Studies on non-thiazolidinedione antidiabetic Agents. 2. Novel oxyiminoalkanoic acid derivatives as potent glucose and lipid lowering agents

Article abstract of DOI:10.1248/cpb.51.138

We previously reported that (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl) methoxy]benzyloxyimino}-2-(4-phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic mice, KKA ^y. This compound a

Full text of DOI:10.1248/cpb.51.138

138
Chem. Pharm. Bull. 51(2) 138—151 (2003)
Vol. 51, No. 2
Studies on Non-Thiazolidinedione Antidiabetic Agents. 2.1) Novel
Oxyiminoalkanoic Acid Derivatives as Potent Glucose and
Lipid Lowering Agents
Hiroshi IMOTO,* Yasuo SUGIYAMA, Hiroyuki KIMURA, and Yu MOMOSE
Takeda Chemical Industries, Ltd., Pharmaceutical Research Division; 2–17–85 Juso-Honmachi, Yodogawa-ku, Osaka
532–8686, Japan. Received September 5, 2002; accepted November 8, 2002
We previously reported that (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-2-(4-
phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic
mice, KKAy. This compound also showed transcriptional activity for peroxisome proliferator-activated receptor
(PPAR)-g. We expanded on the structure–activity relationships of oxyiminoalkanoic acid derivatives based on
this transcriptional activity (in vitro). Insertion of a carbon chain between the imino carbon and the carboxyl
moiety of (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-2-phenylacetic acid (2) resulted
in a marked increase in transcriptional activity at PPARg. In vivo potencies of synthesized compounds, which
showed strong functional activity at PPARg, were tested using KKAy mice. Among these compounds, (E)-4-{4-
[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbutyric acid (27) exhibited marked glu-
cose and lipid lowering activity while showing no significant body weight gain. Compound (27) (TAK-559)
showed favorable pharmacokinetic properties with good absorption and duration, and was considered as an at-
tractive candidate for further evaluation.
Key words antidiabetic agent; oxyiminoalkanoic acid; peroxisome proliferator-activated receptor; type 2 diabetes; KKAy mice
Insulin resistance is a fundamental abnormality of type 2 tor substrate 1 (IRS-1) and phosphatidylinositol (PI) 3-kinase
diabetes and impaired glucose tolerance (IGT).2) Type 2 dia- activation in skeletal muscle of the fatty rats.32) These effects
betes is defined by a high plasma glucose level, which leads were not observed in Wistar lean rats. It was also suggested
to a gradual progression of complications, including neu- that tumor necrosis factor-a (TNF-a) plays a key role in the
ropathy, nephropathy, retinopathy, arteriosclerosis, and coro- systemic insulin resistance of type 2 diabetes.33) Pioglitazone
nary artery disease.3—6) Treatment usually consists of a regi- reduced the TNF-a level in muscle which was accompanied
men of diet and exercise, and oral antihyperglycemic agents by an improvement of metabolic abnormalities in Wistar
such as sulfonylureas, biguanides, and a-glucosidase in- fatty rats.34) A recent study suggests that antidiabetic thiazo-
hibitors. Insulin is also used in severe cases.7) Recent clinical lidinediones interact with a family of nuclear receptors
studies suggested that intensive control of HbA1c levels re- known as the peroxisome proliferator-activated receptor
duced complications for both type 1 and type 2 diabetes, and (PPAR)-g.35) It was also observed that the extent of the acti-
revealed the importance of drugs for reducing plasma glu- vation of PPARg in vitro mirrored antihyperglycemic activity
cose levels.8—11) However, drugs can cause problems includ- in diabetic ob/ob mice.36) There might be a correlation be-
ing compliance, hypoglycemia, and obesity.12,13) Thus, new tween TNF-a and PPARg.
antidiabetic drugs that have improved compliance and re-
duced side effects are still required.
Thiazolidinediones such as pioglitazone, rosiglitazone,
and troglitazone have made a great contribution to therapy
Recently, 2,4-thiazolidinedione analogs, including piogli- for type 2 diabetes. However, weight gain has been reported
tazone (1)14) (Chart 1), have been launched as antidiabetic as a side effect of these drugs.13) Thus, improvement of the
agents.15—17) There are a number of groups that endeavor to thiazolidinedione class of antidiabetic agents is still worth
produce new antidiabetic agents in this area.18—29) Although pursuing.
the mechanisms of insulin resistance and action of 2,4-thia-
In the previous paper, we reported the discovery of two
zolidinedione analogs and related compounds are not yet novel oxyiminoacetic acid derivatives as potent glucose and
fully understood, a number of reports suggest that pioglita- lipid lowering agents, (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxa-
zone reduces insulin resistance. For example, treatment with zol-4-yl)methoxy]benzyloxyimino}-2-phenylacetic acid (2)
pioglitazone increased the insulin action for the decrease of and (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-
hepatic glucose production and for the increase of peripheral benzyloxyimino}-2-(4-phenoxyphenyl)acetic acid (3) (Fig.
glucose utilization in Wistar fatty rats.30,31) In addition, pi- 1).1) These oxyiminoacetic acids showed transcriptional ac-
oglitazone improved the defects of the insulin-stimulated ty- tivity for PPARg, indicating that the mechanisms of action of
rosine phosphorylation of insulin receptors and insulin recep- oxyiminoacetic acid derivatives involve PPARg, at least in
part.36) So, we were interested in finding more potent PPARg
agonists. We synthesized a new series of oxyiminoalkanoic
acids (structure A, Fig. 1) to investigate the effect of linkage
between the imino carbon and carboxy group based on
PPARg transcriptional activity. Compounds, which showed
potent PPARg activity, were tested using KKAy mice37) to
evaluate not only antidiabetic activity but also the effect on
Chart 1
* To whom correspondence should be addressed. e-mail: Imoto_Hiroshi@takeda.co.jp
© 2003 Pharmaceutical Society of Japan

February 2003
139
body weight. In this paper, we describe the synthesis, struc- chloromethyl methyl ether or by tert-butyldimethylsilyl chlo-
ture–activity relationships (SAR), and biological analysis of ride to give 13 followed by reduction with sodium borohy-
oxyiminoalkanoic acids.
dride furnished benzyl alcohols (14). Mitsunobu reaction of
14 with N-hydroxyphthalimide in the presence of diethyl
azodicarboxylate and triphenylphosphine gave phthalimides
Chemistry
The methods used to prepare the oxyiminoalkanoic acids (15), which were converted into alkoxyamines (16) by treat-
are outlined in Chart 2. The starting benzaldehydes (4) were ment with hydrazine. Condensation of 16 with 11, followed
reduced by sodium borohydride to benzyl alcohol derivatives by deprotection of methoxymethyl- or silyl-ether afforded 17
(5), which were treated with thionyl chloride to give benzyl
chlorides (6). Alkylation of oximes (7) with 6 gave imino
ethers (8) (method A). Alternatively, compounds (8) were
synthesized by a three-step process (method B). Alkylation
of N-hydroxyphthalimide with 6 followed by treatment with
hydrazine provided alkoxyamines (10). Condensation of 10
with ketones (11) afforded 8 as a mixture of isomers, which
were easily separated by column chromatography. Saponifi-
cation of 8 with aqueous LiOH afforded the desired alkanoic
acid derivatives (12).
Oxyiminoalkanoic acid derivatives were also prepared by
method C (Chart 3). Protection of 4-hydroxybenzaldehyde by
Reagents: (a) NaBH4; (b) SOCl2; (c) NaH; (d) N-hydroxyphthalimide,
K2CO3; (e) H2NNH2; (f) AcOH, NaOAc; (g) aqueous LiOH.
Chart 2
Fig. 1
Reagents: (a) MOMCl, K2CO3; (b) t-BuMe2SiCl, imidazole; (c) NaBH4; (d) N-hydroxyphthalimide, DEAD, PPh3; (e) H2NNH2; (f) AcOH,
NaOAc; (g) aqueous HCl; (h) Bu4NF; (i) column chromatography; (j) Het-CH2Cl, K2CO3; (k) aqueous LiOH.
Chart 3

140
Vol. 51, No. 2
Reagents: (a) LiAlH4; (b) MsCl, Et3N; (c) NaI; (d) methyl isobutyrate,
LDA; (e) dil. H2SO4.
Reagents: (a) ClCO(CH2)nCO2R2, AlCl3; (b) H2NOH, NaOAc.
Chart 4
Chart 6
Reagents: (a) CDI; (b) t-BuOAc, LDA; (c) NaH, BrCH2CO2Et; (d)
TsOH or CF3CO2H.
Chart 5
as a mixture of isomers (ca. 5 : 1). The major isomer of 17
(or 8 synthesized by method B in Chart 2) is presumed to
have E configuration, considering a report described that re-
actions of alkyl phenyl ketones with methoxyamine yielded
oximes having the hydroxy trans to phenyl.38) (Z)-Isomers of
17 were removed by column chromatography. Only (E)-iso-
mers were used for the next reaction. Alkylation of (E)-17
with appropriate chloromethylheterocycles followed by
saponification with aqueous LiOH yielded oxyiminoalkanoic
acids (19).
The methods employed to prepare the intermediates (7 and
11) in Charts 2 and 3 are shown in Chart 4. Friedel–Crafts
acylation of substituted benzenes with acid chlorides gave
acylated benzenes (11) which were treated with hydroxyl-
amine to provide oximes (7) as a mixture of isomers. These
isomers were easily separated by column chromatography.
The major isomer of oximes is also presumed to have E con-
figuration considering a report.39) This assumption is sup-
ported by X-ray analysis of 27 (data not shown). Compound
(27), prepared from major isomer of methyl 4-(hydroxy-
imino)-4-phenylbutyrate (7a), was identified to have E con-
figuration (the alkoxy of imino group trans to phenyl).
Pyridine analogues (11h—j) were prepared via a four-step
procedure40) (Chart 5). Carbonyldiimidazole (CDI) was used
to condense pyridinecarboxylic acids (20) and lithium eno-
late of tert-butyl acetate to give pyridyl b-keto esters. Alky-
lation of the b-keto esters with ethyl bromoacetate followed
by removal of the tert-butyl group and decarboxylation under
acidic conditions gave the desired pyridyl g-ketoesters
(11h—j).
Reagents: (a) H2N(CH2)nCO2Et·HCl, WSC, HOBt, Et3N; (b) aqueous LiOH.
Chart 7
Treatment of 23 with lithium enolate of methyl isobutyrate
and subsequent deprotection under acidic conditions pro-
vided a,a-dimethylester (11k).
Compounds (2, 26) were condensed with amino acid ethyl
ether to give 24 and 25, which were saponificated with aque-
ous LiOH to give 42 and 43, respectively (Chart 7).
The analytical data of all oxyiminoalkanoic acids (26—57)
synthesized are shown in Tables 1 and 2.
Results and Discussion
All compounds synthesized were evaluated for the ability
to activate PPARg in a transactivation assay in CHO-K1
cells. The results are shown in Tables 1 and 2. First of all, the
effect of inserting an alkyl chain between the imino carbon
and the carboxyl moiety of 2 was scrutinized. Surprisingly, a
marked increase in activity was observed on insertion of
alkyl chains of various lengths. The insertion of one, two, or
a,a-Dimethylester (11k) was synthesized from 2141)
(Chart 6). Reduction of 21 with lithium aluminum hydride
gave alcohol (22). Methanesulfonylation of 22 and subse-
quent reaction with sodium iodide gave iodoalkane (23).

February 2003
141
Table 1. Physical Data and PPARg Transcriptoinal Activities of Oxyiminoalkanoic Acids
Transactivation
PPARg
Entry
R1
R2
2—4
mp (°C)
Formula
Anal.a)
EC50 (mM)c)
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
(CH2)4CO2H
phenyl
phenyl
phenyl
CH2CO2H
(CH2)2CO2H
(CH2)2CO2H
(CH2)2CO2H
(CH2)3CO2H
(CH2)4CO2H
phenyl
4
4
3
2
4
4
4
3
4
4
4
4
4
4
4
4
4
4
4
107—108b)
137—138
108—109
116—117
129—130
112—113
101—102
114—115
84—85
C27H24N2O5
C28H26N2O5
C28H26N2O5
C28H26N2O5
C29H28N2O5
C30H30N2O5
C30H30N2O5
C30H30N2O5
C31H32N2O5
C32H34N2O5
C33H36N2O5
C28H25FN2O5
C34H30N2O6
C27H25N3O5
C27H25N3O5
C27H25N3O5
C29H27N3O6
C29H27N3O6
C32H34N2O5
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
C, H, N
C, H, N
0.053
0.024
0.020
0.69
0.062
0.0025
0.056
0.0035
0.0039
0.26
(CH2)4CO2H
(CH2)5CO2H
(CH2)6CO2H
(CH2)7CO2H
(CH2)2CO2H
(CH2)2CO2H
(CH2)2CO2H
(CH2)2CO2H
(CH2)2CO2H
CONH(CH2)2CO2H
CH2CONHCH2CO2H
(CH2)3C(CH3)2CO2H
116—117
67—68
phenyl
12
4-fluorophenyl
4-phenoxyphenyl
2-pyridyl
3-pyridyl
4-pyridyl
phenyl
139—140
131—132
116—117
158—159
161—162
121—122
176—177
111—112
0.047
0.048
0.045
0.25
0.17
0.11
phenyl
phenyl
0.38
0.032
45
4
148—149
C28H24N2O5
C, H, N
0.83
a) Analytical results were within 0.4% of the theoretical value. b) Decomposed at the temperature. c) EC50, the concentration of test compound required to induce 50%
of the maximum activity.
three carbons at that position in compound (2) resulted in a seems to be more potent at least in vitro assay, though there
30 to 80-fold increase in functional activity (26, 27, 30). is only one example (32 vs. 31).
Compounds with a four-(31, EC50ϭ2.5 nM) or five-(34,
Next, the antidiabetic activities of oxyiminoalkanoic acids
EC50ϭ3.9 nM) carbon insertion were 750- and 490-fold more were evaluated using KKAy mice.37) Test compounds were
active than 2, respectively. Further extension of the carbon selected based on transcriptional activity for PPARg
chain decreased potency (35, 36). Thus, an important rela- (EC50Ͻ0.1 mM). The results are shown in Table 3. A number
tionship was found between the length of the inserted carbon of these compounds significantly reduced plasma glucose
chain and the functional activation of PPARg. Straight chains levels even at a dosage of 0.001% in the diet (but not 28, 30,
were preferable to branched (44 vs. 31), fixed (45 vs. 27), and 33, 38, 44). It is noteworthy that compound (27) showed po-
amide-containing (42, 43 vs. 31) chains as linkages at that tent glucose and lipid lowering activities while showing no
position. Next, the effect of the substitution pattern on the significant body weight gain compared with the control.
central benzene ring was examined. Para- and meta-isomeric These profiles were preferable for antidiabetic agents. Con-
compounds were almost equi-potent (27 vs. 28; 31 vs. 33), sidering the report that describes the structure–activity rela-
and were more potent than the ortho-analogue (27, 28 vs. tionship for PPARg agonist activity in vitro accurately pre-
29). Exchange of the phenyl group adjacent to the imino car- dicts the in vivo glucose lowering activity in diabetic mice,36)
bon with the 3-pyridyl or 4-pyridyl group resulted in a de- it is not clear why compounds (28, 30, 33, 38, 44), which
crease in functional activity (40, 41 vs. 27), although the 2- possessed potent PPARg transcriptional activity, were not as
pyridyl derivative kept potency (39 vs. 27). This result sug- effective for glucose lowering as 27. A possible interpretation
gested that a hydrophobic substituent was preferred at that of this fact is that these compounds might not be absorbed
position. The methyl group at the 5-position of the oxazole sufficiently or might be metabolized rapidly when adminis-
ring played an important role in the activity (46 vs. 27). This tered orally to KKAy mice. Anyway, further investigation of
result is similar to the case of in vivo antihyperglycemic ac- ineffective compounds seemed not to be worth carrying out.
tivity of thiazolidinedione analogs.42) The 5-methyl-1,3-oxa-
Compound (27) was investigated further. Table 4 shows
zole structure was preferable to other azoles (47—50 vs. 27). glucose and lipid lowering activities of 27 and pioglitazone
Substitution of the phenyl moiety on the oxazole ring at the hydrochloride in KKAy mice. Compound (27) exhibited a 9-
2-position of the 2-furyl or 2-thienyl moiety maintained or fold increase in glucose lowering activity and a 50-fold in-
improved potency (51, 52 vs. 27; 56, 57 vs. 31). Extension of crease in lipid lowering activity compared to pioglitazone hy-
the methoxy spacer between the oxazole ring and the central drochloride.
benzene ring did not increase potency (55 vs. 27). E-Isomer
Pharmacokinetic analysis (Table 5) suggested that com-

