Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives

Article abstract of DOI:10.1248/cpb.50.1349

A novel series of oxyiminoacetic acid derivatives were synthesized in an effort to develop a potent antidiabetic agent, which does not contain the 2,4-thiazolidinedione moiety. These compounds were evaluated for glucose and lipid lowering effects in genetically obese and diabetic KKA^y mice. Several of the compounds showed strong antidiabetic activity, including functional potency at peroxisome proliferator-activated receptor (PPAR)-γ. (Z)-2-[4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-2-(4- phenoxyphenyl)acetic acid (25) significantly reduced plasma glucose (33%, p<0.01) and plasma triglycelide levels (43%, p<0.01) even at a dosage of 0.001% in diet. Pharmacokinetic analyses of 25 are also reported.

Full text of DOI:10.1248/cpb.50.1349

October 2002
Chem. Pharm. Bull. 50(10) 1349—1357 (2002)
1349
Studies on Non-Thiazolidinedione Antidiabetic Agents. 1. Discovery of
Novel Oxyiminoacetic Acid Derivatives
Hiroshi IMOTO,* Eikoh IMAMIYA, Yu MOMOSE, Yasuo SUGIYAMA, Hiroyuki KIMURA, and Takashi SOHDA
Takeda Chemical Industries, Ltd., Pharmaceutical Research Division; 2–17–85 Juso-Honmachi, Yodogawa-ku, Osaka
532–8686, Japan. Received May 16, 2002; accepted August 2, 2002
A novel series of oxyiminoacetic acid derivatives were synthesized in an effort to develop a potent antidia-
betic agent, which does not contain the 2,4-thiazolidinedione moiety. These compounds were evaluated for glu-
cose and lipid lowering effects in genetically obese and diabetic KKAy mice. Several of the compounds showed
strong antidiabetic activity, including functional potency at peroxisome proliferator-activated receptor (PPAR)-g.
(Z)-2-[4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid (25) sig-
nificantly reduced plasma glucose (33%, pϽ0.01) and plasma triglycelide levels (43%, pϽ0.01) even at a dosage
of 0.001% in diet. Pharmacokinetic analyses of 25 are also reported.
Key words antidiabetic agent; oxyiminoacetic acid; type 2 diabetes; peroxisome proliferator-activated receptor; KKAy mice
Type 2 diabetes is a multifactorial disease defined by a recent study suggests that antidiabetic thiazolidinediones in-
high plasma glucose level, and is characterized by both in- teract with a family of nuclear receptors known as peroxi-
sulin resistance and impaired insulin secretion by pancreatic some proliferator-activated receptor (PPAR)-g.36) PPARg is
b-cells.1) Clinical studies2—5) indicate a direct relationship one of a subfamily of PPARs encoded by independent genes.
between hyperglycemia and long-term complications such as Three human PPARs, designated PPARa, PPARg, and
neuropathy, nephropathy, retinopathy, arteriosclerosis, and PPARd, have been identified to date.37—39) It was also ob-
coronary artery disease. The disease is also associated with a served that the potency for activation of PPARg in vitro mir-
high degree of morbidity and mortality. Therefore, it is im- rored the in vivo glucose lowering activity in diabetic ob/ob
portant to control blood glucose levels in diabetics, espe- mice.40) This would indicate that the major mechanisms of
cially during the early stage of the disease.6)
action of 2,4-thiazolidinediones involve PPARg.
The fundamental modes of treatment for type 2 diabetes
In the case of those 2,4-thiazolidinediones already on the
are aerobic exercise and energy restriction, and these regimes market, several side effects, such as anemia, edema, and
increase insulin sensitivity.7) However, few patients are able body weight gain, have been reported.41) Naturally it occurs
to achieve a satisfactory control of blood glucose. The most to us to find a new class of compounds with fewer side ef-
commonly used oral antidiabetic agents have been sulfony- fects and a more advanced profile than known 2,4-thiazo-
lureas. These agents increase insulin secretion from pancre- lidinediones. Thus, we focused on the search for a new series
atic b-cells, but sometimes induce severe hypoglycemia and of non-thiazolidinedione compounds with potent antihyper-
weight gain,8) and hyperinsulinemia is known to be a risk glycemic activity in insulin-resistant animal models.
factor for ischemic heart disease.9) In addition, high rates of
First, we selected (Z)-(4-chlorobenzyloxyimino)phenyl-
both primary and secondary failure are observed with these acetic acid (6) (Fig. 1) as a seed compound. Compound (6)
drugs.10—13) Therefore, drugs that ameliorate the insulin re- was found from our in vivo KKAy mice screening to search
sistance without stimulating insulin release from b-cells have for novel glucose and lipid lowering agents. Although com-
been developed for the treatment of type 2 diabetes.
pound (6) has weak antihyperglycemic activity (data not
The prototypical 2,4-thiazolidinedione, ciglitazone (1)14)
(Chart 1) was discovered by our company, and has antihyper-
glycemic activity in insulin-resistant animal models, KKAy
mice15) and Wistar fatty rats,16) but no effect in insulin-defi-
cient animal models of diabetes.17,18) During structure–activ-
ity relationship studies on 2,4-thiazolidinediones and related
compounds, we discovered highly potent compounds, such as
pioglitazone (2),19) and AD-5061 (3)20) (Chart 1). Since the
discovery of ciglitazone (1), a number of pharmaceutical
companies have been evaluating new 2,4-thiazolidinedione
analogs as agents for improving insulin resistance. Troglita-
zone (4)21) was launched first in the market, but had been
withdrawn because of liver toxicity and related deaths associ-
ated with the drug. Nowadays, two 2,4-thiazolidinedione
class agents, pioglitazone (2) and rosiglitazone (5)22) are clin-
ically used. (Chart 1). Many companies are still endeavoring
to find a new glucose lowering agent.23—35) Although the pre-
cise mechanism of action of these drugs remains unknown,
Chart 1
* To whom correspondence should be addressed. e-mail: Imoto_Hiroshi@takeda.co.jp
© 2002 Pharmaceutical Society of Japan

1350
Vol. 50, No. 10
shown), we paid attention to its unique structure. There have Chemistry
been several reports of non-thiazolidine glucose and lipid
The general preparation procedure of oxyiminoacetic acids
lowering agents.28—31,33) However, oxyiminoacetic acid deriv- and their derivatives is outlined in Chart 2. The starting ben-
atives as such agents have not been reported to our knowl- zaldehyde (8) was reduced by sodium borohydride to give
edge. For that reason, much effort was made to find more po- benzyl alcohol (9). Treatment of 9 with thionyl chloride gave
tent oxyiminoacetic acids. Compounds synthesized were benzyl chloride (10). Alkylation of oximes (11) with 10 gave
evaluated first by in vivo KKAy mice screening. Although in alkoxyiminoacetates (12). Saponification of 12 with aqueous
vivo evaluation as first screening might not be efficient than NaOH afforded acetic acid derivatives (13).
in vitro evaluation in general, the screening using KKAy
The methods for preparation of intermediates (11) in Chart
mice, which has been well established to develop pioglita- 2 are shown in Charts 3—5. Friedel–Crafts acylation of sub-
zone (2),19) takes only 4 d to evaluate compounds. In addi- stituted benzenes with ethyl oxalyl chloride gave phenylgly-
tion, compounds having poor pharmacokinetic properties oxylates (14), which were treated with hydroxylamine to pro-
would remove at the early stage of development.
vide oximes (11d, e) as a mixture of E- and Z-isomers (Chart
Early in the modification, we found that replacement of the 3). These isomers were easily separated by column chro-
chloro moiety in 6 with the (5-methyl-2-phenyl-1,3-oxazol- matography.
4-yl)methoxy moiety enhanced the potency [compound (7),
Several oximes were prepared by another method (Chart
Fig. 1]. Encouraged by this result, we planned to synthesize a 4). Diethyl oxalate was converted into a-ketoesters by a reac-
new series of oxyiminoacetic acids (structure A, Fig. 1) to in- tion with Grignard reagents (Rϭbutyl, isopropyl, and 4-bro-
vestigate the effect of the phenyl group of 7, which is posi- mophenyl), or with ethyl phenylacetate in NaOEt/EtOH solu-
tioned a to the carboxyl group, as antidiabetic agents. In this tion followed by de-ethoxycarbonylation (Rϭbenzyl). The
paper, we describe the synthesis, structure–activity relation- resultant ketoesters were treated with hydroxylamine to give
ships (SARs), and biological analysis of oxyiminoacetic oximes (11b, h—j), the isomers of which were separated by
acids.
column chromatography.
Chart 5 shows the method used for preparing ethyl (3-sub-
stitutedphenyl)glyoxylate oxime derivatives [11c (RϭBr) and
11f (Rϭphenoxy)]. Mesylation of 3-phenoxybenzyl alcohol
(16) was followed by treatment with sodium iodide and a re-
action with sodium cyanide to provide 3-phenoxybenzyl
cyanide (17b). Benzyl cyanides [17a (RϭBr: commercially
available) and 17b (Rϭphenoxy)] were reacted with isoamyl
nitrite to give compounds (18a, b), which were treated with
KOH and esterified subsequently to give the desired 11c and
11f. The E- and Z-isomers of 11c and 11f were also sepa-
rated by column chromatography.
In case of aromatic R1 in Fig. 2, the configuration of 11
was presumed by normal phase thin layer chromatography
(TLC). Less polar isomer of 11 on TLC might have Z config-
uration, because the existence of hydrogen bonding between
hydroxime hydrogen and carbonyl oxygen, which diminishes
polarity, could be considered. With regard to methyl 2-(hy-
droxyimino)-2-phenylacetate (11a), the configurations were
determined by 1H-NMR NOESY experiments (Fig. 3). A nu-
Fig. 1
Reagents: (a) NaBH4; (b) SOCl2; (c) NaH; (d) aqueous NaOH.
