Novel imidazole compounds as a new series of potent, orally active inhibitors of 5-lipoxygenase

Article abstract of DOI:10.1016/S0968-0896(03)00436-X

Replacement of the dihydroquinolinone pharmacophore of Zeneca's ZD2138 by ionizable imidazolylphenyl moiety has lead to the discovery of a novel series of potent and orally active 5-lipoxygenase (5-LO) inhibitors. The synthesis and structure-activity relationship (SAR) of this series of compounds are described herein.

Full text of DOI:10.1016/S0968-0896(03)00436-X

Bioorganic & Medicinal Chemistry 11 (2003) 3879–3887
Novel Imidazole Compounds as a New Series of Potent,
Orally Active Inhibitors of 5-Lipoxygenase
Takashi Mano,* Rodney W. Stevens, Kazuo Ando, Kazunari Nakao,
Yoshiyuki Okumura, Minoru Sakakibara, Takako Okumura,
Tetsuya Tamura and Kimitaka Miyamoto
Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan
Received 4March 2003; revised 22 June 2003; accepted 23 June 2003
Abstract—Replacement of the dihydroquinolinone pharmacophore of Zeneca’s ZD2138 by ionizable imidazolylphenyl moiety has
lead to the discovery of a novel series of potent and orally active 5-lipoxygenase (5-LO) inhibitors. The synthesis and structure–
activity relationship (SAR) of this series of compounds are described herein.
# 2003 Elsevier Ltd. All rights reserved.
Introduction
Mitsunobu reaction conditions (method A) or by
alkylation with the appropriate benzyl chlorides using
potassium carbonate in dimethylformamide (DMF)
(method B) as shown in Scheme 1 and Table 1. Benzyl
alcohols 2a–c,f were prepared according to the litera-
ture.7,8 Substituted imidazole benzyl alcohols 2e,i,k–o
were prepared by coupling the appropriate imidazole
derivatives with ethyl 4-fluorobenzoate or with 4-fluor-
obenzonitrile followed by reduction to the correspond-
ing benzyl alcohols (Scheme 2). Alcohol 2d and 2h
were prepared from ethyl 4-(1H-imidazol-2-yl)benzoate
by the selective methylation, and 4-(1H-imidazol-1-yl)-
benzonitrile, respectively, by trifluoromethylation fol-
lowed by reduction (Schemes 3 and 4).9À11 For phar-
macological evaluation all compounds, except 1i and
1n, were submitted as solids, free base or hydrochloride
salt thereof.
Leukotrienes (LTs) have been implicated in a number of
human disease states including asthma, rheumatoid
arthritis, inflammatory bowel diseases and psoriasis.
Accordingly, any agent that controls the release or
actions of the LTs is expected to be of considerable
therapeutic value for the treatment of acute and chronic
inflammatory conditions.1 ICI (ZENECA) has reported
on methyl ether compounds as potent, selective and
non-redox 5-LO inhibitors,2 and in 1992 D2138
(ZD2138) entered phase II studies for asthma and
rheumatoid arthritis.3 While ZD2138 exhibited good
activities in animal models of asthma and inflamma-
tion, the compound was not well orally absorbed and
modifications to improve oral bioavailability by
increasing solubility have been reported.4À6 Herein,
we present work on the development of ionizable
imidazolylphenyl analogues which led to the identifi-
cation of CJ-12,918 (1g), potent and orally active 5-
LO inhibitor.
The inhibitory activities of the compounds for 5-LO,
12-LO, and cyclooxygenase were routinely evaluated in
vitro using heparinized human whole blood (HWB)
quantitating LTB4 as well as 5-HETE (5-hydroxyeicosa-
6,8,11,14-tetraenoic acid), 12-HETE (12-hydroxyeicosa-
5,8,10,14-tetraenoic acid) and HHT (12-hydroxy-
heptadeca-5,8,10-trienoic acid), respectively.12 The in
vivo potency after orally administration of compounds
to mice was determined by PAF (platelet activating
factor)-induced thrombosis assay.13 For selected com-
pounds, inhibition of yeast-induced edema in rats was
determined.14
Results and Discussion
Compounds 1a–o were obtained from phenols 3a,b3a by
condensation with the requisite benzyl alcohols under
*Corresponding author. Tel.: +81-569-74-4430; Fax.: +81-569-74-
4748; e-mail: takashi.mano@japan.pfizer.com
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00436-X