142
Vol. 51, No. 2
Table 2. Physical Data and PPARg Transcriptoinal Activities of Oxyiminoalkanoic Acids
Transactivation
Entry
Het
m
n
mp (°C)
Formula
Anal.a)
PPARg
EC50 (mM)b)
46
47
48
49
50
51
1
1
1
1
1
1
2
2
2
2
2
2
144—145
104—105
96—97
C27H24N2O5
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
0.25
0.16
0.98
0.31
0.36
0.042
C29H28N2O4S
C27H24N2O5
C27H24N2O5
C28H26N2O4S
C26H24N2O6
100—101
99—100
124—125
52
53
1
2
2
2
142—143
oil
C26H24N2O5S
C, H, N
C, H, N
0.017
0.91
C25H27N3O4·3/4AcOEt
54
2
2
72—73
C24H26N4O4
C, H, N
2.1
55
56
2
1
2
4
106—107
112—113
C29H28N2O5
C28H28N2O6
C, H, N
C, H, N
0.34
0.0049
57
1
4
101—102
C28H28N2O5S
C, H, N
0.00084
a) Analytical results were within 0.4% of the theoretical value. b) EC50, the concentration of test compound required to induce 50% of the maximum activity.
pound (27) has favorable pharmacokinetic characteristics.
The AUC0—24 h (261.36Ϯ18.52 mg·h/ml/p.o. and 30.57Ϯ2.11
mg·h/ml/i.v.) and bioavailability (85.5Ϯ8.4%) were high
enough, which suggests that the system is well exposed to
compound (27).
In summary, we showed that a new series of oxyimi-
noalkanoic acid derivatives had strong transcriptional activity
for PPARg and potent antidiabetic effects in genetically
obese and diabetic KKAy mice. Compound (27), which had
strong glucose and lipid lowering activity while showing no
significant body weight gain, exhibited a 9-fold increase in
glucose lowering activity and a 50-fold increase in lipid low-
ering activity compared to pioglitazone hydrochloride. Com-
pound (27, TAK-559) possessed very good pharmacokinetic
characteristics and selected as a candidate for further evalua-
tion.
Experimental
Biological Procedures. (a) PPARg-Retinoid X Receptor a (RXRa)
Heterodimer Transactivation Assay The full-length human PPARg1,
full-length human RXRa and PPAR responsive luciferase reporter were sta-
bly 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.), inoculated 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 white plate was washed
with PBS (Phosphate-buffered saline), and 90 ml of HAM F12 medium con-
taining 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 incu-
bator 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 ac-
tivity was determined using Lumistar (BMG Labtechnologies GmBH, Ger-
many). Induction magnitude 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 cal-

February 2003
143
Table 3. Glucose and Lipid Lowering Activities, and Body Weight Gain in
KKAy Mice Treated with Oxyiminoalkanoic Acids
Wako TG·H (Wako Pure Chemical Ind., Ltd.). The respective values are
shown as percent reduction with respect 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 approximately 200 mg/dl and 80 mg/dl, respectively.
Pharmacokinetic Analysis. (a) Single-Dose Pharmacokinetics Exper-
iments were carried out in SD (IGS) rats (8 weeks old, male). The animals
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, and 24 h for the intra-
venous study; pre, 15, 30 min, 1, 2, 4, 8, and 24 h for the oral study, respec-
tively) from a tail vein. The samples were analyzed by HPLC to calculate
pharmacokinetic parameters such as AUC0—24 h, C5 min, Cmax, Tmax, T1/2, and
bioavailability. AUC0—24 h is the area under the drug plasma concentration
versus time curve. C5 min is the observed plasma concentration 5 min after
administration. 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. Bioavail-
ability is calculated by the following formula:
PG
reductiona—c)
(%)
TG
reductiona—c)
(%)
BW
Entry
gain ratiod)
26
27
28
30
31
32
33
34
37
38
39
44
51
52
56
57
35**
47**
33
47**
63**
19
2.1
1.2
—
27
L
—
50**
57**
L
31**
49**
L
3.5
4.1
—
2.4
1.5
—
2.2
—
2.0
3.4
1.5
3.4
23*
L
L
39**
19e)
19e)
43**
Le)
43**
Le)
40**
49**
48**
48**
L
36*
24
[bioavailability] (%)ϭ[AUC0—24 h (p.o.)ϫdose (i.v.)]/[AUC0—24 h (i.v.)
ϫdose (p.o.)]ϫ100
30**
(b) Analysis of Plasma Samples (i) Sample Preparation: Acetonitrile
was added to each plasma sample (100 ml). The mixture was stirred by irra-
diation with supersonic waves before centrifugal separation was carried out.
The supernatant liquid was subjected to centrifugal condensation under re-
duced pressure at 30 °C. The residue was dissolved in acetonitrile–0.01 mol/l
ammonium acetate (60 : 40, v/v, 200 ml). The mixture was stirred by irradia-
tion with supersonic waves. Then centrifugal separation was carried out to
remove insoluble substances. The supernatant liquid was used for HPLC
analysis.
(ii) HPLC Assay: Inertsil ODS-3 (f4.6ϫ250 mm) was used for HPLC
analysis. Analyses of compounds were carried out using acetonitrile–
0.01 mol/l ammonium acetate (60 : 40, 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 27 was 14.4 min.
a) Maximum reductions in plasma glucose (PG) and plasma triglyceride (TG) levels
at a dosage of 0.001% 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) Statisti-
cally significant at * pϽ0.05, ** pϽ0.01 by Dunnett’s test. d) The ratio of body
weight (BW) gain calculated by the following formula: [BW gain ratio]ϭ[BW gain
(administered)]/[BW gain (control)]. e) At a dosage of 0.01% in the diet.
Table 4. Glucose and Lipid Lowering Activities of 27 and Pioglitazone
Hydrochloride in KKAy Mice
Plasma glucose
lowering activity
ED25 (mg/kg/d)a)
Plasma triglyceride
lowering activity
ED25 (mg/kg/d)a)
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. Data of a
powder X-ray crystal diffraction were determined by RINT1100 Type
(Rigakudenki, Japan) using Cu-Ka1 ray (voltage: 40 kV; electric current:
40 mA) as a ray source and were expressed by angles of diffraction 2q (°)
and spacing d values (Å).
(E)-3-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-3-phenylpropionic Acid (26) (a) A mixture of 4-{[4-(chloro-
methyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (6a, 5.00 g, 15.9
mmol), N-hydroxyphthalimide (2.59 g, 15.9 mmol), potassium carbonate
(4.40 g, 31.9 mmol), and N,N-dimethylformamide (DMF) (50 ml) was stirred
at room temperature for 20 h, then diluted with water (500 ml). The crystals
were collected by filtration, washed with water, and dried under reduced
pressure to give N-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]ben-
zyloxy}phthalimide (9a, 6.49 g, 93%) as colorless crystals, which were used
for next reaction without further purification. mp 155—156 °C. 1H-NMR
(CDCl3) d: 2.43 (3H, s), 4.99 (2H, s), 5.16 (2H, s), 7.01 (2H, d, Jϭ8.8 Hz),
7.42—7.50 (5H, m), 7.70—7.84 (4H, m), 7.98—8.04 (2H, m). IR (KBr)
cmϪ1: 1786, 1736, 1516, 1389, 1257, 974, 698. Anal. Calcd for C26H20N2O5:
C, 70.90; H, 4.58; N, 6.36. Found: C, 70.73; H, 4.67; N, 6.19.
27
0.65
6
0.12
6
Pioglitazone hydrochloride
a) Effective dose for 25% reduction, estimated from a dose–response curve for three
doses.
Table 5. Pharmacokinetic Parameters of Compound 27 in SD(IGS) Ratsa)
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
261.36Ϯ18.52
—
20.04Ϯ1.01
4.00Ϯ0.00
2.83Ϯ0.25
85.5Ϯ8.4
1
30.57Ϯ2.11
6.74Ϯ1.35
—
—
T1/2 (h)
Bioavailability (%)
4.49Ϯ1.04
—
a) The results are the meanϮS.D. of three male animals in each group.
culate the EC50, the effective concentration of test compound required to in-
duce 50% of the maximum activity.
(b) Glucose and Lipid Lowering Experiments The glucose and lipid
lowering activities of the compounds were tested using KKAy mice.37) 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 experi-
mental groups of five animals each based on their blood glucose levels. The
test compounds were given as a dietary admixture at 0.01 or 0.001% in the
diet. The mice were fed the experimental 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 Laborato-
ries, Inc., Tokyo, Japan) or L type Wako Glu 2 (Wako Pure Chemical Ind.,
Ltd., Tokyo, Japan). The plasma triglyceride levels were also determined en-
zymatically using Iatro-MA701 TG kits (Iatron Laboratories, Inc.) or L type
(b) Hydrazine monohydrate (1.15 ml, 23.7 mmol) was added to a solution
of N-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy}phthalim-
ide (9a, 5.22 g, 11.9 mmol) in EtOH (40 ml)–THF (40 ml) at room tempera-
ture. The mixture was refluxed for 3 h. After cooling to room temperature,
the reaction mixture was diluted with aqueous potassium carbonate and ex-

144
Vol. 51, No. 2
tracted with AcOEt. The extract was washed with brine, dried over magne- Table 6. Data of Powder X-Ray Crystal Diffraction of 27 A Form
sium sulfate, and concentrated in vacuo. The residue was recrystallized from
AcOEt–hexane to give 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]ben-
zyloxyamine (10a, 3.32 g, 90%) as colorless crystals. mp 68—69 °C. 1H-
NMR (CDCl3) d: 2.44 (3H, s), 4.64 (2H, s), 5.00 (2H, s), 5.35 (2H, br s),
7.02 (2H, d, Jϭ8.8 Hz), 7.32 (2H, d, Jϭ8.8 Hz), 7.42—7.47 (3H, m), 7.99—
8.05 (2H, m); IR (KBr) cmϪ1: 1610, 1512, 1246, 1176, 1005, 866, 714, 692.
Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.74; H,
5.66; N, 9.04.
(c) A mixture of 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl-
oxyamine (10a, 1.00 g, 3.22 mmol), ethyl benzoylacetate (11a, 0.612 ml,
3.54 mmol), acetic acid (0.554 ml, 9.67 mmol), sodium acetate (528 mg,
6.44 mmol), and EtOH (20 ml) was refluxed for 12 h. The reaction mixture
was diluted with 1 M HCl 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)-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl-
oxyimino}-3-phenylpropionate (1.29 g, 83%) as a colorless oil. 1H-NMR
(CDCl3) d: 1.15 (3H, t, Jϭ7.1 Hz), 2.44 (3H, s), 3.76 (2H, s), 4.09 (2H, q,
Jϭ7.1 Hz), 5.00 (2H, s), 5.20 (2H, s), 7.01 (2H, d, Jϭ8.4 Hz), 7.30—7.50
(8H, m), 7.61—7.67 (2H, m), 7.97—8.05 (2H, m); IR (neat) cmϪ1: 2931,
1738, 1612, 1512, 1240, 1011, 692.
Angle of diffraction: 2q (°)
Spacing: d value (Å)
5.98
10.7
12.1
18.0
21.0
24.6
14.8
8.28
7.30
4.93
4.23
3.62
Table 7. Data of Powder X-Ray Crystal Diffraction of 27 B Form
Angle of diffraction: 2q (°)
Spacing: d value (Å)
5.04
9.92
11.3
14.8
19.1
20.7
21.7
25.1
17.5
8.91
7.81
5.98
4.65
4.29
4.09
3.54
(d) Ethyl (E)-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl-
oxyimino}-3-phenylpropionate (1.16 g, 2.39 mmol) was dissolved in THF
(60 ml)–water (40 ml), then lithium hydroxide monohydrate (402 mg,
9.58 mmol) was added to the mixture. The whole was stirred at room tem-
perature for 18 h. The solution was made acidic by addition of dil. HCl and
extracted with AcOEt. The extract was washed with brine, dried over mag- (2H, d, Jϭ8.8 Hz), 7.31—7.48 (8H, m), 7.60—7.66 (2H, m), 7.98—8.05
nesium sulfate, and concentrated in vacuo to give 26 (1.08 g, 99%) as crys- (2H, m). IR (KBr) cmϪ1: 2931, 1724, 1512, 1250, 1018, 982, 771, 692.
tals. Recrystallization from AcOEt–hexane gave colorless crystals. mp Anal. Calcd for C28H26N2O5: C, 71.47; H, 5.57; N, 5.95. Found: C, 71.46; H,
107—108 °C (dec.). 1H-NMR (CDCl3) d: 2.42 (3H, s), 3.81 (2H, s), 4.98 5.59; N, 5.94. The data of powder X-ray crystal diffraction of 27 B form are
(2H, s), 5.20 (2H, s), 6.98 (2H, d, Jϭ8.8 Hz), 7.28—7.45 (8H, m), 7.59— shown in Table 7.
7.68 (2H, m), 7.97—8.03 (2H, m). IR (KBr) cmϪ1: 2931, 1713, 1610, 1514,
1248, 1022, 764, 692. Anal. Calcd for C27H24N2O5: C, 71.04; H, 5.30; N,
6.14. Found: C, 71.10; H, 5.45; N, 5.97.
(E)-4-{3-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-2-phenylbutyric Acid (29) (a) A mixture of 4-chloromethyl-5-
methyl-2-phenyl-1,3-oxazole (37.0 g, 0.178 mol), salicilaldehyde (25.0 g,
0.205 mol), K2CO3 (27.1 g, 0.196 mol) and DMF (150 ml) was stirred at
(E)-4-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-4-phenylbutyric Acid (27) (a) A mixture of methyl 3-benzoylpro- 70—80 °C for 4 h. The reaction mixture was poured into H2O and extracted
pionate (11b, 15.0 g, 78.0 mmol), hydroxylamine hydrochloride (6.50 g, with AcOEt. The extract was washed with H2O, dried over MgSO4, and con-
93.6 mmol), sodium acetate (9.60 g, 117 mmol), and MeOH (150 ml) was re- centrated in vacuo to give 2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-
fluxed for 8 h. After evaporation of the solvent, the residue was diluted with benzaldehyde (4b, 41.8 g, 77.5%). Recrystallization from AcOEt–Et2O gave
water and extracted with AcOEt. The extract was washed with brine, dried crystals. mp 95 °C. 1H-NMR (CDCl3) d: 2.45 (3H, s), 5.14 (2H, s), 7.07
over magnesium sulfate, and concentrated in vacuo. The residue was chro- (1H, t, Jϭ7.5 Hz), 7.22 (1H, d, Jϭ8.5 Hz), 7.4—7.5 (3H, m), 7.57 (1H, ddd,
matographed on silica gel with AcOEt–hexane (1 : 3, v/v) to give less polar Jϭ8.5, 7.5, 2 Hz), 7.86 (1H, dd, Jϭ8, 2 Hz), 7.95—8.1 (2H, m), 10.51 (1H,
methyl (E)-4-(hydroxyimino)-4-phenylbutyrate [(E)-7a, 14.7 g, 91%] as a s). Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.45;
pale-yellow oil and polar methyl (Z)-4-(hydroxyimino)-4-phenylbutyrate
[(Z)-7a, 1.37 g, 8%] as crystals. Recrystallization of (Z)-7a from AcOEt–
H, 4.99; N, 4.77.
(b) Sodium borohydride (325 mg, 8.59 mmol) was added to a cold
hexane gave colorless crystals. The data for (E)-7a: 1H-NMR (CDCl3) d: (0 °C) stirred solution of 2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-
2.58—2.67 (2H, m), 3.09—3.17 (2H, m), 3.66 (3H, s), 7.35—7.44 (3H, m),
7.56—7.67 (2H, m), 8.00—8.80 (1H, br). IR (neat) cmϪ1: 3406, 2953, 1736,
1439, 1284, 1201, 1174, 937, 762, 696. The data for (Z)-7a: mp 76—77 °C.
benzaldehyde (4b, 5.00 g, 17.0 mmol) in MeOH (30 ml)–THF (30 ml). After
stirring 0.5 h at room temperature, water was added to the reaction mixture,
and the whole was stirred for 1 h. The crystals of 2-[(5-methyl-2-phenyl-1,3-
1H-NMR (CDCl3) d: 2.58 (2H, t, Jϭ7.4 Hz), 2.87 (2H, t, Jϭ7.4 Hz), 3.67 oxazol-4-yl)methoxy]benzyl alcohol (5b, 4.17 g, 83%) were isolated by fil-
(3H, s), 7.30—7.55 (5H, m). IR (KBr) cmϪ1: 3253, 1726, 1435, 1329, 1203,
1169, 962, 897, 764, 696, 638. Anal. Calcd for C11H13NO3: C, 63.76; H,
6.32; N, 6.76. Found: C, 63.65; H, 6.20; N, 6.80.
tration. Recrystallization from AcOEt–acetone gave colorless crystals. mp
1
155—156 °C. H-NMR (CDCl3) d: 2.44 (3H, s), 4.70 (2H, s), 5.07 (2H, s),
6.95—7.00 (2H, m), 7.02—7.07 (1H, m), 7.25—7.34 (1H, m), 7.42—7.47
(b) Sodium hydride (60% in oil, 3.00 g, 75.0 mmol) was added to a solu- (3H, m), 6.95—7.08 (2H, m), 7.24—7.35 (2H, m), 7.40—7.50 (3H, m),
tion of methyl (E)-4-(hydroxyimino)-4-phenylbutyrate [(E)-7a, 15.5 g,
7.97—8.05 (2H, m). Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74.
75.0 mmol] and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl- Found: C, 73.16; H, 5.94; N, 4.66.
1,3-oxazole (6a, 23.5 g, 75.0 mmol) in DMF (100 ml) at 0 °C under nitrogen.
(c) Thionyl chloride (1.69 g, 14.2 mmol) was added to a solution of
The mixture was stirred at that temperature for 2 h. The solution was acidi- 2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl alcohol (5b, 4.00 g,
fied with 1 M HCl, then made basic by addition of aqueous sodium hydrogen 13.5 mmol) in toluene (60 ml), and the mixture was stirred at room tempera-
carbonate, and extracted with AcOEt. The extract was washed with brine, ture for 0.5 h. To the mixture was added ice-cooled water and extracted with
dried over magnesium sulfate, and concentrated in vacuo. The residue was
chromatographed on silica gel with AcOEt–hexane (1 : 3, v/v) to leave an sium sulfate, and concentrated in vacuo to give 4-{[2-(chloromethyl)phe-
oil. The oil was dissolved in THF (100 ml)–MeOH (50 ml), then 2 M NaOH
noxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (6c, 3.50 g, 82%) as crystals.
(50 ml) was added to the mixture. The whole was stirred at room tempera- Recrystallization from AcOEt–hexane gave colorless crystals. mp 103—
ture for 2 h, then made acidic by addition of 1 M HCl (101 ml) and extracted
AcOEt. The extract was washed with ice-cooled brine, dried over magne-
104 °C. 1H-NMR (CDCl3) d: 2.46 (3H, s), 4.68 (2H, s), 5.09 (2H, s), 6.94—
with AcOEt. The extract was washed with brine, dried over magnesium sul- 7.10 (2H, m), 7.25—7.50 (5H, m), 7.97—8.05 (2H, m). Anal. Calcd for
fate, and concentrated in vacuo to give crystals, which were recrystallized C18H16NO2Cl: C, 68.90; H, 5.14; N, 4.46. Found: C, 69.14; H, 5.10; N, 4.67.
from AcOEt–hexane to give 27 (24.5 g, 86%) as colorless crystals (A form):
mp 126—127 °C. The data of powder X-ray crystal diffraction of 27 A form tion of methyl (E)-4-(hydroxyimino)-4-phenylbutyrate [(E)-7a, 990 mg,
are shown in Table 6.
5.15 mmol] and 4-[(2-chloromethylphenoxy)methyl]-5-methyl-2-phenyl-1,3-
A part of these crystals were recrystallized again from EtOH to give col- oxazole (6c, 1.50 g, 4.78 mmol) in DMF (40 ml) at 0 °C under nitrogen.
(d) Sodium hydride (60% in oil, 200 mg, 5.00 mmol) was added to a solu-
1
orless crystals (B form). mp 137—138 °C. H-NMR (CDCl3) d: 2.43 (3H,
After stirring for 2 h, the mixture was acidified with 2 M HCl and extracted
with AcOEt. The extract was washed with brine, dried over magnesium sul-
s), 2.54—2.63 (2H, m), 3.01—3.11 (2H, m), 5.01 (2H, s), 5.17 (2H, s), 7.02