Chart 2

October 2002
1351
Fig. 3
Reagents: (a) ClCOCO2Et, AlCl3; (b) H2NOH, NaOAc.
Chart 3
Reagents: (a) RB(OH)2, Pd(PPh3)4, K2CO3, heat; (b) aqueous NaOH.
Chart 6
clear Overhauser effect (NOE) was observed between Ha and
Hb of the polar isomer of 11a, which was proved to have E
configuration. On the other hand, no NOE was observed be-
tween Hc and Hd of the less polar isomer of 11a, which was
turned out to have Z configuration. These results are consid-
ered to support the validity of the predictions of the configu-
ration using TLC. In cases of 11h and 11j, which have
aliphatic R in Chart 4 (11h, Rϭbutyl; 11j, Rϭbenzyl), single
isomers were obtained. The configuration is presumed as E,
because 11i (Rϭisopropyl) was obtained as a mixture of iso-
mers probably by reason of steric repulsion between hydroxy
group and bulky isopropyl group.
Reagents: (a) RMgX; (b) Na, EtOH, then ethyl phenylacetate; (c) NaCl, DMSO,
H2O, heat; (d) H2NOH, NaOAc.
Chart 4
Compounds (29, 30) were prepared by Suzuki coupling of
the appropriate (phenyl or styryl) boronic acid with 19 and
subsequent saponification with aqueous NaOH (Chart 6).
The analytical data of the synthesized oxyiminoacetic
acids (7, 20—35) are shown in Table 1.
Results and Discussion
The biological activities of the compounds prepared (7,
20—35) were tested using genetically obese and diabetic
KKAy mice.15) The results are shown in Table 2.
Reagents: (a) MsCl, Et3N; (b) NaI; (c) NaCN, DMSO; (d) isoamyl nitrite, Na, EtOH;
(e) 4 M KOH; (f) H2SO4, EtOH.
We initially examined the effect of introducing a func-
tional group to the phenyl ring of 7, which is positioned a to
the carboxyl group. Introduction of a bromo group as an
electron withdrawer at the meta- or para-position increased
the potency in vivo (21, 23 vs. 7). Introduction of a methoxy
group as an electron donator at the para-position did not af-
fect the activity (24 vs. 7), whereas introduction of a larger
phenoxy group at the same position markedly increased ac-
tivity. Compound (25) significantly reduced plasma glucose
(33%, pϽ0.01) and plasma triglycelide levels (43%, pϽ0.01)
even at a dosage of 0.001% in diet. Introduction of a phenyl
group or a styryl group instead of a phenoxy group in 25 did
Chart 5
Fig. 2

1352
Vol. 50, No. 10
Table 1. Physical Data of Oxyiminoacetic Acids
Entry
R1
R2
mp (°C)
Formula
C26H22N2O5
Anal.a)
7
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Phenyl
CO2H
CO2H
Phenyl
CO2H
171—172b)
142—143b)
189—190b)
159—160b)
181—182b)
183—184b)
184—185b)
152—153b)
173—174b)
Amorphous
193—194b)
194—195b)
147—148
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C26H22N2O5
4-Bromophenyl
CO2H
3-Bromophenyl
4-Methoxyphenyl
4-Phenoxyphenyl
CO2H
3-Phenoxyphenyl
CO2H
4-Biphenyl
4-Styrylphenyl
CO2H
C26H21BrN2O5
C26H21BrN2O5
C26H21BrN2O5
C27H24N2O6·1/10H2O
C32H26N2O6
C32H26N2O6·1/4H2O
C32H26N2O6
C32H26N2O6
C32H26N2O5·1/4H2O
C34H28N2O5·1/4H2O
C21H20N2O5
C24H26N2O5
C23H24N2O5
4-Bromophenyl
CO2H
CO2H
CO2H
4-Phenoxyphenyl
CO2H
3-Phenoxyphenyl
CO2H
CO2H
Methyl
Butyl
CO2H
CO2H
112—114
140—142
Isopropyl
CO2H
CO2H
Isopropyl
Benzyl
128—129
C23H24N2O5
C27H24N2O5
143—144b)
a) Analytical results were within 0.4% of the theoretical value. b) Decomposed at the temperature.
Table 3. PPARg Transcriptional Activity of Oxyiminoacetic Acids
Table 2. Glucose and Lipid Lowering Activities of Oxyiminoacetic Acids
in KKAy Mice
Transactivationa)
Glucose lowering activitya—c) Lipid lowering activitya—c)
Entry
PPARg
EC50 (mM)
Dose (%)
Dose (%)
Entry
7
25
33
1.9
0.001
0.01
0.03
0.001
0.01
0.03
0.40
0.79
0.69
7
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
17
15
32**
L
47**
2 (Pioglitazone)
20
44**
24
27
24
82**
12
32
16
L
34
L
L
66**
L
44**
28*
40**
21
49**
30*
26
L
19
26
30*
L
a) EC50, the concentration of test compound required to induce 50% of the maxi-
mum activity.
33**
43**
KKAy mice. Therefore, it could be said that the recognition
of the configuration of the oximes is somewhat loose for in
vivo potency.
An exchange of the phenyl ring positioned a to the car-
boxyl group for alkyl moieties did not increase potency (31,
32, 34, 35) except in 33. Compound (33) significantly re-
duced of plasma glucose (38%, pϽ0.01) and plasma
triglycelide levels (66%, pϽ0.01) at a dosage of 0.01% in
diet. Taking into account the fact that only 33 has Z-configra-
tion among compounds (31—35), the results described above
support our assumption that the Z-configration is more potent
than the E-configuration.
38**
L
L
L
2 (Pioglitazone)
54**d)
47*d)
a) Maximum reductions in plasma glucose and plasma triglyceride levels at a
dosage of 0.001, 0.01, or 0.03% in the diet were calculated as percent reduction with
respect to the control value. b) L indicates less than a 15% reduction at that dose.
c) Statistically significant at (*) pϽ0.05, (**) pϽ0.01 by Dunnett’s test. d) From ref-
erence 35.
To clarify whether the mechanisms of action of the oxy-
iminoacetic acid derivatives involved PPARg or not, the
functional potency at PPARg of several compounds was in-
not increase potency (29, 30 vs. 25). Attachment of a phe- vestigated. Compounds (7, 25, 33) were selected on the basis
noxy group at the meta-position decreased potency (27 vs. of their activity in KKAy mice. As shown in Table 3, these
25). Those results indicate that an introduction of bulky, but three compounds possessed functional activity at PPARg.
not solid structure at the para-position of the phenyl group is This means that the mechanisms of action of the oxyimi-
important to increase in vivo potency.
noacetic acid derivatives involve PPARg, at least in part.
Between the two regioisomers of oxime, the Z-configura- Compounds [25 (EC50ϭ0.40 mM) and 33 (EC50ϭ0.79 mM)]
tion seemed to be more potent than the E-configuration (21 had increased functional activity compared to 7 (EC50ϭ1.9
vs. 22; 25 vs. 26; etc.), while compound (26), which has the mM), which paralleled the glucose and lipid lowering activity
E-configuration, caused a significant reduction in the plasma in diabetic KKAy mice.
glucose level (30%, pϽ0.05) at a dosage of 0.01% in diet in
Finally, we selected 25 for pharmacokinetic analysis. The

October 2002
1353
Table 4. Pharmacokinetic Parameters of Compound 25 in SD(IGS) Ratsa)
mum activity.
Pharmacokinetic Analysis. (a) Single-Dose Pharmacokinetics Ex-
periments were carried out in SD (IGS) rats (8 weeks old, male). The ani-
mals were fed the CE-2 diet and water ad libitum. They were dosed with the
drug at 1 mg/kg/i.v. as an N,N-dimethylacetamide–PEG 400 (1 : 1) solution,
or at 10 mg/kg/p.o. as a 0.5% MC suspension. Blood samples were collected
at different time points (pre, 5, 10, 15, 30 min, 1, 2, 4, 8, 24 h for the intra-
venous study; pre, 15, 30 min, 1, 2, 4, 8, 24 h for the oral study, respectively)
from a tail vein. The samples were analyzed by HPLC to calculate pharma-
cokinetic parameters such as AUC0—24 h, C5 min, Cmax, Tmax, T1/2, and bioavail-
ability. AUC0—24 h is the area under the drug plasma concentration versus
time curve. C5 min is the observed plasma concentration 5 min after adminis-
tration. Cmax is the observed maximum plasma concentration. Tmax is the
time at which Cmax is achieved. T1/2 is the half-life of the drug. Bioavailabil-
ity is calculated by the following formula:
Pharmacokinetic parameter
p.o.
i.v.
Dose (mg/kg)
AUC0—24 h (mg·h/ml)
C5 min (mg/ml)
Cmax (mg/ml)
Tmax (h)
10
1
6.42Ϯ0.57
9.08Ϯ0.90
—
33.99Ϯ5.27
—
7.08Ϯ1.99
1.00Ϯ0.00
2.47Ϯ0.07
53.0Ϯ9.5
—
T1/2 (h)
Bioavailability (%)
2.32Ϯ0.53
—
a) The results are the meanϮS.D. of three male animals in each group.
results are shown in Table 4. The data revealed that 25 had
desirable pharmacokinetic characteristics with good bioavail-
ability (53.0Ϯ9.5%).
[bioavailability] (%)ϭ[AUC0—24 h (p.o.)ϫdose (i.v.)]
/[AUC0—24 h (i.v.)ϫdose (p.o.)]ϫ100
(b) Analysis of Plasma Samples (i) Sample Preparation: Acetoni-
trile was added to each plasma sample (100 ml). The mixture was stirred by
irradiation with supersonic waves before centrifugal separation was carried
out. The supernatant liquid was subjected to centrifugal condensation under
reduced pressure at 30 °C. The residue was dissolved in acetonitrile–
0.01 mol/l ammonium acetate (55 : 45, v/v, 200 ml). The mixture was stirred
by irradiation with supersonic waves. Then centrifugal separation was car-
ried out to remove insoluble substances. The supernatant liquid was used for
HPLC analysis.
