in vitro)
IC50 [μM]
Sterols
FA
3.0
2.7
3.0
Changing rate
in the serum†
TC
TG
⫺11.2
⫺39.9
⫺6.6
⫺75.7
⫺57.0
⫺37.1
Administered p.o. (0.5% HPMC), 100 mg/kg, at 2 wk; into male
S.D. rats (n⫽5).
Table 6. Decreasing effect on the serum cholesterol (TC)
and trigliceride (TG) level of (R)-4j, pravastatin and bezafibrate in WHHL rabbit. Administered p.o. (0.5% HPMC), at
1 wk; into WHHL rabbit (n=5).
Change rate in serum; in male S.D.Rats (n⫽5), administered p.o.
(0.5% HPMC), at 2 weeks.
Administered p.o., at 1 week.
Table 4. AUC value of the compounds in serum and liver.
(R)-4j
dose [mg/kg]
50
TC
TG
⫺11.2
⫺31.5
Pravastatin
dose [mg/kg]
30
100
⫺14.7
⫺12.5
⫺22.2
⫺13.1
Bezafibrate
dose [mg/kg]
30
100
⫺6.7
⫺11.9
⫺5.6
0.9
AUC†
Compound
Serum
[μg h/mL]
Liver
[μg h/g]
4e
4h
4j
4k
4q
4s
4u
4v
61.9
110.0
65.5
39.4
53.4
54.5
74.8
344.0
339.8
662.1
668.5
232.1
485.5
244.4
327.7
1018.9
Methyl-4-oxiranylethoxybenzoate (2b)
†
See experimental section.
with AcOEt and washed with water and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by silicagel column chromatography (AcOEt : n-hexane ⫽ 1:2) to give 2a as white
solid (5.32 g, 78 %); mp. 50⫺52 °C.
(R)-Methyl-4-oxiranylmethoxybenzoate ((R)-2a)
A mixture of (R)-(-)-glycidyl nosylate (150 g, 0.58 mol, 99.3 % enantiomeric excess (e.e.)), methyl 4-hydroxybenzoate (104 g, 0.55
mol) and K2CO3 (104 g, 0.75 mol) in 2-butanone (1.5 l) was stirred
4 h at 80 °C. The mixture was filtered and concentrated in vavuo. To
the residue was extracted with AcOEt and washed with water and
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by silicagel column chromatography (AcOEt : n-hexane ⫽ 1:3) to give (R)-2a as white solid (100 g, 87 %, 92 % e.e.).
The enantiomeric excess (e.e.) was determined by CHIRALCEL OJ
column using the eluent of n-hexane/EtOH/TFA ⫽ (80/20/0.2).
The enantiomer (S)-2a was prepared as same method from (S)-(⫹)glycidyl nosylate.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
A solution of methyl 4-(2,2-dimethyl-1,3-dioxolane-4-ylethoxy)benzoate (6.1 g, 21.8 mmol) in EtOH (5 mL) was treated with 2N HCl
(5 mL) to remove the acetonide protecting group. The mixture was
evaporated and purified by silicagel column chromatography
(CHCl3 : MeOH ⫽ 20:1) to give methyl 4-(3,4-dihydroxy-1-butoxy)benzoate as crystal (6.72 g, 98 %). p-Toluenesulfonyl chloride
(5.66 g, 29.7 mmol) was added to the solution of methyl 4-(3,4dihydroxy-1-butoxy)benzoate (6.5 g, 27 mmol) in pyridine (60 mL)
at 0 °C and stirred overnight at room temperature. The mixture was
concentrated and diluted with CH2Cl2 then washed with 1N H2SO4
and water, dried over MgSO4, and evaporated in vacuo. The residue
was diluted with THF (20 mL) and DBU (6.09 g, 40 mmol) was
added and stirred 4 h at room temperature. The mixture was extracted with AcOEt, washed with water, and evaporated in vacuo.
To the residue, Et2O was added and precipitates were filtered off.
The filtrate was evaporated to give 2b as yellow oil (2.5 g, 42 %).
1
H-NMR (CDCl3) δ: 1.88⫺2.02 (1H, m), 2.18⫺2.26 (1H, m), 2.59
(1H, dd, J ⫽ 4.9, 2.6 Hz), 2.84 (1H, dd, J ⫽ 4.9, 4.2 Hz), 3.13⫺3.18
(1H, m), 3.89 (3H, s), 4.14⫺4.21 (2H, m), 6.92 (2H, d, J ⫽ 9.2 Hz),
7.99 (2H, d, J ⫽ 9.2 Hz).
Methyl-4-[3-(4-bromo-2-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3j)
A mixture of lithium bromide monohydrate (304 mg, 2.9 mmol) and
tri-n-butylphosphine oxide (633 mg, 2.9 mmol) in toluene (10 mL)
was heated to distill the solvent then additional xylene was added.
To the mixture, a solution of 4-bromo-2-fluorophenyl isocyanate
(1j) (10.8 g, 50 mmol) and 2a (10.4 g, 50 mmol) in xylene (30 mL)
was added at 140 °C. The mixture was stirred at the same temperature for 2 h then evaporated under reduced pressure. To the residue,
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
EtOH was added and the precipitates were collected by suction and
washed with EtOH to give 3j as white solid (14.5 g, 68 %).; mp.
154⫺155 °C. 1H-NMR (DMSO-d6) δ: 3.90 (3H, s), 4.05 (1H, dd,
J ⫽ 8.9, 5.9 Hz), 4.20⫺4.36 (3H, m), 4.99⫺5.08 (1H, m), 6.94 (2H,
d, J ⫽ 9.2 Hz), 7.32⫺7.37 (2H, m), 7.45⫺7.53 (1H, m), 8.01 (2H,
d, J ⫽ 9.2Hz). Anal. Calcd. for C18H15BrFNO5: C, 50.96; H,3.56;
N,3.30. Found: C, 51.03; H, 3.56; N, 3.13.
The other compounds 3a⫺i and 3k⫺3x were prepared by the same
method as 3j.
(R)-(⫺)-Methyl-4-[3-(4-bromo-2-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate ((R)-(ⴚ)-3j)
A mixture of lithium bromide monohydrate (2.83 g, 27 mmol) and
tri-n-butylphosphine oxide (5.59 g, 27 mmol) in toluene (150 mL)
was heated to distill the solvent then xylene (100 mL) was added.
To the mixture, a solution of 4-bromo-2-fluorophenyl isocyanate
(1j) (97.6 g, 0.45 mol) and (R)-2a (94 g, 0.45 mol) in xylene (200
mL) was added at 140 °C. The mixture was stirred at the same temperature for 4 h then evaporated under reduced pressure. To the
residue, EtOH was added and the precipitates were corrected by
suction and washed with EtOH to give (R)-(ⴚ)-3j as white solid
(268 g, 82 %, 92 % e.e.); mp 136⫺137 °C.; [α]25
D ⫺76.8° (c 1.0,
CH2Cl2). ; Anal. Calcd. for C18H15BrFNO5: C, 50.96; H, 3.56; N,
3.30. Found: C, 50.89; H, 3.53; N, 3.29. The enantiomeric excess
(e.e.) was determined by CHIRALCEL OD column using the eluent
of n-hexane/EtOH/TFA ⫽ (80/20/0.2).
The enantiomer (S)-(ⴙ)-3j was prepared as same method from (S)2a. Mp. 133-135 °C; [α]25
D 82.8° (c 1.0, CH2Cl2). Anal. Calcd. for
C18H15BrFNO5: C, 50.96; H, 3.56; N, 3.30. Found: C, 50.84; H,
3.49; N, 3.21.
