Synthesis and biological activity of novel 5-(omega-aryloxyalkyl)oxazole derivatives as brain-derived neurotrophic factor inducers.

Article abstract of DOI:10.1248/cpb.51.565

A novel series of 5-(omega-aryloxyalkyl)oxazole derivatives was prepared and their effects on brain-derived neurotrophic factor (BDNF) production were evaluated in human neuroblastoma (SK-N-SH) cells. Syntheses were performed by construction of an oxazole

Full text of DOI:10.1248/cpb.51.565

May 2003
Chem. Pharm. Bull. 51(5) 565—573 (2003)
565
w
Synthesis and Biological Activity of Novel 5-( -Aryloxyalkyl)oxazole
Derivatives as Brain-Derived Neurotrophic Factor Inducers
Tsuyoshi MAEKAWA, ,a Nozomu SAKAI,a Hiroyuki TAWADA,c Katsuhito MURASE,b Masatoshi HAZAMA,b
*
a
Yasuo SUGIYAMA,d and Yu MOMOSE
a Medicinal Chemistry Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.:
b Pharmacology Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.:
c Chemical Development Laboratories, Pharmaceutical Production Division, Takeda Chemical Industries, Ltd.; 2–17–85
Jusohonmachi, Yodogawa-ku, Osaka 532–8686, Japan: and d Strategic Product Planning Department, Takeda Chemical
Industries, Ltd.; 4–1–1 Doshomachi, Chuo-ku, Osaka 540–8645, Japan.
Received February 5, 2003; accepted February 12, 2003
A novel series of 5-(w-aryloxyalkyl)oxazole derivatives was prepared and their effects on brain-derived neu-
rotrophic factor (BDNF) production were evaluated in human neuroblastoma (SK-N-SH) cells. Syntheses were
performed by construction of an oxazole ring as a key reaction. Most of the 5-(w-aryloxyalkyl)oxazole derivatives
markedly increased BDNF production in SK-N-SH cells. 4-(4-Chlorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-5-
[3-(2-methoxyphenoxy)propyl]-1,3-oxazole, one of the most promising compounds, showed potent activity
(EC50؍7.9 mM) and the improvement of the motor nerve conduction velocity and the tail-flick response accompa-
nied by a recovery of the brain-derived neurotrophic factor level in the sciatic nerve of streptozotocin (STZ)-dia-
betic rats.
Key words 5-(w-aryloxyalkyl)oxazole; brain-derived neurotrophic factor; diabetic neuropathy; diabetic complication; strepto-
zotocin (STZ)-diabetic rat
Diabetes, obesity, and cardiovascular disease are risk fac- rotrophin-4 (NT-4) that are released from the neuron itself or
tors for mortality and morbidity. The number of people with its target tissues,7) are a small gene family of structurally and
diabetes is growing rapidly and it is now estimated that about functionally related neurotrophic factors. Among these neu-
5% of the population of developed countries is afflicted.1) Di- rotrophins, NGF has been tested the most extensively in ani-
abetes often leads to long-term complications such as neu- mal models of diabetic neuropathy with encouraging re-
ropathy, nephropathy, retinopathy, cataract, and angiopathy. sults.8—11) Recombinant human nerve growth factor (rhNGF)
Among them, diabetic neuropathy is the most prevalent com- was tested in clinical trials for the treatment of patients with
plication of diabetes mellitus in both type 1 and type 2 pa- diabetes.12) However, it has not shown clear efficacy probably
tients. The average prevalence of neuropathy in diabetic pa- because of limited delivery to the nervous system. Based
tients is estimated at 50% approximately.2) The maintenance upon these facts, we hypothesized that one way to treat dia-
of blood glucose at an appropriate level is a good way to pre- betic neuropathy would be to increase the endogenous pro-
vent diabetic complications, because there is a link between duction of neurotrophic factors.
hyperglycemia and the development of the disease.3) The
In the previous paper, Meguro and his colleagues reported
practical control of blood glucose, however, has been difficult that five-membered heteroaryl alkanoic acid derivatives, es-
to achieve the normal level at present. Therefore, agents able pecially w-oxazolylalkanoic acids (1), acted as antidiabetic
to prevent or ameliorate diabetic complications without strict agents promoting the glucose-dependent secretion of insulin
glycemic control are needed. While aldose reductase in- (Chart 1).13) We found that a series of 5-(w-aryloxyalkyl)ox-
hibitors, for example, have been extensively studied,4,5) they azole derivatives (2, Chart 1), prepared in the course of stud-
have had limited effects on the progression of neuropathy; or ies on novel insulin secretagogues, increased the endogenous
been withdrawn from the world markets excepting some production of neurotrophic factors, especially BDNF, both in
countries because of adverse effects. Although positive vitro and in vivo. It is well-known that BDNF supports the
symptoms such as pain can be treated with anticonvulsants or subsets of sensory neurons involved in mechanical pressure
antidepressants, frequent side effects limit their usage for sensation and pain sensation.14) Furthermore, BDNF pro-
chronic pain.
motes the survival of motorneurons, unlike NGF.15) There-
The pathogenesis of diabetic neuropathy is still unclear fore, compounds able to increase the endogenous production
though the disease is recognized to be multifactorial. There of BDNF might be clinically useful in the treatment of dia-
are many candidates of causative factor, including the activa- betic neuropathy.
tion of a polyol pathway, oxidative stress, insufficient blood
supply to the nerves, autoimmune reactions, etc.5) Among
them, a lack of neurotrophic support has been focused on be-
cause of its importance for the nervous system.6) Neu-
rotrophic factors play pivotal roles in maintaining neural phe-
notypes and are already in clinical trials for the treatment of
diseases of the peripheral nervous system. Neurotrophins, in-
cluding nerve growth factor (NGF), brain-derived neu-
rotrophic factor (BDNF), neurotrophin-3 (NT-3) and neu-
We describe in this paper the syntheses and biological ef-
Chart 1
* To whom correspondence should be addressed. e-mail: Maekawa_Tsuyoshi@takeda.co.jp
© 2003 Pharmaceutical Society of Japan

566
Vol. 51, No. 5
fects on diabetic neuropathy of a novel class of 5-(w-aryl- subsequent introduction of an azolyl moiety onto the oxazole
oxyalkyl)oxazole derivatives. The structure–activity relation- ring yielded the desired 5-(w-aryloxyalkyl)oxazoles 13.
ships of these compounds are also discussed.
Biology
Chemistry
In Vitro. Cell Culture Human neuroblastoma cells (SK-
The general synthetic pathways for the preparation of 5- N-SH) were purchased from American Type Culture Collec-
(w-aryloxyalkyl)oxazole derivatives 13 listed in Table 3 are tion (Rockville, MD, U.S.A.). The cells were maintained in
shown in Charts 2 and 3.
Dulbecco’s modified Eagle’s medium (DMEM) supple-
The key intermediates, 2-chlorooxazoles 7, were synthe- mented with 10% (v/v) fetal calf serum. Prior to treatment
sized from the starting acyl chlorides 3 via a six-step process with compounds, 5ϫ104/ml of the cells were seeded into
(Chart 2). The Friedel–Crafts reaction of 3 with chloroben- poly-lysine-coated 48-well dishes at 0.3 ml/well and incu-
zene gave w-(4-chlorobenzoyl)alkanoic acid esters 4. After bated for 8 d.
bromination of 4, subsequent treatment with sodium formate
Measurement of BDNF17) in Culture Supernatant The
in methanol gave the corresponding a-hydroxyketones. In- growth medium was replaced with 0.2 ml of DMEM contain-
troduction of a phenoxycarbonyl moiety to the hydroxy ing 1% (w/v) bovine serum albumin and incubated for an-
group of a-hydroxyketones yielded a-phenoxycarbonyloxy- other 2 d. The collected culture supernatants were kept at
ketones 5. Cyclization of 5 was carried out by a reaction with Ϫ80 °C until the BDNF assay. Human BDNF was measured
ammonium acetate in acetic acid to yield 4-(4-chlorophenyl)- using an enzyme-linked immuno-sorbent assay system built
oxazolones 6. 2-Chlorooxazoles 7, the key intermediates, up with commercial items. Briefly, monoclonal anti-human
were obtained by treatment of 6 with phosphoryl chloride in BDNF antibody (R&D, Minneapolis, MN, U.S.A.) was
the presence of pyridine.
coated on immunoplates at 1 mg/ml, and blocked with a com-
The routes used to synthesize the targeted 5-(w-aryloxy- mercial buffer (Promega, Madison, WI, U.S.A.). The col-
alkyl)oxazole derivatives 13 from the key intermediates 7 are lected culture supernatants were directly applied onto the
shown in Chart 3. Introduction of an azolyl group at the 2- plates, which were incubated at room temperature for 2 h.
position of the oxazole ring was achieved by reacting the 2- After repeated washes, the plates were incubated with the
chlorooxazoles 7 with the corresponding azoles in the pres- secondary anti-BDNF antibody (Promega) and successively
ence of potassium carbonate in N,N-dimethylformamide with HRP-conjugated anti-goat IgG antibody (Promega).