(ii) HPLC Assay: Inertsil ODS-3 (f 4.6ϫ250 mm) was used for HPLC
analysis. Analyses of compounds were carried out using acetonitrile–
0.01 mol/l ammonium acetate (55 : 45, v/v) as a mobile phase at a flow rate
of 1.0 ml/min at 40 °C, and the detection wavelength was 270 nm. Under
these conditions, the retention time for 25 was 21.6 min.
Chemical Methods Melting points were recorded on a Yanagimoto
micro melting point apparatus and are uncorrected. Elemental analyses (C,
H, N) were carried out at Takeda Analytical Research Laboratories, Ltd.,
and all values are within Ϯ0.4% of calculated values unless otherwise noted.
IR spectra were recorded on a JASCO IR-810. 1H-NMR spectra were
recorded on a Varian Gemini-200 spectrometer in solutions of CDCl3 or
DMSO-d6 using tetramethylsilane as an internal standard. Chemical shifts
are expressed as d (ppm) values for protons relative to the internal standard.
All compounds exhibited 1H-NMR spectra and analytical data consistent
with their proposed structures. Column chromatography was performed with
a Merck Silica Gel 60 (0.063—0.200 mm). The following abbreviations are
used: sϭsinglet, dϭdoublet, tϭtriplet, qϭquartet, quinϭquintet, sextϭsex-
tet, septϭseptet, mϭmultiplet, brϭbroad, dec.ϭdecomposed.
In summary, we demonstrated that a new series of oxyimi-
noacetic acid derivatives had potent antidiabetic activities in
genetically obese and diabetic KKAy mice. (Z)-2-[4-[(5-
Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-
2-(4-phenoxyphenyl)acetic acid (25) showed particularly
strong antidiabetic activity. Several selected compounds ex-
hibited PPARg transcriptional activity. This means that the
mechanisms of action of the oxyiminoacetic acid derivatives
involve PPARg, at least in part. Pharmacokinetic analysis
showed that compound (25) possessed very good pharmaco-
kinetic characteristics. Further structural modification of
oxyiminoacetic acid and an expanded SAR study will be dis-
cussed in our next paper.
Experimental
Biological Procedures. (a) Glucose and Lipid Lowering Experi-
ments The glucose and lipid lowering activities of the compounds were
tested using KKAy mice.15) After being fed a powdered laboratory chow
(CE-2, Clea Japan, Inc., Tokyo, Japan) over 3 d, female mice (9—13 weeks
old) were divided into experimental groups of five animals each based on
their blood glucose levels. The test compounds were given as a dietary ad-
mixture at 0.03, 0.01, or 0.001% in the diet. The mice were fed the experi-
mental diet and water ad libitum for 4 d. Blood samples were taken from the
orbital vein. The plasma glucose levels were determined enzymatically using
Iatrochem-GLU(A) (Iatron Laboratories, Inc., Tokyo, Japan) or L type Wako
Glu 2 (Wako Pure Chemical Ind., Ltd., Tokyo, Japan). The plasma triglyc-
eride levels were also determined enzymatically using Iatro-MA701 TG kits
(Iatron Laboratories, Inc.) or L type Wako TG·H (Wako Pure Chemical
Ind., Ltd.). The respective values are shown as percent reduction with re-
spect to the control value. A 0.001% dosage was approximately 1.3—
1.6 mg/kg/d. In case of diabetic KKAy mice, the control values of PG and
TG were approximately 450—550 mg/dl and 550—700 mg/dl, respectively.
In case of normal C57BL mice, the values of PG and TG were approxi-
mately 200 mg/dl and 80 mg/dl, respectively.
(b) PPARg-Retinoid X Receptor a (RXRa) Heterodimer Transacti-
vation Assay The full-length human PPARg1, full-length human RXRa
and PPAR responsive luciferase reporter were stably expressed in CHO-K1
cells. These cells were cultured in HAM F12 medium (NISSUI SEIYAKU)
containing 10% fetal bovine serum (Life Technologies, Inc., U.S.A.), inocu-
lated into a 96-well white plate (Corning Coaster Corporation, U.S.A.) at a
density of 2ϫ104 cells/well, and cultured in a carbonate gas incubator at
37 °C overnight. The 96-well white plate was washed with PBS (phosphate-
buffered saline), and 90 ml of HAM F12 medium containing 0.1% fatty acid-
free bovine serum albumin (BSA) and 10 ml of test substance were added.
The plate was then cultured in the carbonate gas incubator at 37 °C for 48 h.
The medium was removed, 40 ml of PICAGENE 7.5 (Wako Pure Chemical
Ind., Ltd.) was added, and after stirring, luciferase activity was determined
using Lumistar (BMG Labtechnologies GmBH, Germany). Induction mag-
nitude was calculated based on the luciferase activity of each test substance
with the luciferase activity in the non-treatment group assigned a value of 1.
The values of concentration and induction magnitude were analyzed using a
PRISM 2.01 (GraphPad Software Inc., U.S.A.) to calculate the EC50, the ef-
fective concentration of test compound required to induce 50% of the maxi-
(E)-2-(4-Bromophenyl)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)-
methoxy]benzyloxyimino}acetic Acid (22) (a) Sodium borohydride
(4.31 g, 114 mmol) was added to a cold (0 °C) stirred solution of 4-[(5-
methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzaldehyde (8, 33.42 g, 114
mmol) in MeOH (150 ml)–THF (30 ml). After stirring 0.5 h at room temper-
ature, water was added to the reaction mixture, and the whole was stirred for
1 h. The crystals of 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl
alcohol (9, 32.9 g, 98%) were isolated by filtration. Recrystallization from
AcOEt–Et2O gave pale-yellow crystals. mp 128—129 °C. 1H-NMR (CDCl3)
d: 1.67 (1H, br s), 2.43 (3H, s), 4.63 (2H, s), 4.99 (2H, s), 7.00 (2H, d,
Jϭ8.8 Hz), 7.31 (2H, d, Jϭ8.8 Hz), 7.40—7.47 (3H, m), 7.98—8.04 (2H,
m). IR (KBr) cmϪ1: 3262, 1508, 1238, 1236, 1007, 718. Anal. Calcd for
C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.15; H, 5.85; N, 4.73.
(b) Thionyl chloride (1.85 ml, 25.4 mmol) was added to a solution of
4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl alcohol (9, 5.00 g,
16.9 mmol) in toluene (40 ml), and the mixture was stirred at room tempera-
ture for 0.5 h. To the mixture was added ice-cooled water and extracted with
AcOEt. The extract was washed with ice-cooled brine, dried over magne-
sium sulfate, and concentrated in vacuo to give 4-{[4-(chloromethyl)phe-
noxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (10, 5.23 g, 99%) as crystals.
Recrystallization from AcOEt–hexane gave colorless crystals. mp 108—
1
109 °C. H-NMR (CDCl3) d: 2.44 (3H, s), 4.58 (2H, s), 5.00 (2H, s), 7.01
(2H, d, Jϭ8.8 Hz), 7.33 (2H, d, Jϭ8.8 Hz), 7.40—7.50 (3H, m), 7.98—8.05
(2H, m). IR (KBr) cmϪ1: 1514, 1240, 1011, 835, 717, 654. Anal. Calcd for
C18H16NO2Cl: C, 68.90; H, 5.14; N, 4.46. Found: C, 68.91; H, 5.19; N, 4.36.
(c) A solution of 4-bromophenylmagnesium bromide, prepared from p-
dibromobenzene (25.0 g, 106 mmol), magnesium (2.43 g, 100 mmol), and
Et2O (250 ml), was added dropwise to a solution of diethyl oxalate (32.5 g,
223 mmol) in Et2O (250 ml) at Ϫ78 °C under nitrogen. After stirring at

1354
Vol. 50, No. 10
yl)methoxy]benzyloxyimino}acetic Acid (21) Using the procedures for
preparation of 22, steps d and e, 21 (81% yield) was prepared from ethyl
(Z)-2-(4-bromophenyl)-2-(hydroxyimino)acetate [(Z)-11b] and 4-{[4-
(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (10) as col-
orless crystals. mp 189—190 °C (AcOEt, dec.). 1H-NMR (DMSO-d6) d:
2.50 (3H, s), 5.01 (2H, s), 5.17 (2H, s), 7.06 (2H, d, Jϭ8.6 Hz), 7.36 (2H, d,
Jϭ8.6 Hz), 7.47 (2H, d, Jϭ8.8 Hz), 7.48—7.57 (3H, m), 7.69 (2H, d,
Jϭ8.8 Hz), 7.90—7.98 (2H, m). IR (KBr) cmϪ1: 1736, 1512, 1240, 1009,
831, 716. Anal. Calcd for C26H21N2O5Br: C, 59.90; H, 4.06; N, 5.37. Found:
C, 59.81; H, 4.40; N, 5.01.
(Z)-2-(3-Bromophenyl)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-
yl)methoxy]benzyloxyimino}acetic Acid (23) (a) An EtOH (30 ml) so-
lution of (3-bromophenyl)acetonitrile (17a, 17.8 g, 90.8 mmol) was added
dropwise to a solution of NaOEt [prepared from Na (2.51 g, 109 mmol) and
EtOH (40 ml)] at 0 °C under nitrogen. To this was added isoamyl nitrite
(18.3 ml, 136 mmol) dropwise at 0 °C. The whole was stirred at room tem-
perature for 18 h, then diluted with ether. The mixture was washed with 1 M
HCl, aqueous sodium hydrogen carbonate, and brine, dried over magnesium
sulfate, and concentrated in vacuo. The residue was chromatographed on sil-
ica gel with AcOEt–hexane (1 : 4, v/v) to give 2-(3-bromophenyl)-2-(hy-
droxyimino)acetonitrile (18a, 19.9 g, 97%) as orange slurry. Recrystalliza-
tion from AcOEt–hexane gave orange crystals. mp 91—93 °C. 1H-NMR
(CDCl3) d: 7.35 (1H, t, Jϭ7.9 Hz), 7.63 (1H, br d, Jϭ7.9 Hz), 7.73 (1H, br d,
Jϭ7.9 Hz), 7.97 (1H, br s), 8.71 (1H, br s). IR (KBr) cmϪ1: 3302, 1593,
1475, 1423, 1277, 1074, 991, 793, 689. Anal. Calcd for C8H5N2OBr: C,
42.70; H, 2.24; N, 12.45. Found: C, 42.92; H, 2.25; N, 12.24.