Methyl-4-(3-phenyl-2-oxo-5-oxazolidinyl)methoxybenzoate (3a)
H-NMR (CDCl3) δ: 3.89 (3H, s), 4.06 (1H, dd, J ⫽ 8.9, 5.9 Hz),
4.22 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.28 (2H, d, J ⫽ 4.6 Hz), 4.96⫺5.05
(1H, m), 6.93 (2H, d, J ⫽ 8.9 Hz), 7.13⫺7.19 (1H, m), 7.36⫺7.43
(2H, m), 7.54⫺7.59 (2H, m), 8.00 (2H, d, J ⫽ 8.9 Hz).
1
Methyl-4-[3-(2-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3b)
1
H-NMR (CDCl3) δ: 3.89 (3H, s), 4.06 (1H, dd, J ⫽ 8.9, 5.6 Hz),
4.21⫺4.36 (3H, m), 5.00⫺5.08 (1H, m), 6.95 (2H, d, J ⫽ 8.9 Hz),
7.12⫺7.32 (3H, m), 7.53⫺7.61 (1H, m), 8.01 (2H, d, J ⫽ 8.9Hz).
Anal. Calcd. for C18H16FNO5: C, 62.61; H, 4.67; N, 4.06. Found:
C, 62.66; H, 4.71; N, 4.04.
Methyl-4-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3c)
1
H-NMR (CDCl3) δ: 3.89 (3H, s), 4.05 (1H, dd, J ⫽ 8.9, 6.3 Hz),
4.20 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.25⫺4.33 (2H, m), 4.97⫺5.06 (1H,
m), 6.82⫺6.90 (1H, m), 6.92 (2H, d, J ⫽ 8.9 Hz), 7.24⫺7.50 (3H,
m), 8.00 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for C18H16FNO5: C,
62.61; H, 4.67; N, 4.06. Found: C, 62.81; H, 4.64; N, 4.13.
Methyl-4-[3-(4-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3d)
H-NMR (CDCl3) δ: 3.89 (3H, s), 4.05 (1H, dd, J ⫽ 8.9, 5.9 Hz),
4.20 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.28 (2H, d, J ⫽ 4.6 Hz), 4.96⫺5.05
(1H, m), 6.3 (2H, d, J ⫽ 8.9 Hz), 7.09 (2H, dd, J ⫽ 8.9, 8.9 Hz), 5.53
(2H, m), 8.00 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for C18H16FNO5: C,
62.61; H, 4.67; N, 4.06. Found: C, 62.74; H, 4.59; N, 4.06.
1
Synthesis and Activity of 4-Substituted Benzoic Acid
Methyl-4-[3-(4-chlorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3e)
1
H-NMR (CDCl3) δ: 3.89 (3H, s), 4.05 (1H, dd, J ⫽ 8.9, 5.9 Hz),
4.20 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.25⫺4.34 (2H, m), 5.05⫺5.14 (1H,
m), 6.92 (2H, d, J ⫽ 8.9 Hz), 7.36 (2H, d, J ⫽ 8.9 Hz), 7.53 (2H,
d, J ⫽ 8.9 Hz), 8.01 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for
C18H16ClNO5: C, 59.76; H, 4.46; N, 3.87. Found: C, 59.88; H, 4.39;
N, 3.88.
Methyl-4-[3-(4-bromophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3f)
H-NMR (CDCl3) δ: 3.89 (3H, s), 4.04 (1H, dd, J ⫽ 8.9, 5.9 Hz),
4.19 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.23⫺4.33 (2H, m), 4.96⫺5.06 (1H,
m), 6.92 (2H, d, J ⫽ 8.9 Hz), 7.45⫺7.53 (4H, m), 8.00 (2H, d, J ⫽
8.9 Hz). Anal. Calcd. for C18H16BrNO5: C, 53.22; H, 3.97; N, 3.45.
Found: C, 53.19; H, 3.85; N, 3.40.
1
Methyl-4-[3-(2,4-difluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3g)
1
H-NMR (CDCl3) δ: 3.90 (3H, s), 4.23 (1H, dd, J ⫽ 8.6, 5.6 Hz),
4.17⫺4.36 (3H, m), 4.99⫺5.09 (1H, m), 6.88⫺6.99 (2H, m), 6.95
(2H, d, J ⫽ 8.9 Hz), 7.47⫺7.57 (1H, m), 8.02 (2H, d, J ⫽ 8.9 Hz).
Anal. Calcd. for C18H15F2NO5: C, 59.51; H, 4.16; N, 3.86. Found:
C, 59.51; H, 4.16; N, 3.87.
Methyl-4-[3-(2,4-dichlorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3h)
1
H-NMR (CDCl3) δ: 3.90 (3H, s), 4.01 (1H, dd, J ⫽ 8.9, 5.6 Hz),
4.17 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.24⫺4.38 (2H, m), 5.02⫺5.11 (1H,
m), 6.96 (2H, d, J ⫽ 8.9 Hz), 7.33 (1H, dd, J ⫽ 8.6, 2.3 Hz), 7.39
(1H, d, J ⫽ 8.6 Hz), 7.50 (1H, d, J ⫽ 2.3 Hz), 8.02 (2H, d, J ⫽ 8.9
Hz). Anal. Calcd. for C18H15Cl2NO5: C, 54.56; H, 3.82; N, 3.54.
Found: C, 54.41; H, 3.76; N, 3.53.
Methyl-4-[3-(3,4-dichlorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3i)
H-NMR (CDCl3) δ: 3.89 (3H, s), 4.07 (1H, d, J ⫽ 8.9, 5.9 Hz),
4.19 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.23⫺4.34 (2H, m), 4.98-5.08 (1H,
m), 6.92 (2H, d, J ⫽ 8.9 Hz), 7.42⫺7.52 (2H, m), 7.70 (1H, d, J ⫽
2.3 Hz), 8.00 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for C18H15Cl2NO5:
C, 54.56; H, 3.82; N, 3.54. Found: C, 54.60; H, 3.72; N, 3.59.
1
Methyl-4-[3-(4-methylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3k)
1
H-NMR (CDCl3) δ: 2.33 (3H, s), 3.89 (3H, s), 4.03 (1H, dd, J ⫽
8.9, 6.1 Hz), 4.19 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.26 (2H, d, J ⫽ 4.6
Hz), 4.94⫺5.03 (1H, m), 6.92 (2H, d, J ⫽ 9.2 Hz), 7.19 (2H, d, J ⫽
8.5 Hz), 7.44 (2H, d, J ⫽ 8.5 Hz), 8.00 (2H, d, J ⫽ 9.2 Hz). Anal.
Calcd. for C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found: C, 66.85;
H, 5.54; N, 4.06.
Methyl-4-[3-(4-ethylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3l)
H-NMR (CDCl3) δ: 1.23 (3H, t, J ⫽ 7.6 Hz), 2.64 (2H, q, J ⫽ 7.6
Hz), 3.89 (3H, s), 4.04 (1H, dd, J ⫽ 8.9, 5.9 Hz), 4.20 (1H, dd, J ⫽
8.9, 8.9 Hz), 4.27 (2H, d, J ⫽ 4.6 Hz), 4.94⫺5.04 (1H, m), 6.93 (2H,
d, J ⫽ 8.9 Hz), 7.22 (2H, d, J ⫽ 8.6 Hz), 7.47 (2H, d, J ⫽ 8.6 Hz),
8.00 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for C20H21NO5: C, 67.59; H,
5.96; N, 3.94. Found: C, 67.50; H, 5.83; N, 3.93.
1
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Ohno et al.