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T. Mano et al. / Bioorg. Med. Chem. 11 (2003) 3879–3887
Scheme 1. Method A: 3a or 3b, DEAD, TEA, THF; Method B: (i)
SOCl2; (ii) 3b, K2CO3, DMF. Generic groups presented as heteroaryl
are defined in Table 1.
Scheme 5. Evolution of imidazole 5-LOI from ZD2138.
pounds,5,6 since high lipophilicity was thought to cause
low aqueous solubility.16 Since ZD2138 is structurally
non-ionizable in the physiological pH range, (i.e., pH
1.4–817) our strategy was to enhance aqueous solubility
by incorporating an ionizable functional group into the
drug molecule.4
It has been reported that the position of the amidic
fragment in the dihydroquinolinone ring of ZD2138,
and analogues, is important for in vitro potency.3a We
speculated that imidazol-1-yl would mimic the amide
function of ZD2138 and introduce a basic ionizable
center (Scheme 5). Imidazole 1a was synthesized and, as
anticipated, found to exhibit 5-LO inhibitor activity
(HWB with an IC50 of 0.91 mM). To further test this
hypothesis pyrrol-1-yl (1b), 1,2-pyrazol-1-yl (1c) and 1-
methylimidazol-2-ly (1d) analogues were synthesized
(Table 2). While 1b (IC50=1.7 mM) had comparable in
vitro activity to 1a, the other compounds did not exhibit
meaningful inhibitory activity (1c, 8% inhibition (5–
11%, n=2) at 1 mM; 1d, 1% inhibition at 0.3 mM). On
the other hand, while 1a protected mice from PAF-
induced thrombosis on oral dosing (ED50=7 mg/kg), 1b
was inactive at 30 mg/kg. Based on these findings, SAR
studies around 1H-imidazol-1-yl compound 1a were
further pursued (Table 3).
Scheme 2. (i) 2-R-1H-imidazole, base; (ii) Dibal-H, THF or Dibal-H,
CH2Cl2 then NaBH4, EtOH.
Scheme 3. (i) NH2CH2CH2NH+3 4-MePhSO3À; (ii) BaMnO4; (iii)
MeOCOCO2Me, K2CO3; (iv) Dibal-H, CH2Cl2.
Initial SAR was focused on potentiation of intrinsic
inhibitory activity as assessed in the HWB assay. Two-
substituted imidazole analogues showed 2–9-fold higher
in vitro potency than 1a, as exemplified by 1e, 1i, 1m,
1n, and 1o. While small alkyl group (e.g., 1e or 1i)
retained oral activities, those compounds with steric
demanding substituent at position 2 (1m, 1n, and 1o)
were inactive at the highest dose tested (30 mg/kg).
Four-substituted imidazole analogues as exemplified by
the 4-methyl regioisomer 1f had significantly reduced in
vitro potency (41% inhibition at 10 mM). In order to
evaluate the effect of a fluorine atom (i.e., X=F in
Table 2), which was reported to be important with
ZD2138 and its analogues,3a we prepared fluoro deri-
vatives (1g,h,j–l) but found that the fluorine substituent
had only a marginal effect on potency (e.g., 1e and 1i
with 1g and 1j, respectively).
Scheme 4. (i) 4-fluorobenzonitrile, K2CO3, DMSO; (ii) n-BuLi, THF;
(iii) TMS-CF3, CuI, KF, DMF, 1-methyl-2-pyrrolidone; (iv) Dibal-H,
CH2Cl2; (v) NaBH4, EtOH.
The physicochemical profile of a drug, including solu-
bility and permeability, inherently affects pharmacoki-
netics and structure–activity relationships (SAR).15
When a drug is administered orally as solid, disintegra-
tion and dissolution of the drug in the gastrointestinal
fluid are the initial steps in drug absorption, followed by
absorption of the drug through the gastrointestinal
tract. It has been reported that bioavailability of
ZD2138 could be improved by enhancing aqueous
solubility, viz., by reducing lipophilicity (log P) of com-
Since 1g (CJ-12,918) was one of the most potent com-
pounds (HWB, LTB4 IC50=0.068Æ0.019 mM, n=5;