(b) A mixture of 2-(3-bromophenyl)-2-(hydroxyimino)acetonitrile (18a,
19.0 g, 84.4 mmol), 4 M KOH (100 ml) and 2-methoxyethanol (100 ml) was
refluxed for 4 h. After cooling to room temperature, the mixture was made
acidic by addition of 1 M HCl and extracted with AcOEt. The extract was
washed with brine, dried over magnesium sulfate, and concentrated in vacuo
to leave an oil. The oil was dissolved in EtOH (200 ml), and conc. H2SO4
(catalytic amount) was added. The whole was refluxed for 48 h, then cooled
to room temperature, diluted with aqueous sodium hydrogen carbonate and
extracted with AcOEt. The extract was washed with brine, dried over mag-
nesium sulfate, and concentrated in vacuo. The residue was chro-
matographed on silica gel with AcOEt–hexane (1 : 3, v/v) to give less polar
ethyl (Z)-2-(3-bromophenyl)-2-(hydroxyimino)acetate [(Z)-11c, 3.31 g,
14%] as a pale-brown oil and polar ethyl (E)-2-(3-bromophenyl)-2-(hy-
droxyimino)acetate as crystals. Recrystallization of (E)-adduct from
AcOEt–hexane gave colorless crystals [(E)-11c, 1.52 g, 7%]. The data for
(Z)-11c: 1H-NMR (CDCl3) d: 1.41 (3H, t, Jϭ7.1 Hz), 4.47 (2H, q,
Jϭ7.1 Hz), 7.23—7.32 (1H, m), 7.45—7.60 (2H, m), 7.72—7.75 (1H, m),
8.56 (1H, br s). IR (neat) cmϪ1: 3377, 1730, 1560, 1317, 1215, 1039, 960,
789, 689. The data for (E)-11c: mp 113—114 °C. 1H-NMR (CDCl3) d: 1.36
(3H, t, Jϭ7.1 Hz), 4.36 (2H, q, Jϭ7.1 Hz), 7.28—7.47 (2H, m), 7.55—7.61
(1H, m), 7.65—7.68 (1H, m), 9.08 (1H, br s). IR (KBr) cmϪ1: 3230, 1734,
1194, 1024, 754. Anal. Calcd for C10H10NO3Br: C, 44.14; H, 3.70; N, 5.15.
Found: C, 44.18; H, 3.71; N, 5.20.
Ϫ78 °C for 1 h, the reaction mixture was allowed to warm to 0 °C. To the
mixture was added dil. HCl. The organic layer was separated, washed with
aqueous sodium hydrogen carbonate and brine, dried over magnesium sul-
fate, and concentrated in vacuo. The residue was chromatographed on silica
gel with AcOEt–hexane (1 : 15, v/v) to leave an oil. The oil was dissolved in
EtOH (100 ml), then hydroxylamine hydrochloride (4.17 g, 60.0 mmol) and
sodium acetate (6.15 g, 75.0 mmol) were added to the mixture. The whole
was refluxed for 18 h. After evaporation of the solvent, the residue was di-
luted with water and extracted with AcOEt. The extract was washed with
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
was recrystallized from isoPr2O–hexane to give more polar ethyl (E)-2-(4-
bromophenyl)-2-(hydroxyimino)acetate [(E)-11b, 4.31 g, 16%] as colorless
crystals. The mother liquid was concentrated in vacuo. The residue was
chromatographed on silica gel with AcOEt–hexane (1 : 3, v/v) to give less
polar (Z)-adduct [(Z)-11b, 5.31 g, 20%] as a colorless oil. The data for (E)-
1
11b: mp 163—164 °C. H-NMR (CDCl3) d: 1.36 (3H, t, Jϭ7.1 Hz), 4.35
(2H, q, Jϭ7.1 Hz), 7.39 (2H, d, Jϭ8.8 Hz), 7.59 (2H, d, Jϭ8.8 Hz), 8.83
(1H, br s). IR (KBr) cmϪ1: 3244, 1732, 1390, 1203, 1026, 1007, 766. Anal.
Calcd for C10H10NO3Br: C, 44.14; H, 3.70; N, 5.15. Found: C, 44.43; H,
3.78; N, 5.22. The data for (Z)-11b: 1H-NMR (CDCl3) d: 1.40 (3H, t,
Jϭ7.1 Hz), 4.45 (2H, q, Jϭ7.1 Hz), 7.43 (2H, d, Jϭ8.6 Hz), 7.54 (2H, d,
Jϭ8.6 Hz), 8.47 (1H, s). IR (neat) cmϪ1: 3419, 2983, 1736, 1491, 1319,
1217, 1036, 945, 829.
(d) Sodium hydride (60% in oil, 255 mg, 6.37 mmol) was added to a so-
lution of ethyl (E)-2-(4-bromophenyl)-2-(hydroxyimino)acetate [(E)-11b,
1.73 g, 6.37 mmol] and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-
phenyl-1,3-oxazole (10, 2.00 g, 6.37 mmol) in N,N-dimethylformamide
(DMF) (20 ml) at room temperature under nitrogen. After stirring at room
temperature for 1 h, the mixture was diluted with 1 M HCl (10 ml), made
basic by addition of aqueous sodium hydrogen carbonate, and extracted with
AcOEt. The extract was washed with brine, dried over magnesium sulfate,
and concentrated in vacuo. The residue was chromatographed on silica gel
with AcOEt–hexane (1 : 3, v/v) to give ethyl (E)-2-(4-bromophenyl)-2-{4-
[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}acetate
(2.54 g, 73%) as crystals. Recrystallization from AcOEt–hexane gave color-
less crystals. mp 105—106 °C. 1H-NMR (CDCl3) d: 1.35 (3H, t, Jϭ7.1 Hz),
2.43 (3H, s), 4.34 (2H, q, Jϭ7.1 Hz), 4.99 (2H, s), 5.24 (2H, s), 7.00 (2H, d,
Jϭ8.6 Hz), 7.23—7.33 (4H, m), 7.39—7.54 (5H, m), 7.99—8.05 (2H, m).
IR (KBr) cmϪ1: 1724, 1514, 1252, 1209, 1066, 982, 822, 710. Anal. Calcd
for C28H25N2O5Br: C, 61.21; H, 4.59; N, 5.10. Found: C, 61.24; H, 4.55; N,
5.09.
(e) Ethyl (E)-2-(4-bromophenyl)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-
4-yl)methoxy]benzyloxyimino}acetate (600 mg, 1.09 mmol) was dissolved
in THF (6 ml)–MeOH (3 ml), and 1 M NaOH (3 ml) was added to the mix-
ture. The whole was stirred at 40 °C for 1 h, then made acidic by addition of
1 M HCl (3.3 ml) and extracted with AcOEt. The extract was washed with
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
was recrystallized from AcOEt–hexane to give 22 (561 mg, 99%) as color-
1
less crystals. mp 159—160 °C (dec.). H-NMR (DMSO-d6) d: 2.45 (3H, s),
(c) Using the procedure for preparation of 22, step d, ethyl (Z)-2-(3-bro-
mophenyl)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}acetate (48% yield) was prepared from ethyl (Z)-2-(3-bromophenyl)-
2-(hydroxyimino)acetate [(Z)-11c] and 4-{[4-(chloromethyl)phenoxy]-
5.01 (2H, s), 5.16 (2H, s), 7.04 (2H, d, Jϭ8.8 Hz), 7.29—7.38 (4H, m),
7.49—7.55 (3H, m), 7.62 (2H, d, Jϭ8.8 Hz), 7.92—7.98 (2H, m). IR (KBr)
cmϪ1: 1711, 1514, 1240, 978, 831, 714, 690. Anal. Calcd for C26H21N2O5Br:
C, 59.90; H, 4.06; N, 5.37. Found: C, 59.75; H, 4.10; N, 5.34.
1
methyl}-5-methyl-2-phenyl-1,3-oxazole (10) as a pale-yellow oil. H-NMR
(Z)-2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-2-phenylacetic Acid (7) Using the procedures for preparation of
22, steps b, d, and e, 7 (54% yield) was prepared from 4-[(5-methyl-2-
phenyl-1,3-oxazol-4-yl)methoxy]benzyl alcohol (9) and ethyl (Z)-2-(hydroxy-
imino)-2-phenylacetate [(Z)-11a] as colorless crystals. mp 171—172 °C
(CDCl3) d: 1.33 (3H, t, Jϭ7.1 Hz), 2.44 (3H, s), 4.41 (2H, q, Jϭ7.1 Hz),
5.00 (2H, s), 5.20 (2H, s), 7.01 (2H, d, Jϭ8.8 Hz), 7.20—7.56 (8H, m),
7.73—7.76 (1H, m), 7.99—8.06 (2H, m). IR (neat) cmϪ1: 2933, 1738, 1610,
1512, 1221, 997, 692.