February 2003
145
fate, and concentrated in vacuo. The residue was chromatographed on silica phenylpentanoate (11c, 8.00 g, 36.3 mmol), hydroxylamine hydrochloride
gel with AcOEt–hexane (1 : 4, v/v) to give methyl (E)-4-{2-[(5-methyl-2- (3.03 g, 43.6 mmol), sodium acetate (4.47 g, 54.5 mmol), and EtOH (70 ml)
phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbutyrate (1.65 g, was refluxed for 15 h. After evaporation of the solvent, the residue was dis-
1
71%) as a colorless oil. H-NMR (CDCl3) d: 2.43 (3H, s), 2.53—2.63 (2H, solved in water and extracted with AcOEt. The extract was washed with
m), 3.04—3.13 (2H, m), 3.61 (3H, s), 5.07 (2H, s), 5.33 (2H, s), 6.95—7.08
(2H, m), 7.25—7.50 (8H, m), 7.57—7.65 (2H, m), 7.97—8.04 (2H, m).
(e) Methyl (E)-4-{2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl-
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)-5-(hydroxyimino)-5-phenylpentanoate [(E)-7b, 7.55 g, 88%] as
oxyimino}-4-phenylbutyrate (1.60 g, 3.30 mmol) was dissolved in THF crystals. Recrystallization from hexane gave colorless crystals. mp 28—
(10 ml)–MeOH (5 ml), and 1 M NaOH (5 ml) was added to the mixture. The
whole was stirred at room temperature for 2 h, then made acidic by addition
of 1 M HCl (5.5 ml) and extracted with AcOEt. The extract was washed with
30 °C. 1H-NMR (CDCl3) d: 1.25 (3H, t, Jϭ7.1 Hz), 1.83—1.99 (2H, m),
2.39 (2H, t, Jϭ7.3 Hz), 2.82—2.91 (2H, m), 4.13 (2H, q, Jϭ7.1 Hz), 7.33—
7.42 (3H, m), 7.60—7.70 (3H, m). IR (KBr) cmϪ1: 3388, 2980, 1732, 1201,
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue 1155, 937, 766, 696. Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95.
was recrystallized from AcOEt–hexane to give 29 (1.42 g, 91%) as colorless Found: C, 66.50; H, 7.42; N, 5.97.
crystals. mp 116—117 °C. 1H-NMR (CDCl3) d: 2.46 (3H, s), 2.63—2.72
(b) Using the procedures for preparation of 29, steps d and e, 30 (80%
(2H, m), 2.96—3.05 (2H, m), 5.00 (2H, s), 5.19 (2H, s), 6.96—7.08 (2H, yield) was prepared from ethyl (E)-5-(hydroxyimino)-5-phenylpentanoate
m), 7.25—7.48 (8H, m), 7.53—7.63 (2H, m), 7.97—8.04 (2H, m). Anal. [(E)-7b] and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-
Calcd for C28H26N2O5: C, 71.47; H, 5.57; N, 5.95. Found: C, 71.41; H, 5.66; oxazole (6a) as colorless crystals. mp 129—130 °C (AcOEt–hexane). 1H-
N, 5.59.
(E)-4-{3-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
NMR (CDCl3) d: 1.74 (2H, quin, Jϭ7.6 Hz), 2.25 (2H, t, Jϭ7.6 Hz), 2.44
(3H, s), 2.80 (2H, t, Jϭ7.6 Hz), 5.00 (2H, s), 5.16 (2H, s), 7.00 (2H, d,
imino}-4-phenylbutyric Acid (28) (a) Using the procedure for prepara- Jϭ8.6 Hz), 7.32—7.47 (8H, m), 7.60—7.68 (2H, m), 7.98—8.04 (2H, m).
tion of 29, step c, 3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl IR (KBr) cmϪ1: 2926, 1701, 1514, 1236, 1009, 924, 692. Anal. Calcd for
alcohol (5a, 84% yield) was prepared from 3-[(5-methyl-2-phenyl-1,3-oxa- C29H28N2O5: C, 71.88; H, 5.82; N, 5.78. Found: C, 71.82; H, 5.75; N, 5.66.
zol-4-yl)methoxy]benzaldehyde (4a) as colorless crystals. mp 101—102 °C
(E)-6-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
(AcOEt–hexane). 1H-NMR (CDCl3) d: 2.45 (3H, s), 4.69 (2H, d, Jϭ6.2 Hz), imino}-6-phenylhexanoic Acid (31) (a) A mixture of 4-[(5-methyl-2-
5.01 (2H, s), 6.95—7.00 (2H, m), 7.02—7.07 (1H, m), 7.25—7.34 (1H, m),
7.42—7.47 (3H, m), 7.99—8.05 (2H, m). IR (KBr) cmϪ1: 3304, 1595, 1252,
1009, 779, 720. Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74.
Found: C, 73.27; H, 5.85; N, 4.60.
phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyamine (10a, 500 mg, 1.61 mmol),
ethyl 6-oxo-6-phenylhexanoate (11d, 415 mg, 1.77 mmol), acetic acid (0.276
ml, 4.83 mmol), sodium acetate (264 mg, 3.22 mmol), and EtOH (20 ml) was
refluxed for 13 h, then diluted with AcOEt, washed with 1 M HCl, brine,
(b) Using the procedure for preparation of 29, step d, 4-{[3-(chloro- dried over magnesium sulfate, and concentrated in vacuo. The residue was
methyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (6b, 84% yield) chromatographed on silica gel with AcOEt–hexane (1 : 4, v/v) to give less
was prepared from 3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl polar ethyl (E)-6-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl-
alcohol (5a) as colorless crystals. mp 79—80 °C (AcOEt–hexane). 1H-NMR oxyimino}-6-phenylhexanoate (620 mg, 73%) as a colorless oil and polar
(CDCl3) d: 2.45 (3H, s), 4.57 (2H, s), 5.01 (2H, s), 6.95—7.03 (2H, m),
ethyl (Z)-6-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-6-phenylhexanoate (120 mg, 14%) as a colorless oil. The data for
7.06—7.08 (1H, m), 7.24—7.33 (1H, m), 7.40—7.48 (3H, m), 7.97—8.05
(2H, m). IR (KBr) cmϪ1: 2879, 1599, 1446, 1255, 1014, 704. Anal. Calcd (E)-adduct: 1H-NMR (CDCl3) d: 1.22 (3H, t, Jϭ7.1 Hz), 1.45—1.73 (4H,
for C18H16NO2Cl: C, 68.90; H, 5.14; N, 4.46. Found: C, 69.15; H, 5.18; N, m), 2.28 (2H, t, Jϭ7.3 Hz), 2.44 (3H, s), 2.78 (2H, t, Jϭ7.5 Hz), 4.09 (2H, q,
4.68.
(c) Using the procedure for preparation of 26, step a, N-{3-[(5-methyl-2-
phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy}phthalimide (9b, 90% yield) was
Jϭ7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 7.01 (2H, d, Jϭ8.4 Hz), 7.33—7.48
(8H, m), 7.58—7.64 (2H, m), 7.99—8.05 (2H, m). IR (neat) cmϪ1: 2931,
1734, 1610, 1512, 1238, 1011, 694. The data for (Z)-adduct: 1H-NMR
prepared from 4-{[3-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl- (CDCl3) d: 1.22 (3H, t, Jϭ7.1 Hz), 1.38—1.71 (4H, m), 2.26 (2H, t,
1,3-oxazole (6b) as colorless crystals. mp 146—147 °C (AcOEt–hexane). Jϭ7.3 Hz), 2.43 (3H, s), 2.53 (2H, t, Jϭ7.5 Hz), 4.09 (2H, q, Jϭ7.1 Hz),
1H-NMR (CDCl3) d: 2.45 (3H, s), 5.02 (2H, s), 5.21 (2H, s), 6.99—7.06
(1H, m), 7.13 (1H, d, Jϭ7.6 Hz), 7.20—7.27 (1H, m), 7.32 (1H, d,
4.99 (2H, s), 5.02 (2H, s), 6.97 (2H, d, Jϭ8.4 Hz), 7.23—7.47 (10H, m),
7.97—8.05 (2H, m). IR (neat) cmϪ1: 2931, 1712, 1612, 1512, 1238, 1009,
Jϭ7.6 Hz), 7.39—7.47 (3H, m), 7.70—7.80 (4H, m), 7.98—8.05 (2H, m). 696.
IR (KBr) cmϪ1: 1726, 1599, 1491, 1394, 1171, 974, 876, 787, 690. Anal.
(b) Using the procedure for preparation of 29, step e, 31 (90% yield)
Calcd for C26H20N2O5·1/4H2O: C, 70.18; H, 4.64; N, 6.30. Found: C, 70.37; was prepared from ethyl (E)-6-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)-
H, 4.49; N, 6.37. methoxy]benzyloxyimino}-6-phenylhexanoate as colorless crystals. mp
(d) Using the procedure for preparation of 26, step b, 3-[(5-methyl-2- 112—113 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 1.23—1.52 (4H, m),
phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyamine (10b, 97% yield) was pre- 2.12 (2H, t, Jϭ7.3 Hz), 2.45 (3H, s), 2.78 (2H, t, Jϭ6.9 Hz), 5.03 (2H, s),
pared from N-{3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy}- 5.16 (2H, s), 7.00 (2H, d, Jϭ8.8 Hz), 7.32—7.45 (8H, m), 7.57—7.63 (2H,
phthalimide (9b) as pale-yellow crystals. mp 81—82 °C (AcOEt–hexane). m), 7.96—8.01 (2H, m). IR (KBr) cmϪ1: 2937, 1728, 1512, 1240, 1176,
1H-NMR (CDCl3) d: 2.45 (3H, s), 4.69 (2H, s), 5.01 (2H, s), 5.41 (2H, br s), 1030, 920, 692. Anal. Calcd for C30H30N2O5: C, 72.27; H, 6.06; N, 5.62.
6.94—7.06 (3H, m), 7.32 (1H, d, Jϭ8.0 Hz), 7.40—7.48 (3H, m), 7.99—
8.05 (2H, m). IR (KBr) cmϪ1: 2910, 1601, 1444, 1255, 1016, 779, 716.
Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.77; H,
5.81; N, 8.39.
Found: C, 71.99; H, 6.12; N, 5.56.
(Z)-6-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-6-phenylhexanoic Acid (32) Using the procedure for preparation
of 29, step e, 32 (99% yield) was prepared from ethyl (Z)-6-{4-[(5-methyl-2-
(e) Using the procedure for preparation of 26, step c, methyl (E)-4-{3-[(5- phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-6-phenylhexanoate
as
colorless crystals. mp 101—102 °C (AcOEt–hexane). H-NMR (CDCl3) d:
tyrate (61% yield) was prepared from 3-[(5-methyl-2-phenyl-1,3-oxazol-4- 1.13—1.45 (4H, m), 1.99—2.08 (2H, m), 2.45—2.52 (5H, m), 4.98 (2H, s),
yl)methoxy]benzyloxyamine (10b) and methyl 4-oxo-4-phenylbutyrate 5.06 (2H, s), 7.00 (2H, d, Jϭ8.8 Hz), 7.26—7.47 (10H, m), 7.96—8.02 (2H,
(11b) as a colorless oil. H-NMR (CDCl3) d: 2.43 (3H, s), 2.53—2.62 (2H, m). IR (KBr) cmϪ1: 2941, 1713, 1510, 1234, 997, 696. Anal. Calcd for
1
methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbu-
1
m), 3.04—3.13 (2H, m), 3.62 (3H, s), 5.01 (2H, s), 5.22 (2H, s), 6.94—7.08
(3H, m), 7.28—7.48 (7H, m), 7.60—7.66 (2H, m), 7.97—8.05 (2H, m). IR
(neat) cmϪ1: 2949, 1738, 1448, 1260, 1173, 1024, 775, 692.
C30H30N2O5: C, 72.27; H, 6.06; N, 5.62. Found: C, 72.30; H, 6.21; N, 5.39.
(E)-6-{3-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-6-phenylhexanoic Acid (33) (a) Using the procedure for prepara-
(f) Using the procedure for preparation of 29, step e, 28 (82% yield) tion of 26, step c, ethyl (E)-6-{3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)-
was prepared from methyl (E)-4-{3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)- methoxy]benzyloxyimino}-6-phenylhexanoate (58% yield) was prepared
methoxy]benzyloxyimino}-4-phenylbutyrate as colorless crystals. mp 108—
from 3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyamine (10b)
109 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 2.46 (3H, s), 2.61 (2H, t, and ethyl 6-oxo-6-phenylhexanoate (11d) as a colorless oil. 1H-NMR
Jϭ7.5 Hz), 3.15 (2H, t, Jϭ7.5 Hz), 5.11 (2H, s), 5.25 (2H, s), 6.91—6.97 (CDCl3) d: 1.21 (3H, t, Jϭ7.1 Hz), 1.47—1.80 (4H, m), 2.29 (2H, t,
(2H, m), 7.20—7.50 (8H, m), 7.59—7.65 (2H, m), 7.96—8.02 (2H, m). IR Jϭ7.5 Hz), 2.43 (3H, s), 2.80 (2H, t, Jϭ7.5 Hz), 4.08 (2H, q, Jϭ7.1 Hz),
(KBr) cmϪ1: 1716, 1603, 1489, 1277, 1014, 881, 690. Anal. Calcd for 5.01 (2H, s), 5.20 (2H, s), 6.93—7.08 (3H, m), 7.25—7.47 (7H, m), 7.58—
C28H26N2O5: C, 71.48; H, 5.57; N, 5.95. Found: C, 71.59; H, 5.45; N, 5.81.
(E)-5-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-5-phenylpentanoic Acid (30) (a) A mixture of ethyl 5-oxo-5-
7.64 (2H, m), 7.97—8.05 (2H, m). IR (neat) cmϪ1: 2933, 1732, 1448, 1263,
1024, 775, 692.
(b) Using the procedure for preparation of 29, step e, 33 (88% yield)