(DMF) to give the desired w-(2-azolyloxazolyl)alkanoic acid Color development was achieved by adding substrate solu-
esters 8 as shown in Table 1 (method A). A 2-phenyloxazole tion (TMB peroxidase EIA substrate kit, Bio-Rad, Richmond,
derivative (8d) was prepared by the Suzuki coupling reaction CA, U.S.A.). The BDNF concentration was determined by
of 7a with phenylboronic acid (method A). Introduction of measuring absorbance at 450 nm. The concentration required
the azolyl moiety at C-2 of the oxazole was also achieved via for a 50% increase, the EC50, was obtained from regression
the corresponding carboxylic acids 10 (method B). After hy- analysis.
drolysis of 7, the residual carboxylic acid derivatives 10 were
In Vivo. Animals and Experimental Design Six-week-
treated with various azoles and subsequently esterified to old male Sprague Dawley rats (Clea Japan, Inc., Tokyo,
give w-(2-azolyloxazolyl)alkanoic acid esters 8. Reduction Japan) were intravenously injected with 70 mg/kg of strepto-
of 8 with lithium aluminum hydride (LAH) afforded the cor- zotocin (STZ) (Sigma, St. Louis, MO, U.S.A.). Three weeks
responding alcohols 9 (Table 2), which were transformed later, they were divided into 3 groups so that mean body
into the desired 5-(w-aryloxyalkyl)oxazole derivatives 13 by weights and blood glucose levels were similar among the
the Mitsunobu-type reaction16) with the phenols possessing groups. In the treatment group, 10 mg/kg/d of compound 13a
various substituents. Alternatively the 5-(w-aryloxyalkyl)ox- suspended in 0.5% (w/v) methylcellulose at 5 ml/kg was
azoles 13 were also prepared by method C. Reduction of 7 orally administered for 4 weeks. For the untreated STZ-dia-
with diisobutyl aluminum hydride (DIBAL-H) afforded the betic rats and normal rats, only 0.5% (w/v) methylcellulose
corresponding alcohols 11. Conversion of the hydroxy group was given.
into the aryloxy group by the Mitsunobu-type reaction and
Nerve Conduction Velocity At the end of the treatment
Chart 2

May 2003
567
Chart 3
Table 1. Physical Data and Yields of w-(5-Oxazolyl)alkanoates 8
Compd.
Ar
n
R
Methoda)
B
Yield (%)
76c)
mp (°C)
70—71
Recryst. solvente)
A-H
8a
2
Et
8b
8c
8d
8e
2
2
2
3
Et
Et
B
B
76c)
71c)
88d)
67c)
67—68
99—100
oil
A-IP
A-IP
—
Me
Et
Ab)
B
72—73
A-IP
8f
4
5
Et
Et
A
A
88d)
87d)
93—94
oil
EA-IP
—
8g
a) See Chart 3 and Chemistry section. b) Prepared by the Suzuki coupling reaction. c) Yield based on 10. d) Yield based on 7. e) Aϭacetone, EAϭethyl acetate,
Hϭhexane, IPϭisopropyl ether.

568
Vol. 51, No. 5
Table 2. Physical Data and Yields of w-(5-Oxazolyl)alkyl Alcohols 9
Results and Discussion
The effects on BDNF production of the novel 5-(w-aryl-
oxyalkyl)oxazole derivatives described above are summa-
rized in Table 3. The 2-azolyloxazole derivatives 13a—g
strongly promoted the production. The 2-methylimidazolyl
(13a, EC50ϭ7.9 mM), imidazolyl (13b, EC50ϭ5.7 mM), pyra-
zolyl (13e, EC50ϭ6.5 mM), and benzimidazolyl (13g, EC50ϭ
5.1 mM) derivatives were also highly active. On the other
hand, compound 13f with a 1,2,4-triazolyl group at the 2-po-
sition on the oxazole ring exhibited a slight loss of activity
(EC50ϭ13.9 mM). With regard to the substituent of the imida-
zole ring at C2 on the oxazole ring, introduction of a rela-
tively bulky group such as a 2-ethyl (13c, EC50ϭ9.8 mM) or a
2-propyl (13d, EC50ϭ9.7 mM) group resulted in a minor de-
crease in activity. It is worth noting that replacement of the
C2 azolyl moiety by a phenyl group (13h) significantly re-
duced the BDNF level (EC50Ͼ50.0 mM). These findings indi-
cated that an azolyl moiety of the proper size at the 2-posi-
tion on the oxazole ring was necessary for a good effect on
BDNF production by the 5-(w-aryloxyalkyl)oxazole series.
We next directed our attention to a substituent on the ben-
zene ring, which was linked by an oxygen atom with the 5-
alkylene chain of the oxazole ring. Compound 13m with a 2-
methylthio moiety (EC50ϭ11.0 mM), which was very similar
to a 2-methoxy group, showed less activity than compound
13a, whereas replacement of the 2-methoxy group of 13a by
a 2-ethoxy group (13k, EC50ϭ6.5 mM) resulted in retention of
activity. Furthermore, replacement of the methoxy group of
13a by a cyano (13n, EC50ϭ5.5 mM) and a methyl group
(13o, EC50ϭ6.1 mM) slightly increased activity. Removal of
the 2-methoxy group, however, resulted in a reduction of the
BDNF content (13i, EC50ϭ13.1 mM). In addition, compound
Yielda)
(%)
mp
(°C)
Recryst.
solventc)
Compd.
Ar
n
9a
9b
9c
2
2
2
77
130—131
114—115
75—76
A-IP
A-IP
E-H
68
29b)
9d
9e
9f
2
2
3
42
82
88
139—140
76—77
ME-IP
E-H
110—111
A-IP
9g
9h
4
5
79
90
94—95
70—71
EA
A-IP
a) Yield based on 8. b) Yield based on 7a (See Experimental). c) Aϭacetone,
Eϭdiethyl ether, EAϭethyl acetate, Hϭhexane, IPϭisopropyl ether, MEϭmethanol.
period, rats were anaesthetized with pentobarbital sodium 13j replaced by a hydroxy group (EC50ϭ36.0 mM) was less
(Dabbott laboratories) by intraperitoneal injection (50 active than compound 13a. Compounds with a relatively
mg/kg). Motor nerve conduction velocity was measured be- bulky group such as an iso-propoxy (13l, EC50ϭ9.4 mM) or
tween sciatic notch and knee in the nerve branch to tibialis an iso-propyl (13p, EC50Ͼ50.0 mM) group exhibited de-
anterior muscle with Neuropack 2 (Nihon Kohden), which is creased activity. It is of note that the position of the substitu-
representative of the whole sciatic nerve in terms of suscepti- tion on the benzene ring greatly influenced potency. The
bility to diabetes and treatment effects. Nerve temperature para-isomer (13r, EC50ϭ6.7 mM) was as active as the corre-
was monitored and regulated between 36.5 and 37.5 °C.
sponding ortho-isomer 13o, whereas the meta-analogue
Tail Flick Response Each animal was gently held and (13q, EC50ϭ10.3 mM) was about 1.7 times less active than
its tail was exposed to the radiant heat of a specialized device 13o. In addition, compounds possessing two substituents
to evoke a tail-flick response (Model 33, IITC Inc. Woodland such as 13s (EC50ϭ46.8 mM) or 13t (EC50ϭ14.8 mM) showed
Hills, CA, U.S.A.), and the latency until the tail flicked was reduced activity compared with the corresponding mono-
automatically recorded.
substituted derivative 13o. These results showed that a
Nerve BDNF Levels At the end of the experiment, the lipophilic substituent of the proper size, especially at the 2-
sciatic nerve was obtained and stored at Ϫ80 °C until further position on the benzene ring, was required for an optimal ef-
analysis. The protein level of BDNF in the sciatic nerve was fect on BDNF production by the 5-(w-aryloxyalkyl)oxazole
determined by enzyme-linked immunosorbent assay (ELISA) derivatives. The length of the methylene chain between the
as reported previously (Inoue et al., 1997). Briefly, the super- oxazole ring and the phenoxy moiety was also investigated.
natants from sciatic nerve homogenates were applied onto Compound 13u (EC50ϭ29.8 mM) with a tetramethylene unit
immunoplates coated with anti-BDNF antibody. After incu- (mϭ4) was about 5-fold less active than compound 13o. As
bation and washes, the plates were incubated with biotiny- compounds 13v (mϭ5, EC50Ͼ50.0 mM) and 13w (mϭ6,
lated anti-BDNF antibody. Then, streptavidin-conjugated b- EC50Ͼ50.0 mM) show, the activity reduced in accordance
galactosidase was added to the plates, to be followed by an with prolonging length of the methylene chain between the
enzymic reaction with the substrate, 4-methylumbelliferyl-b- oxazole ring and the phenoxy group.
D-galactosidase, and the measurement of fluorescence pro-
Compound 13a, one of the most promising compounds,
duced by excitation at 355 nm and emission at 460 nm. The was examined for oral therapeutic effects on diabetic neu-
nonspecific reaction was quantified from a paralleled reac- ropathy in STZ-diabetic rats as a typical type 1 diabetic
tion in non-coated wells and subtraction from the specific an- model. Furthermore, the tissue level of BDNF was evaluated
tibody-coated wells.
after oral administration of 13a. As shown in Table 4, the un-

May 2003
569
Table 3. Physical Data, Yields, and BDNF Production Activities of 5-(w-Aryloxyalkyl)oxazoles 13
BDNF production activity
Yielda)
(%)
mp
(°C)
Recryst.
solventd)
Compd.