1
(d) Using the procedure for preparation of 22, step e, 23 (91% yield)
was prepared from ethyl (Z)-2-(3-bromophenyl)-2-{4-[(5-methyl-2-phenyl-
1,3-oxazol-4-yl)methoxy]benzyloxyimino}acetate as colorless crystals. mp
(AcOEt–hexane, dec.). H-NMR (DMSO-d6) d: 2.45 (3H, s), 5.01 (2H, s),
5.16 (2H, s), 7.06 (2H, d, Jϭ8.8 Hz), 7.36 (2H, d, Jϭ8.8 Hz), 7.40—7.58
(8H, m), 7.91—7.98 (2H, m). IR (KBr) cmϪ1: 2929, 1730, 1610, 1514,
1240, 995, 690. Anal. Calcd for C26H22N2O5: C, 70.58; H, 5.01; N, 6.33.
Found: C, 70.49; H, 5.08; N, 6.16.
1
181—182 °C (AcOEt–hexane, dec.). H-NMR (DMSO-d6) d: 2.45 (3H, s),
5.01 (2H, s), 5.18 (2H, s), 7.07 (2H, d, Jϭ8.4 Hz), 7.32—7.58 (7H, m),
7.65—7.74 (2H, m), 7.90—7.98 (2H, m). IR (KBr) cmϪ1: 1732, 1610, 1514,
1238, 997, 806, 716. Anal. Calcd for C26H21N2O5Br: C, 59.90; H, 4.06; N,
5.37. Found: C, 59.84; H, 4.07; N, 5.36.
(E)-2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-2-phenylacetic Acid (20) Using the procedures for preparation of
22, steps d and e, 20 (70% yield) was prepared from methyl (E)-2-(hydroxy-
imino)-2-phenylacetate [(E)-11a] and 4-{[4-(chloromethyl)phenoxy]methyl}-
5-methyl-2-phenyl-1,3-oxazole (10) as colorless crystals. mp 142—143 °C
(Z)-2-(4-Methoxyphenyl)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-
yl)methoxy]benzyloxyimino}acetic Acid (24) (a) A mixture of ethyl 4-
methoxyphenylglyoxylate (15.0 g, 72.0 mmol), hydroxylamine hydrochloride
(6.00 g, 86.4 mmol), sodium acetate (8.86 g, 108 mmol), and EtOH (150 ml)
was refluxed for 12 h. After evaporation of the solvent, the residue was di-
luted with water and extracted with AcOEt. The extract was washed with
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
was chromatographed on silica gel with AcOEt–hexane (1 : 2, v/v) to give
1
(AcOEt–isoPr2O, dec.). H-NMR (DMSO-d6) d: 2.45 (3H, s), 5.01 (2H, s),
5.16 (2H, s), 7.04 (2H, d, Jϭ8.8 Hz), 7.32 (2H, d, Jϭ8.8 Hz), 7.40 (5H, s
like), 7.48—7.56 (3H, m), 7.90—7.98 (2H, m). IR (KBr) cmϪ1: 2939, 1714,
1514, 1242, 1211, 974, 706. Anal. Calcd for C26H22N2O5: C, 70.58; H, 5.01;
N, 6.33. Found: C, 70.52; H, 5.14; N, 6.28.
(Z)-2-(4-Bromophenyl)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-

October 2002
1355
1
less polar ethyl (Z)-2-(hydroxyimino)-2-(4-methoxyphenyl)acetate [(Z)-11d,
8.99 g, 56%] as crystals and polar ethyl (E)-2-(hydroxyimino)-2-(4-
methoxyphenyl)acetate [(E)-11d, 4.97 g, 31%] as crystals. Recrystallization
of (Z)-11d from AcOEt–hexane gave colorless crystals. Recrystallization of
(E)-11d from AcOEt–hexane also gave colorless crystals. The data for (Z)-
11d: mp 81—82 °C. 1H-NMR (CDCl3) d: 1.40 (3H, t, Jϭ7.1 Hz), 3.83 (3H,
s), 4.45 (2H, q, Jϭ7.1 Hz), 6.91 (2H, d, Jϭ9.2 Hz), 7.51 (2H, d, Jϭ9.2 Hz),
8.43 (1H, br s). IR (KBr) cmϪ1: 3304, 1701, 1516, 1248, 1039, 947, 829.
Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C, 59.15; H,
hexane, dec.). H-NMR (CDCl3) d: 2.44 (3H, s), 5.01 (2H, s), 5.15 (2H, s),
6.87—7.05 (6H, m), 7.09—7.18 (1H, m), 7.23—7.45 (7H, m), 7.58 (2H, d,
Jϭ8.8 Hz), 7.96—8.03 (2H, m). IR (KBr) cmϪ1: 1730, 1537, 1489, 1236,
989, 916, 868, 694. Anal. Calcd for C32H26N2O6: C, 71.90; H, 4.90; N, 5.24.
Found: C, 71.62; H, 4.98; N, 5.22.
(E)-2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-2-(4-phenoxyphenyl)acetic Acid (26) Using the procedures for
preparation of 22, steps d and e, 26 (81% yield) was prepared from ethyl
(E)-2-(hydroxyimino)-2-(4-phenoxyphenyl)acetate [(E)-11e] and 4-{[4-
(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (10) as col-
1
5.61; N, 6.25. The data for (E)-11d: mp 128—129 °C. H-NMR (CDCl3) d:
1
1.36 (3H, t, Jϭ7.1 Hz), 3.85 (3H, s), 4.35 (2H, q, Jϭ7.1 Hz), 6.96 (2H, d,
Jϭ9.0 Hz), 7.56 (2H, d, Jϭ9.0 Hz), 9.33 (1H, br s). IR (KBr) cmϪ1: 3259,
1730, 1614, 1292, 1178, 1024, 818, 797, 764. Anal. Calcd for C11H13NO4:
C, 59.19; H, 5.87; N, 6.27. Found: C, 59.19; H, 5.65; N, 6.30.
orless crystals. mp 152—153 °C (AcOEt–hexane, dec.). H-NMR (CDCl3)
d: 2.44 (3H, s), 5.01 (2H, s), 5.25 (2H, s), 6.94—7.09 (6H, m), 7.11—7.21
(1H, m), 7.28—7.48 (7H, m), 7.58 (2H, d, Jϭ8.8 Hz), 7.98—8.05 (2H, m).
IR (KBr) cmϪ1: 1722, 1587, 1487, 1238, 978, 689. Anal. Calcd for
C32H26N2O6·1/4H2O: C, 71.30; H, 4.95; N, 5.20. Found: C, 71.33; H, 4.94;
N, 5.12.
(b) Using the procedure for preparation of 22, step d, ethyl (Z)-2-(4-
methoxyphenyl)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl-
oxyimino}acetate (94% yield) was prepared from ethyl (Z)-2-(hydroxy-
imino)-2-(4-methoxyphenyl)acetate [(Z)-11d] and 4-{[4-(chloromethyl)phe-
noxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (10) gave colorless crystals.
mp 101—102 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 1.33 (3H, t,
Jϭ7.1 Hz), 2.43 (3H, s), 3.82 (3H, s), 4.39 (2H, q, Jϭ7.1 Hz), 4.99 (2H, s),
5.17 (2H, s), 6.89 (2H, d, Jϭ8.8 Hz), 7.00 (2H, d, Jϭ8.8 Hz), 7.32 (2H, d,
Jϭ8.8 Hz), 7.40—7.48 (3H, m), 7.50 (2H, d, Jϭ8.8 Hz), 7.98—8.05 (2H,
m). IR (KBr) cmϪ1: 1731, 1512, 1223, 1169, 1024, 993, 924, 814, 692.
Anal. Calcd for C29H28N2O6: C, 69.59; H, 5.64; N, 5.60. Found: C, 69.56; H,
5.64; N, 5.65.
(Z)-2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-2-(3-phenoxyphenyl)acetic Acid (27) (a) Methanesulfonyl chlo-
ride (14.6 ml, 188 mmol) was added to a solution of 3-phenoxybenzyl alco-
hol (16, 25.0 g, 125 mmol) and triethylamine (26.3 ml, 188 mmol) in AcOEt
(300 ml) at 0 °C, and the mixture was stirred for 1 h. The mixture was
washed with brine, dried over magnesium sulfate, and concentrated in vacuo
to leave an oil. The oil was dissolved in acetone (300 ml), then sodium io-
dide (37.5 g, 250 mmol) was added to the solution. The whole was stirred at
room temperature for 1 h. After evaporation of the solvent, the residue was
dissolved in water and extracted with AcOEt. The extract was washed with
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
was dissolved in DMSO (100 ml), then sodium cyanide (7.35 g, 150 mmol)
was added to the mixture. The whole was stirred at room temperature for
15 h, then diluted with AcOEt. The mixture was washed with water and
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
was chromatographed on silica gel with AcOEt–hexane (1 : 7, v/v) to give 2-
(c) Using the procedure for preparation of 22, step e, 24 (90% yield)
was prepared from ethyl (Z)-2-(4-methoxyphenyl)-2-{4-[(5-methyl-2-
phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}acetate as colorless crys-
1
tals. mp 183—184 °C (AcOEt, dec.). H-NMR (DMSO-d6) d: 2.45 (3H, s),
3.79 (3H, s), 5.01 (2H, s), 5.12 (2H, s), 7.02 (2H, d, Jϭ8.8 Hz), 7.05 (2H, d,
Jϭ8.8 Hz), 7.36 (2H, d, Jϭ8.8 Hz), 7.47 (2H, d, Jϭ8.8 Hz), 7.48—7.56 (3H,
m), 7.90—7.98 (2H, m). IR (KBr) cmϪ1: 1726, 1610, 1512, 1238, 1176,
1028, 1003, 837. Anal. Calcd for C27H24N2O6·1/10H2O: C, 68.37; H, 5.14;
N, 5.91. Found: C, 68.13; H, 5.35; N, 5.81.
1
(3-phenoxyphenyl)acetonitrile (17b, 8.36 g, 32%) as a pale-yellow oil. H-
NMR (CDCl3) d: 3.72 (2H, s), 6.90—7.20 (6H, m), 7.28—7.43 (3H, m). IR
(neat) cmϪ1: 3061, 2252, 1585, 1487, 1252, 1211, 775, 692.