146
Vol. 51, No. 2
was prepared from ethyl (E)-6-{3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)- 1693, 1514, 1252, 1024, 937, 690. Anal. Calcd for C33H36N2O5: C, 73.31; H,
methoxy]benzyloxyimino}-6-phenylhexanoate as colorless crystals. mp 6.71; N, 5.18. Found: C, 73.00; H, 6.49; N, 5.19.
114—115 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 1.45—1.70 (4H, m),
(E)-4-(4-Fluorophenyl)-4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-
2.30 (2H, t, Jϭ6.8 Hz), 2.49 (3H, s), 2.82 (2H, t, Jϭ6.8 Hz), 5.07 (2H, s), yl)methoxy]benzyloxyimino}butyric Acid (37) (a) Ethyl succinyl chlo-
5.19 (2H, s), 6.92—7.05 (2H, m), 7.15 (1H, br s), 7.29—7.48 (7H, m), ride (40.8 ml, 286 mmol) was added dropwise to a suspension of aluminum
7.57—7.63 (2H, m), 7.97—8.02 (2H, m). IR (KBr) cmϪ1: 2935, 1701, 1599,
chloride (41.6 g, 312 mmol) in 1,2-dichloroethane (300 ml) at 0 °C, and the
1446, 1261, 1028, 916, 692. Anal. Calcd for C30H30N2O5: C, 72.27; H, 6.06; mixture was stirred at 0 °C for 0.5 h. To this was added 4-fluorobenzene
N, 5.62. Found: C, 72.08; H, 6.04; N, 5.78.
(E)-7-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
(25.0 g, 260 mmol). The whole was stirred at 60 °C for 15 h, then poured
onto ice (500g). After stirring at room temperature for 1 h, the organic layer
imino}-7-phenylheptanoic Acid (34) (a) Using the procedure for prepara- was separated, washed with brine, dried over magnesium sulfate, and con-
tion of 26, step c, ethyl (E)-7-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)- centrated in vacuo to leave an oil. The oil was dissolved in EtOH (300 ml),
methoxy]benzyloxyimino}-7-phenylheptanoate (77% yield) was prepared then hydroxylamine hydrochloride (21.7 g, 312 mmol) and sodium acetate
from 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyamine (10a)
(32.0 g, 390 mmol) were added. The whole was refluxed for 20 h. After evap-
and ethyl 7-oxo-7-phenylheptanoate (11e) as a colorless oil. 1H-NMR oration of the solvent, the residue was dissolved in water and extracted with
(CDCl3) d: 1.08—1.70 (9H, m), 2.24 (2H, t, Jϭ7.5 Hz), 2.44 (3H, s), 2.76 AcOEt. The extract was washed with brine, dried over magnesium sulfate,
(2H, t, Jϭ7.5 Hz), 4.11 (2H, q, Jϭ7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 7.02 and concentrated in vacuo. The residue was chromatographed on silica gel
(2H, d, Jϭ8.8 Hz), 7.33—7.48 (8H, m), 7.57—7.63 (2H, m), 7.99—8.05 with AcOEt–hexane (1 : 4, v/v) to give ethyl (E)-4-(4-fluorophenyl)-4-(hy-
(2H, m). IR (neat) cmϪ1: 2933, 1732, 1612, 1514, 1238, 1176, 1011, 694.
droxyimino)butyrate [(E)-7c, 7.45 g, 12%] as a brown oil. 1H-NMR (CDCl3)
(b) Using the procedure for preparation of 29, step e, 34 (82% yield) d: 1.23 (3H, t, Jϭ7.1 Hz), 2.56—2.65 (2H, m), 3.05—3.14 (2H, m), 4.11
was prepared from ethyl (E)-7-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)- (2H, q, Jϭ7.1 Hz), 7.01—7.14 (2H, m), 7.56—7.66 (2H, m), 8.05—8.40
methoxy]benzyloxyimino}-7-phenylheptanoate as colorless crystals. mp (1H, br). IR (neat) cmϪ1: 3402, 1734, 1512, 1234, 1161, 839.
84—85 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 1.15—1.58 (6H, m), 2.11
(b) Using the procedures for preparation of 29, steps d and e, 37 (47%
(2H, t, Jϭ7.5 Hz), 2.46 (3H, s), 2.74 (2H, t, Jϭ7.5 Hz), 5.03 (2H, s), 5.15 yield) was prepared from ethyl (E)-4-(4-fluorophenyl)-4-(hydroxyimino)bu-
(2H, s), 7.01 (2H, d, Jϭ8.8 Hz), 7.32—7.47 (8H, m), 7.60—7.66 (2H, m),
7.97—8.03 (2H, m). IR (KBr) cmϪ1: 2935, 1726, 1512, 1238, 1176, 1009,
937, 690. Anal. Calcd for C31H32N2O5: C, 72.64; H, 6.29; N, 5.46. Found: C,
72.38; H, 6.28; N, 5.50.
tyrate [(E)-7c] and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-
1,3-oxazole (6a) as colorless crystals. mp 139—140 °C (AcOEt–hexane).
1H-NMR (CDCl3) d: 2.43 (3H, s), 2.52—2.63 (2H, m), 2.97—3.07 (2H, m),
5.00 (2H, s), 5.15 (2H, s), 6.97—7.10 (4H, m), 7.23—7.46 (5H, m), 7.56—
7.66 (2H, m), 7.97—8.04 (2H, m). IR (KBr) cmϪ1: 2926, 1720, 1510, 1249,
(E)-8-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-8-phenyloctanoic Acid (35) (a) A mixture of 4-[(5-methyl-2- 1020, 928, 835. Anal. Calcd for C28H25N2O5F: C, 68.84; H, 5.16; N, 5.73.
phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyamine (10a, 1.50 g, 4.83 mmol), Found: C, 68.68; H, 5.07; N, 5.69.
ethyl 8-oxo-8-phenyloctanoate (11f, 2.54 g, 9.67 mmol), acetic acid (0.830
(E)-4-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
ml, 14.5 mmol), sodium acetate (793 mg, 9.67 mmol), and EtOH (40 ml) was imino}-4-(4-phenoxyphenyl)butyric Acid (38) (a) Ethyl succinyl chlo-
refluxed for 18 h, then diluted with AcOEt. The mixture was washed with
water and brine, dried over magnesium sulfate, and concentrated in vacuo.
ride (14.3 ml, 100 mmol) was added dropwise to a suspension of aluminum
chloride (14.7 g, 110 mmol) in CH2Cl2 (120 ml) at 0 °C, and the mixture was
The residue was chromatographed on silica gel with AcOEt–hexane (1 : 5, stirred at 0 °C for 0.5 h. The mixture was added dropwise to a solution of
v/v) to give less polar ethyl (E)-8-{4-[(5-methyl-2-phenyl-1,3-oxazol-4- diphenylether (34.0 g, 200 mmol) in CH2Cl2 (50 ml) at 0 °C. The whole was
yl)methoxy]benzyloxyimino}-8-phenyloctanoate (2.02 g, 76%) as a color- stirred at 0 °C for 3 h, then poured onto ice (200 g). After stirring at room
less oil and polar ethyl (Z)-8-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)- temperature for 1 h, the organic layer was separated, washed with brine,
methoxy]benzyloxyimino}-8-phenyloctanoate (408 mg, 15%) as a colorless dried over magnesium sulfate, and concentrated in vacuo to leave an oil. The
oil. The data for (E)-adduct: 1H-NMR (CDCl3) d: 1.18—1.65 (11H, m), oil was dissolved in EtOH (150 ml), then hydroxylamine hydrochloride
2.25 (2H, t, Jϭ7.5 Hz), 2.44 (3H, s), 2.75 (2H, t, Jϭ7.5 Hz), 4.12 (2H, q, (8.34 g, 120 mmol) and sodium acetate (12.3 g, 150 mmol) were added. The
Jϭ7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 7.01 (2H, d, Jϭ8.8 Hz), 7.33—7.46 whole was refluxed for 15 h. After evaporation of the solvent, the residue
(8H, m), 7.58—7.64 (2H, m), 7.99—8.05 (2H, m). IR (neat) cmϪ1: 2933, was dissolved in water and extracted with AcOEt. The extract was washed
1732, 1612, 1514, 1240, 1176, 1011, 694. The data for (Z)-adduct: 1H-NMR with brine, dried over magnesium sulfate, and concentrated in vacuo. The
(CDCl3) d: 1.20—1.65 (11H, m), 2.25 (2H, t, Jϭ7.5 Hz), 2.43 (3H, s), 2.50 residue was chromatographed on silica gel with AcOEt–hexane (1 : 4, v/v)
(2H, t, Jϭ7.2 Hz), 4.12 (2H, q, Jϭ7.1 Hz), 4.99 (2H, s), 5.02 (2H, s), 6.97 to give ethyl (E)-4-(hydroxyimino)-4-(4-phenoxyphenyl)butyrate [(E)-7d,
(2H, d, Jϭ8.6 Hz), 7.25 (2H, d, Jϭ8.6 Hz), 7.27—7.48 (8H, m), 7.99—8.04
10.5 g, 34%] as a colorless oil. 1H-NMR (CDCl3) d: 1.23 (3H, t, Jϭ7.1 Hz),
2.57—2.66 (2H, m), 3.06—3.15 (2H, m), 4.12 (2H, q, Jϭ7.1 Hz), 6.97—
(2H, m). IR (neat) cmϪ1: 2929, 1732, 1610, 1512, 1238, 1174, 1009, 696.
(b) Using the procedure for preparation of 29, step e, 35 (92% yield) 7.19 (5H, m), 7.31—7.42 (2H, m), 7.59 (2H, d, Jϭ9.2 Hz), 7.90—8.60 (1H,
was prepared from ethyl (E)-8-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)- br). IR (neat) cmϪ1: 3401, 1734, 1587, 1489, 1240, 872, 694.
methoxy]benzyloxyimino}-8-phenyloctanoate as colorless crystals. mp
(b) Using the procedure for preparation of 29, step d, ethyl (E)-4-{4-[(5-
methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-(4-phe-
116—117 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 1.07—1.52 (8H, m),
2.10 (2H, t, Jϭ7.4 Hz), 2.46 (3H, s), 2.74 (2H, t, Jϭ7.4 Hz), 5.01 (2H, s), noxyphenyl)butyrate (66% yield) was prepared from ethyl (E)-4-(hydroxy-
5.17 (2H, s), 7.00 (2H, d, Jϭ8.4 Hz), 7.30—7.47 (8H, m), 7.60—7.67 (2H,
m), 7.98—8.04 (2H, m). IR (KBr) cmϪ1: 2926, 1720, 1514, 1244, 1012,
777, 694. Anal. Calcd for C32H34N2O5: C, 72.98; H, 6.51; N, 5.32. Found: C,
72.92; H, 6.39; N, 5.23.
imino)-4-(4-phenoxyphenyl)butyrate [(E)-7d] and 4-{[4-(chloromethyl)phe-
noxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (6a) as colorless crystals. mp
118—119 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 1.21 (3H, t, Jϭ7.1 Hz),
2.44 (3H, s), 2.49—2.59 (2H, m), 2.99—3.09 (2H, m), 4.09 (2H, q,
Jϭ7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 6.94—7.18 (7H, m), 7.31—7.47 (7H,
(E)-9-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-9-phenylnonanoic Acid (36) A mixture of 4-[(5-methyl-2-phenyl- m), 7.61 (2H, d, Jϭ8.8 Hz), 7.99—8.05 (2H, m). IR (KBr) cmϪ1: 1734,
1,3-oxazol-4-yl)methoxy]benzyloxyamine (500 mg, 1.61 mmol), methyl 9- 1587, 1487, 1238, 1144, 1001, 945, 908, 694. Anal. Calcd for C36H34N2O6:
oxo-9-phenylnonanoate (11g, 464 mg, 1.77 mmol), sodium acetate (264 mg, C, 73.20; H, 5.80; N, 4.74. Found: C, 73.16; H, 6.17; N, 4.72.
3.22 mmol), 1 M HCl (3 ml), and EtOH (20 ml) was refluxed for 72 h. The
(c) Using the procedure for preparation of 29, step e, 38 (99% yield)
mixture was diluted with AcOEt, washed with water and brine, dried over was prepared from ethyl (E)-4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)-
magnesium sulfate, and concentrated in vacuo. The residue was chro- methoxy]benzyloxyimino}-4-(4-phenoxyphenyl)butyrate as colorless crys-
1
matographed on silica gel with AcOEt–hexane (1 : 6, v/v) to leave an oil. tals. mp 131—132 °C (AcOEt–hexane). H-NMR (CDCl3) d: 2.43 (3H, s),
The oil was dissolved in THF (10 ml)–MeOH (5 ml), then 1 M NaOH (5 ml)
2.55—2.64 (2H, m), 2.99—3.08 (2H, m), 5.00 (2H, s), 5.15 (2H, s), 6.93—
was added to the mixture. The whole was stirred at room temperature for 7.17 (7H, m), 7.29—7.47 (7H, m), 7.60 (2H, d, Jϭ9.2 Hz), 7.98—8.04 (2H,
1 h, then made acidic by addition of dil. HCl and extracted with AcOEt. The m). IR (KBr) cmϪ1: 2929, 1722, 1587, 1510, 1489, 1240, 1018, 839, 692.
extract was washed with brine, dried over magnesium sulfate, and concen- Anal. Calcd for C34H30N2O6: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.36; H,
trated in vacuo. The residue was recrystallized from AcOEt–hexane to give 5.40; N, 5.04.
36 (323 mg, 37%) as colorless crystals. mp 67—68 °C. 1H-NMR (CDCl3) d:
1.05—1.60 (10H, m), 2.17 (2H, t, Jϭ7.3 Hz), 2.47 (3H, s), 2.76 (2H, t,
(E)-4-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-4-(2-pyridyl)butyric Acid (39) (a) Carbonyldiimidazole (7.25 g,
Jϭ7.3 Hz), 5.02 (2H, s), 5.15 (2H, s), 7.01 (2H, d, Jϭ8.8 Hz), 7.32—7.48 44.7 mmol) was added to a solution of 2-pyridinecarboxylic acid (5.00 g,
(8H, m), 7.61—7.67 (2H, m), 7.99—8.05 (2H, m). IR (KBr) cmϪ1: 2920,
40.6 mmol) in THF (200 ml) at 0 °C. The mixture was stirred at 0 °C for