Methyl-4-[3-(4-isopropylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3m)
H-NMR (CDCl3) δ: 1.24 (6H, d, J ⫽ 6.9 Hz), 2.82-2.96 (1H, m),
3.89 (3H, s), 4.05 (1H, dd, J ⫽ 8.9, 5.9 Hz), 4.21 (1H, dd, J ⫽ 8.9,
8.9 Hz), 4.27 (2H, d, J ⫽ 4.6 Hz), 4.95⫺5.04 (1H, m), 6.93 (2H, d,
J ⫽ 8.9 Hz), 7.25 (2H, d, J ⫽ 8.6 Hz), 7.48 (2H, d, J ⫽ 8.6 Hz),
8.00 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for C21H23NO5: C, 68.28; H,
6.28; N, 3.79. Found: C, 68.26; H, 6.30; N, 3.95.
1
Methyl-4-[3-(4-n-butylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3n)
1
H-NMR (CDCl3) δ: 0.92 (3H, t, J ⫽ 7.3 Hz), 1.27-1.42 (2H, m),
1.52-1.64 (2H, m), 2.60 (2H, t, J ⫽ 7.6 Hz), 3.89 (3H, s), 4.04 (1H,
dd, J ⫽ 8.9, 5.9 Hz), 4.20 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.27 (2H, d,
J ⫽ 4.6 Hz), 4.94⫺5.04 (1H, m), 6.93 (2H, d, J ⫽ 8.9 Hz), 7.20
(2H, d, J ⫽ 8.9 Hz), 7.46 (2H, d, J ⫽ 8.9 Hz), 8.00 (2H, d, J ⫽ 8.9
Hz). Anal. Calcd. for C22H25NO5: C, 68.91; H, 6.57; N, 3.65.
Found: C, 68.88; H, 6.62; N, 3.65.
Methyl-4-[3-(4-isobutylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3o)
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
Hz), 4.94⫺5.03 (1H, m), 6.92 (2H, d, J ⫽ 9.2 Hz), 6.93 (2H, d, J ⫽
8.9 Hz), 7.46 (2H, d, J ⫽ 8.9 Hz), 8.00 (2H, d, J ⫽ 9.2 Hz). Anal.
Calcd. for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found: C, 63.83;
H, 5.37; N, 3.97.
Methyl 4-[3-(4-ethoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3t)
H-NMR (CDCl3) δ: 1.36 (3H, t, J ⫽ 6.9 Hz), 3.89 (3H, s),
3.97⫺4.19 (4H, m), 4.27 (2H, d, J ⫽ 5.0 Hz), 4.95⫺5.05 (1H, m),
6.92⫺7.02 (4H, m), 7.23⫺7.41 (2H, m), 8.01 (2H, d, J ⫽ 8.9 Hz).
1
Methyl-4-[3-(4-isopropoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3u)
H-NMR (CDCl3) δ: 1.33 (6H, d, J ⫽ 6.3 Hz), 3.89 (3H, s), 4.02
(1H, dd, J ⫽ 8.9, 5.9 Hz), 4.19 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.27 (2H,
d, J ⫽ 4.6 Hz), 4.47⫺4.56 (1H, m), 4.94⫺5.03 (1H, m), 6.91 (2H,
d, J ⫽ 8.9 Hz), 6.93 (2H, d, J ⫽ 8.9 Hz), 7.44 (2H, d, J ⫽ 8.9 Hz),
8.01 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for C21H23NO6: C, 65.44; H,
6.01; N, 3.63. Found: C, 65.40; H, 6.20; N, 3.85.
1
Methyl-4-[3-(4-trifluoromethoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3v)
H-NMR (CDCl3) δ: 0.90 (6H, d, J ⫽ 6.6 Hz), 1.79⫺1.90 (1H, m),
2.46 (2H, d, J ⫽ 7.3 Hz), 3.89 (3H, s), 4.05 (1H, dd, J ⫽ 8.9, 6.1
Hz), 4.22 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.27⫺4.34 (2H, m), 4.97⫺5.05
(1H, m), 6.94 (2H, d, J ⫽ 8.9 Hz), 7.16 (2H, d, J ⫽ 8.6 Hz), 7.46
(2H, d, J ⫽ 8.6 Hz), 8.00 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for
C22H25NO5: C, 68.91; H, 6.57; N, 3.65. Found: C, 68.91; H, 6.60;
N, 3.63.
1
H-NMR (CDCl3) δ: 3.89 (3H, s), 4.08 (1H, dd, J ⫽ 8.9, 5.9 Hz),
4.22 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.27⫺4.31 (2H, m), 5.00⫺5.06 (1H,
m), 6.93 (2H, d, J ⫽ 8.9 Hz), 7.26 (2H, d, J ⫽ 9.2 Hz), 7.61 (2H,
d, J ⫽ 9.2 Hz), 8.01 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for
C19H16F3NO6: C, 55.48; H, 3.92; N, 3.41. Found: C, 55.47; H, 3.87;
N, 3.41.
Methyl-4-[3-(4-tert-butylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3p)
Methyl-4-[3-(2,4-dimethoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3w)
1
H-NMR (CDCl3) δ: 1.32 (9H, s), 3.89 (3H, s), 4.05 (1H, dd, J ⫽
8.9, 5.9 Hz), 4.21 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.27 (2H, d, 4.6 Hz),
4.95⫺5.04 (1H, m), 6.93 (2H, d, J ⫽ 8.9 Hz), 7.41 (2H, d, J ⫽ 8.9
Hz), 7.49 (2H, d, J ⫽ 8.9 Hz), 8.00 (2H, d, J ⫽ 8.9 Hz). Anal.
Calcd. for C22H25NO5: C, 68.91; H, 6.57; N, 3.65. Found: C, 68.97;
H, 6.69; N, 3.69.
1
H-NMR (CDCl3) δ: 3.81 (6H, s), 3.84⫺3.90 (1H, m), 3.90 (3H, s),
4.10 (1H, dd, J ⫽ 8.7, 8.7 Hz), 4.27 (2H, d, J ⫽ 5.0 Hz), 4.94⫺5.03
(1H, m), 6.48⫺6.53 (2H, m), 6.96 (2H, d, J ⫽ 8.9 Hz), 7.24⫺7.23
(1H, m), 8.02 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for C20H21NO7: C,
62.01; H, 5.46; N, 3.62. Found: C, 62.06; H, 5.47; N, 3.61.
1
Methyl-4-[3-(4-trifluoromethyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3q)
H-NMR (CDCl3) δ: 3.89 (3H, s), 4.11 (1H, dd, J ⫽ 8.9, 5.9 Hz),
4.25 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.26⫺4.36 (2H, m), 5.00⫺5.09 (1H,
m), 6.92 (2H, d, J ⫽ 8.9 Hz), 7.64 (2H, d, J ⫽ 8.9 Hz), 7.71 (2H,
d, J ⫽ 8.9 Hz), 8.00 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for
C19H16F3NO5: C, 57.73; H, 4.08; N, 3.54. Found: C, 57.73; H, 3.99;
N, 3.60.
1
Methyl-4-[3-(4-methoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3r)
H-NMR (CDCl3) δ: 3.82 (3H, s), 3.88 (3H, s), 4.03 (1H, dd, J ⫽
8.9, 5.9 Hz), 4.19 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.23⫺4.31 (2H, m),
4.94⫺5.03 (1H, m), 6.68⫺6.73 (1H, m), 6.92 (2H, d, J ⫽ 8.9 Hz),
7.03⫺7.08 (1H, m), 7.25⫺7.32 (2H, m), 7.99 (2H, d, J ⫽ 8.9 Hz).