Ar
R1
R2
R3
m
EC50 (mM)e)
13a
13b
13c
OMe
OMe
OMe
H
H
H
H
H
H
3
3
3
54
84—85
109—110
78—79
E-H
EA-H
A-IP
7.9
5.7
9.8
34
53b)
13d
13e
OMe
OMe
H
H
H
H
3
3
39b)
51
89—90
A-H
A-H
9.7
6.5
103—104
13f
13g
13h
OMe
OMe
OMe
H
H
H
H
H
H
3
3
3
42
106—107
116—117
88—89
A-H
A-IP
IP-H
13.9
5.1
77b)
36
Ͼ50.0
13i
13j
H
H
H
H
H
3
3
33
76—77
E-H
13.1
36.0
OH
50c)
110—111
A-IP
13k
13l
OEt
OiPr
SMe
H
H
H
H
H
H
3
3
3
57
93
60
96—97
76—77
EA-H
A-IP
A-H
6.5
9.4
13m
118—119
11.0
13n
13o
CN
Me
H
H
H
H
3
3
82
60
136—137
110—111
A-IP
A-IP
5.5
6.1
13p
13q
13r
13s
iPr
H
H
Me
H
H
H
3
3
3
3
80
56
58
49
83—84
62—63
oil
E-IP
A-IP
—
Ͼ50.0
10.3
6.7
H
Me
H
Me
Me
102—104
E-IP
46.8
13t
Me
Me
H
H
Me
H
3
4
39
66
76—77
71—72
A-IP
A-IP
14.8
29.8
13u
13v
Me
Me
H
H
H
H
5
6
66
62
61—62
70—71
E-IP
E-H
Ͼ50.0
Ͼ50.0
13w
a) Yield based on 9. b) Yield based on 12. c) Yield from 13l (See Experimental). d) Aϭacetone, Eϭdiethyl ether, EAϭethyl acetate, Hϭhexane, IPϭisopropyl ether.
e) Concentration required to induce BDNF production by 50%.

570
Vol. 51, No. 5
Table 4. Effects of 13a Treatment on Body Weight, Plasma Glucose, MNCV, Tail-Flick Response and BDNF Level
Body weight
(g)
Plasma glucose
(mg/dl)
MNCV
(m/s)
Tail-flick response
(s)
BDNF
(pg/g wet tissue)
Rat
Treatment
Normal
STZ-diabetic
STZ-diabetic
—
—
13a
470Ϯ36**
294Ϯ24
299Ϯ32
148Ϯ12**
528Ϯ38
588Ϯ125
44.90Ϯ3.70**
36.24Ϯ2.69
42.08Ϯ3.69**
3.99Ϯ0.41
4.54Ϯ0.82
3.25Ϯ0.64**
2.76Ϯ0.62
2.50Ϯ0.49
3.45Ϯ0.47**
Three weeks after injection with STZ-diabetic rats were treated with or without 10 mg/kg/d (p.o.) of 13a for 4 weeks. Data are means and S.D. (nϭ6—8). ** pϽ0.01, com-
pared with untreated STZ-diabetic rats (t-test).
(MgSO4), and concentrated in vacuo to give methyl 4-bromo-5-(4-
treated STZ-diabetic rats showed the significantly reduced
motor nerve conduction velocity (MNCV). They also exhib-
ited the impaired tail-flick response, which is one of the indi-
cators of the function of sensory neurons. Treatment with
chlorophenyl)-5-oxopentanoate (89.5 g, 88%) as a colorless oil. 1H-NMR
(CDCl3) d: 2.3—2.6 (2H, m), 3.71 (3H, s), 5.3—5.4 (1H, m), 7.48 (2H, d,
Jϭ8.5 Hz), 7.98 (2H, d, Jϭ8.5 Hz).
A mixture of methyl 4-bromo-5-(4-chlorophenyl)-5-oxopentanoate (89.5
13a (10 mg/kg/d p.o., for 4 weeks) significantly improved g, 280 mmol) and HCO2Na (76.2 g, 1.12 mol) in MeOH (400 ml) was re-
fluxed for 12 h. After removal of the solvent, the residue was diluted with
water and extracted with AcOEt. The organic layer was washed with water,
dried (MgSO4), and concentrated in vacuo to give an oil. The oil was dis-
solved in tetrahydrofuran (THF) (400 ml) and then pyridine (22.0 g,
both the MNCV and the tail-flick response without changing
the plasma glucose level. The level of nerve BDNF declined
in the untreated STZ-diabetic rats compared with normal
rats, but administration of 13a significantly restored BDNF
production.
278 mmol) was added. After addition of ClCO2Ph (43.8 g, 280 mmol) to the
ice-cooled mixture, the resultant was stirred at room temperature for 1 h.
The reaction mixture was poured into water and extracted with AcOEt. The
organic layer was washed with brine, dried (MgSO4), and concentrated in
vacuo to give the title compound (5a, 61.2 g, 56%) as colorless crystals. mp
97—98 °C (MeOH). 1H-NMR (CDCl3) d: 1.85—2.85 (4H, m), 3.70 (3H, s),
5.93 (1H, dd, Jϭ3, 9 Hz), 7.1—7.45 (5H, m), 7.48 (2H, d, Jϭ7.5 Hz), 8.02
(2H, d, Jϭ7.5 Hz). Anal. Calcd for C19H17ClO6: C, 60.57; H, 4.55. Found: C,
60.81; H, 4.60. Ethyl 7-(4-chlorophenyl)-7-oxo-6-(phenoxycarbonyloxy)-
heptanoate (5c, nϭ4) and ethyl 8-(4-chlorophenyl)-8-oxo-7-(phenoxycar-
bonyloxy)octanoate (5d, nϭ5) were obtained similarly.
In summary, we showed that a series of 5-(w-aryloxy-
alkyl)oxazole derivatives enhance BDNF production in
human neuroblastoma cells. The results of the SAR studies
identified that the azolyl moiety at the 2-position on the oxa-
zole ring and the lipophilic substituent of the proper size, es-
pecially at the 2-position on the benzene ring connected with
the propyloxy-spacer to the oxazole ring, were required for
an optimal effect on BDNF production by the 5-(w-aryloxy-
alkyl)oxazole derivatives. Compound 13a, one of the most
promising compounds, produced on improvement in both the
MNCV and the tail-flick response accompanied by a recov-
ery of the BDNF level in STZ-diabetic rats. These results
suggest that 5-(w-aryloxyalkyl)oxazole derivatives might be
5c: Yield 58% from 4c (a colorless oil). 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jϭ7 Hz), 1.45—2.05 (6H, m), 2.32 (2H, t, Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz),
5.79 (1H, t, Jϭ6 Hz), 7.15—7.45 (5H, m), 7.47 (2H, d, Jϭ8.5 Hz), 7.90 (2H,
d, Jϭ8.5 Hz).
5d: Yield 24% from 4d (a colorless oil). 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jϭ7 Hz), 1.25—1.7 (6H, m), 1.85—2.0 (2H, m), 2.29 (2H, t, Jϭ7.5 Hz),
4.12 (2H, q, Jϭ7 Hz), 5.79 (1H, t, Jϭ6 Hz), 7.15—7.45 (5H, m), 7.48 (2H,
clinically useful in the treatment of diabetic neuropathy. Fur- d, Jϭ8.5 Hz), 7.90 (2H, d, Jϭ8.5 Hz).
ther investigation of this series as a remedy for diabetic neu-
ropathy is underway.
Methyl 6-(4-Chlorophenyl)-6-oxo-5-(phenoxycarbonyloxy)hexanoate
(5b, n؍3) A mixture of methyl adipoyl chloride (3b, 17.9 g, 100 mmol),
aluminum chloride (26.7 g, 200 mmol), and chlorobenzene (33.8 g, 300
mmol) was stirred at room temperature for 2 h, poured into 1 N HCl and ex-
tracted with AcOEt. The extract was washed with brine, dried (MgSO4), and
concentrated in vacuo to give colorless crystals. The crystals were dissolved
in CH2Cl2 (200 ml) and bromine (16.0 g, 100 mmol) was added dropwise to
the solution at room temperature. The reaction mixture was washed succes-
sively with aqueous Na2SO3, saturated aqueous NaHCO3, and water. The or-
ganic layer was separated, dried (MgSO4), and concentrated in vacuo to give
methyl 5-bromo-6-(4-chlorophenyl)-6-oxohexanoate (31.7 g, 95%) as a col-
Experimental
All melting points were determined on a Yanagimoto micro melting point
apparatus, and are uncorrected. The 1H-NMR spectra were recorded on a
Varian Gemini-200 (200 MHz) spectrometer. Chemical shifts are given in d
values (ppm) using tetramethylsilane as an internal standard, and coupling
constants (J) are given in hertz. Elemental Analyses were performed by
Takeda Analytical Research Laboratories, Ltd. and results obtained were
within Ϯ0.4% of the theoretical values. Column chromatography was per-
formed using SiO2 (Merck Kieselgel 60, 70—230 mesh).
Methyl 5-(4-Chlorophenyl)-5-oxopentanoate (4a, n؍2) A mixture of
methyl glutaryl chloride (3a, 57.9 g, 0.352 mol), aluminum chloride (93.9 g,
0.704 mol), and chlorobenzene (158 g, 1.40 mol) was stirred at room temper-
ature for 2 h, poured into 1 N HCl and extracted with ethyl acetate (AcOEt).