(Z)-2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-2-(4-phenoxyphenyl)acetic Acid (25) (a) Ethyl chloroglyoxylate
(22.3 ml, 200 mmol) was added dropwise to a suspension of aluminum chlo-
ride (29.3 g, 220 mmol) in CH2Cl2 (250 ml) at 0 °C under nitrogen, and the
mixture was stirred at 0 °C for 0.5 h. The mixture was added dropwise over a
period of 0.5 h to diphenyl ether (63.5 ml, 400 mmol) at 0 °C. The whole was
stirred at 0 °C for 2 h, then poured onto ice (250 g). After stirring at room
temperature for 1 h, the organic layer was separated, washed with water and
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
was chromatographed on silica gel with AcOEt–hexane (1 : 10, v/v) to give
ethyl (4-phenoxyphenyl)glyoxylate (38.0 g, 70%) as a colorless oil. 1H-NMR
(CDCl3) d: 1.42 (3H, t, Jϭ7.1 Hz), 4.44 (2H, q, Jϭ7.1 Hz), 6.98—7.13 (4H,
m), 7.20—7.29 (1H, m), 7.37—7.47 (2H, m), 8.01 (2H, d, Jϭ9.0 Hz). IR
(neat) cmϪ1: 2983, 1734, 1682, 1585, 1489, 1250, 1200, 1161, 1020, 872,
750.
(b) An EtOH (15 ml) solution of 2-(3-phenoxyphenyl)acetonitrile (17b,
8.30 g, 39.7 mmol) was added dropwise to a solution of NaOEt [prepared
from Na (1.09 g, 47.6 mmol) and EtOH (20 ml)] at 0 °C under nitrogen. To
this was added isoamyl nitrite (7.99 ml, 59.5 mmol) dropwise at 0 °C. The
whole was stirred at room temperature for 15 h, then diluted with ether. The
mixture was washed with 1 M HCl, aqueous sodium hydrogen carbonate, and
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
was chromatographed on silica gel with AcOEt–hexane (1 : 4, v/v) to give an
oil. The oil was crystallized from AcOEt–hexane to give 2-(hydroxyimino)-
2-(3-phenoxyphenyl)acetonitrile (18b, 4.25 g, 45%) as pale-yellow crystals.
mp 124—125 °C. 1H-NMR (CDCl3) d: 7.01—7.20 (4H, m), 7.33—7.55
(5H, m), 8.75 (1H, br s). IR (KBr) cmϪ1: 3290, 2247, 1591, 1487, 1288,
1228, 1072, 1001, 881, 696. Anal. Calcd for C14H10N2O2: C, 70.58; H, 4.23;
N, 11.76. Found: C, 70.79; H, 4.10; N, 11.67.
(c)
A solution of 2-(hydroxyimino)-2-(3-phenoxyphenyl)acetonitrile
(b) A mixture of ethyl (4-phenoxyphenyl)glyoxylate (37.9 g, 140 mmol),
hydroxylamine hydrochloride (11.7 g, 168 mmol), sodium acetate (17.3 g,
210 mmol), and EtOH (200 ml) was refluxed for 15 h. After evaporation of
the solvent, the residue was diluted with water and extracted with AcOEt.
The extract was washed with brine, dried over magnesium sulfate, and con-
centrated in vacuo. The residue was recrystallized from toluene–hexane to
give ethyl (E)-2-(hydroxyimino)-2-(4-phenoxyphenyl)acetate [(E)-11e,
11.0 g, 28%] as crystals. The mother liquid was concentrated in vacuo. The
residue was chromatographed on silica gel with AcOEt–hexane (1 : 4, v/v) to
give ethyl (Z)-2-(hydroxyimino)-2-(4-phenoxyphenyl)acetate [(Z)-11e,
23.6 g, 59%] as a colorless oil. Recrystallization of (E)-11e from AcOEt–
(18b, 3.00 g, 12.6 mmol) and KOH (3.40 g, 60.4 mmol) in EtOH
(15 ml)–water (15 ml) was refluxed for 24 h. After cooling to room tempera-
ture, the mixture was made acidic by addition of 1 M HCl and extracted with
AcOEt. The extract was washed with brine, dried over magnesium sulfate,
and concentrated in vacuo to leave an oil. The oil was dissolved in MeOH
(30 ml), then conc. H2SO4 (catalytic amount) was added. The whole was re-
fluxed for 24 h. After cooling to room temperature, the mixture was diluted
with aqueous sodium hydrogen carbonate and extracted with AcOEt. The
extract was washed with brine, dried over magnesium sulfate, and concen-
trated in vacuo. The residue was chromatographed on silica gel with
AcOEt–hexane (1 : 2, v/v) to give less polar ethyl (Z)-2-(hydroxyimino)-2-
(3-phenoxyphenyl)acetate [(Z)-11f, 1.14 g, 33%] as a yellow oil and polar
ethyl (E)-2-(hydroxyimino)-2-(3-phenoxyphenyl)acetate [(E)-11f, 746 mg,
22%] as crystals. Recrystallization of (E)-11f from AcOEt–hexane gave col-
orless crystals. The data for (Z)-11f: 1H-NMR (CDCl3) d: 3.95 (3H, s),
6.99—7.18 (4H, m), 7.21—7.28 (2H, m), 7.31—7.41 (3H, m), 8.33 (1H, s).
IR (neat) cmϪ1: 3415, 1741, 1578, 1489, 1435, 1246, 881, 694. The data for
(E)-11f: mp 122—123 °C. 1H-NMR (CDCl3) d: 3.88 (3H, s), 7.02—7.24
(6H, m), 7.30—7.46 (3H, m), 8.83 (1H, br s). IR (KBr) cmϪ1: 3217, 1738,
1491, 1244, 1012, 768. Anal. Calcd for C15H13NO4: C, 66.41; H, 4.83; N,
5.16. Found: C, 66.29; H, 4.95; N, 5.21.
1
hexane gave colorless crystals. The data for (E)-11e: mp 131—132 °C. H-
NMR (CDCl3) d: 1.37 (3H, t, Jϭ7.1 Hz), 4.36 (2H, q, Jϭ7.1 Hz), 6.99—
7.22 (5H, m), 7.33—7.44 (2H, m), 7.55 (2H, d, Jϭ9.0 Hz), 9.25 (1H, br s).
IR (KBr) cmϪ1: 3240, 1732, 1489, 1255, 1198, 1053, 1007, 764. Anal. Calcd
for C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C, 67.42; H, 5.21; N,
4.93. The data for (Z)-11e: 1H-NMR (CDCl3) d: 1.40 (3H, t, Jϭ7.1 Hz),
4.46 (2H, q, Jϭ7.1 Hz), 6.95—7.08 (4H, m), 7.11—7.20 (1H, m), 7.32—
7.42 (2H, m), 7.53 (2H, d, Jϭ8.8 Hz), 8.42—8.49 (1H, m). IR (neat) cmϪ1
:
3417, 1734, 1587, 1489, 1240, 1038, 943, 694.
(c) Using the procedures for preparation of 22, steps d and e, 25 (89%
yield) was prepared from ethyl (Z)-2-(hydroxyimino)-2-(4-phenoxyphenyl)-
acetate [(Z)-11e] and 4-{[4-(chloromethyl)-phenoxy]methyl}-5-methyl-2-
phenyl-1,3-oxazole (10) as colorless crystals. mp 184—185 °C (AcOEt–
(d) Using the procedures for preparation of 22, steps d and e, 27 (62%
yield) was prepared from ethyl (Z)-2-(hydroxyimino)-2-(3-phenoxyphenyl)-
acetate [(Z)-11f] and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-

1356
Vol. 50, No. 10
m), 4.31 (2H, q, Jϭ7.1 Hz), 9.15—9.40 (1H, br). IR (KBr) cmϪ1: 3232,
2956, 1726, 1446, 1174, 1020, 995, 762. Anal. Calcd for C8H15NO3: C,
55.47; H, 8.73; N, 8.09. Found: C, 55.65; H, 8.54; N, 8.07.
phenyl-1,3-oxazole (10) as colorless crystals. mp 173—174 °C (AcOEt–
hexane, dec.). H-NMR (CDCl3) d: 2.44 (3H, s), 5.01 (2H, s), 5.16 (2H, s),
6.89 (2H, d, Jϭ8.6 Hz), 6.97—7.15 (4H, m), 7.20—7.45 (10H, m), 7.97—
8.03 (2H, m). IR (KBr) cmϪ1: 2926, 1726, 1512, 1489, 1244, 999, 692.
Anal. Calcd for C32H26N2O6: C, 71.90; H, 4.90; N, 5.24. Found: C, 72.05; H,
5.06; N, 5.00.
1
(b) Using the procedures for preparation of 22, steps d and e, 32 (68%
yield) was prepared from ethyl (E)-2-(hydroxyimino)hexanoate [(E)-11h]
and 4-{[4-(chloromethyl)phenoxy]-methyl}-5-methyl-2-phenyl-1,3-oxazole
(10) as colorless crystals. mp 112—114 °C (AcOEt–hexane). 1H-NMR
(CDCl3) d: 0.88 (3H, t, Jϭ7.2 Hz), 1.21—1.55 (4H, m), 2.44 (3H, s), 2.53—
2.61 (2H, m), 5.01 (2H, s), 5.19 (2H, s), 7.03 (2H, d, Jϭ8.8 Hz), 7.30 (2H, d,
Jϭ8.8 Hz), 7.38—7.47 (3H, m), 7.98—8.05 (2H, m). IR (KBr) cmϪ1: 3427,
2958, 1713, 1514, 1234, 1020, 982, 717. Anal. Calcd for C24H26N2O5: C,
68.23; H, 6.20; N, 6.63. Found: C, 68.25; H, 6.20; N, 6.66.