Anal. Calcd. for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found: C,
63.85; H, 5.29; N, 3.94.
1
Methyl-4-[3-(4-methoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3s)
1
H-NMR (CDCl3) δ: 3.81 (3H, s), 3.89 (3H, s), 4.02 (1H, dd, J ⫽
8.9, 5.9 Hz), 4.18 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.27 (2H, d, J ⫽ 4.6
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Methyl-4-[3-(4-nitrophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3x)
H-NMR (DMSO-d6) δ: 3.82 (3H, s), 4.05 (1H, dd, J ⫽ 9.2, 6.1
Hz), 4.34 (1H, dd, J ⫽ 9.2, 9.2 Hz), 4.38 (1H, dd, J ⫽ 11.2, 6.6
Hz), 4.44 (1H, dd, J ⫽ 11.2, 3.3 Hz), 5.17 (1H, m), 7.70 (2H, d,
J ⫽ 8.9 Hz), 7.85 (2H, d, J ⫽ 9.3 Hz), 7.92 (2H, d, J ⫽ 8.9 Hz),
8.31 (2H, d, J ⫽ 9.3 Hz). Anal. Calcd. for C18H16N2O7: C, 58.07;
H, 4.33; N, 7.52. Found: C, 58.03; H, 4.30; N, 7.38.
1
Methyl 4-[3-(4-chlorophenyl)-2-oxo-5-oxazolidinyl]ethoxybenzoate
(3y)
A mixture of lithium bromide monohydrate (30 mg, 0.3 mmol) and
tri-n-butylphosphine oxide (63 mg, 0.3 mmol) in toluene (5 mL) was
heated to distill the solvent then additional xylene was added. To
the mixture, a solution of 1e (889 mg, 4 mmol) and 2b (614 mg, 4
mmol) in xylene (2 mL) was added at 140 °C. The mixture was
stirred at the same temperature for 2 h then evaporated under reduced pressure. To the residue EtOH was added and the precipitates
were corrected by suction and washed with EtOH to give 3y as
white solid (1.13 g, 75 %). Mp. 139⫺141 °C; 1H-NMR (CDCl3) δ:
2.27⫺2.35 (2H, m), 3.80 (1H, dd, J ⫽ 7.7, 7.1 Hz), 3.89 (3H, s),
4.18 (1H, dd, J ⫽ 8.6, 8.6 Hz), 4.23⫺4.29 (2H, m), 4.92⫺4.98 (1H,
m), 6.91 (2H, d, J ⫽ 9.2 Hz), 7.34 (2H, d, J ⫽ 9.2 Hz), 7.49 (2H,
d, J ⫽ 9.2 Hz), 8.00 (2H, d, J ⫽ 9.2 Hz).
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
Methyl-4-[3-(4-chlorobenzyl)-2-oxo-5-oxazolidinyl]methoxybenzoate (3z)
A mixture of lithium bromide monohydrate (53 mg, 0.5 mmol) and
tri-n-butylphosphine oxide (110 mg, 0.5 mmol) in toluene (5 mL)
was heated to distill the solvent then additional xylene was added.
To the mixture, a solution of 4-chlorobenzoyl isocyanate (1z)
(1.68 g, 10 mmol) and 2a (2.08 g, 10 mmol) in xylene (5 mL) was
added at 140 °C. The mixture was stirred at the same temperature
for 2 h then evaporated under reduced pressure. The residue was
purified by silicagel column chromatography (AcOEt : n-hexane ⫽
1:1) and recrystallized from EtOH and isopropyl ether to give 3z as
white solid (2.3 g, 61 %). Mp. 67-70 °C; 1H-NMR (CDCl3) δ: 3.43
(1H, dd, J ⫽ 9.0, 5.9 Hz), 3.59 (1H, dd, J ⫽ 8.9, 8.9 Hz), 3.89 (3H,
s), 4.09⫺4.21 (2H, m), 4.39 (1H, d, J ⫽ 15.2 Hz), 4.49 (1H, d, J ⫽
15.2 Hz), 4.80⫺4.89 (1H, m), 6.86 (2H, d, J ⫽ 8.9 Hz), 7.26 (2H,
d, J ⫽ 8.6 Hz), 7.34 (2H, d, J ⫽ 8.6 Hz), 7.99 (2H, d, J ⫽ 8.9 Hz).
Anal. Calcd. for C19H18ClNO5: C, 59.76; H, 4.46; N, 3.87. Found:
C, 59.68; H, 4.49; N, 3.92.
4-[3-(4-Bromo-2-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid (4j)
A solution of 3j (14.5 g, 34 mmol) in the acetic acid (120 mL) and
conc. HCl (40 mL) was stirred overnight at 90 °C, after cooling,
Et2O (100 mL) was added. The resulting precipitate was collected,
and the filtrate was condensed to give a precipitate, the solid was
washed with water to give 4j (12.2 g, 87 %) as white solid. Mp.
204⫺205 °C; 1H-NMR (DMSO-d6) δ: 3.90 (1H, dd, J ⫽ 8.9, 5.9
Hz), 4.21 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.29⫺4.43 (2H, m), 5.08⫺5.16
(1H, m), 7.07 (2H, d, J ⫽ 8.9 Hz), 7.48⫺7.61 (2H, m), 7.72 (1H,
dd, J ⫽ 10.5, 2.0 Hz), 7.92 (2H, d, J ⫽ 8.9 Hz), 12.66 (1H, br.s).
Anal. Calcd. for C17H13BrFNO5: C, 49.78; H, 3.19; N, 3.41. Found:
C, 49.63; H, 3.18; N, 3.35.
(R)-(⫺)-4-[3-(4-Bromo-2-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid ((R)-(ⴚ)-4j)
A solution of (R)-(ⴚ)-3j (160 g, 378 3mol) in the acetic acid (1.2 l)
and conc. HCl (0.4 l) was stirred overnight at 90 °C. The mixture
was condensed in vacuo and water (1.2 l) was added. After cooling,
the resulting precipitate was collected and washed with EtOH to
give (R)-(ⴚ)-4j (149 g, 96 %, 92 % e.e.) as white solid; mp
194⫺195 °C. [α]25
D ⫺102° (c 0.5, MeOH). The enantiomeric excess
(e.e.) was determined by CHIRALCEL OD column using the eluent
of n-hexane/EtOH/TFA ⫽ (80/20/0.2).
The enantiomer (S)-(ⴙ)-4j was prepared as same method from (S)(ⴙ)-3j. Physical data: Mp. 186⫺188 °C; [α]25
D 93.6° (c 0.5, MeOH).
4-[3-(4-Isopropoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
acid (4u)
To a solution of 3u (0.47 g, 1.2 mmol) in MeOH (30 mL) 1N NaOH
(5mL) was added and stirred overnight at 65 °C. The mixture was
concentrated in vacuo and conc. HCl was added. The precipitate
was filtered and washed with water to give 4u (0.4 g, 89 %) as white
solid. Mp. 231⫺232 °C; 1H-NMR (DMSO-d6) δ: 1.25 (6H, d, J ⫽
5.9 Hz), 3.89 (1H, dd, J ⫽ 9.1, 6.4 Hz), 4.20 (1H, dd, J ⫽ 9.1, 9.1
Hz), 4.28⫺4.41 (2H, m), 4.51⫺4.65 (1H, m), 5.00⫺5.10 (1H, m),
6.95 (2H, d, J ⫽ 8.9 Hz), 7.06 (2H, d, J ⫽ 8.9 Hz), 7.46 (2H, d,
J ⫽ 8.9 Hz), 7.90 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for C20H21NO6:
C, 64.68; H, 5.70; N, 3.77. Found: C, 64.79; H, 5.78; N, 3.85.