February 2003
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0.5 h and at room temperature for additional 2 h. This solution was added imino}-4-(4-pyridyl)butyric Acid (41) (a) Using the procedure for prepa-
dropwise to a precooled (Ϫ78 °C) solution of tert-butyl lithioacetate, ob-
ration of 39, step a, ethyl 4-oxo-4-(4-pyridyl)butyrate (11j, 31% yield) was
tained from tert-butyl acetate (17.5 ml, 130 mmol) and LDA (130 mmol) at prepared from 4-pyridinecarboxylic acid as a pale-brown oil. 1H-NMR
Ϫ78 °C, in THF (100 ml) over 1 h under nitrogen. After the reaction temper- (CDCl3) d: 1.27 (3H, t, Jϭ7.1 Hz), 2.78 (2H, t, Jϭ6.5 Hz), 3.30 (2H, t,
ature was kept at this temperature for 15 min, it was quenched by addition of Jϭ6.5 Hz), 4.17 (2H, q, Jϭ7.1 Hz), 7.76 (2H, d, Jϭ6.2 Hz), 8.83 (2H, d,
1 M HCl (250 ml) and extracted with AcOEt. The extract was washed with Jϭ6.2 Hz). IR (neat) cmϪ1: 2981, 1734, 1701, 1408, 1223, 1174, 1030, 814.
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue
(b) Using the procedure for preparation of 26, step c, ethyl 4-{4-[(5-
was chromatographed on silica gel with AcOEt–hexane (1 : 4, v/v) to leave methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-(4-
an oil. The oil was dissolved in THF (100 ml), cooled to 0 °C, then sodium
hydride (60% in oil, 1.06 g, 26.4 mmol) was added. The mixture was stirred
pyridyl)butyrate (92% yield, E : Zϭca. 3 : 1) was prepared from 4-[(5-
methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyamine (10a) and ethyl
at 0 °C for 10 min, then ethyl bromoacetate (2.00 ml, 18.0 mmol) was added 4-oxo-4-(4-pyridyl)butyrate (11j) as a colorless oil. 1H-NMR (CDCl3) d:
in one portion, and the whole was stirred at 0 °C for 8 h. After addition of 1.16—1.31 (3H, m), 2.44 (3H, s), 2.48—4.63 (2H, m), 2.77—2.86 (0.5H,
0.1 M HCl (300 ml) and extraction with AcOEt, the extract was washed with m), 3.02 (1.5H, t, Jϭ7.9 Hz), 4.02—4.18 (2H, m), 5.00 (2.5H, s like), 5.20
brine, dried over magnesium sulfate, and concentrated in vacuo. The residue (1.5H, s), 6.95—7.22 (2H, m), 7.20—7.56 (7H, m), 7.99—8.05 (2H, m),
was chromatographed on silica gel with AcOEt–hexane (1 : 5, v/v) to leave 8.59—8.66 (2H, m). IR (neat) cmϪ1: 2929, 1734, 1512, 1238, 1176, 1011,
an oil. The oil was dissolved in toluene (200 ml) and treated with p-toluene- 824, 714.
sulfonic acid monohydrate (2.00 g, 10.5 mmol) at 80 °C for 20 h. After cool-
(c) Using the procedure for preparation of 29, step e, 41 (75% yield) was
ing to room temperature, the solution was diluted with AcOEt, washed with prepared from ethyl 4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-
saturated aqueous sodium hydrogen carbonate and brine, dried over magne- benzyloxyimino}-4-(4-pyridyl)butyrate as colorless crystals. mp 161—
sium sulfate, and concentrated in vacuo. The residue was chromatographed 162 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 2.43 (3H, s), 2.58 (2H, t,
on silica gel with AcOEt–hexane (1 : 2, v/v) to give ethyl 4-oxo-4-(2- Jϭ7.5 Hz), 3.05 (2H, t, Jϭ7.5 Hz), 5.00 (2H, s), 5.20 (2H, s), 7.02 (2H, d,
1
pyridyl)butyrate (11h, 1.56 g, 19%) as a colorless oil. H-NMR (CDCl3) d: Jϭ8.8 Hz), 7.35 (2H, d, Jϭ8.8 Hz), 7.38—7.46 (3H, m), 7.58 (2H, d,
1.26 (3H, t, Jϭ7.1 Hz), 2.76 (2H, d, Jϭ6.7 Hz), 3.57 (2H, d, Jϭ6.7 Hz), 4.16 Jϭ6.2 Hz), 7.98—8.04 (2H, m), 8.51 (2H, d, Jϭ6.2 Hz). IR (KBr) cmϪ1
:
(2H, q, Jϭ7.1 Hz), 7.48 (1H, dd, Jϭ4.8, 7.6 Hz), 7.84 (1H, dt, Jϭ1.8, 2929, 1730, 1610, 1512, 1236, 1018, 837, 714. Anal. Calcd for C27H25N3O5:
7.6 Hz), 8.05 (1H, d, Jϭ7.6 Hz), 8.69 (1H, dd, Jϭ1.8, 4.8 Hz). IR (neat) C, 68.78; H, 5.34; N, 8.91. Found: C, 68.85; H, 5.32; N, 8.74.
cmϪ1: 2983, 1732, 1701, 1215, 995, 779.
(Z)-3-(2-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
(b) Using the procedure for preparation of 26, step c, ethyl (E)-4-{4-[(5- imino}-2-phenylacetoamido)propionic Acid (42) (a) Triethylamine
methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-(2- (0.222 ml, 1.58 mmol) was added to a solution of b-alanine ethyl ester hy-
pyridyl)butyrate (75% yield) was prepared from 4-[(5-methyl-2-phenyl-1,3- drochloride (243 mg, 1.58 mmol) in DMF (7 ml). The mixture was stirred
oxazol-4-yl)methoxy]benzyloxyamine (10a) and ethyl 4-oxo-4-(2-pyridyl)- room temperature for 0.5 h. To this was added (Z)-{4-[(5-methyl-2-phenyl-
butyrate (11h) as a colorless oil. 1H-NMR (CDCl3) d: 1.23 (3H, t,
Jϭ7.1 Hz), 2.44 (3H, s), 2.55—2.64 (2H, m), 3.19—3.28 (2H, m), 4.07 (2H,
1,3-oxazol-4-yl)methoxy]benzyloxyimino}phenylacetic acid (2, 700 mg,
1.58 mmol), WSC (303 mg, 1.58 mmol), and HOBt (242 mg, 1.58 mmol).
q, Jϭ7.1 Hz), 5.00 (2H, s), 5.19 (2H, s), 7.01 (2H, d, Jϭ8.8 Hz), 7.19—7.24 The whole was stirred at room temperature for 18 h, then diluted with
(1H, m), 7.36 (2H, d, Jϭ8.8 Hz), 7.39—7.46 (3H, m), 7.64 (1H, dt, Jϭ1.8, AcOEt. The mixture was washed with diluted HCl, aqueous potassium car-
7.6 Hz), 7.87 (1H, d, Jϭ8.0 Hz), 7.99—8.05 (2H, m), 8.54—8.59 (1H, m). bonate, and brine, dried over magnesium sulfate, and concentrated in vacuo.
IR (neat) cmϪ1: 2929, 1732, 1512, 1238, 1176, 1011, 775, 714.
The residue was chromatographed on silica gel with AcOEt–hexane
(c) Using the procedure for preparation of 29, step e, 39 (87% yield) (2 : 3, v/v) to give ethyl (Z)-3-(2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)-
was prepared from ethyl (E)-4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)- methoxy]benzyloxyimino}-2-phenylacetoamido)propionate (24, 829 mg,
1
methoxy]benzyloxyimino}-4-(2-pyridyl)butyrate as colorless crystals. mp 97%) as a colorless oil. H-NMR (CDCl3) d: 1.23 (3H, t, Jϭ7.1 Hz), 2.44
116—117 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 2.44 (3H, s), 2.72—
(3H, s), 2.60 (2H, d, Jϭ6.0 Hz), 3.63—3.74 (2H, m), 4.10 (2H, q,
2.80 (2H, m), 3.10—3.18 (2H, m), 5.01 (2H, s), 5.21 (2H, s), 7.02 (2H, d, Jϭ7.1 Hz), 5.00 (2H, s), 5.16 (2H, s), 6.48—6.60 (1H, m), 7.01 (2H, d,
Jϭ8.8 Hz), 7.30—7.48 (6H, m), 7.77 (1H, dt, Jϭ1.8, 7.4 Hz), 7.91—8.05 Jϭ8.8 Hz), 7.29—7.48 (8H, m), 7.58—7.65 (2H, m), 7.97—8.05 (2H, m).
(3H, m), 8.53—8.58 (1H, m). IR (KBr) cmϪ1: 2935, 1720, 1512, 1252, IR (neat) cmϪ1: 2931, 1732, 1664, 1514, 1240, 1178, 1007, 692.
1020, 982, 789. Anal. Calcd for C27H25N3O5: C, 68.78; H, 5.34; N, 8.91.
Found: C, 68.70; H, 5.34; N, 8.92.
(E)-4-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
(b) Ethyl (Z)-3-(2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]ben-
zyloxyimino}-2-phenylacetoamido)propionate (24, 720 mg, 1.33 mmol) was
dissolved in THF (6 ml), water (4 ml), and MeOH (4 ml), then lithium hy-
imino}-4-(3-pyridyl)butyric Acid (40) (a) Using the procedure for prepa- droxide monohydrate (167 mg, 3.99 mmol) was added. The whole was
ration of 39, step a, ethyl 4-oxo-4-(3-pyridyl)butyrate (11i, 38% yield) was
stirred at room temperature for 1.5 h, then made acidic by addition of 1 M
prepared from 3-pyridinecarboxylic acid as a colorless oil. 1H-NMR HCl (4.1 ml) and extracted with AcOEt. The extract was washed with brine,
(CDCl3) d: 1.28 (3H, t, Jϭ7.1 Hz), 2.79 (2H, t, Jϭ6.6 Hz), 3.33 (2H, t, dried over magnesium sulfate, and concentrated in vacuo. The residue was
Jϭ6.6 Hz), 4.17 (2H, q, Jϭ7.1 Hz), 7.43 (1H, dd, Jϭ4.8, 8.0 Hz), 8.23— recrystallized from AcOEt–hexane to give 42 (661 mg, 97%) as colorless
8.30 (1H, m), 8.80 (1H, dd, Jϭ1.6, 4.8 Hz), 9.22 (1H, d, Jϭ2.2 Hz). IR crystals. mp 121—122 °C. 1H-NMR (CDCl3) d: 2.38—2.47 (5H, m), 3.50—
(neat) cmϪ1: 2983, 1732, 1698, 1587, 1223, 1174, 1028, 706.
3.60 (2H, m), 5.02 (2H, s), 5.18 (2H, s), 6.10—6.20 (1H, m), 6.98 (2H, d,
(b) Using the procedure for preparation of 26, step c, ethyl 4-{4-[(5- Jϭ8.8 Hz), 7.27—7.50 (8H, m), 7.61—7.69 (2H, m), 7.92—7.99 (2H, m).
methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-(3- IR (KBr) cmϪ1: 3319, 2935, 1711, 1666, 1514, 1250, 991, 689. Anal. Calcd
pyridyl)butyrate (73% yield, E : Zϭca. 4 : 1) was prepared from 4-[(5- for C29H27N3O6: C, 67.83; H, 5.30; N, 8.18. Found: C, 67.51; H, 5.28; N,
methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyamine (10a) and ethyl 8.10.
4-oxo-4-(3-pyridyl)butyrate (11i) as a colorless oil. 1H-NMR (CDCl3) d:
(E)-2-(3-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
1.16—1.30 (3H, m), 2.44 (3H, s), 2.51—2.64 (2H, m), 2.86 (0.4H, t, imino}-3-phenylpropanamido)acetic Acid (43) (a) Using the procedure
Jϭ6.9 Hz), 3.05 (1.6H, t, Jϭ7.9 Hz), 4.02—4.18 (2H, m), 5.00 (2.4H, s for preparation of 42, step a, ethyl (E)-2-(3-{4-[(5-methyl-2-phenyl-1,3-oxa-
like), 5.18 (1.6H, s), 6.95—7.06 (2H, m), 7.23—7.48 (6H, m), 7.71—7.78 zol-4-yl)methoxy]benzyloxyimino}-3-phenylpropanamido)acetate (25, 86%
(0.2H, m), 7.91—8.05 (2.8H, m), 8.53—8.61 (1H, m), 8.66—8.69 (0.2H, yield) was prepared from (E)-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)-
m), 8.85—8.88 (0.8H, m). IR (neat) cmϪ1: 2929, 1732, 1512, 1238, 1011,
712.
methoxy]benzyloxyimino}-3-phenylpropionic acid (26) and glycine ethyl
ester hydrochloride as colorless crystals. mp 144—145 °C (AcOEt–hexane).
(c) Using the procedure for preparation of 29, step e, 40 (77% yield) was 1H-NMR (CDCl3) d: 1.23 (3H, t, Jϭ7.1 Hz), 2.44 (3H, s), 3.78 (2H, s), 3.88
prepared from ethyl 4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]- (2H, d, Jϭ5.2 Hz), 4.16 (2H, q, Jϭ7.1 Hz), 5.00 (2H, s), 5.28 (2H, s), 6.65—
benzyloxyimino}-4-(3-pyridyl)butyrate as colorless crystals. mp 158— 6.80 (1H, br), 7.02 (2H, d, Jϭ8.8 Hz), 7.32—7.47 (8H, m), 7.74—7.81 (2H,
159 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 2.43 (3H, s), 2.63 (2H, t, m), 7.98—8.04 (2H, m). IR (KBr) cmϪ1: 3296, 1730, 1645, 1238, 1009,
Jϭ7.5 Hz), 3.07 (2H, t, Jϭ7.5 Hz), 5.00 (2H, s), 5.18 (2H, s), 7.01 (2H, d,
690. Anal. Calcd for C31H31N3O6: C, 68.75; H, 5.77; N, 7.76. Found: C,
Jϭ8.6 Hz), 7.23—7.50 (6H, m), 7.97—8.09 (3H, m), 8.52—8.56 (1H, m), 68.62; H, 5.63; N, 7.84.
8.91—8.93 (1H, m). IR (KBr) cmϪ1: 2933, 1705, 1610, 1516, 1254, 1018,
939, 712. Anal. Calcd for C27H25N3O5: C, 68.78; H, 5.34; N, 8.91. Found: C,
68.43; H, 5.49; N, 8.67.
(b) Using the procedure for preparation of 42, step b, 43 (92% yield)
was prepared from ethyl (E)-2-(3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)-
methoxy]benzyloxyimino}-3-phenylpropanamido)acetate (25) as colorless
crystals. mp 176—177 °C (THF–hexane). 1H-NMR (DMSO-d6) d: 2.45 (3H,
(E)-4-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-