The extract was washed with water, dried (MgSO4), and concentrated in
vacuo to give the title compound (4a, 77.0 g, 91%) as colorless crystals. mp
34—35 °C (hexane). 1H-NMR (CDCl3) d: 2.0—2.1 (2H, m), 2.45 (2H, t,
Jϭ7 Hz), 3.03 (2H, t, Jϭ7 Hz), 3.69 (3H, s), 7.44 (2H, d, Jϭ8.5 Hz), 7.91
(2H, d, Jϭ8.5 Hz). Ethyl 7-(4-chlorophenyl)-7-oxoheptanoate (4c, nϭ4) and
ethyl 8-(4-chlorophenyl)-8-oxooctanoate (4d, nϭ5) were obtained similarly.
4c: Yield 97% (a colorless oil). 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jϭ7 Hz), 1.3—1.8 (6H, m), 2.32 (2H, t, Jϭ7 Hz), 2.95 (2H, t, Jϭ7.5 Hz),
4.13 (2H, q, Jϭ7 Hz), 7.44 (2H, d, Jϭ8.5 Hz), 7.90 (2H, d, Jϭ8.5 Hz).
4d: Yield 90% (a colorless oil). 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jϭ7 Hz), 1.2—1.9 (8H, m), 2.2—2.4 (2H, m), 2.93 (2H, t, Jϭ7.5 Hz), 4.13
(2H, q, Jϭ7 Hz), 7.43 (2H, d, Jϭ8.5 Hz), 7.90 (2H, d, Jϭ8.5 Hz).
1
orless oil. H-NMR (CDCl3) d: 1.6—2.05 (2H, m), 2.1—2.3 (2H, m), 2.42
(2H, t, Jϭ7 Hz), 3.68 (3H, s), 5.08 (1H, dd, Jϭ6.5, 8 Hz), 7.47 (2H, d,
Jϭ8.5 Hz), 7.96 (2H, d, Jϭ8.5 Hz).
A mixture of methyl 5-bromo-6-(4-chlorophenyl)-6-oxohexanoate (31.7 g,
95 mmol), HCO2Na (25.8 g, 379 mmol), and MeOH (150 ml) was refluxed
for 12 h. After removal of the solvent, the residue was diluted with water and
extracted with AcOEt. The organic layer was washed with brine, dried
(MgSO4), and concentrated in vacuo to give an oil. The oil was dissolved in
THF (200 ml) and then pyridine (8.27 g, 105 mmol) was added. After addi-
tion of ClCO2Ph (16.4 g, 105 mmol) to the mixture with cooling, the resul-
tant was stirred at room temperature for 1 h. The reaction mixture was
poured into water and extracted with AcOEt. The extract was washed with
brine, dried (MgSO4), and concentrated in vacuo to leave an oil which was
purified by column chromatography on SiO2 (200 g) with AcOEt–hexane
(1 : 4, v/v) to give the title compound (5b, 24.8 g, 63% yield from 3b) as a
1
colorless oil. H-NMR (CDCl3) d: 1.8—2.1 (4H, m), 2.40 (2H, t, Jϭ7 Hz),
3.67 (3H, s), 5.82 (1H, dd, Jϭ4.5, 7.5 Hz), 7.15—7.45 (5H, m), 7.48 (2H, d,
Jϭ9 Hz), 7.91 (2H, d, Jϭ9 Hz).
Methyl 5-(4-Chlorophenyl)-5-oxo-4-(phenoxycarbonyloxy)pentanoate
(5a, n؍2) Bromine (51.1 g, 320 mmol) was added dropwise to a stirred so-
lution of 4a (77.0 g, 320 mmol) in CH2Cl2 (400 ml) at room temperature.
The reaction mixture was washed successively with aqueous Na2SO3, satu-
rated aqueous NaHCO3, and water. The organic layer was separated, dried
Methyl 3-[4-(4-Chlorophenyl)-2-oxo-2,3-dihydro-5-oxazolyl]propionate
(6a, n؍2)
A mixture of 5a (61.2 g, 162 mmol), NH4OAc (62.6 g,
812 mmol), and AcOH (300 ml) was refluxed for 2 h. The reaction mixture
was concentrated, and diluted with water to give the title compound (6a,

May 2003
571
36.3 g, 79%) as colorless crystals. mp 147—148 °C (MeOH). 1H-NMR
(CDCl3) d: 2.71 (2H, t, Jϭ7 Hz), 2.97 (2H, t, Jϭ7 Hz), 3.68 (3H, s), 7.35—
7.5 (4H, m), 9.75 (1H, br s). Anal. Calcd for C13H12ClNO4: C, 55.43; H,
4.29; N, 4.97. Found: C, 55.48; H, 4.37; N, 5.00. Methyl 4-[4-(4-
chlorophenyl)-2-oxo-2,3-dihydro-5-oxazolyl]butyrate (6b, nϭ3), ethyl 5-[4-
(4-chlorophenyl)-2-oxo-2,3-dihydro-5-oxazolyl]pentanoate (6c, nϭ4), and
ethyl 6-[4-(4-chlorophenyl)-2-oxo-2,3-dihydro-5-oxazolyl]hexanoate (6d,
nϭ5) were obtained similarly.
General Procedure for Method B. 3-[2-Chloro-4-(4-chlorophenyl)-5-
oxazolyl]propionic Acid (10a, n؍2) To an ice-cooled suspension of 7a
(56.6 g, 189 mmol) in EtOH (300 ml) was added dropwise 1 N NaOH
(226 ml). After stirring at room temperature for 1 h, the reaction mixture was
poured into ice-water and acidified with 6 N HCl (40 ml) to give the title
compound (10a, 51.6 g, 96%) as colorless crystals. mp 167—168 °C
1
(AcOEt). H-NMR (CDCl3) d: 2.81 (2H, t, Jϭ7 Hz), 3.20 (2H, t, Jϭ7 Hz),
7.41 (2H, d, Jϭ8.5 Hz), 7.58 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
C12H9Cl2NO3: C, 50.38; H, 3.17; N, 4.90. Found: C, 50.43; H, 3.16; N, 4.96.
4-[2-Chloro-4-(4-chlorophenyl)-5-oxazolyl]butyric acid (10b, nϭ3) was
similarly obtained from 7b in 76% yield. mp 150—151 °C (acetone–
6b: Yield 69%. mp 121—122 °C (acetone–isoPr2O). 1H-NMR (CDCl3) d:
1.9—2.1 (2H, m), 2.41 (2H, t, Jϭ7 Hz), 2.71 (2H, t, Jϭ7 Hz), 3.65 (3H, s),
7.34 (2H, d, Jϭ9 Hz), 7.43 (2H, d, Jϭ9 Hz). Anal. Calcd for C14H14ClNO4:
C, 56.86; H, 4.77; N, 4.74. Found: C, 56.97; H, 4.77; N, 4.81.
1
AcOEt). H-NMR (CDCl3) d: 2.0—2.2 (2H, m), 2.48 (2H, t, Jϭ7 Hz), 2.94
6c: Yield 71%. mp 143—144 °C (acetone–isoPr2O). 1H-NMR (CDCl3) d:
1.25 (3H t, Jϭ7 Hz), 1.55—1.85 (4H, m), 2.25—2.4 (2H, m), 2.6—2.7 (2H,
m), 4.12 (2H, q, Jϭ7 Hz), 7.31 (2H, d, Jϭ8.5 Hz), 7.42 (2H, d, Jϭ8.5 Hz),
10.05 (1H, br s). Anal. Calcd for C16H18ClNO4: C, 59.35; H, 5.60; N, 4.33.
Found: C, 59.22; H, 5.55; N, 4.38.
(2H, t, Jϭ7 Hz), 7.39 (2H, d, Jϭ8.5 Hz), 7.55 (2H, d, Jϭ8.5 Hz). Anal.
Calcd for C13H11Cl2NO3: C, 52.02; H, 3.69; N, 4.67. Found: C, 52.12; H,
3.48; N, 4.89.
Ethyl 3-[4-(4-Chlorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-5-oxa-
zolyl]propionate (8a) A mixture of 10a (10.0 g, 35 mmol), 2-methylimi-
dazole (17.2 g, 209 mmol), K2CO3 (24.2 g, 175 mmol), and DMF (80 ml)
was stirred at 120—130 °C for 10 h. The reaction mixture was poured into
water and adjusted pH at 6 with 2 N HCl to give colorless crystals. Recrystal-
lization from MeOH gave 3-[4-(4-chlorophenyl)-2-(2-methyl-1H-imidazol-
1-yl)-5-oxazolyl]propionic acid (9.79 g, 84%) as colorless prisms. mp 196—
197 °C. 1H-NMR (dimethyl sulfoxide (DMSO)-d6) d: 2.64 (3H, s), 2.73 (2H,
t, Jϭ7 Hz), 3.19 (2H, t, Jϭ7 Hz), 6.99 (1H, d, Jϭ1.5 Hz), 7.55 (2H, d,
Jϭ8.5 Hz), 7.66 (1H, d, Jϭ1.5 Hz), 7.76 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
C16H14ClN3O3: C, 57.93; H, 4.25; N, 12.67. Found: C, 57.69; H, 4.22; N,
12.69.
6d: Yield 87%. mp 113—114 °C (acetone–isoPr2O). 1H-NMR (CDCl3) d:
1.25 (3H, t, Jϭ7 Hz), 1.3—1.8 (6H, m), 2.29 (2H, t, Jϭ7.5 Hz), 2.63 (2H, t,
Jϭ7.5 Hz), 4.12 (2H, q, Jϭ7 Hz), 7.31 (2H, d, Jϭ8.5 Hz), 7.42 (2H, d,
Jϭ8.5 Hz), 9.91 (1H, br s). Anal. Calcd for C17H20ClNO4: C, 60.45; H, 5.97;
N, 4.15. Found: C, 60.37; H, 5.80; N, 4.17.