The other compounds 4a⫺i, 4k⫺4t, 4v⫺4z were prepared by the
same method as 4j.
Synthesis and Activity of 4-Substituted Benzoic Acid
4-(3-Phenyl-2-oxo-5-oxazolidinyl)methoxybenzoic acid (4a)
H-NMR (DMSO-d6) δ: 3.95 (1H, dd, J ⫽ 9.1, 6.4 Hz), 4.25 (1H,
dd, J ⫽ 9.1, 9.1 Hz), 4.30⫺4.42 (2H, m), 5.08⫺5.10 (1H, m), 7.05
(2H, d, J ⫽ 8.9 Hz), 7.11⫺7.17 (1H, m), 7.41 (2H, dd, J ⫽ 7.6, 7.6
Hz), 7.59 (2H, d, J ⫽ 7.6 Hz), 7.90 (2H, d, J ⫽ 8.9 Hz), 12.69 (1H,
br.s). Anal. Calcd. for C17H15NO5: C, 65.17; H, 4.83; N, 4.47.
Found: C, 65.34; H, 4.87; N, 4.45.
1
4-[3-(2-Fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4b)
acid
1
H-NMR (DMSO-d6) δ: 3.90 (1H, dd, J ⫽ 8.9, 5.9 Hz), 4.21 (1H,
dd, J ⫽ 8.9, 8.9 Hz), 4.29⫺4.43 (2H, m), 5.08⫺5.17 (1H, m), 7.08
(2H, d, J ⫽ 8.9 Hz), 7.25⫺7.40 (3H, m), 7.56⫺7.62 (1H, m), 7.92
(2H, d, J ⫽ 8.9 Hz), 12.67 (1H, br.s). Anal. Calcd. for C17H14FNO5:
C, 61.63; H, 4.26; N, 4.23. Found: C, 61.89; H, 4.24; N, 4.22.
4-[3-(3-Fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4c)
acid
1
H-NMR (DMSO-d6) δ: 3.96 (1H, dd, J ⫽ 9.2, 6.1 Hz), 4.25 (1H,
dd, J ⫽ 9.2, 9.2 Hz), 4.30⫺4.42 (2H, m), 5.06⫺5.15 (1H, m),
6.94⫺7.02 (1H, m), 7.05 (2H, d, J ⫽ 8.9 Hz), 7.34⫺7.58 (3H, m),
7.90 (2H, d, J ⫽ 8.9 Hz), 12.68 (1H, s). Anal. Calcd. for
C17H14FNO5: C, 61.63; H, 4.26; N, 4.23. Found: C, 61.83; H, 4.22;
N, 4.22.
4-[3-(4-Fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4d)
acid
1
H-NMR (DMSO-d6) δ: 3.94 (1H, dd, J ⫽ 8.9, 6.3 Hz), 4.24 (1H,
dd, J ⫽ 8.9, 8.9 Hz), 4.30⫺4.42 (2H, m), 5.04⫺5.13 (1H, m), 7.05
(2H, d, J ⫽ 8.9 Hz), 7.56 (2H, dd, J ⫽ 8.9, 8.9 Hz), 7.61 (2H, dd,
J ⫽ 8.9, 5.0 Hz), 7.90 (2H, d, J ⫽ 8.9 Hz). Anal. Calcd. for
C17H14FNO5: C, 61.63; H, 4.26; N, 4.23. Found: C, 61.79; H, 4.28;
N, 4.25.
4-[3-(4-Chlorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4e)
acid
H-NMR (DMSO-d6) δ: 3.94 (1H, dd, J ⫽ 9.2, 6.3 Hz), 4.24 (1H,
dd, J ⫽ 9.2, 9.2 Hz), 4.30⫺4.42 (2H, m), 5.06⫺5.14 (1H, m), 7.05
(2H, d, J ⫽ 8.9 Hz), 7.47 (2H, d, J ⫽ 8.9 Hz), 7.62 (2H, d, J ⫽ 8.9
Hz), 7.90 (2H, d, J ⫽ 8.9 Hz), 12.65 (1H, br.s). Anal. Calcd. for
C17H14ClNO5: C, 58.72; H, 4.06; N, 4.03. Found: C, 58.69; H, 4.00;
N, 3.96.
1
4-[3-(4-Bromophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4f)
acid
1
H-NMR (DMSO-d6) δ: 3.93 (1H, dd, J ⫽ 8.9, 6.3 Hz), 4.23 (1H,
dd, J ⫽ 8.9, 8.9 Hz), 4.30⫺4.42 (2H, m), 5.05⫺5.14 (1H, m), 7.05
(2H, d, J ⫽ 8.8 Hz), 7.54⫺7.88 (4H, m), 7.90 (2H, d, J ⫽ 8.8 Hz),
12.68 (1H, br.s). Anal. Calcd. for C17H13BrNO5: C, 52.06; H, 3.60;
N, 3.57. Found: C, 52.02; H, 3.50; N, 3.56.
4-[3-(2,4-Difluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
acid (4g)
1
H-NMR (DMSO-d6) δ: 3.87 (1H, dd, J ⫽ 8.9, 5.9 Hz), 4.17 (1H,
dd, J ⫽ 8.9, 8.9 Hz), 4.29⫺4.43 (2H, m), 5.09⫺5.17 (1H, m), 7.08
(2H, d, J ⫽ 8.6 Hz), 7.10⫺7.23 (1H, m), 7.40⫺7.48 (1H, m),
7.59⫺7.68 (1H, m), 7.92 (2H, d, J ⫽ 8.6 Hz), 12.65 (1H, br.s). Anal.
Calcd. for C17H13F2NO5: C, 58.46; H, 3.75; N, 4.01. Found: C,
58.54; H, 3.76; N, 4.01.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
155
156
Ohno et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
4-[3-(2,4-Dichlorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
acid (4h)
1
H-NMR (DMSO-d6) δ: 3.84 (1H, dd, J ⫽ 8.6, 5.8 Hz), 4.14 (1H,
dd, J ⫽ 8.6, 8.6 Hz), 4.29⫺4.44 (2H, m), 5.10⫺5.19 (1H, m), 7.10
(2H, d, J ⫽ 8.9 Hz), 7.65 (1H, dd, J ⫽ 8.6, 2.3 Hz), 7.64 (1H, d,
J ⫽ 8.6 Hz), 7.80 (1H, d, J ⫽ 2.3 Hz), 7.92 (2H, d, J ⫽ 8.9 Hz).
Anal. Calcd. for C17H13Cl2NO5: C, 53.42; H, 3.43; N, 3.66. Found:
C, 53.32; H, 3.41; N, 3.70.
4-[3-(3,4-Dichlorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
acid (4i)
1
H-NMR (DMSO-d6) δ: 3.97 (1H, dd, J ⫽ 9.2, 6.1 Hz), 4.25 (1H,
dd, J ⫽ 9.2, 9.2 Hz), 4.30⫺4.42 (2H, m), 5.07⫺5.16 (1H, m), 7.05
(2H, d, J ⫽ 8.9 Hz), 7.57 (1H, dd, J ⫽ 8.9, 2.6 Hz), 7.67 (1H, d,
J ⫽ 8.9 Hz), 7.87⫺7.93 (1H, m), 7.90 (2H, d, J ⫽ 8.9 Hz). Anal.
Calcd. for C17H13Cl2NO5: C, 53.42; H, 3.43; N, 3.66. Found: C,
53.31; H, 3.41; N, 3.70.