148
Vol. 51, No. 2
s), 3.70—3.80 (4H, m), 5.00 (2H, s), 5.14 (2H, s), 7.03 (2H, d, Jϭ8.4 Hz),
7.34—7.40 (5H, m), 7.47—7.57 (3H, m), 7.59—7.67 (2H, m), 7.92—7.98
(2H, m), 8.28—8.35 (1H, m). IR (KBr) cmϪ1: 3296, 1728, 1643, 1514,
1236, 1014, 692. Anal. Calcd for C29H27N3O6: C, 67.83; H, 5.30; N, 8.18.
Found: C, 67.60; H, 5.41; N, 7.96.
1516, 1248, 1171, 1034, 985, 690. Anal. Calcd for C32H34N2O5: C, 72.98; H,
6.51; N, 5.32. Found: C, 73.02; H, 6.37; N, 5.10.
(E)-3-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-1-indancarboxylic Acid (45) Using the procedure for preparation
of 26, step c, 45 (69% yield) was prepared from 4-[(5-methyl-2-phenyl-1,3-
oxazol-4-yl)methoxy]benzyloxyamine (10a) and 3-oxo-1-indancarboxylic
acid (11l) as colorless crystals. mp 148—149 °C (AcOEt–hexane). 1H-NMR
(CDCl3) d: 2.43 (3H, s), 3.11 (1H, dd, Jϭ8.6, 19.0 Hz), 3.31 (1H, dd, Jϭ4.4,
19.0 Hz), 4.12—4.20 (1H, m), 5.00 (2H, s), 5.16 (2H, s), 7.00 (2H, d,
Jϭ8.6 Hz), 7.28—7.46 (7H, m), 7.50—7.57 (1H, m), 7.68—7.74 (1H, m),
7.96—8.04 (2H, m). IR (KBr) cmϪ1: 2922, 1722, 1514, 1240, 1007, 916,
760, 716. Anal. Calcd for C28H24N2O5: C, 71.78; H, 5.16; N, 5.98. Found: C,
71.71; H, 5.19; N, 5.75.
(E)-4-Phenyl-4-{4-[(2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}butyric Acid (46) (a) Chloromethyl methyl ether (34.2 ml, 450
mmol) was added dropwise to a cold (0 °C) stirred suspension of 4-hydroxy-
benzaldehyde (50.0 g, 409 mmol), potassium carbonate (84.9 g, 614 mmol),
and DMF (150 ml). The whole was stirred at 0 °C for 1 h and at room tem-
perature for additional 11 h, then diluted with 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 THF
(300 ml) and MeOH (50 ml). The solution was cooled to 0 °C, then sodium
borohydride (7.76 g, 205 mmol) was added portionwise. The whole was
stirred at 0 °C for 0.5 h, then quenched by addition of water carefully 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 (2 : 3, v/v) to give 4-(methoxymethoxy)-
benzyl alcohol (14a, 56.7 g, 82%) as a colorless oil. 1H-NMR (CDCl3) d:
3.48 (3H, s), 4.63 (2H, s), 5.18 (2H, s), 7.03 (2H, d, Jϭ8.8 Hz), 7.30 (2H, d,
Jϭ8.8 Hz). IR (neat) cmϪ1: 3388, 2899, 1612, 1512, 1232, 1151, 1078,
1003, 922, 818.
(E)-2,2-Dimethyl-6-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-
benzyloxyimino}-6-phenylhexanoic Acid (44) (a) To a suspension of
lithium aluminum hydride (949 mg, 25.0 mmol) in Et2O (30 ml) was added
an Et2O (15 ml) solution of 2-[2-(methoxycarbonyl)ethyl]-2-phenyl-1,3-
dioxolane41) (21, 5.00 g, 21.1 mmol) at 0 °C under nitrogen. The mixture was
stirred at 0 °C for 0.5 h. The reaction was quenched by addition of water, and
the precipitate was removed by filtration. The filtrate was 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 (2 : 3, v/v) to give 2-(3-hydroxypropyl)-2-phenyl-1,3-
1
dioxolane (22, 3.81 g, 87%) as a colorless oil. H-NMR (CDCl3) d: 1.61—
1.72 (2H, m), 2.02 (2H, t, Jϭ6.4 Hz), 3.63 (2H, t, Jϭ6.3 Hz), 3.74—3.87
(2H, m), 3.95—4.08 (2H, m), 7.24—7.49 (5H, m). IR (neat) cmϪ1: 3390,
2954, 1446, 1190, 1045, 957, 704.
(b) Methanesulfonyl chloride (1.81 ml, 23.4 mmol) was added to a solu-
tion of 2-(3-hydroxypropyl)-2-phenyl-1,3-dioxolane (22, 3.75 g, 18.0 mmol)
and triethylamine (5.05 ml, 36.0 mmol) in AcOEt (100 ml) at 0 °C. The mix-
ture was stirred for 0.5 h, then washed with brine, dried over magnesium sul-
fate, and concentrated in vacuo to leave an oil. The oil was dissolved in ace-
tone (100 ml), then sodium iodide (5.40 g, 36.0 mmol) was added to the so-
lution. The whole was stirred at 60 °C for 2 h. After evaporation of the sol-
vent, the residue was dissolved in water and extracted with AcOEt. The ex-
tract was washed with brine, dried over magnesium sulfate, and concentrated
in vacuo to give 2-(3-iodopropyl)-2-phenyl-1,3-dioxolane (23, 5.41 g, 94%)
as crystals. Recrystallization from AcOEt–hexane gave colorless crystals.
mp 71—73 °C. 1H-NMR (CDCl3) d: 1.83—2.05 (4H, m), 3.17 (2H, t,
Jϭ6.7 Hz), 3.69—3.86 (2H, m), 3.93—4.11 (2H, m), 7.28—7.48 (5H, m).
IR (KBr) cmϪ1: 2885, 1444, 1227, 1039, 899, 704. Anal. Calcd for
C12H15O2I: C, 45.30; H, 4.75. Found: C, 45.39; H, 4.74.
(c) n-Butyllithium (1.6 M solution in hexane, 2.16 ml, 3.46 mmol) was
added dropwise to a cold (Ϫ20 °C) stirred solution of diisopropylamine
(0.529 ml, 3.77 mmol) in THF (5 ml), and the mixture was stirred for 20 min.
The mixture was cooled to Ϫ78 °C, and a THF (5 ml) solution of methyl
isobutyrate (0.397 ml, 3.46 mmol) was added dropwise over a period of
0.5 h. The whole was stirred at Ϫ78 °C for 20 min, then 2-(3-iodopropyl)-2-
phenyl-1,3-dioxolane (23, 1.00 g, 3.14 mmol) and HMPA (0.602 ml, 3.46
mmol) were added. The mixture was stirred at Ϫ40 °C for 3 h. The reaction
was quenched by addition of dil. 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 acetone (30 ml), then 1 M
H2SO4 (10 ml) was added to the solution. The whole was refluxed for 3 h,
then diluted with AcOEt, washed with water, brine, dried over magnesium
sulfate, and concentrated in vacuo. The residue was chromatographed on sil-
ica gel with AcOEt–hexane (1 : 7, v/v) to give methyl 2,2-dimethyl-6-oxo-6-
phenylhexanoate (11k, 350 mg, 45%) as a colorless oil. 1H-NMR (CDCl3) d:
1.20 (6H, s), 1.55—1.80 (4H, m), 2.96 (2H, t, Jϭ6.8 Hz), 3.65 (3H, s),
7.41—7.61 (3H, m), 7.92—8.02 (2H, m). IR (neat) cmϪ1: 2951, 1732, 1687,
1449, 1244, 1047, 692.
(b) Diethyl azodicarboxylate (40% in toluene, 142 g, 325 mmol) was
added dropwise to a stirred solution of 4-(methoxymethoxy)benzyl alcohol
(14a, 50.0 g, 297 mmol), N-hydroxyphthalimide (44.1 g, 270 mmol), and
triphenylphosphine (83.7 g, 319 mmol) in THF (900 ml) at room temperature
under nitrogen. The reaction was completed within 1 h. After evaporation of
the solvent, the residue was chromatographed on silica gel with AcOEt–
hexane (1 : 1, v/v) to remove triphenylphosphine oxide. The obtained crys-
tals were washed with solvent (AcOEt : hexaneϭ1 : 5). The crystals were
dissolved in EtOH (50 ml) and THF (200 ml), then hydrazine monohydrate
(33.7 ml, 694 mmol) was added dropwise. The whole was refluxed for 3 h,
then cooled to room temperature, diluted with aqueous potassium carbonate
and extracted with AcOEt. The extract was washed with brine, dried over
magnesium sulfate, and concentrated in vacuo. To the residue was added
cold (0 °C) isoPr2O, and the crystals were removed by filtration. The filtrate
was concentrated in vacuo to give crude [4-(methoxymethoxy)benzyloxy]-
1
amine (16a, 28.9 g, 58%) as a colorless oil. H-NMR (CDCl3) d: 3.48 (3H,
s), 4.63 (2H, s), 5.18 (2H, s), 7.04 (2H, d, Jϭ8.6 Hz), 7.30 (2H, d,
Jϭ8.6 Hz). IR (neat) cmϪ1: 3315, 2902, 1612, 1508, 1232, 1151, 1078,
1001, 846.
(c) A mixture of crude [4-(methoxymethoxy)benzyloxy]amine (16a, 4.99
g, 27.2 mmol), methyl 4-oxo-4-phenylbutyrate (11b, 5.71 g, 29.7 mmol),
acetic acid (5.10 ml, 89.1 mmol), sodium acetate (4.87 g, 59.4 mmol), and
MeOH (200 ml) was refluxed for 15 h. After evaporation of the half of the
solvent, the mixture was diluted with AcOEt, washed with dil. HCl, brine,
dried over magnesium sulfate, and concentrated in vacuo to leave an oil. The
oil was dissolved in MeOH (5 ml) and THF (50 ml), then 1 M HCl (10 ml)
was added. The whole was refluxed for 3 h. After cooling to room tempera-
ture, the mixture was diluted with water and extracted with AcOEt. The ex-
tract was washed with brine, dried over magnesium sulfate, and concentrated
in vacuo. The residue was chromatographed on silica gel with AcOEt–
hexane (2 : 5, v/v) to give methyl (E)-4-[(4-hydroxybenzyloxy)imino]-4-
phenylbutyrate (17a, 4.24 g, 50%) as a colorless oil. 1H-NMR (CDCl3) d:
2.50—2.59 (2H, m), 3.01—3.10 (2H, m), 3.63 (3H, s), 4.97—5.05 (1H, m),
5.14 (2H, s), 6.82 (2H, d, Jϭ8.8 Hz), 7.25—7.38 (5H, m), 7.59—7.65 (2H,
m). IR (neat) cmϪ1: 3404, 1738, 1714, 1516, 1443, 1211, 1020, 694.
(d) A mixture of 4-(chloromethyl)-2-phenyl-1,3-oxazole (250 mg, 1.29
mmol), methyl (E)-4-[(4-hydroxybenzyloxy)imino]-4-phenylbutyrate (17a,
369 mg, 1.18 mmol), potassium carbonate (325 mg, 2.35 mmol), and DMF
(7 ml) was stirred at room temperature for 17 h, then diluted with water and
extracted with AcOEt. The extract was washed with water, brine, dried over
magnesium sulfate, and concentrated in vacuo. The residue was chro-
matographed on silica gel with AcOEt–hexane (2 : 9, v/v) to give methyl
(E)-4-phenyl-4-{4-[(2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-
(d) Using the procedure for preparation of 26, step c, methyl (E)-2,2-di-
methyl-6-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxy-
imino}-6-phenylhexanoate (47% yield) was prepared from 4-[(5-methyl-2-
phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyamine (10a) and methyl 2,2-di-
1
methyl-6-oxo-6-phenylhexanoate (11k) as a colorless oil. H-NMR (CDCl3)
d: 1.10 (6H, s), 1.35—1.65 (4H, m), 2.44 (3H, s), 2.73 (2H, t, Jϭ7.3 Hz),
3.55 (3H, s), 5.00 (2H, s), 5.15 (2H, s), 7.02 (2H, d, Jϭ8.8 Hz), 7.33—7.48
(8H, m), 7.57—7.63 (2H, m), 7.99—8.05 (2H, m). IR (neat) cmϪ1: 2947,
1732, 1512, 1240, 1009, 694.
(e) Methyl (E)-2,2-dimethyl-6-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-
yl)methoxy]benzyloxyimino}-6-phenylhexanoate (340 mg, 0.629 mmol) was
dissolved in THF (5 ml)–MeOH (5 ml), then 4 M KOH (5 ml) was added. The
whole was refluxed for 1.5 h. After cooling to room temperature, the mixture
was made acidic by addition of dil. HCl and extracted with AcOEt. The ex-
tract was washed with brine, dried over magnesium sulfate, and concentrated
in vacuo. The residue was chromatographed on silica gel with AcOEt–
hexane (1 : 1, v/v) to give 44 (275 mg, 83%) as crystals. Recrystallization
from AcOEt–hexane gave colorless crystals. mp 111—112 °C. 1H-NMR
(CDCl3) d: 1.09 (6H, s), 1.35—1.55 (4H, m), 2.44 (3H, s), 2.73 (2H, t,
Jϭ6.6 Hz), 5.02 (2H, s), 5.15 (2H, s), 7.01 (2H, d, Jϭ8.8 Hz), 7.32—7.47
(8H, m), 7.56—7.62 (2H, m), 7.98—8.04 (2H, m). IR (KBr) cmϪ1: 1714,