Methyl 3-[2-Chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (7a, n؍
2) A mixture of 6a (74.0 g, 263 mmol), phosphoryl chloride (161 g,
1.05 mol), and pyridine (20.8 g, 263 mmol) was stirred at 125 °C for 1.5 h.
The reaction mixture was concentrated, and diluted with ice-water. After
stirring at room temperature for 0.5 h, the resultant was extracted with
AcOEt. The extract was washed with brine, dried (MgSO4), and concen-
trated in vacuo to give the title compound (7a, 57.4 g, 73%) as colorless
A mixture of 3-[4-(4-chlorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-5-ox-
azolyl]propionic acid (500 mg, 1.51 mmol), K2CO3 (310 mg, 2.24 mmol), io-
doethane (350 mg, 2.24 mmol), and DMF (10 ml) was stirred at room tem-
perature for 16 h. The reaction mixture was poured into water and extracted
with AcOEt. The extract was washed with water, dried (MgSO4), and con-
centrated in vacuo to give the title compound (8a, 495 mg, 90%) as colorless
crystals. mp 70—71 °C (acetone–hexane). 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jϭ7 Hz), 2.77 (3H, s), 2.77 (2H, t, Jϭ7.5 Hz), 3.27 (2H, t, Jϭ7.5 Hz), 4.16
(2H, q, Jϭ7 Hz), 7.01 (1H, d, Jϭ1.5 Hz), 7.43 (2H, d, Jϭ8.5 Hz), 7.46 (1H,
d, Jϭ1.5 Hz), 7.66 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C18H18ClN3O3: C,
60.09; H, 5.04; N, 11.68. Found: C, 59.82; H, 4.87; N, 11.70. Compounds
8b, 8c, and 8e were obtained similarly. The yields, recrystallization solvents,
and melting points were listed in Table 1.
1
crystals. mp 71—72 °C (AcOEt–hexane). H-NMR (CDCl3) d: 2.72 (2H, d,
Jϭ7 Hz), 3.18 (2H, d, Jϭ7 Hz), 3.68 (3H, s), 7.37 (2H, d, Jϭ8.5 Hz), 7.58
(2H, d, Jϭ8.5 Hz). Anal. Calcd for C13H11Cl2NO3: C, 52.02; H, 3.69; N,
4.67. Found: C, 52.21; H, 3.68; N, 4.71. Methyl 4-[2-chloro-4-(4-
chlorophenyl)-5-oxazolyl]butyrate (7b, nϭ3), ethyl 5-[2-chloro-4-(4-
chlorophenyl)-5-oxazolyl]pentanoate (7c, nϭ4), and ethyl 6-[2-chloro-4-(4-
chlorophenyl)-5-oxazolyl]hexanoate (7d, nϭ5) were obtained similarly.
7b: Yield 78%. mp 73—74 °C (acetone–isoPr2O). 1H-NMR (CDCl3) d:
1.95—2.15 (2H, m), 2.41 (2H, t, Jϭ7 Hz), 2.92 (2H, t, Jϭ7.5 Hz), 3.67 (3H,
s), 7.40 (2H, d, Jϭ8.5 Hz), 7.56 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
C14H13Cl2NO3: C, 53.52; H, 4.17; N, 4.46. Found: C, 53.71; H, 4.12; N,
4.58.
1
8b: H-NMR (CDCl3) d: 1.25 (3H, t, Jϭ7 Hz), 2.77 (2H, d, Jϭ7.5 Hz),
7c: Yield 78% (a colorless oil). 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jϭ7 Hz), 1.6—1.85 (4H, m), 2.34 (2H, t, Jϭ6.5 Hz), 2.86 (2H, t, Jϭ7 Hz),
4.13 (2H, q, Jϭ7 Hz), 7.39 (2H, d, Jϭ8.5 Hz), 7.53 (2H, d, Jϭ8.5 Hz).
7d: Yield 70% (a colorless oil). 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jϭ7 Hz), 1.3—1.85 (6H, m), 2.31 (2H, t, Jϭ7.5 Hz), 2.85 (2H, t, Jϭ7.5 Hz),
4.13 (2H, q, Jϭ7 Hz), 7.39 (2H, d, Jϭ8.5 Hz), 7.53 (2H, d, Jϭ8.5 Hz).
General Procedure for Method A. Ethyl 5-[4-(4-Chlorophenyl)-2-(2-
methyl-1H-imidazol-1-yl)-5-oxazolyl]pentanoate (8f) A mixture of 7c
(10.0 g, 29.2 mol), 2-methylimidazole (7.20 g, 87.7 mmol), K2CO3 (12.1 g,
87.5 mmol), and DMF (80 ml) was stirred at 120—130 °C for 2 h. The reac-
tion mixture was poured into water and extracted with AcOEt. The extract
was washed with brine, dried (MgSO4), and concentrated in vacuo to give
the title compound (8f, 9.97 g, 88%) as colorless crystals. mp 93—94 °C
(AcOEt–isoPr2O). 1H-NMR (CDCl3) d: 1.25 (3H, t, Jϭ7 Hz), 1.7—1.9 (4H,
m), 2.36 (2H, t, Jϭ7 Hz), 2.77 (3H, s), 2.94 (2H, t, Jϭ7 Hz), 4.13 (2H, q,
Jϭ7 Hz), 7.01 (1H, d, Jϭ1.5 Hz), 7.42 (2H, d, Jϭ8.5 Hz), 7.48 (1H, d,
Jϭ1.5 Hz), 7.60 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C20H22ClN3O3: C, 61.93;
H, 5.72; N, 10.83. Found: C, 62.06; H, 5.72; N, 10.85. Compound 8g was
obtained similarly. The yield was displayed in Table 1.
3.26 (2H, d, Jϭ7.5 Hz), 4.16 (2H, q, Jϭ7 Hz), 7.20 (1H, dd, Jϭ1, 1.5 Hz),
7.43 (2H, d, Jϭ8.5 Hz), 7.58 (1H, t, Jϭ1.5 Hz), 7.65 (2H, d, Jϭ8.5 Hz), 8.23
(1H, t, Jϭ1 Hz), 8.91 (1H, s). Anal. Calcd for C17H16ClN3O3: C, 59.05; H,
4.66; N, 12.15. Found: C, 59.14; H, 4.64; N, 12.22.
8c: 1H-NMR (CDCl3) d: 1.24 (3H, t, Jϭ7 Hz), 2.82 (2H, t, Jϭ7.5 Hz),
3.30 (2H, t, Jϭ7.5 Hz), 4.15 (2H, q, Jϭ7 Hz), 7.45 (2H, d, Jϭ8.5 Hz), 7.69
(2H, d, Jϭ8.5 Hz), 8.18 (1H, s), 8.91 (1H, s). Anal. Calcd for C16H15ClN4O3:
C, 55.42; H, 4.36; N, 16.16. Found: C, 55.63; H, 4.40; N, 16.30.
8e: 1H-NMR (CDCl3) d: 1.24 (3H, t, Jϭ7 Hz), 2.0—2.2 (2H, m), 2.43
(2H, t, Jϭ7 Hz), 2.78 (3H, s), 2.99 (2H, t, Jϭ7.5 Hz), 4.12 (2H, q, Jϭ7 Hz),
7.01 (1H, d, Jϭ1.5 Hz), 7.42 (2H, d, Jϭ8.5 Hz), 7.48 (1H, d, Jϭ1.5 Hz),
7.63 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C19H20ClN3O3: C, 61.04; H, 5.39; N,
11.24. Found: C, 61.23; H, 5.46; N, 11.41.
3-[4-(4-Chlorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-5-oxazolyl]-1-
propanol (9a) Lithium aluminum hydride (1.20 g, 31.6 mmol) was added
portionwise to a stirred solution of 8a (10.8 g, 0.030 mol) in THF (120 ml) at
0 °C. After stirring at the same temperature for 2 h, the reaction mixture was
quenched with water (3 ml) and the insoluble material was removed by filtra-
tion. The filtrate was concentrated in vacuo to give colorless crystals. Re-
crystallization from acetone–isoPr2O gave the title compound (9a, 7.35 g,
1
8g: H-NMR (CDCl3) d: 1.25 (3H, t, Jϭ7 Hz), 1.35—1.9 (6H, m), 2.31
1
77%) as colorless prisms, mp 130—131 °C. H-NMR (CDCl3) d: 1.60 (1H,
(2H, t, Jϭ7.5 Hz), 2.77 (3H, s), 2.91 (2H, t, Jϭ7.5 Hz), 4.12 (2H, q,
Jϭ7 Hz), 7.01 (1H, d, Jϭ1.5 Hz), 7.42 (2H, d, Jϭ8.5 Hz), 7.48 (1H, d,
Jϭ1.5 Hz), 7.60 (2H, d, Jϭ8.5 Hz).
br s), 1.95—2.1 (2H, m), 2.78 (3H, s), 3.06 (2H, t, Jϭ7.5 Hz), 3.7—3.8 (2H,
m), 7.00 (1H, d, Jϭ1.5 Hz), 7.42 (2H, d, Jϭ8.5 Hz), 7.47 (1H, d, Jϭ1.5 Hz),
7.66 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C16H16ClN3O2: C, 60.48; H, 5.07; N,
13.22. Found: C, 60.48; H, 4.89; N, 13.16. Compounds 9b and 9d—h were
obtained similarly. The yields, recrystallization solvents, and melting points
were listed in Table 2.