7.05 (2H, d, J ⫽ 8.9 Hz), 7.09 (2H, d, J ⫽ 8.6 Hz), 7.49 (2H, d,
J ⫽ 8.6 Hz), 7.90 (2H, d, J ⫽ 8.9 Hz), 12.68 (1H, br.s). Anal. Calcd.
for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.61; H,
6.18; N, 3.86.
4-[3-(4-tert-Butylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid
(4p)
1
H-NMR (DMSO-d6) δ: 1.27 (9H, s), 3.92 (1H, dd, J ⫽ 9.2, 6.2
Hz), 4.22 (1H, dd, J ⫽ 9.2, 9.2 Hz), 4.29⫺4.42 (2H, m), 5.03⫺5.10
(1H, m), 7.05 (2H, d, J ⫽ 8.9 Hz), 7.41 (2H, d, J ⫽ 8.9 Hz), 7.50
(2H, d, J ⫽ 8.9 Hz), 7.90 (2H, d, J ⫽ 8.9 Hz), 12.66 (1H, br.s).
Anal. Calcd. for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C,
68.10; H, 6.27; N, 3.73.
4-[3-(4-Trifluoromethylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid (4q)
H-NMR (DMSO-d6) δ: 4.00 (1H, dd, J ⫽ 9.2, 5.9 Hz), 4.30 (1H,
dd, J ⫽ 9.2, 9.2 Hz), 4.34⫺4.44 (2H, m), 5.09⫺5.18 (1H, m), 7.05
(2H, d, J ⫽ 8.9 Hz), 7.77 (2H, d, J ⫽ 9.2 Hz), 7.82 (2H, d, J ⫽ 9.2
Hz), 7.90 (2H, d, J ⫽ 8.9 Hz), 12.66 (1H, br.s). Anal. Calcd. for
C18H14F3NO5: C, 56.70; H, 3.70; N, 3.67. Found: C, 56.82; H, 3.73;
N, 3.74.
1
4-[3-(4-Methylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4k)
acid
1
H-NMR (DMSO-d6) δ: 2.29 (3H, s), 3.91 (1H, dd, J ⫽ 9.1, 6.4
Hz), 4.21 (1H, dd, J ⫽ 9.1, 9.1 Hz), 4.29⫺4.41 (2H, m), 5.03⫺5.11
(1H, m), 7.05 (2H, d, J ⫽ 8.9 Hz), 7.21 (2H, d, J ⫽ 8.6 Hz), 7.47
(2H, d, J ⫽ 8.6 Hz), 7.90 (2H, d, J ⫽ 8.9 Hz), 12.66 (1H, br.s).
Anal. Calcd. for C18H17NO5: C, 66.05; H, 5.23; N, 4.28. Found: C,
66.16; H, 5.24; N, 4.26.
4-[3-(4-Ethylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4l)
acid
H-NMR (DMSO-d6) δ: 1.17 (3H, t, J ⫽ 7.6 Hz), 2.59 (2H, q, J ⫽
7.6 Hz), 3.92 (1H, dd, J ⫽ 9.2, 6.3 Hz), 4.22 (1H, dd, J ⫽ 9.2, 9.2
Hz), 4.29⫺4.41 (2H, m), 5.02⫺5.12 (1H, m), 7.05 (2H, d, J ⫽ 8.9
Hz), 7.24 (2H, d, J ⫽ 8.6 Hz), 7.49 (2H, d, J ⫽ 8.6 Hz), 7.90 (2H,
d, J ⫽ 8.9 Hz). Anal. Calcd. for C19H19NO5: C, 66.85; H, 5.61; N,
4.10. Found: C, 66.88; H, 5.63; N, 4.20.
1
4-[3-(4-Isopropylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid
(4m)
1
H-NMR (DMSO-d6) δ: 1.20 (6H, d, J ⫽ 7.1 Hz), 2.85⫺2.92 (1H,
m), 3.92 (1H, dd, J ⫽ 9.0, 6.3 Hz), 4.22 (1H, dd, J ⫽ 9.0, 9.0 Hz),
4.30⫺4.40 (2H, m), 7.05 (2H, d, J ⫽ 8.9 Hz), 7.27 (2H, d, J ⫽ 8.7
Hz), 7.49 (2H, d, J ⫽ 8.7 Hz), 7.90 (2H, d, J ⫽ 9.0 Hz), 12.68 (1H,
br.s). Anal. Calcd. for C20H21NO5: C, 67.59; H, 5.96; N, 3.94.
Found: C, 67.81; H, 5.91; N, 4.00.
4-[3-(4-n-Butylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4n)
acid
1
H-NMR (DMSO-d6) δ: 0.89 (3H, t, J ⫽ 7.3 Hz), 1.25⫺1.36 (2H,
m), 1.48⫺1.59 (2H, m), 2.49⫺2.59 (2H, m), 3.92 (1H, dd, J ⫽ 9.1,
6.4 Hz), 4.22 (1H, dd, J ⫽ 9.1, 9.1 Hz), 4.29⫺4.41 (2H, m),
5.03⫺5.09 (1H, m), 7.05 (2H, d, J ⫽ 8.9 Hz), 7.22 (2H, d, J ⫽ 8.8
Hz), 7.48 (2H, d, J ⫽ 8.8 Hz), 7.90 (2H, d, J ⫽ 7.9 Hz), 12.66 (1H,
br.s). Anal. Calcd. for C21H23NO5: C, 68.28; H, 6.28; N, 3.79.
Found: C, 68.28; H, 6.24; N, 3.81.
4-[3-(4-Isobutylphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4o)
acid
1
H-NMR (DMSO-d6) δ: 0.86 (6H, d, J ⫽ 6.6 Hz), 1.74-1.89 (1H,
m), 7.43 (2H, d, J ⫽ 7.3 Hz), 3.92 (1H, dd, J ⫽ 9.2, 6.3 Hz), 4.22
(1H, dd, J ⫽ 9.2, 9.2 Hz), 4.29⫺4.41 (2H, m), 5.02⫺5.12 (1H, m),
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
4-[3-(3-Methoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid
(4r)
1
H-NMR (DMSO-d6) δ: 3.77 (3H, s), 3.94 (1H, dd, J ⫽ 9.2, 6.3
Hz), 4.23 (1H, dd, J ⫽ 9.2, 9.2 Hz), 4.29⫺4.42 (2H, m), 5.03⫺5.13
(1H, m), 6.71⫺6.76 (1H, m), 7.05 (2H, d, J ⫽ 8.8 Hz), 7.10⫺7.14
(1H, m), 7.23⫺7.34 (2H, m), 7.90 (2H, d, J ⫽ 8.8 Hz), 12.68 (1H,
br.s). Anal. Calcd. for C18H17NO6: C, 62.97; H, 4.99; N, 4.08.
Found: C, 63.14; H, 5.02; N, 4.16.
4-[3-(4-Methoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid
(4s)
1
H-NMR (DMSO-d6) δ: 3.75 (3H, s), 3.90 (1H, dd, J ⫽ 8.9, 6.3
Hz), 4.20 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.29⫺4.41 (2H, m), 5.02⫺5.08
(1H, m), 6.98 (2H, d, J ⫽ 8.9 Hz), 7.06 (2H, d, J ⫽ 8.9 Hz), 7.49
(2H, d, J ⫽ 8.9 Hz), 7.90 (2H, d, J ⫽ 8.9 Hz), 12.66 (1H, br.s).
Anal. Calcd. for C18H17NO6: C, 62.97; H, 4.99; N, 4.08. Found: C,
63.13; H, 4.86; N, 4.02.