(E)-2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-2-(3-phenoxyphenyl)acetic Acid (28) Using the procedures for
preparation of 22, steps d and e, 28 (62% yield) was prepared from ethyl
(E)-2-(hydroxyimino)-2-(3-phenoxyphenyl)acetate [(E)-11f] and 4-{[4-
(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (10) as col-
1
orless amorphous. mp 55—65 °C. H-NMR (CDCl3) d: 2.45 (3H, s), 5.01
(Z)-3-Methyl-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]ben-
zyloxyimino}butyric Acid (33) (a) Isopropylmagnesium bromide
(0.67 M solution in THF, 100 ml, 67 mmol) was added dropwise to a solution
of diethyl oxalate (19.6 g, 134 mmol) in Et2O (400 ml) at Ϫ78 °C under ni-
trogen. The mixture was stirred at Ϫ78 °C for 1 h, then allowed to warm to
0 °C, and added dil. HCl. The organic layer was separated, washed with
aqueous sodium hydrogen carbonate and brine, dried over magnesium sul-
fate, and concentrated in vacuo to leave an oil. The oil was dissolved in
EtOH (100 ml), then hydroxylamine hydrochloride (5.59 g, 80.4 mmol) and
sodium acetate (8.24 g, 101 mmol) were added to the mixture. The whole
was refluxed for 15 h. After evaporation of the solvent, the residue was dis-
solved in water and extracted with AcOEt. The extract was washed with
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
was chromatographed on silica gel with AcOEt–hexane (1 : 4, v/v) to give
ethyl 2-(hydroxyimino)-3-methylbutyrate (11i, 7.74 g, 73%, mixture of iso-
mers, E : Zϭca. 3 : 1) as slurry. Recrystallization from hexane gave colorless
crystals of (E)-11i (1.91 g, 18%). Concentration of the mother liquid gave a
mixture of isomers (5.69 g, 53%, E : Zϭ2.3 : 1) as slurry. The data for (E)-
(2H, s), 5.22 (2H, s), 6.98—7.48 (16H, m), 7.98—8.05 (2H, m). IR (KBr)
cmϪ1: 1718, 1583, 1489, 1240, 993, 690. Anal. Calcd for C32H26N2O6: C,
71.90; H, 4.90; N, 5.24. Found: C, 71.63; H, 4.70; N, 5.04.
(Z)-2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-2-[(E)-4-styrylphenyl]acetic Acid (30) A mixture of ethyl (Z)-2-
(4-bromophenyl)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]ben-
zyloxyimino}acetate (19, 830 mg, 1.51 mmol), (E)-styrylboronic acid
(268 mg, 1.81 mmol), potassium carbonate (626 mg, 4.53 mmol), toluene
(20 ml), EtOH (2 ml), and water (2 ml) was stirred at room temperature
under argon for 0.5 h. To this was added tetrakis(triphenylphosphine)palla-
dium(0) (105 mg, 0.091 mmol), and the mixture was refluxed for 14 h. After
cooling to room temperature, the mixture was washed with brine, dried over
magnesium sulfate, and concentrated in vacuo. The residue was chro-
matographed on silica gel with AcOEt–hexane (1 : 3, v/v) to leave an oil.
The oil was dissolved in THF (10 ml)–MeOH (5 ml), and 1 M NaOH (5 ml)
was added to the mixture. The whole was stirred at 40 °C for 2 h, then made
acidic by addition of dil. HCl and extracted with AcOEt. The extract was
washed with brine, dried over magnesium sulfate, and concentrated in
vacuo. The residue was recrystallized from AcOEt–hexane to give 30
(634 mg, 77%) as pale-yellow crystals. mp 194—195 °C (dec.). 1H-NMR
(DMSO-d6) d: 2.45 (3H, s), 5.01 (2H, s), 5.17 (2H, s), 7.07 (2H, d,
Jϭ8.8 Hz), 7.22—7.44 (7H, m), 7.47—7.58 (5H, m), 7.60—7.73 (4H, m),
7.90—7.98 (2H, m). IR (KBr) cmϪ1: 1732, 1610, 1514, 1240, 1003, 690.
Anal. Calcd for C34H28N2O5·1/4H2O: C, 74.37; H, 5.23; N, 5.10. Found: C,
74.29; H, 5.44; N, 4.94.
1
11i: mp 54—55 °C. H-NMR (CDCl3) d: 1.24 (6H, d, Jϭ7.0 Hz), 1.35 (3H,
t, Jϭ7.1 Hz), 3.49 (1H, sept, Jϭ7.0 Hz), 4.29 (2H, q, Jϭ7.1 Hz), 9.79 (1H,
br s). IR (KBr) cmϪ1: 3269, 2985, 1732, 1431, 1186, 1018, 771. Anal. Calcd
for C7H13NO3: C, 52.82; H, 8.23; N, 8.80. Found: C, 52.72; H, 7.96; N, 8.72.
The data for (Z)-11i: 1H-NMR (CDCl3) d: 1.17 (6H, d, Jϭ6.6 Hz), 1.36 (3H,
t, Jϭ7.1 Hz), 2.80 (1H, sept, Jϭ6.6 Hz), 4.36 (2H, q, Jϭ7.1 Hz), 9.75 (1H,
br s).
(b) Sodium hydride (60% in oil, 255 mg, 6.37 mmol) was added to a so-
lution of ethyl 2-(hydroxyimino)-3-methylbutyrate (11i, E : Zϭ2.3 : 1, 1.01 g,
6.37 mmol) and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-
1,3-oxazole (10, 2.00 g, 6.37 mmol) in DMF (20 ml) at room temperature
under nitrogen. The mixture was stirred at room temperature for 1 h, then di-
luted with 1 M HCl (10 ml), made basic by addition of aqueous sodium hy-
drogen carbonate, and extracted with AcOEt. The extract was washed with
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
was chromatographed on silica gel with AcOEt–hexane–CH2Cl2 (1 : 10 : 10,
v/v) to give less polar ethyl (Z)-3-methyl-2-{4-[(5-methyl-2-phenyl-1,3-
oxazol-4-yl)methoxy]benzyloxyimino}butyrate (640 mg, 23%) as a colorless
oil and polar ethyl (E)-3-methyl-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-
yl)methoxy]benzyloxyimino}butyrate (1.34 g, 48%) as a colorless oil. The
(Z)-2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-2-(4-biphenyl)acetic Acid (29) Using the procedures for prepara-
tion of 30, 29 (60% yield) was prepared from ethyl (Z)-2-(4-bromophenyl)-
2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}acetate
(19) and phenylboronic acid as pale-yellow crystals. mp 193—194 °C
1
(AcOEt–isoPr2O, dec.). H-NMR (DMSO-d6) d: 2.45 (3H, s), 5.02 (2H, s),
5.19 (2H, s), 7.07 (2H, d, Jϭ8.8 Hz), 7.34—7.82 (14H, m), 7.90—7.98 (2H,
m). IR (KBr) cmϪ1: 1724, 1512, 1240, 993, 920, 806, 699. Anal. Calcd for
C32H26N2O5·1/4H2O: C, 73.48; H, 5.11; N, 5.36. Found: C, 73.52; H, 5.00;
N, 5.33.
2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-
propionic Acid (31) Using the procedures for preparation of 22, steps d
and e, 31 (70% yield) was prepared from ethyl (E)-2-(hydroxyimino)-
propanoate [(E)-11g] and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-
2-phenyl-1,3-oxazole (10) as colorless crystals. mp 147—148 °C
(AcOEt–isoPr2O). 1H-NMR (CDCl3) d: 2.07 (3H, s), 2.44 (3H, s), 5.01 (2H,
s), 5.21 (2H, s), 7.04 (2H, d, Jϭ8.8 Hz), 7.32 (2H, d, Jϭ8.8 Hz), 7.42—7.49
(3H, m), 7.99—8.05 (2H, m). IR (KBr) cmϪ1: 2949, 1714, 1612, 1510,
1240, 1173, 1018, 984, 800, 689. Anal. Calcd for C21H20N2O5: C, 66.31; H,
5.30; N, 7.36. Found: C, 66.14; H, 5.26; N, 7.33.
2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-
hexanoic Acid (32) (a) Butylmagnesium chloride (0.90 M solution in
THF, 100 ml, 90 mmol) was added dropwise to a solution of diethyl oxalate
(26.3 g, 180 mmol) in Et2O (400 ml) at Ϫ78 °C under nitrogen. The mixture
was stirred at Ϫ78 °C for 1 h, then allowed to warm to 0 °C, and added dil.
HCl. The organic layer was separated, washed with aqueous sodium hydro-
gen carbonate and brine, dried over magnesium sulfate, and concentrated in
vacuo to leave an oil. The oil was dissolved in EtOH (150 ml), then hydroxy-
lamine hydrochloride (7.50 g, 108 mmol) and sodium acetate (11.1 g,
135 mmol) were added to the mixture. The whole was refluxed for 13 h.
After evaporation of the solvent, the residue was dissolved in water and ex-
tracted with AcOEt. The extract was washed with brine, dried over magne-
sium sulfate, and concentrated in vacuo. The residue was chromatographed
on silica gel with AcOEt–hexane (1 : 4, v/v) to give ethyl (E)-2-(hydroxy-
imino)hexanoate [(E)-11h, 11.0 g, 71%] as crystals. Recrystallization from
hexane gave colorless crystals (8.26 g, 53%). mp 49—50 °C. 1H-NMR
(CDCl3) d: 0.92 (3H, t, Jϭ7.1 Hz), 1.27—1.60 (7H, m), 2.58—2.66 (2H,
1
data for (Z)-adduct: H-NMR (CDCl3) d: 1.14 (6H, d, Jϭ6.8 Hz), 1.28 (3H,
t, Jϭ7.1 Hz), 2.43 (3H, s), 2.70 (1H, sept, Jϭ6.8 Hz), 4.29 (2H, q,
Jϭ7.1 Hz), 4.99 (2H, s), 5.03 (2H, s), 6.98 (2H, d, Jϭ8.8 Hz), 7.27 (2H, d,
Jϭ8.8 Hz), 7.41—7.49 (3H, m), 7.97—8.05 (2H, m). IR (neat) cmϪ1: 2972,
1734, 1512, 1238, 1190, 1018, 714. The data for (E)-adduct: 1H-NMR
(CDCl3) d: 1.17 (6H, d, Jϭ7.0 Hz), 1.35 (3H, t, Jϭ7.1 Hz), 2.44 (3H, s),
3.40 (1H, sept, Jϭ7.0 Hz), 4.30 (2H, q, Jϭ7.1 Hz), 5.00 (2H, s), 5.17 (2H,
s), 7.01 (2H, d, Jϭ8.8 Hz), 7.32 (2H, d, Jϭ8.8 Hz), 7.40—7.48 (3H, m),
7.97—8.05 (2H, m). IR (neat) cmϪ1: 2968, 1722, 1512, 1302, 1240, 1186,
997, 777.