Methyl 3-[4-(4-Chlorophenyl)-2-phenyl-5-oxazolyl]propionate (8d)
A mixture of 7a (1.50 g, 5.0 mmol), phenylboronic acid (650 mg, 7.05
mmol), NaHCO3 (1.68 g, 20.0 mmol), tetrakis(triphenylphosphine)palladium
(0) (250 mg, 0.22 mmol), water (25 ml), EtOH (25 ml), and toluene (50 ml)
was refluxed for 12 h under N2. The reaction mixture was concentrated and
the residue was purified by chromatography on SiO2 (50 g) with
hexane–AcOEt (6 : 1,v/v) to give the title compound (8d, 1.50 g, 88%) as a
colorless oil. 1H-NMR (CDCl3) d: 2.82 (2H, t, Jϭ7.5 Hz), 3.29 (2H, t,
Jϭ7.5 Hz), 3.70 (3H, s), 7.3—7.5 (5H, m), 7.69 (2H, d, Jϭ8.5 Hz), 8.0—8.1
(2H, m).
1
9b: H-NMR (CDCl3) d: 1.86 (1H, br s), 1.95—2.1 (2H, m), 3.06 (2H, t,
Jϭ7.5 Hz), 3.77 (2H, t, Jϭ6 Hz), 7.19 (1H, br s), 7.42 (2H, d, Jϭ8.5 Hz),
7.59 (1H, t, Jϭ1.5 Hz), 7.65 (2H, d, Jϭ8.5 Hz), 8.23 (1H, br s). Anal. Calcd
for C15H14ClN3O2: C, 59.31; H, 4.65; N, 13.83. Found: C, 59.51; H, 4.60; N,
13.84.
1
9d: H-NMR (CDCl3) d: 1.46 (1H, br s), 2.0—2.15 (2H, m), 3.11 (2H, t,

572
Vol. 51, No. 5
C21H19ClN4O3: C, 61.39; H, 4.66; N, 13.64. Found: C, 61.52; H, 4.63; N,
13.77.
13h: H-NMR (CDCl3) d: 2.25—2.4 (2H, m), 3.20 (2H, t, Jϭ7 Hz), 3.86
(3H, s), 4.10 (2H, t, Jϭ6 Hz), 6.8—7.0 (4H, m), 7.34 (2H, d, Jϭ8.5 Hz),
7.4—7.5 (3H, m), 7.67 (2H, d, Jϭ8.5 Hz), 7.95—8.1 (2H, m). Anal. Calcd
for C25H22ClNO3: C, 71.51; H, 5.28; N, 3.34. Found: C, 71.36; H, 5.35; N,
3.37.
Jϭ7.5 Hz), 3.75—3.8 (2H, m), 7.44 (2H, d, Jϭ8.5 Hz), 7.68 (2H, d,
Jϭ8.5 Hz), 8.18 (1H, s), 8.91 (1H, s). Anal. Calcd for C14H13ClN4O2: C,
55.18; H, 4.30; N, 18.39. Found: C, 55.12; H, 4.29; N, 18.38.
1
9e: 1H-NMR (CDCl3) d: 1.95—2.15 (2H, m), 3.07 (2H, t, Jϭ7.5 Hz),
3.77 (2H, t, Jϭ7.5 Hz), 7.3—7.6 (5H, m), 7.70 (2H, d, Jϭ9 Hz), 8.15—8.2
(2H, m). Anal. Calcd for C18H16ClNO2: C, 68.90; H, 5.14; N, 4.46. Found:
C, 68.93; H, 5.02; N, 4.51.
13i: 1H-NMR (CDCl3) d: 2.2—2.35 (2H, m), 2.76 (3H, s), 3.16 (2H, t,
Jϭ7 Hz), 4.05 (2H, t, Jϭ6 Hz), 6.85—7.0 (2H, m), 7.00 (1H, d, Jϭ2 Hz),
7.2—7.3 (3H, m), 7.36 (2H, d, Jϭ8.5 Hz), 7.42 (1H, d, Jϭ2 Hz), 7.61 (2H,
d, Jϭ8.5 Hz). Anal. Calcd for C22H20ClN3O2·3/4H2O: C, 64.86; H, 5.32; N,
10.31. Found: C, 65.10; H, 4.99; N, 10.40.
9f: 1H-NMR (CDCl3) d: 1.6—1.95 (5H, m), 2.77 (3H, s), 2.96 (2H, t,
Jϭ7.5 Hz), 3.65—3.8 (2H, m), 7.00 (1H, d, Jϭ1.5 Hz), 7.42 (2H, d,
Jϭ8.5 Hz), 7.47 (1H, d, Jϭ1.5 Hz), 7.62 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
C17H18ClN3O2: C, 61.54; H, 5.47; N, 12.66. Found: C, 61.79; H, 5.60; N,
12.90.
1
9g: 1H-NMR (CDCl3) d: 1.35—1.9 (7H, m), 2.77 (3H, s), 2.93 (2H, t,
Jϭ7.5 Hz), 3.6—3.75 (2H, m), 7.00 (1H, d, Jϭ1.5 Hz), 7.42 (2H, d,
Jϭ8.5 Hz), 7.48 (1H, d, Jϭ1.5 Hz), 7.61 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
C18H20ClN3O2: C, 62.52; H, 5.83; N, 12.15. Found: C, 62.55; H, 5.73; N,
12.12.
13k: H-NMR (CDCl3) d: 1.41 (3H, t, Jϭ7 Hz), 2.2—2.35 (2H, m), 2.75
(3H, s), 3.16 (2H, t, Jϭ7 Hz), 4.0—4.15 (4H, m), 6.8—6.95 (4H, m), 6.99
(1H, d, Jϭ2 Hz), 7.36 (2H, d, Jϭ8.5 Hz), 7.41 (1H, d, Jϭ2 Hz), 7.64 (2H, d,
Jϭ8.5 Hz). Anal. Calcd for C24H24ClN3O3: C, 65.82; H, 5.52; N, 9.60.
Found: C, 65.85; H, 5.41; N, 9.62.
1
9h: 1H-NMR (CDCl3) d: 1.3—1.9 (9H, m), 2.77 (3H, s), 2.91 (2H, t,
Jϭ7.5 Hz), 3.65 (2H, t, Jϭ7.5 Hz), 7.01 (1H, d, Jϭ1.5 Hz), 7.42 (2H, d,
Jϭ8.5 Hz), 7.47 (1H, d, Jϭ1.5 Hz), 7.61 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
C19H22ClN3O2: C, 63.42; H, 6.16; N, 11.68. Found: C, 63.46; H, 6.25; N,
11.71.
13l: H-NMR (CDCl3) d: 1.32 (6H, d, Jϭ6 Hz), 2.2—2.3 (2H, m), 2.76
(3H, s), 3.19 (2H, t, Jϭ7 Hz), 4.09 (2H, t, Jϭ6 Hz), 4.4—4.55 (1H, m),
6.8—6.95 (4H, m), 6.99 (1H, d, Jϭ2 Hz), 7.36 (2H, d, Jϭ8.5 Hz), 7.41 (1H,
d, Jϭ2 Hz), 7.63 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C25H26ClN3O3: C,
66.44; H, 5.80; N, 9.30. Found: C, 66.33; H, 5.92; N, 9.53.
13m: 1H-NMR (CDCl3) d: 2.2—2.35 (2H, m), 2.43 (3H, s), 2.79 (3H, s),
3.25 (2H, t, Jϭ7 Hz), 4.11 (2H, t, Jϭ6 Hz), 6.77 (1H, d, Jϭ8 Hz), 6.95—7.2
(4H, m), 7.35 (2H, d, Jϭ8.5 Hz), 7.44 (1H, d, Jϭ2 Hz), 7.65 (2H, d,
Jϭ8.5 Hz). Anal. Calcd for C23H22ClN3O2S: C, 62.79; H, 5.04; N, 9.55.
Found: C, 62.46; H, 5.30; N, 9.67.
3-[4-(4-Chlorophenyl)-2-(1H-pyrazol-1-yl)-5-oxazolyl]-1-propanol (9c)
A mixture of 10a (1.50 g, 5.24 mmol), pyrazole (1.43 g, 21.0 mmol), K2CO3
(2.90 g, 21.0 mmol), and DMF (30 ml) was stirred at 120—130 °C for 5 h.