4-[3-(4-Ethoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4t)
acid
H-NMR (DMSO-d6) δ: 1.32 (3H, t, J ⫽ 6.9 Hz), 3.80 (1H, dd,
J ⫽ 8.9, 5.6 Hz), 4.04⫺4.13 (3H, m), 4.25⫺4.40 (2H, m), 5.02⫺5.09
(1H, m), 6.95⫺7.13 (2H, m), 7.09 (2H, d, J ⫽ 8.9 Hz), 7.27⫺7.37
(2H, m), 7.92 (2H, d, J ⫽ 8.9 Hz), 12.67 (1H, br.s). Anal. Calcd.
for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found: C, 63.62; H,
5.29; N, 3.93.
1
4-[3-(4-Trifluoromethoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid (4v)
H-NMR (DMSO-d6) δ: 3.97 (1H, dd, J ⫽ 9.1, 6.1 Hz), 4.27 (1H,
dd, J ⫽ 9.1, 9.1 Hz), 4.33⫺4.43 (2H, m), 5.06⫺5.15 (1H, m), 7.05
(2H, d, J ⫽ 8.9 Hz), 7.3 (2H, d, J ⫽ 9.2 Hz), 7.71 (2H, d, J ⫽ 9.2
Hz), 7.90 (2H, d, J ⫽ 8.9 Hz), 12.69 (1H, br.s). Anal. Calcd. for
C18H14F3NO6: C, 54.42; H, 3.55; N, 3.53. Found: C, 54.33; H, 3.53;
N, 3.51.
1
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
Synthesis and Activity of 4-Substituted Benzoic Acid
4-[3-(2,4-Dimethoxyphenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
acid (4w)
1
H-NMR (DMSO-d6) δ: 3.67 (1H, dd, J ⫽ 8.7, 6.1 Hz), 3.78 (3H,
s), 3.90 (3H, s), 4.00 (1H, dd, J ⫽ 8.7, 8.7 Hz), 4.24⫺4.39 (2H, m),
4.99⫺5.08 (1H, m), 6.57 (1H, dd, J ⫽ 8.6, 2.6 Hz), 6.67 (1H, d, J ⫽
2.6 Hz), 7.10 (2H, d, J ⫽ 8.9 Hz), 7.24 (1H, d, J ⫽ 8.6 Hz), 7.92
(2H, d, J ⫽ 8.9 Hz), 12.67 (1H, br.s). Anal. Calcd. for C19H19NO7:
C, 61.12; H, 5.13; N, 3.75. Found: C, 61.12; H, 5.53; N, 3.83.
4-[3-(4-Nitrophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4x)
acid
1
H-NMR (DMSO-d6) δ: 4.04 (1H, dd, J ⫽ 9.2, 6.0 Hz), 4.34 (1H,
dd, J ⫽ 9.2, 9.2 Hz), 4.38 (1H, dd, J ⫽ 11.2, 6.6 Hz), 4.44 (1H, dd,
J ⫽ 11.2, 3.3 Hz), 5.17 (1H, m), 7.04 (2H, d, J ⫽ 8.9 Hz), 7.85 (2H,
d, J ⫽ 9.3 Hz), 7.92 (2H, d, J ⫽ 8.9 Hz), 8.31 (2H, d, J ⫽ 9.3 Hz),
12.68 (1H, s). Anal. Calcd. for C17H14N2O7: C, 56.99; H, 3.94; N,
7.82. Found: C, 57.13; H, 4.16; N, 7.82.
4-[3-(4-Chlorophenyl)-2-oxo-5-oxazolidinyl]ethoxybenzoic
(4y)
acid
A solution of 3y (0.97 g, 2.7 mmol) in the acetic acid (6 mL) and
conc. HCl (2 mL) was stirred overnight at 90 °C, after cooling, Et2O
(20 mL) was added. The resulting precipitate was collected and
washed with water to give 4y (837 mg, 86 %) as white solid. Mp.
206⫺207 °C; 1H-NMR (DMSO-d6) δ: 2.21⫺2.29 (2H, m), 3.86 (1H,
dd, J ⫽ 8.9, 7.3 Hz), 4.17⫺4.24 (3H, m), 4.90⫺4.96 (1H, m), 7.05
(2H, d, J ⫽ 8.9 Hz), 7.45 (2H, d, J ⫽ 8.9 Hz), 7.59 (2H, d, J ⫽
8.9 Hz), 7.90 (2H, d, J ⫽ 8.9 Hz), 12.64 (1H, s). Anal. Calcd. for
C18H16ClNO5: C, 59.76; H, 4.46; N, 3.87. Found: C, 59.83; H, 4.23;
N, 3.88.
4-[3-(4-Chlorobenzyl)-2-oxo-5-oxazolidinyl]methoxybenzoic
(4z)
acid
A solution of 3z (2.0 g, 5.3 mmol) in the acetic acid (18 mL) and
conc. HCl (6 mL) was stirred overnight at 90 °C, after cooling, Et2O
(40 mL) was added. The resulting precipitate was collected and
washed with water to give 4z (1.44 g, 75 %) as white solid; Mp.
197⫺199 °C.
H-NMR (DMSO-d6) δ: 3.61 (1H, dd, J ⫽ 8.9, 8.9 Hz), 4.17 (1H,
dd, J ⫽ 11.1, 4.9 Hz), 4.28 (1H, dd, J ⫽ 11.1, 3.0 Hz), 4.32 (1H, d,
J ⫽ 15.5 Hz), 4.46 (1H, d, J ⫽ 15.5 Hz), 4.88⫺4.97 (1H, m), 6.99
(2H, d, J ⫽ 8.8 Hz), 7.35 (2H, d, J ⫽ 8.5 Hz), 7.46 (2H, d, J ⫽ 8.5
Hz), 7.89 (2H, d, J ⫽ 8.8 Hz), 12.60 (1H, br.s). Anal. Calcd. for
C18H16ClNO5: C, 59.76; H, 4.46; N, 3.87. Found: C, 59.68; H, 4.49;
N, 3.92.
1
Methyl-3-{4-[3-(4-chlorophenyl)-2-oxo-5-oxazolidinyl]methoxy}phenylpropianate (6)
A mixture of epibromohydrin (2.5 mL, 30 mmol), methyl 3-(4hydroxyphenyl)propionate (4.1 g, 22.8 mmol) and K2CO3 (4.7 g, 34
mmol) in 2-butanone (50 mL) was refluxed for 8 h and extracted
with AcOEt. The extract was washed with water and brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified
by silicagel column chromatography (AcOEt : n-hexane ⫽ 2:3) to
give methyl 3-(4-oxyranylmethoxyphenyl)propionate (5) as white
solid (4.6 g, 86 %). A mixture of lithium bromide monohydrate (34
mg, 0.33 mmol) and tri-n-butylphosphine oxide (71 mg, 0.33 mmol)
in toluene (5 mL) was heated to distill the solvent then additional
xylene was added. To the mixture, a solution of 1e (1.0 g, 6.5 mmol)
and 5 (1.54 g, 6.5 mmol) in xylene (2 mL) was added at 140 °C. The
mixture was stirred at the same temperature for 2 h then evaporated
under reduced pressure. To the residue EtOH was added and the
precipitates were corrected by suction and washed with EtOH to
give 6 as white solid (2.15 g, 85 %). Mp. 133⫺134 °C; 1H-NMR
(CDCl3) δ: 2.59 (2H, t, J ⫽ 7.7 Hz), 2.90 (2H, t, J ⫽ 7.7 Hz), 3.66
(3H, s), 4.04 (1H, dd, J ⫽ 8.9, 5.9 Hz), 4.11⫺4.21 (3H, m),
4.92⫺5.02 (1H, m), 6.83 (2H, d, J ⫽ 8.6 Hz), 7.12 (2H, d, J ⫽ 8.6
Hz), 7.35 (2H, d, J ⫽ 8.9 Hz), 7.53 (2H, d, J ⫽ 8.9 Hz). Anal.