February 2003
149
1
1236, 1011, 764, 692.
butyrate (320 mg, 58%) as a colorless oil. H-NMR (CDCl3) d: 2.50—2.60
(2H, m), 3.02—3.11 (2H, m), 3.62 (3H, s), 5.10 (2H, s), 5.17 (2H, s), 7.01
(2H, d, Jϭ8.8 Hz), 7.32—7.40 (5H, m), 7.41—7.49 (3H, m), 7.60—7.66
(2H, m), 7.74 (1H, s), 8.03—8.09 (2H, m). IR (neat) cmϪ1: 2949, 1738,
1512, 1246, 1024, 716, 692.
(b) Using the procedure for preparation of 42, step b, 50 (75% yield)
was prepared from methyl (E)-4-{4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)-
methoxy]benzyloxyimino}-4-phenylbutyrate as colorless crystals. mp 99—
100 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 2.53 (3H, s), 2.54—2.63 (2H,
m), 3.01—3.11 (2H, m), 5.17 (2H, s), 5.18 (2H, s), 7.04 (2H, d, Jϭ8.8 Hz),
7.32—7.45 (8H, m), 7.60—7.66 (2H, m), 7.86—7.92 (2H, m). IR (KBr)
cmϪ1: 2926, 1716, 1610, 1514, 1240, 1020, 926, 760, 692. Anal. Calcd for
C28H26N2O4S: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.97; H, 5.42; N, 5.65.
(E)-4-(4-{[2-(2-Furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyloxy-
imino)-4-phenylbutyric Acid (51) (a) Using the procedure for prepara-
tion of 46, step d, methyl (E)-4-(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]-
methoxy}benzyloxyimino)-4-phenylbutyrate (67% yield) was prepared from
4-(chloromethyl)-2-(2-furyl)-5-methyl-1,3-oxazole and methyl (E)-4-[(4-hy-
(e) Using the procedure for preparation of 42, step b, 46 (87% yield)
was prepared from methyl (E)-4-phenyl-4-{4-[(2-phenyl-1,3-oxazol-4-yl)-
methoxy]benzyloxyimino}butyrate as colorless crystals. mp 144—145 °C
(AcOEt–hexane). 1H-NMR (CDCl3) d: 2.55—2.64 (2H, m), 3.02—3.11
(2H, m), 5.09 (2H, s), 5.17 (2H, s), 7.01 (2H, d, Jϭ8.4 Hz), 7.33—7.40 (5H,
m), 7.42—7.48 (3H, m), 7.60—7.66 (2H, m), 7.73 (1H, s), 8.02—8.08 (2H,
m). IR (KBr) cmϪ1: 2931, 1720, 1610, 1512, 1252, 1180, 1018, 984, 714.
Anal. Calcd for C27H24N2O5: C, 71.04; H, 5.30; N, 6.14. Found: C, 71.01; H,
5.33; N, 6.17.
(E)-4-Phenyl-4-{4-[(2-phenyl-1,3-thiazol-4-yl)methoxy]benzyloxy-
imino}butyric Acid (47) (a) Using the procedure for preparation of 46,
step d, methyl (E)-4-phenyl-4-{4-[(2-phenyl-1,3-thiazol-4-yl)methoxy]ben-
zyloxyimino}butyrate (63% yield) was prepared from 4-(chloromethyl)-2-
phenyl-1,3-thiazole and methyl (E)-4-[(4-hydroxybenzyloxy)imino]-4-phenyl-
1
droxybenzyloxy)imino]-4-phenylbutyrate (17a) as a colorless oil. H-NMR
(CDCl3) d: 2.42 (3H, s), 2.50—2.59 (2H, m), 3.01—3.11 (2H, m), 3.62 (3H,
s), 5.00 (2H, s), 5.16 (2H, s), 6.51—6.54 (1H, m), 6.95—7.02 (3H, m),
7.28—7.40 (5H, m), 7.52—7.55 (1H, m), 7.59—7.66 (2H, m). IR (neat)
cmϪ1: 2951, 1738, 1512, 1238, 1012, 754.
(b) Using the procedure for preparation of 42, step b, 51 (79% yield)
was prepared from methyl (E)-4-(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]-
methoxy}benzyloxyimino)-4-phenylbutyrate as colorless crystals. mp 124—
125 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 2.41 (3H, s), 2.54—2.63 (2H,
m), 3.01—3.10 (2H, m), 4.99 (2H, s), 5.16 (2H, s), 6.50—6.54 (1H, m),
6.96—7.03 (3H, m), 7.30—7.40 (5H, m), 7.52—7.54 (1H, m), 7.60—7.65
(2H, m). IR (KBr) cmϪ1: 2929, 1724, 1612, 1512, 1250, 1018, 982, 750.
Anal. Calcd for C26H24N2O6: C, 67.82; H, 5.25; N, 6.08. Found: C, 67.67; H,
5.29; N, 5.97.
(E)-4-(4-{[5-Methyl-2-(2-thienyl)-1,3-oxazol-4-yl]methoxy}benzyloxy-
imino)-4-phenylbutyric Acid (52) (a) Using the procedure for preparation
of 46, step d, methyl (E)-4-(4-{[5-methyl-2-(2-thienyl)-1,3-oxazol-4-yl]-
methoxy}benzyloxyimino)-4-phenylbutyrate (63% yield) was prepared from
4-(chloromethyl)-5-methyl-2-(2-thienyl)-1,3-oxazole and methyl (E)-4-[(4-
hydroxybenzyloxy)imino]-4-phenylbutyrate (17a) as a colorless oil. 1H-
NMR (CDCl3) d: 2.41 (3H, s), 2.50—2.60 (2H, m), 3.02—3.11 (2H, m),
3.63 (3H, s), 4.98 (2H, s), 5.16 (2H, s), 6.99 (2H, d, Jϭ8.8 Hz), 7.10 (1H,
dd, Jϭ3.6, 5.0 Hz), 7.32—7.42 (6H, m), 7.59—7.66 (3H, m). IR (neat)
cmϪ1: 2949, 1738, 1512, 1238, 1174, 1011, 725, 696.
(b) Using the procedure for preparation of 42, step b, 52 (88% yield)
was prepared from methyl (E)-4-(4-{[5-methyl-2-(2-thienyl)-1,3-oxazol-4-
yl]methoxy}benzyloxyimino)-4-phenylbutyrate as colorless crystals. mp
142—143 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 2.41 (3H, s), 2.54—
2.63 (2H, m), 3.01—3.10 (2H, m), 4.97 (2H, s), 5.16 (2H, s), 6.99 (2H, d,
Jϭ8.8 Hz), 7.09 (1H, dd, Jϭ3.6, 5.0 Hz), 7.32—7.42 (6H, m), 7.60—7.65
(3H, m). IR (KBr) cmϪ1: 2929, 1724, 1512, 1248, 982, 723. Anal. Calcd for
C26H24N2O5S: C, 65.53; H, 5.08; N, 5.88. Found: C, 65.56; H, 4.91; N, 5.75.
(E)-4-{4-[2-(Methyl-2-pyridylamino)ethoxy]benzyloxyimino}-4-
phenylbutyric Acid (53) (a) Using the procedure for preparation of 29,
step b, 4-[2-(methyl-2-pyridylamino)ethoxy]benzyl alcohol (5c, 94% yield)
was prepared from 4-[2-(methyl-2-pyridylamino)ethoxy]benzaldehyde (4c)
as a colorless oil. 1H-NMR (CDCl3) d: 3.15 (3H, s), 3.98 (2H, t, Jϭ5.5 Hz),
4.19 (2H, t, Jϭ5.5 Hz), 4.61 (2H, d, Jϭ5.4 Hz), 6.50—6.59 (2H, m), 6.89
(2H, d, Jϭ8.8 Hz), 7.27 (2H, d, Jϭ8.8 Hz), 7.40—7.50 (1H, m), 8.13—8.18
(1H, m). IR (neat) cmϪ1: 3325, 2931, 1601, 1504, 1246, 1007, 770.
(b) Using the procedures for preparation of 29, steps c, d, and e, 53 (41%
yield) was prepared from 4-[2-(methyl-2-pyridylamino)ethoxy]benzyl alco-
hol (5c) and (E)-4-(hydroxyimino)-4-phenylbutyrate [(E)-7a] as a colorless
oil. 1H-NMR (CDCl3) d: 2.51—2.62 (2H, m), 3.00—3.09 (2H, m), 3.13
(3H, s), 3.97 (2H, t, Jϭ5.6 Hz), 4.19 (2H, t, Jϭ5.6 Hz), 5.14 (2H, s), 6.50—
6.59 (2H, m), 6.87 (2H, d, Jϭ8.8 Hz), 7.24—7.51 (6H, m), 7.59—7.65 (2H,
m), 8.13—8.18 (1H, m). IR (neat) cmϪ1: 2929, 1732, 1608, 1504, 1423,
1246, 770. Anal. Calcd for C25H27N3O4_3/4AcOEt: C, 67.32; H, 6.66; N,
8.41. Found: C, 67.20; H, 6.63; N, 8.59.
1
butyrate (17a) as a colorless oil. H-NMR (CDCl3) d: 2.50—2.60 (2H, m),
3.02—3.11 (2H, m), 3.62 (3H, s), 5.17 (2H, s), 5.28 (2H, s), 7.02 (2H, d,
Jϭ8.8 Hz), 7.31—7.49 (9H, m), 7.59—7.65 (2H, m), 7.93—7.99 (2H, m).
IR (neat) cmϪ1: 2949, 1738, 1610, 1512, 1242, 1003, 766, 692.
(b) Using the procedure for preparation of 42, step b, 47 (90% yield)
was prepared from methyl (E)-4-phenyl-4-{4-[(2-phenyl-1,3-thiazol-4-yl)-
methoxy]benzyloxyimino}butyrate as colorless crystals. mp 104—105 °C
(AcOEt–hexane). 1H-NMR (CDCl3) d: 2.55—2.64 (2H, m), 3.02—3.11
(2H, m), 5.17 (2H, s), 5.28 (2H, s), 7.02 (2H, d, Jϭ8.8 Hz), 7.24—7.51 (9H,
m), 7.58—7.66 (2H, m), 7.91—7.99 (2H, m). IR (KBr) cmϪ1: 2929, 1726,
1610, 1514, 1250, 1016, 980, 762, 694. Anal. Calcd for C27H24N2O4S: C,
68.62; H, 5.12; N, 5.93. Found: C, 68.49; H, 5.09; N, 5.76.
(E)-4-Phenyl-4-{4-[(3-phenylisoxazol-5-yl)methoxy]benzyloxyimino}-
butyric Acid (48) (a) Using the procedure for preparation of 46, step
d, methyl (E)-4-phenyl-4-{4-[(3-phenylisoxazol-5-yl)methoxy]benzyloxy-
imino}butyrate (62% yield) was prepared from 5-(chloromethyl)-3-phenyl-
isoxazole and methyl (E)-4-[(4-hydroxybenzyloxy)imino]-4-phenylbutyrate
(17a) as a colorless oil. 1H-NMR (CDCl3) d: 2.50—2.60 (2H, m), 3.02—
3.11 (2H, m), 3.62 (3H, s), 5.17 (2H, s), 5.22 (2H, s), 6.66 (1H, s), 6.99 (2H,
d, Jϭ8.8 Hz), 7.34—7.49 (8H, m), 7.59—7.65 (2H, m), 7.78—7.84 (2H, m).
IR (neat) cmϪ1: 2949, 1738, 1612, 1508, 1240, 1026, 770, 694.
(b) Using the procedure for preparation of 42, step b, 48 (97% yield) was
prepared from methyl (E)-4-phenyl-4-{4-[(3-phenylisoxazol-5-yl)methoxy]-
benzyloxyimino}butyrate as colorless crystals. mp 96—97 °C (AcOEt–
hexane). 1H-NMR (CDCl3) d: 2.55—2.64 (2H, m), 3.02—3.11 (2H, m),
5.17 (2H, s), 5.21 (2H, s), 6.65 (1H, s), 6.99 (2H, d, Jϭ8.8 Hz), 7.29—7.48
(8H, m), 7.59—7.65 (2H, m), 7.77—7.84 (2H, m). IR (KBr) cmϪ1: 2927,
1707, 1614, 1512, 1244, 1011, 768, 694. Anal. Calcd for C27H24N2O5: C,
71.04; H, 5.30; N, 6.14. Found: C, 71.18; H, 5.31; N, 6.00.
(E)-4-Phenyl-4-{4-[(5-phenylisoxazol-3-yl)methoxy]benzyloxyimino}-
butyric Acid (49) (a) Using the procedure for preparation of 46, step
d, methyl (E)-4-phenyl-4-{4-[(5-phenylisoxazol-3-yl)methoxy]benzyloxy-
imino}butyrate (63% yield) was prepared from 3-(chloromethyl)-5-phenyl-
isoxazole and methyl (E)-4-[(4-hydroxybenzyloxy)imino]-4-phenylbutyrate
(17a) as a colorless oil. 1H-NMR (CDCl3) d: 2.50—2.59 (2H, m), 3.01—
3.11 (2H, m), 3.62 (3H, s), 5.16 (2H, s), 5.21 (2H, s), 6.66 (1H, s), 7.01 (2H,
d, Jϭ8.8 Hz), 7.34—7.53 (8H, m), 7.57—7.65 (2H, m), 7.74—7.82 (2H, m).
IR (neat) cmϪ1: 2949, 1738, 1612, 1512, 1242, 1020, 766, 692.
(b) Using the procedure for preparation of 42, step b, 49 (80% yield) was
prepared from methyl (E)-4-phenyl-4-{4-[(5-phenylisoxazol-3-yl)methoxy]-
benzyloxyimino}butyrate as colorless crystals. mp 100—101 °C (AcOEt–
hexane). 1H-NMR (CDCl3) d: 2.54—2.64 (2H, m), 3.02—3.11 (2H, m),
5.17 (2H, s), 5.21 (2H, s), 6.65 (1H, s), 7.01 (2H, d, Jϭ8.8 Hz), 7.32—7.50
(8H, m), 7.57—7.66 (2H, m), 7.75—7.81 (2H, m). IR (KBr) cmϪ1: 2927,
1701, 1610, 1514, 1454, 1234, 1012, 766, 690. Anal. Calcd for C27H24N2O5:
C, 71.04; H, 5.30; N, 6.14. Found: C, 70.99; H, 5.22; N, 6.13.
(E)-4-{4-[(5-Methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzyloxy-
imino}-4-phenylbutyric Acid (50) (a) Using the procedure for prepara-
tion of 46, step d, methyl (E)-4-{4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)-
methoxy]benzyloxyimino}-4-phenylbutyrate (71% yield) was prepared from
4-(chloromethyl)-5-methyl-2-phenyl-1,3-thiazole and methyl (E)-4-[(4-hy-
(E)-4-{4-[2-(Methyl-2-pyrimydylamino)ethoxy]benzyloxyimino}-4-
phenylbutyric Acid (54) (a) Using the procedure for preparation of 29,
step b, 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzyl alcohol (5d, 91%
yield) was prepared from 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzalde-
hyde (4d) as colorless crystals. mp 73—74 °C (AcOEt–hexane). 1H-NMR
(CDCl3) d: 3.29 (3H, s), 3.98—4.05 (2H, m), 4.17—4.24 (2H, m), 4.61 (2H,
d, Jϭ6.0 Hz), 6.48 (1H, t, Jϭ4.8 Hz), 6.90 (2H, d, Jϭ8.6 Hz), 7.27 (2H, d,
Jϭ8.6 Hz), 8.31 (2H, d, Jϭ4.8 Hz). IR (KBr) cmϪ1: 2938, 1587, 1529, 1410,
1240, 1036, 797. Anal. Calcd for C14H17N3O2: C, 64.85; H, 6.61; N, 16.20.
Found: C, 65.09; H, 6.32; N, 16.09.
1
droxybenzyloxy)imino]-4-phenylbutyrate (17a) as a colorless oil. H-NMR
(CDCl3) d: 2.50—2.60 (5H, m), 3.02—3.11 (2H, m), 3.62 (3H, s), 5.17 (2H,
s), 5.18 (2H, s), 7.04 (2H, d, Jϭ8.6 Hz), 7.33—7.51 (8H, m), 7.58—7.66
(2H, m), 7.85—7.93 (2H, m). IR (neat) cmϪ1: 2949, 1738, 1612, 1512,
(b) Using the procedures for preparation of 29, steps c and d, methyl (E)-