The reaction mixture was poured into water and adjusted pH at 6 with 2 N
HCl to give 3-[4-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)-5-oxazolyl]propionic
acid (1.44 g, 87%) as colorless crystals. mp 171—172 °C (MeOH). 1H-NMR
(DMSO-d6) d: 2.70 (2H, t, Jϭ7.5 Hz), 3.20 (2H, t, Jϭ7.5 Hz), 6.67 (1H, t,
Jϭ2 Hz), 7.57 (2H, d, Jϭ9 Hz), 7.80 (2H, d, Jϭ2 Hz), 7.92 (1H, d, Jϭ2 Hz),
8.48 (1H, d, Jϭ2 Hz). Anal. Calcd for C15H12ClN3O3: C, 56.70; H, 3.81; N,
13.23. Found: C, 56.56; H, 3.61; N, 13.13. Lithium aluminum hydride
(190 mg, 5.01 mmol) was added portionwise to a stirred solution of 3-[4-
(4-chlorophenyl)-2-(1H-pyrazol-1-yl)-5-oxazolyl]propionic acid (1.44 g) in
THF (30 ml) at 0 °C. After stirring at the same temperature for 2 h, the reac-
tion mixture was quenched with water (0.5 ml) and the insoluble material
was removed by filtration. The filtrate was concentrated in vacuo and the
residue was purified by chromatography on SiO2 (40 g). Elution with
AcOEt–hexane (2 : 3, v/v) gave colorless crystals. Recrystallization from
Et2O–hexane gave the title compound (9c, 450 mg, 33%) as colorless
prisms, mp 75—76 °C. 1H-NMR (CDCl3) d: 1.95—2.15 (2H, m), 3.08 (2H,
t, Jϭ7.5 Hz), 3.76 (2H, t, Jϭ7 Hz), 6.53 (1H, dd, Jϭ2, 2.5 Hz), 7.42 (2H, d,
Jϭ8.5 Hz), 7.69 (2H, d, Jϭ8.5 Hz), 7.81 (1H, dd, Jϭ0.5, 2 Hz), 8.27 (1H,
dd, Jϭ0.5, 2.5 Hz). Anal. Calcd for C15H14ClN3O2: C, 59.31; H, 4.65; N,
13.83. Found: C, 59.19; H, 4.62; N, 13.58.
13n: 1H-NMR (CDCl3) d: 2.2—2.4 (2H, m), 2.76 (3H, s), 3.26 (2H, t,
Jϭ7 Hz), 4.11 (2H, t, Jϭ6 Hz), 6.86 (1H, d, Jϭ8.5 Hz), 6.95—7.1 (2H, m),
7.36 (2H, d, Jϭ8.5 Hz), 7.4—7.5 (1H, m), 7.5—7.6 (2H, m). 7.63 (2H, d,
Jϭ8.5 Hz). Anal. Calcd for C23H19ClN4O2: C, 65.95; H, 4.57; N, 13.38.
Found: C, 65.86; H, 4.66; N, 13.35.
13o: 1H-NMR (CDCl3) d: 2.24 (3H, s), 2.25—2.35 (2H, m), 2.76 (3H, s),
3.18 (2H, t, Jϭ7 Hz), 4.07 (2H, t, Jϭ6 Hz), 6.77 (1H, d, Jϭ8 Hz), 6.88 (1H,
t, Jϭ8 Hz), 6.99 (1H, d, Jϭ2 Hz), 7.1—7.2 (2H, m), 7.34 (2H, d, Jϭ8.5 Hz),
7.41 (1H, d, Jϭ2 Hz), 7.61 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
C23H22ClN3O2: C, 67.73; H, 5.44; N, 10.30. Found: C, 67.71; H, 5.45; N,
10.38.
1
13p: H-NMR (CDCl3) d: 1.22 (6H, t, Jϭ7 Hz), 2.2—2.4 (2H, m), 2.77
(3H, s), 3.19 (2H, t, Jϭ7 Hz), 3.3—3.4 (1H, m), 4.08 (2H, t, Jϭ6 Hz), 6.79
(1H, d, Jϭ8 Hz), 6.9—7.0 (1H, m), 7.00 (1H, d, Jϭ2 Hz), 7.1—7.3 (2H, m),
7.36 (2H, d, Jϭ8.5 Hz), 7.42 (1H, d, Jϭ2 Hz), 7.62 (2H, d, Jϭ8.5 Hz). Anal.
Calcd for C25H26ClN3O2·1/4H2O: C, 68.18; H, 6.06; N, 9.54. Found: C,
68.39; H, 6.12; N, 9.77.
1
13q: H-NMR (CDCl3) d: 2.2—2.3 (2H, m), 2.32 (3H, s), 2.76 (3H, s),
3.15 (2H, t, Jϭ7 Hz), 4.03 (2H, t, Jϭ6 Hz), 6.65—6.75 (1H, m), 6.75—6.85
(1H, m), 7.00 (1H, d, Jϭ2 Hz), 7.1—7.2 (2H, m), 7.36 (2H, d, Jϭ8.5 Hz),
7.42 (1H, d, Jϭ2 Hz), 7.62 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
C23H22ClN3O2: C, 67.73; H, 5.44; N, 10.30. Found: C, 67.77; H, 5.41; N,
10.27.
4-(4-Chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-methyl-1H-
imidazol-1-yl)oxazole (13a) A solution of diethyl azodicarboxylate in
toluene (40%, 875 mg, 2.01 mmol) was added dropwise to a stirred solution
of 9a (320 mg, 1.01 mmol), 2-methoxyphenol (250 mg, 2.01 mmol), and tri-
butylphosphine (405 mg, 2.00 mmol) in THF (10 ml) at room temperature.
After stirring for 4 h, the reaction mixture was concentrated in vacuo to give
an oil which was purified by chromatography on SiO2 (40 g). Elution with
AcOEt–hexane (1 : 1, v/v) gave the title compound (13a, 230 mg, 54%) as
colorless crystals. mp 84—85 °C (Et2O–hexane). 1H-NMR (CDCl3) d: 2.2—
2.4 (2H, m), 2.76 (3H, s), 3.19 (2H, t, Jϭ7 Hz), 3.84 (3H, s), 4.10 (2H, t,
Jϭ6 Hz), 6.8—6.95 (4H, m), 6.99 (1H, d, Jϭ1.5 Hz), 7.35 (2H, d,
Jϭ8.5 Hz), 7.43 (1H, d, Jϭ1.5 Hz), 7.63 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
C23H22ClN3O3: C, 65.17; H, 5.23; N, 9.91. Found: C, 65.18; H, 5.18; N,
9.98. Compounds 13b, 13e, 13f, 13h, 13i, and 13k—w were obtained simi-
larly. The yields, recrystallization solvents, and melting points were listed in
Table 3.
1
13r: H-NMR (CDCl3) d: 2.15—2.3 (2H, m), 2.29 (3H, s), 2.76 (3H, s),
3.15 (2H, t, Jϭ7 Hz), 4.02 (2H, t, Jϭ6 Hz), 6.76 (2H, d, Jϭ8.5 Hz), 6.99
(1H, d, Jϭ2 Hz), 7.08 (2H, d, Jϭ8.5 Hz), 7.36 (2H, d, Jϭ8.5 Hz), 7.42 (1H,
d, Jϭ2 Hz), 7.61 (2H, d, Jϭ8.5 Hz).
1
13s: H-NMR (CDCl3) d: 2.15 (3H, s), 2.2—2.35 (2H, m), 2.28 (3H, s),
2.76 (3H, s), 3.18 (2H, t, Jϭ7 Hz), 4.04 (2H, t, Jϭ6 Hz), 6.65 (1H, d,
Jϭ8 Hz), 6.80 (1H, d, Jϭ8 Hz), 6.99 (1H, d, Jϭ2 Hz), 7.03 (1H, t, Jϭ8 Hz),
7.35 (2H, d, Jϭ8.5 Hz), 7.41 (1H, d, Jϭ2 Hz), 7.61 (2H, d, Jϭ8.5 Hz). Anal.
Calcd for C24H24ClN3O2: C, 68.32; H, 5.73; N, 9.96. Found: C, 68.13; H,
5.76; N, 10.10.
1
13t: H-NMR (CDCl3) d: 2.15—2.3 (2H, m), 2.20 (3H, s), 2.26 (3H, s),
1
2.76 (3H, s), 3.17 (2H, t, Jϭ7 Hz), 4.03 (2H, t, Jϭ6 Hz), 6.65 (1H, d,
Jϭ8.5 Hz), 6.9—7.0 (3H, m), 7.34 (2H, d, Jϭ8.5 Hz), 7.41 (1H, d, Jϭ2 Hz),
7.61 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C24H24ClN3O2: C, 68.32; H, 5.73; N,
9.96. Found: C, 68.09; H, 5.61; N, 10.08.
13b: H-NMR (CDCl3) d: 2.2—2.4 (2H, m), 3.19 (2H, t, Jϭ7 Hz), 3.84
(3H, s), 4.10 (2H, t, Jϭ6 Hz), 6.8—7.0 (4H, m), 7.19 (1H, br s), 7.35 (2H, d,
Jϭ8.5 Hz), 7.55 (1H, s), 7.61 (2H, d, Jϭ8.5 Hz), 8.19 (1H, s). Anal. Calcd
for C22H20ClN3O3: C, 64.47; H, 4.92; N, 10.25. Found: C, 64.40; H, 5.06; N,
10.20.