Calcd. for C20H20ClNO5: C, 61.62; H, 5.17; N, 3.59. Found: C,
61.75; H, 5.17; N, 3.57.
3-{4-[3-(4-Chlorophenyl)-2-oxo-5-oxazolidinyl]methoxyphenyl}propionic acid (7)
A solution of 6 (0.72 g, 1.85 mmol) in the acetic acid (10 mL) and
conc. HCl (2.5 mL) was stirred overnight at 90 °C, after cooling,
water was added. The resulting precipitate was collected and washed
with water and MeOH to give 7 (548 mg, 79 %) as white solid; mp.
162⫺163 °C; 1H-NMR (DMSO-d6) δ: 2.48 (2H, t, J ⫽ 7.4 Hz), 2.75
(2H, t, J ⫽ 7.4 Hz), 3.91 (1H, dd, J ⫽ 9.2, 6.3 Hz), 4.16⫺4.28 (3H,
m), 5.00⫺5.09 (1H, m), 6.86 (2H, d, J ⫽ .6 Hz), 7.15 (2H, d, J ⫽
8.6 Hz), 7.46 (2H, d, J ⫽ 9.1 Hz), 7.62 (2H, d, J ⫽ 9.1 Hz), 12.08
(1H, br.s). Anal. Calcd. for C19H18ClNO5: C, 60.71; H, 4.83; N,
3.73. Found: C, 60.70; H, 5.56; N, 3.77.
4-Oxiranylmethoxybenzaldehyde (8)
A mixture of 4-hydroxybenzaldehyde (18.3 g, 150 mmol), epibromohydrin (16.5 mL, 195 mmol) and K2CO3 (31g, 225 mmol) in 2butanone (150 mL) was refluxed for 4 h. The mixture was concentrated in vacuo and extracted with AcOEt, washed with water, brine,
dried over MgSO4, and concentrated in vacuo. The residue was purified by silicagel column chromatography (AcOEt : n-hexane ⫽ 2:3)
to give 8 as white solid (19.85 g, 74 %). 1H-NMR (CDCl3) δ: 2.79
(1H, dd, J ⫽ 7.4, 5.0 Hz), 2.94 (1H, dd, J ⫽ 5.0, 4.3 Hz), 3.39 (1H,
m), 4.02 (1H, dd, J ⫽ 11.2, 5.9 Hz), 4.35 (1H, dd, J ⫽ 11.2, 2.9
Hz), 7.03 (2H, d, J ⫽ 8.9 Hz), 7.85 (2H, d, J ⫽ 8.9 Hz), 9.93 (1H,
s). MS m/z: 179(M⫹)
4-[3-(4-Chlorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzaldehyde
(9)
A mixture of lithium bromide monohydrate (115 mg, 1.1 mmol) and
tri-n-butylphosphine oxide (240 mg, 1.1 mmol) in toluene (10 mL)
was heated to distill the solvent then additional xylene was added.
To the mixture, a solution of 1e (3.36 g, 21.9 mmol) and 8 (3.9 g,
21.9 mmol) in xylene (8 mL) was added at 140 °C. The mixture was
stirred at the same temperature for 1.5 h then evaporated under
reduced pressure. To the residue EtOH was added and the precipitates were corrected and recrystallized from EtOH to give 9 as white
solid (5.0 g, 69 %). Mp. 113⫺115 °C; 1H-NMR (DMSO-d6) δ: 3.94
(1H, dd, J ⫽ 9.1, 6.1 Hz), 4.27 (1H, dd, J ⫽ 9.1, 9.1 Hz), 4.37⫺4.46
(2H, m), 5.07⫺5.14 (1H, m), 7.16 (2H, d, J ⫽ 8.8 Hz), 7.47 (2H, d,
J ⫽ 9.0 Hz), 7.63 (2H, d, J ⫽ 9.0 Hz), 7.89 (2H, d, J ⫽ 8.8 Hz),
9.89(1H, s).
4-[3-(4-Chlorophenyl)-2-oxo-5-oxazolidinyl]methoxycinnamic acid
(10)
A solution of 9 (400 mg, 1.2 mmol), malonic acid (188 mg, 1.8
mmol) and piperidine (0.05 mL) in pyridine (4 mL) was stirred 2.5
h at 100 °C, then evaporated under reduced pressure and 2N HCl
was added. The resulting precipitate was collected and washed with
water and MeOH to give 10 (380 mg, 84 %) as white solid. Mp.
223⫺224 °C; 1H-NMR (DMSO-d6) δ: 3.93 (1H, dd, J ⫽ 9.2, 6.3
Hz), 4.24 (1H, dd, J ⫽ 9.2, 9.2 Hz), 4.29⫺4.39 (2H, m), 5.03⫺5.12
(1H, m), 6.39 (1H, d, J ⫽ 15.8 Hz), 7.00 (2H, d, J ⫽ 8.6 Hz), 7.47
(2H, d, J ⫽ 9.1 Hz), 7.54 (1H, d, J ⫽ 15.8 Hz), 7.62 (2H, d, J ⫽
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
157
158
Ohno et al.
9.1 Hz), 7.65 (2H, d, J ⫽ .6 Hz). Anal. Calcd. for C19H16ClNO5: C,
61.05; H, 4.31; N, 3.75. Found: C, 61.33; H, 4.41; N, 4.17.
Biology
Inhibitory activities toward sterol and fatty-acid biosynthesis in rat
liver slices in vitro
Male Wister rats (weighing about 200 g) were killed, and their livers
taken out, perfused with cold Krebs-Ringer bicarbonate (KRB)
solution and cut into small slices. Using the small liver slices, tests
were carried out according to the methods of Bortz [11] and Tsujita
[12]. Small liver slices (100 mg) were weighed and added to KRB (1
mL) containing [14C]acetic acid (2 μCi / 2 μmol) and the prescribed
amount of test compounds, and the mixture was reacted by shaking
at 37 °C for 2 h under an atmosphere of 95 % O2/5 %CO2. Thereafter, the reaction mixture was mixed with a 15 % solution of KOH
in EtOH (1 mL), and further heated at 75 °C for 2 h. After cooling,
petroleum ether (2 mL) was added to the mixture, which was then
shaken and separated into layers. The organic layer (upper layer)
was extracted and concentrated to dryness. Digitonin solution (1
mL) was then added and sterols were collected from the resulting
precipitation fraction. This fraction was washed with diethyl ether
and dissolved in acetic acid (1 mL), and the radioactivity of the
sample was measured to determine the inhibitory activity toward
sterol biosynthesis. On the basis of the value obtained in the control
test, in which the above procedure was repeated with the exception
of the test compound, the concentration (μM) of the test compound
producing 50 % inhibition (IC50) was determined. Hydrochloric acid
was added to the lower layer obtained by extraction with petroleum
ether, and the mixture was extracted with petroleum ether under
acidic conditions. The organic layer was concentrated and then the
radioactivity was measured likewise to determine the inhibitory activity toward fatty-acid biosynthesis. As above, on the basis of the
inhibitory activity for fatty acid obtained in the control test, the
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2005, 338, 147−158
50 % inhibitory concentration (IC50) of the test compounds was determined. The results obtained are shown in Table 2. Data presented
here are mean values of at least three separate experiments.
References
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