150
Vol. 51, No. 2
4-{4-[2-(methyl-2-pyrimydylamino)ethoxy]benzyloxyimino}-4-phenylbu-
chromatographed on silica gel with AcOEt–hexane (1 : 4, v/v) to give 4-
tyrate (51% yield) was prepared from 4-[2-(methyl-2-pyrimidylamino)- (tert-butyldimethylsilyloxy)benzyl alcohol (14b, 27.7 g, 79%) as a colorless
ethoxy]benzyl alcohol (5d) and methyl (E)-4-(hydroxyimino)-4-phenylbu-
tyrate [(E)-7a] as a dark-red oil. H-NMR (CDCl3) d: 2.49—2.58 (2H, m),
3.00—3.09 (2H, m), 3.30 (3H, s), 3.62 (3H, s), 4.02 (2H, t, Jϭ5.7 Hz), 4.21 1261, 916, 839, 781.
oil. 1H-NMR (CDCl3) d: 0.19 (6H, s), 0.98 (9H, s), 4.61 (2H, s), 6.83 (2H, d,
1
Jϭ8.4 Hz), 7.23 (2H, d, Jϭ8.4 Hz). IR (neat) cmϪ1: 3323, 2930, 1610, 1510,
(2H, t, Jϭ5.7 Hz), 5.14 (2H, s), 6.48 (1H, t, Jϭ4.8 Hz), 6.90 (2H, d,
Jϭ8.4 Hz), 7.29—7.38 (5H, m), 7.59—7.65 (2H, m), 8.31 (2H, d,
(b) Diethyl azodicarboxylate (40% in toluene, 54.0 g, 113 mmol) was
added dropwise to a stirred solution of 4-(tert-butyldimethylsilyloxy)benzyl
Jϭ4.8 Hz). IR (neat) cmϪ1: 2949, 1738, 1589, 1514, 1408, 1248, 1026, 800, alcohol (14b, 27.5 g, 113 mmol), N-hydroxyphthalimide (16.8 g, 103 mmol),
694.
and triphenylphosphine (31.1 g, 118 mmol) in THF (450 ml) at room temper-
(c) Using the procedure for preparation of 29, step e, 54 (92% yield) was ature under nitrogen. The reaction mixture was stirred at room temperature
prepared from methyl (E)-4-{4-[2-(methyl-2-pyrimydylamino)ethoxy]ben- for 18 h. After evaporation of the solvent, the residue was diluted with
zyloxyimino}-4-phenylbutyrate as colorless crystals. mp 72—73 °C
isoPr2O (200 ml). The precipitate was removed by filtration, and the filtrate
(AcOEt–hexane). 1H-NMR (CDCl3) d: 2.52—2.61 (2H, m), 3.00—3.09 was concentrated in vacuo. The residue was chromatographed on silica gel
(2H, m), 3.25 (3H, s), 4.01 (2H, t, Jϭ5.5 Hz), 4.22 (2H, t, Jϭ5.5 Hz), 5.14 with AcOEt–hexane–toluene (1 : 10 : 10, v/v) to give N-[4-(tert-butyl-
(2H, s), 6.49 (1H, t, Jϭ4.8 Hz), 6.88 (2H, d, Jϭ8.4 Hz), 7.28—7.38 (5H, m),
dimethylsilyloxy)benzyloxy]phthalimide (15a, 17.4 g, 43%) as crystals. Re-
7.59—7.65 (2H, m), 8.33 (2H, d, Jϭ4.8 Hz). IR (KBr) cmϪ1: 2935, 1713, crystallization from AcOEt–hexane gave colorless crystals. mp 76—77 °C.
1593, 1556, 1514, 1410, 1250, 984, 797. Anal. Calcd for C24H26N4O4: C, 1H-NMR (CDCl3) d: 0.17 (6H, s), 0.96 (9H, s), 5.14 (2H, s), 6.83 (2H, d,
66.34; H, 6.03; N, 12.89. Found: C, 66.49; H, 6.20; N, 12.70.
Jϭ8.6 Hz), 7.40 (2H, d, Jϭ8.6 Hz), 7.70—7.84 (4H, m). IR (KBr) cmϪ1
:
(E)-4-{4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyloxy-
2927, 1722, 1512, 1257, 912, 698. Anal. Calcd for C21H25NO4Si: C, 65.77;
imino}-4-phenylbutyric Acid (55) (a) Sodium hydride (60% in oil, H, 6.57; N, 3.65. Found: C, 65.89; H, 6.48; N, 3.91.
649 mg, 16.2 mmol) was added portionwise to a solution of 2-(5-methyl-2-
(c) Hydrazine monohydrate (1.25 ml, 25.8 mmol) was added dropwise to a
phenyl-1,3-oxazol-4-yl)ethanol (3.00 g, 14.8 mmol) in DMF (60 ml) at room solution of N-[4-(tert-butyldimethylsilyloxy)benzyloxy]phthalimide (15a,
temperature under nitrogen. The mixture was stirred at room temperature for 5.00 g, 12.9 mmol) in THF (40 ml) and EtOH (10 ml) at room temperature.
1 h. A DMF (15 ml) solution of 4-fluorobenzaldehyde (2.02 g, 16.2 mmol) The whole was heated at 60 °C for 1 h, then cooled to room temperature, di-
was added dropwise to the mixture. The whole was stirred at room tempera- luted with aqueous potassium carbonate and extracted with AcOEt. The ex-
ture for 12 h. The mixture was poured onto ice (50 g), then the solvent was tract was washed with brine, dried over magnesium sulfate, and concentrated
evaporated in vacuo. The residue was diluted with AcOEt, washed with in vacuo to give crude [4-(tert-butyldimethylsilyloxy)benzyloxy]amine (16b,
water, brine, dried over magnesium sulfate, and concentrated in vacuo. The 3.15 g, 95%) as a colorless oil. 1H-NMR (CDCl3) d: 0.19 (6H, s), 0.98 (9H,
residue was chromatographed on silica gel with AcOEt–hexane (1 : 4, v/v) to s), 4.62 (2H, s), 5.20—5.50 (2H, br), 6.83 (2H, d, Jϭ8.6 Hz), 7.24 (2H, d,
leave an oil. The oil was dissolved in THF (20 ml)–MeOH (20 ml), then Jϭ8.6 Hz). IR (neat) cmϪ1: 2930, 1608, 1512, 1261, 916, 841, 781.
sodium borohydride (321 mg, 8.49 mmol) was added at 0 °C. The mixture
(d) A mixture of crude [4-(tert-butyldimethylsilyloxy)benzyloxy]amine
was stirred at 0 °C for 1 h, then quenched by addition of water and extracted (16b, 5.31 g, 20.6 mmol), ethyl 6-oxo-6-phenylhexanoate (11d, 6.76 g,
with AcOEt. The extract was washed with brine, dried over magnesium 28.9 mmol), acetic acid (3.54 ml, 61.8 mmol), sodium acetate (3.38 g, 41.2
sulfate, and concentrated in vacuo. The residue was dissolved in toluene mmol), and EtOH (150 ml) was refluxed for 18 h. After evaporation of the
(20 ml), then thionyl chloride (0.888 ml, 12.2 mmol) was added at 0 °C. The solvent, the mixture was diluted with AcOEt, washed with dil. HCl and
mixture was stirred at 0 °C for 1 h, and the solvent was evaporated in vacuo brine, dried over magnesium sulfate, and concentrated in vacuo to leave an
to give 4-{2-[4-(chloromethyl)phenoxy]ethyl}-5-methyl-2-phenyl-1,3-oxa- oil. The oil was dissolved in THF (100 ml), then tetrabutylammonium fluo-
zole (6d, 2.51 g, 52%) as crystals. Recrystallization from AcOEt–hexane ride trihydrate (6.89 g, 21.8 mmol) was added. The whole was stirred at
gave pale-yellow crystals. mp 93—94 °C. 1H-NMR (CDCl3) d: 2.38 (3H, s),
2.98 (2H, d, Jϭ6.7 Hz), 4.25 (2H, d, Jϭ6.7 Hz), 4.56 (2H, s), 6.88 (2H, d,
room temperature for 1 h, then added water and extracted with AcOEt. The
extract was washed with brine, dried over magnesium sulfate, and concen-
Jϭ8.8 Hz), 7.29 (2H, d, Jϭ8.8 Hz), 7.40—7.49 (3H, m), 7.95—8.02 (2H, trated in vacuo. The residue was chromatographed on silica gel with
m). IR (KBr) cmϪ1: 1608, 1516, 1248, 1180, 1026, 710, 689, 667. Anal. AcOEt–hexane (2 : 7, v/v) to give ethyl (E)-6-[(4-hydroxybenzyloxy)imino]-
1
Calcd for C19H18NO2Cl: C, 69.62; H, 5.53; N, 4.27. Found: C, 69.69; H, 6-phenylhexanoate (17b, 5.64 g, 77%) as a colorless oil. H-NMR (CDCl3)
5.61; N, 4.36.
d: 1.22 (3H, t, Jϭ7.1 Hz), 1.45—1.75 (4H, m), 2.23—2.31 (2H, m), 2.73—
(b) Using the procedure for preparation of 29, step d, methyl (E)-4-{4-[2- 2.81 (2H, m), 4.09 (2H, q, Jϭ7.1 Hz), 5.04 (1H, s), 5.13 (2H, s), 6.82 (2H, d,
(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyloxyimino}-4-phenylbu- Jϭ8.2 Hz), 7.25—7.38 (5H, m), 7.58—7.64 (2H, m). IR (neat) cmϪ1: 3390,
tyrate (26% yield) was prepared from methyl (E)-4-(hydroxyimino)-4-
phenylbutyrate [(E)-7a] and 4-{2-[4-(chloromethyl)phenoxy]ethyl}-5-methyl-
2935, 1708, 1518, 1213, 1024, 766, 696.
(e) Using the procedure for preparation of 46, step d, ethyl (E)-6-(4-{[2-
2-phenyl-1,3-oxazole (6d) as colorless crystals. mp 73—74 °C (AcOEt– (2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyloxyimino)-6-phenyl-
hexane). 1H-NMR (CDCl3) d: 2.38 (3H, s), 2.49—2.58 (2H, m), 2.95—3.09 hexanoate (88% yield) was prepared from 4-(chloromethyl)-2-(2-furyl)-5-
(4H, m), 3.61 (3H, s), 4.25 (2H, t, Jϭ6.7 Hz), 5.14 (2H, s), 6.90 (2H, d, methyl-1,3-oxazole and ethyl (E)-6-[(4-hydroxybenzyloxy)imino]-6-phenyl-
Jϭ8.6 Hz), 7.27—7.46 (8H, m), 7.59—7.65 (2H, m), 7.95—8.00 (2H, m). hexanoate (17b) as a colorless oil. 1H-NMR (CDCl3) d: 1.22 (3H, t,
IR (KBr) cmϪ1: 1734, 1514, 1254, 1020, 984, 710, 690. Anal. Calcd for Jϭ7.1 Hz), 1.45—1.75 (4H, m), 2.28 (2H, t, Jϭ7.1 Hz), 2.42 (3H, s), 2.73—
C30H30N2O5: C, 72.27; H, 6.06; N, 5.62. Found: C, 72.24; H, 5.93; N, 5.62.
2.82 (2H, m), 4.09 (2H, q, Jϭ7.1 Hz), 5.00 (2H, s), 5.15 (2H, s), 6.51—6.54
(c) Using the procedure for preparation of 29, step e, 55 (99% yield) (1H, m), 6.95—7.03 (3H, m), 7.30—7.39 (5H, m), 7.53—7.64 (3H, m). IR
was prepared from methyl (E)-4-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)- (neat) cmϪ1: 2931, 1732, 1512, 1238, 1012, 730.
ethoxy]benzyloxyimino}-4-phenylbutyrate as colorless crystals. mp 106—
(f) Using the procedure for preparation of 42, step b, 56 (98% yield)
was prepared from ethyl (E)-6-(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]-
107 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 2.37 (3H, s), 2.53—2.62 (2H,
m), 2.94—3.09 (4H, m), 4.24 (2H, t, Jϭ6.8 Hz), 5.14 (2H, s), 6.89 (2H, d, methoxy}benzyloxyimino)-6-phenylhexanoate as colorless crystals. mp
Jϭ8.4 Hz), 7.29—7.45 (8H, m), 7.59—7.65 (2H, m), 7.94—8.00 (2H, m). 112—113 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 1.35—1.55 (4H, m),
IR (KBr) cmϪ1: 2924, 1728, 1512, 1244, 1026, 775, 690. Anal. Calcd for 2.15—2.23 (2H, m), 2.43 (3H, s), 2.74—2.82 (2H, m), 5.01 (2H, s), 5.15
C29H28N2O5: C, 71.88; H, 5.82; N, 5.78. Found: C, 71.84; H, 5.89; N, 5.64.
(E)-6-(4-{[2-(2-Furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyloxy-
(2H, s), 6.49—6.53 (1H, m), 6.94—7.01 (3H, m), 7.33—7.39 (5H, m),
7.52—7.55 (1H, m), 7.57—7.63 (2H, m). IR (KBr) cmϪ1: 2970, 1713, 1514,
imino)-6-phenylhexanoic Acid (56) (a) tert-Butyldimethylsilyl chloride 1240, 1022, 939, 758. Anal. Calcd for C28H28N2O6: C, 68.84; H, 5.78; N,
(24.1 g, 160 mmol) was added to a stirred mixture of 4-hydroxybenzalde- 5.73. Found: C, 68.58; H, 5.82; N, 5.75.
hyde (17.8 g, 145 mmol), imidazole (19.8 g, 292 mmol), and DMF (100 ml).
(E)-6-(4-{[5-Methyl-2-(2-thienyl)-1,3-oxazol-4-yl]methoxy}benzyloxy-
The whole was stirred at room temperature for 1.5 h, then diluted with water imino)-6-phenylhexanoic Acid (57) (a) Using the procedure for prepara-
and extracted with AcOEt. The extract was washed with brine, dried over tion of 46, step d, ethyl (E)-6-(4-{[5-methyl-2-(2-thienyl)-1,3-oxazol-4-yl]-
magnesium sulfate, and concentrated in vacuo to leave an oil. The oil was methoxy}benzyloxyimino)-6-phenylhexanoate (95% yield) was prepared
dissolved in THF (300 ml) and MeOH (40 ml). The solution was cooled to from 4-(chloromethyl)-5-methyl-2-(2-thienyl)-1,3-oxazole and ethyl (E)-6-
0 °C, then sodium borohydride (11.1 g, 292 mmol) was added portionwise. [(4-hydroxybenzyloxy)imino]-6-phenylhexanoate (17b) as a colorless oil.
The whole was stirred at 0 °C for 0.5 h, then quenched by addition of water 1H-NMR (CDCl3) d: 1.22 (3H, t, Jϭ7.1 Hz), 1.45—1.75 (4H, m), 2.28 (2H,
carefully and extracted with AcOEt. The extract was washed with brine, t, Jϭ7.1 Hz), 2.41 (3H, s), 2.77 (2H, t, Jϭ7.4 Hz), 4.09 (2H, q, Jϭ7.1 Hz),
dried over magnesium sulfate, and concentrated in vacuo. The residue was
4.98 (2H, s), 5.15 (2H, s), 6.99 (2H, d, Jϭ8.8 Hz), 7.09 (1H, dd, Jϭ3.6,

February 2003
151
5.0 Hz), 7.31—7.42 (6H, m), 7.58—7.65 (3H, m). IR (neat) cmϪ1: 2931,
1732, 1512, 1238, 1024, 725, 696.
2678 (2001).
21) Oguchi M., Wada K., Honma H., Tanaka A., Kaneko T., Sakakibara S.,
Ohsumi J., Serizawa N., Fujiwara T., Horikoshi H., Fujita T., J. Med.
Chem., 43, 3052—3066 (2000).
22) Nomura M., Kinoshita S., Satoh H., Maeda T., Murakami K., Tsunoda
M., Miyachi H., Awano K., Bioorg. & Med. Chem. Lett., 9, 533—538
(1999).
23) 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).
24) 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).
(b) Using the procedure for preparation of 42, step b, 57 (92% yield)
was prepared from ethyl (E)-6-(4-{[5-methyl-2-(2-thienyl)-1,3-oxazol-4-yl]-
methoxy}benzyloxyimino)-6-phenylhexanoate as colorless crystals. mp
101—102 °C (AcOEt–hexane). 1H-NMR (CDCl3) d: 1.40—1.55 (4H, m),
2.15—2.24 (2H, m), 2.42 (3H, s), 2.74—2.82 (2H, m), 5.00 (2H, s), 5.16
(2H, s), 6.98 (2H, d, Jϭ8.6 Hz), 7.09 (1H, dd, Jϭ3.6, 5.0 Hz), 7.31—7.42
(6H, m), 7.57—7.67 (3H, m). IR (KBr) cmϪ1: 2929, 1713, 1514, 1240,
1022, 937, 729, 690. Anal. Calcd for C28H28N2O5S: C, 66.65; H, 5.59; N,
5.55. Found: C, 66.52; H, 5.66; N, 5.64.
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; Koji Onishi, Nobuyuki
Amano, Midori Ono, and Fumio Hariguchi for pharmacokinetic analysis;
Akio Takabatake for measurement of powder X-ray crystal diffractions.
25) 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).
26) Shinkai H., Onogi S., Tanaka M., Shibata T., Iwao M., Wakitani K.,
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28) Hulin B., Newton L. S., Lewis D. M., Genereux P. E., Gibbs E. M.,
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