(c) Using the procedure for preparation of 22, step e, 33 (96% yield)
was prepared from ethyl (Z)-3-methyl-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-
4-yl)methoxy]benzyloxyimino}butyrate as colorless crystals. mp 140—
1
142 °C (AcOEt–hexane). H-NMR (CDCl3) d: 1.15 (6H, d, Jϭ7.0 Hz), 2.44
(3H, s), 2.93 (1H, sept, Jϭ7.0 Hz), 5.00 (2H, s), 5.14 (2H, s), 6.98 (2H, d,
Jϭ8.8 Hz), 7.29 (2H, d, Jϭ8.8 Hz), 7.40—7.48 (3H, m), 7.97—8.04 (2H,
m). IR (KBr) cmϪ1: 2974, 1722, 1514, 1244, 1005, 935, 878, 716. Anal.
Calcd for C23H24N2O5: C, 67.63; H, 5.92; N, 6.86. Found: C, 67.79; H, 5.86;
N, 6.83.
(E)-3-Methyl-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]ben-
zyloxyimino}butyric Acid (34) Using the procedure for preparation of 22,
step e, 34 (85% yield) was prepared from ethyl (E)-3-methyl-2-{4-[(5-
methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}butyrate as col-
orless crystals. mp 128—129 °C (AcOEt–hexane). 1H-NMR (CDCl3) d:

October 2002
1357
1045—1050 (1981).
17) Fujita T., Sugiyama Y., Taketomi S., Sohda T., Kawamatsu Y., Iwa-
tsuka H., Suzuoki Z., Diabetes, 32, 804—810 (1983).
18) Chang A. Y., Wyse B. M., Gilchrist B. J., Peterson T., Diani A. R., Di-
abetes, 32, 830—838 (1983).
1.22 (6H, d, Jϭ7.0 Hz), 2.44 (3H, s), 3.41 (1H, sept, Jϭ7.0 Hz), 5.01 (2H,
s), 5.17 (2H, s), 7.03 (2H, d, Jϭ8.8 Hz), 7.29 (2H, d, Jϭ8.8 Hz), 7.40—7.48
(3H, m), 7.98—8.05 (2H, m). IR (KBr) cmϪ1: 2935, 1711, 1514, 1257,
1188, 985, 833, 714. Anal. Calcd for C23H24N2O5: C, 67.63; H, 5.92; N,
6.86. Found: C, 67.86; H, 5.94; N, 6.94.
19) Sohda T., Momose Y., Meguro K., Kawamatsu Y., Sugiyama Y., Ikeda
H., Arzneim.-Forsch., 40, 37—42 (1990).
20) Sohda T., Mizuno K., Momose Y., Ikeda H., Fujita T., Meguro K., J.
Med. Chem., 35, 2617—2626 (1992).
21) Yoshioka T., Fujita T., Kanai T., Aizawa Y., Kurumada T., Hasegawa
K., Horikoshi H., J. Med. Chem., 32, 421—428 (1989).
22) Cantello B. C., Cawthorne M. A., Cottam G. P., Duff P. T., Haigh D.,
Hindley R. M., Lister C. A., Smith S. A., Thurlby P. L., J. Med. Chem.,
37, 3977—3985 (1994).
(E)-2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-3-phenylpropionic Acid (35) (a) Ethyl phenylacetate (25.8 g,
157 mmol) and diethyl oxalate (45.9 g, 314 mmol) were added to a solution
of NaOEt [prepared from Na (7.22 g, 314 mmol) and EtOH (400 ml)]. The
mixture was heated at 70 °C for 1.5 h with continuous removal of EtOH. The
residue was partitioned between 1 M HCl (350 ml) and AcOEt (500 ml), and
the two layers were separated. The organic layer was washed with brine,
dried over magnesium sulfate, and concentrated in vacuo to leave an oil. The
oil was dissolved in DMSO (150 ml)–water (15 ml), then NaCl (9.18 g,
157 mmol) was added to the mixture. The whole was heated at 130 °C for
1.5 h, then poured into water and extracted with AcOEt. The extract was
washed with brine, dried over magnesium sulfate, and concentrated in vacuo
to leave an oil. The oil was dissolved in EtOH (100 ml), then hydroxylamine
hydrochloride (3.34 g, 48.0 mmol) and sodium acetate (4.92 g, 60.0 mmol)
were added to the solution. The whole was refluxed for 17 h. After evapora-
tion of the solvent, the residue was diluted with water and extracted with
AcOEt. The extract was washed with brine, dried over magnesium sulfate,
and concentrated in vacuo. The residue was chromatographed on silica gel
with AcOEt–hexane (1 : 3, v/v) to give ethyl (E)-2-(hydroxyimino)-3-
phenylpropionate [(E)-11j, 6.94 g, 21%] as crystals. Recrystallization from
AcOEt–hexane gave colorless crystals. mp 54—55 °C. 1H-NMR (CDCl3) d:
1.32 (3H, t, Jϭ7.1 Hz), 3.99 (2H, s), 4.28 (2H, q, Jϭ7.1 Hz), 7.15—7.35
(5H, m), 9.58 (1H, br s). IR (KBr) cmϪ1: 3365, 1730, 1452, 1213, 1132,
1024, 719. Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.80; H, 6.21; N, 7.06.
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(2000).
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K. N., Reddy A. K., Rajesh B. M., Reddy P. G., Chakrabarti R., Vikra-
madithyan R. K., Rajagopalan R., Mamidi R. N. V. S., Jajoo H. K.,
Subramaniam S., J. Med. Chem., 41, 1619—1630 (1998).
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Padakanti S., Chakrabarti R., Vikramadithyan R. K., Misra P., Juluri
S., Mamidi N. V. S. R., Rajagopalan R., J. Med. Chem., 44, 2675—
2678 (2001).
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Ohsumi J., Serizawa N., Fujiwara T., Horikoshi H., Fujita T., J. Med.
Chem., 43, 3052—3066 (2000).
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M., Miyachi H., Awano K., Bioorg. & Med. Chem. Lett., 9, 533—538
(1999).
28) Henke B. R., Blanchard S. G., Brackeen M. F., Brown K. K., Cobb J.
E., Collins J. L., Harrington W. W., Jr., Hashim M. A., Hull-Ryde E.
A., Kaldor I., Kliewer S. A., Lake D. H., Leesnitzer L. M., Lehmann J.
M., Lenhard J. M., Orband-Miller L. A., Miller J. F., Mook R. A., Jr.,
Noble S. A., Oliver W., Jr., Parks D. J., Plunket K. D., Szewczyk J. R.,
Willson T. M., J. Med. Chem., 41, 5020—5036 (1998).
29) Collins J. L., Blanchard S. G., Boswell G. E., Charifson P. S., Cobb J.
E., Henke B. R., Hull-Ryde E. A., Kazmierski W. M., Lake D. H.,
Leesnitzer L. M., Lehmann J., Lenhard J. M., Orband-Miller L. A.,
Gray-Nunez Y., Parks D. J., Plunkett K. D., Tong W., J. Med. Chem.,
41, 5037—5054 (1998).
30) Cobb J. E., Blanchard S. G., Boswell E. G., Brown K. K., Charifson P.
S., Cooper J. P., Collins J. L., Dezube M., Henke B. R., Hull-Ryde E.
A., Lake D. H., Lenhard J. M., Oliver W., Jr., Oplinger J., Pentti M.,
Parks D. J., Plunket K. D., Tong W., J. Med. Chem., 41, 5055—5069
(1998).
(b) Using the procedures for preparation of 22, steps d and e, 35 (58%
yield) was prepared from ethyl (E)-2-(hydroxyimino)-3-phenylpropionate
[(E)-11j] and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-
oxazole (10) as colorless crystals. mp 143—144 °C (AcOEt–isoPr2O, dec.).
1H-NMR (DMSO-d6) d: 2.45 (3H, s), 3.81 (2H, s), 5.02 (2H, s), 5.20 (2H,
s), 7.04 (2H, d, Jϭ8.8 Hz), 7.10—7.33 (7H, m), 7.48—7.55 (3H, m), 7.91—
7.98 (2H, m). IR (KBr) cmϪ1: 2935, 1716, 1514, 1238, 993, 833, 694. Anal.
Calcd for C27H24N2O5: C, 71.04; H, 5.30; N, 6.14. Found: C, 70.96; H, 5.19;
N, 6.06.
Acknowledgments We thank Junichi Sakamoto, Kazutoshi Kawakami,
and Shinji Moriyama for in vitro testing; Hiroyuki Odaka, Masami Suzuki,
Yoko Suwa, and Noriko Suzuki for in vivo testing; and Koji Onishi,
Nobuyuki Amano, and Yoshinobu Nohara for pharmacokinetic analysis;
Mika Murabayashi for 1H-NMR NOESY experiments.
31) Shinkai H., Onogi S., Tanaka M., Shibata T., Iwao M., Wakitani K.,
Uchida I., J. Med. Chem., 41, 1927—1933 (1998).
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