1
13u: H-NMR (CDCl3) d: 1.9—2.1 (4H, m), 2.20 (3H, s), 2.77 (3H, s),
1
3.01 (2H, t, Jϭ7 Hz), 4.02 (2H, t, Jϭ6 Hz), 6.75—6.9 (2H, m), 7.01 (1H, d,
Jϭ2 Hz), 7.1—7.2 (2H, m), 7.37 (2H, d, Jϭ8.5 Hz), 7.46 (1H, d, Jϭ2 Hz),
7.60 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C24H24ClN3O2: C, 68.32; H, 5.73; N,
9.96. Found: C, 68.18; H, 5.65; N, 9.85.
13e: H-NMR (CDCl3) d: 2.25—2.4 (2H, m), 3.21 (2H, t, Jϭ7 Hz), 3.85
(3H, s), 4.09 (2H, t, Jϭ6 Hz), 6.51 (1H, dd, Jϭ1.5, 2.5 Hz), 6.8—7.0 (4H,
m), 7.32 (2H, d, Jϭ8.5 Hz), 7.65 (2H, d, Jϭ8.5 Hz), 7.81 (1H, d, Jϭ1.5 Hz),
8.22 (1H, d, Jϭ2.5 Hz). Anal. Calcd for C22H20ClN3O3: C, 64.47; H, 4.92; N,
10.25. Found: C, 64.41; H, 4.98; N, 10.22.
1
13v: H-NMR (CDCl3) d: 1.6—1.9 (6H, m), 2.18 (3H, s), 2.77 (3H, s),
1
2.95 (2H, t, Jϭ7 Hz), 3.97 (2H, t, Jϭ6 Hz), 6.75—6.9 (2H, m), 7.00 (1H, d,
Jϭ2 Hz), 7.1—7.2 (2H, m), 7.41 (2H, d, Jϭ8.5 Hz), 7.46 (1H, d, Jϭ2 Hz),
7.61 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C25H26ClN3O2: C, 68.88; H, 6.01; N,
13f: H-NMR (CDCl3) d: 2.25—2.4 (2H, m), 3.23 (2H, t, Jϭ7 Hz), 3.84
(3H, s), 4.10 (2H, t, Jϭ6 Hz), 6.8—7.0 (4H, m), 7.35 (2H, d, Jϭ8.5 Hz),
7.65 (2H, d, Jϭ8.5 Hz), 8.17 (1H, s), 8.86 (1H, s). Anal. Calcd for

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573
9.64. Found: C, 68.89; H, 5.99; N, 9.58.
C24H24ClN3O3: C, 65.82; H, 5.52; N, 9.60. Found: C, 65.94; H, 5.41; N,
13w: 1H-NMR (CDCl3) d: 1.4—1.6 (4H, m), 1.7—1.9 (4H, m), 2.21 (3H, 9.54. Compounds 13d and 13g were obtained similarly. The yields, recrys-
s), 2.77 (3H, s), 2.92 (2H, t, Jϭ7 Hz), 3.95 (2H, t, Jϭ6 Hz), 6.75—6.9 (2H, tallization solvents, and melting points were listed in Table 3.
m), 7.00 (1H, d, Jϭ2 Hz), 7.1—7.2 (2H, m), 7.41 (2H, d, Jϭ8.5 Hz), 7.46
(1H, d, Jϭ2 Hz), 7.61 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C26H28ClN3O2: C, 2.25—2.40 (2H, m), 3.11 (2H, t, Jϭ7 Hz), 3.19 (2H, t, Jϭ7 Hz), 3.84 (3H,
69.40; H, 6.27; N, 9.34. Found: C, 69.28; H, 6.13; N, 9.21. s), 4.10 (2H, t, Jϭ6 Hz), 6.8—6.95 (4H, m), 7.01 (1H, d, Jϭ2 Hz), 7.35 (2H,
13d: 1H-NMR (CDCl3) d: 1.03 (3H, t, Jϭ7 Hz), 1.75—1.95 (2H, m),
4-(4-Chlorophenyl)-5-[3-(2-hydroxyphenoxy)propyl]-2-(2-methyl-1H- d, Jϭ8.5 Hz), 7.40 (1H, d, Jϭ2 Hz), 7.63 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
imidazol-1-yl)oxazole (13j) To a solution of 13l (200 mg, 0.44 mmol) in C25H26ClN3O3·1/4H2O: C, 65.79; H, 5.85; N, 9.21. Found: C, 65.84; H,
CH2Cl2 (5 ml) was added titanium tetrachloride (380 mg, 2.0 mmol) at 0 °C. 5.76; N, 9.15.
The reaction mixture was stirred at the same temperature for 1 h, quenched
with saturated aqueous NaHCO3, and extracted with AcOEt. The extract was 3.83 (3H, s), 4.14 (2H, t, Jϭ6 Hz), 6.8—7.0 (4H, m), 7.35—7.5 (4H, m),
washed with brine, dried (MgSO4), and concentrated in vacuo to give pale 7.70 (2H, d, Jϭ8.5 Hz), 7.8—7.9 (1H, m), 8.2—8.3 (1H, m), 8.50 (1H, s).
13g: 1H-NMR (CDCl3) d: 2.30—2.40 (2H, m), 3.26 (2H, t, Jϭ6.5 Hz),
yellow crystals. Recrystallization from acetone–isoPr2O gave the title com-
Anal. Calcd for C26H22ClN3O3: C, 67.90; H, 4.82; N, 9.14. Found: C, 67.65;
pound (13j, 90 mg, 50%) as pale yellow prisms, mp 110—111 °C. 1H-NMR H, 4.81; N, 9.01.
(CDCl3) d: 2.2—2.4 (2H, m), 2.79 (3H, s), 3.16 (2H, t, Jϭ7 Hz), 4.15 (2H, t,
Jϭ6 Hz), 5.55 (1H, br s), 6.8—7.0 (4H, m), 6.97 (1H, d, Jϭ2 Hz), 7.38 (2H,
Acknowledgements We thank H. Odaka, T. Miyazaki, A. Shintani and
d, Jϭ8.5 Hz), 7.43 (1H, d, Jϭ2 Hz), 7.58 (2H, d, Jϭ8.5 Hz). Anal. Calcd for N. Iwakami for the biological assays.
C22H20ClN3O3·1/4H2O: C, 63.77; H, 4.99; N, 10.14. Found: C, 64.00; H,
5.03; N, 9.81.
References
General Procedure for Method C. 3-(2-Chloro-4-chlorophenyl-5-oxa-
zolyl)-1-propanol (11, n؍2) A solution of diisobutylaluminum hydride in
hexane (1.0 M, 65.0 ml, 65.0 mmol) was added dropwise to a stirred solution
of 7a (9.00 g, 30.0 mol) in THF (100 ml) at Ϫ78 °C followed by stirring at
0 °C for 1 h. The reaction mixture was quenched with Na2SO4·10H2O
(10.0 g) and the insoluble material was removed by filtration. The filtrate was
concentrated in vacuo to give the title compound (11, 7.00 g, 86%) as an
amorphous powder. 1H-NMR (CDCl3) d: 1.9—2.1 (2H, m), 2.99 (2H, t,
Jϭ7 Hz), 3.73 (2H, t, Jϭ6 Hz), 7.38 (2H, d, Jϭ8.5 Hz), 7.53 (2H, d,
Jϭ8.5 Hz). Anal. Calcd for C12H11Cl2NO2: C, 52.96; H, 4.07; N, 5.15.
Found: C, 53.35; H, 4.09; N, 5.28.
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(12, n؍2)
A mixture of 11 (1.28 g, 4.70 mmol), 2-methoxyphenol
(931 mg, 7.50 mol), tributylphosphine (1.52 g, 7.50 mmol), 1,1Ј-(azodicar-
bonyl)dipiperidine (1.90 g, 7.50 mmol), and THF (10 ml) was stirred at room
temperature for 1 h. The reaction mixture was concentrated in vacuo and the
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(12, 1.00 g, 56%) as colorless crystals. mp 81—82 °C (AcOEt–hexane). 1H- 11) Hellweg R., Wohrle M., Hartung H.-D., Stracke H., Hock C., Federlin
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4.06 (2H, t, Jϭ6 Hz), 6.8—7.0 (4H, m), 7.31 (2H, d, Jϭ8.5 Hz), 7.55 (2H, d, 12) Apfel S. C., Kessler J. A., Adornato B. T., Litchy W. J., Sanders C.,
Jϭ8.5 Hz). Anal. Calcd for C19H17Cl2NO3: C, 60.33; H, 4.53; N, 3.70.
Found: C, 60.39; H, 4.52; N, 3.81.
4-(4-Chlorophenyl)-2-(2-ethyl-1H-imidazol-1-yl)-5-[3-(2-methoxyphe-
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13) Meguro K., Tawada H., Sugiyama Y., Fujita T., Kawamatsu Y., Chem.
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noxy)propyl]oxazole (13c) A mixture of 12 (1.00 g, 2.64 mol), 2-ethylimi- 14) Ernfors P., Lee K.-F., Jaenisch R., Nature (London), 368, 147—150
dazole (960 mg, 10.0 mmol), K2CO3 (1.38 g, 10.0 mmol), and DMF (20 ml) (1994).
was stirred at 120—130 °C for 2 h. The reaction mixture was poured into 15) Sendtner M., Holtmann B., Kolbeck R., Thoenen H., Barde Y., Nature
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the title compound (13c, 618 mg, 53%) as pale yellow prisms, mp 78— 16) Tsunoda T., Yamamiya Y., Ito S., Tetrahedron Lett., 34, 1639—1642
1
79 °C. H-NMR (CDCl3) d: 1.40 (3H, t, Jϭ7 Hz), 2.2—2.35 (2H, m), 2.72
(1993).
(2H, t, Jϭ7 Hz), 3.15 (2H, q, Jϭ7 Hz), 3.19 (2H, t, Jϭ7 Hz), 3.84 (3H, s), 17) Inoue S., Susukida M., Ikeda K., Murase K., Hayashi K., Biochem.
4.10 (2H, t, Jϭ6 Hz), 6.8—6.95 (4H, m), 7.02 (1H, d, Jϭ2 Hz), 7.35 (2H, d,
Jϭ8.5 Hz), 7.42 (1H, d, Jϭ2 Hz), 7.63 (2H, d, Jϭ8.5 Hz). Anal. Calcd for
Biophys. Res. Commun., 238, 468—472 (1997).