T. Mano et al. / Bioorg. Med. Chem. 11 (2003) 3879–3887
3881
Table 1. Synthetic data for 1a-–o
No.
Heteroaryla
Substituentb
X
2c
3d
Methode
1a
1b
1c
1d
1e
1f
1g
1g HCl
1h
1i
1j HClf
1k HClf
1l HClf
1m
1-Im
—
—
—
1-Me
2-Me
4-Me
2-Me
2-Me
2-CF3
2-Et
H
H
H
F
H
H
F
F
F
H
F
F
2a
2b
2c
2d
2e
2f
2e
2e
2h
2i
2i
2k
2l
2m
2n
2o
3a
3a
3a
3b
3a
3a
3b
3b
3b
3a
3b
3b
3b
3a
3a
3a
A
A
A
B
A
A
B
B
B
A
A
B
B
A
A
A
1-Pyrrolyl
1-Pyrazolyl
2-Im
1-Im
1-Im
1-Im
1-Im
1-Im
1-Im
1-Im
1-Im
1-Im
1-Im
1-Im
1-Im
2-Et
2-(1-Pr)
2-(2-Pr)
2-Ph
2-Bn
2-(2-Py)
Figure 1. In vitro potency and selectivity of 1g HCl on production of
5-LO metabolites, LTB4 and 5-HETE, cyclooxygenase and 12-LO
metabolites, HHT and 12-HETE, respectively, in human whole blood
stimulated with A23187. Each point represents the meanÆSEM
(n=3).
F
H
H
H
1n
1o
a1-Im=1H-imidazol-1-yl; 2-Im=1H-imidazol-2-yl.
bNumbers hyphened to acronyms for substiutents indicate substitution
position on heteroaryls.
cSyntheses are described in text.
dStructures are described in Scheme 1.
eMethods A and B are indicated in Scheme 1.
fHydrochloride salt was the sole final form provided for biological
evaluation.
Table 2. 5-LO Inhibitory activities for evolving azole seriesa
a
No. Heteroaryl
X
H
HWB IC50 (mM) LTB4 PAF ED50 (mg/kg)a
1a
0.91
7
Figure 2. The effect of 1g HCl inhibition on PAF-induced thrombosis
in mice. The compound was perorally administered 45 min prior to
PAF challenge. Each point represents the meanÆSEM (n=3).
1b
1c
1d
H
H
F
1.7
>30
NTb
>30
and cyclooxygenase (Fig. 1). The in vitro activity was
found to be comparable to that of ZD2138 (HWB,
LTB4 IC50=0.047Æ0.09 mM, no inhibition of 12-HETE
or HHT at 3 mM, n=6). Figure 2 shows the oral activity
of 1g HCl with an ED50 of 2.0Æ1.0 mg/kg (n=3,ÆSD)
or 1.8Æ0.9 mgA/mL (mgA indicates the weight in mg of
1g calculated as free base) in the PAF-induced throm-
bosis model in mice. Furthermore, 1g HCl inhibited
yeast-induced foot edema formation in rats with an
ED40 of 5Æ2 mgA/kg po (n=3, ÆSD), compared with
11Æ3 mg/kg for ZD2138. Thus the elicited pharmaco-
logical activity suggested that 1g would heal or alleviate
inflammatory diseases mediated by 5-LO products.
(5, 10% inh. at 1 mM)
(1% inh. at 0.3 mM)
aNumber of determinations was one otherwise mentioned.
bNot tested.
PAF-induced thrombosis, ED50=4.3Æ0.9 mg/kg,
n=3,ÆSD), it was selected for further characterization
as the hydrochloride salt. No inhibition of 12-HETE or
HHT was observed with 1g HCl at the highest concen-
tration (3 mM) tested, which corresponds to higher than
50-fold selectivity ratios for 5-LO compared to 12-LO
In Zeneca’s publications they discussed the aqueous
solubility issue of ZD2138 and its analogues, estimating
the solubility of ZD2138 to be 1.5 mg/mL, which is close

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T. Mano et al. / Bioorg. Med. Chem. 11 (2003) 3879–3887
Table 4. Comparison of Physicochemical Properties of CJ-12,918
hydrochloride (1g HCl) and ZD2138
Solubility (mgA/mL)
pKa
log P
pH 1.2a
pH 6.5b
NaTC/POPCc
1g HCl
ZD2138
6.9
—
3.7
2.8e
4.2
0.0013
0.0018
0.0012
0.0066
0.0042
d
aSimulated gastric fluid (USP) without enzyme.
bPhosphate buffered saline (PBS).
cSodium taurocholate (3 mM) and 1-palmitoyl-2-oleoyl-l-a-phospha-
tidylcholine (0.75 mM) in PBS at pH 6.5.
dNot exist in physiological pH range.
ePredicted with ACD/LogP DB, version 5.16; Advanced Chemistry
Development Inc.: Toronto, Ontario, Canada, 2001.
Table 5. Comparison of Pharmacokinetic Parameters in Male
Cynomolgus Monkeys of CJ-12,918 hydrochloride (1g HCl) and
ZD2138 at 5 mgA/kga
Figure 3. Mean serum concentration of 1g HCl and ZD2138 in three
male monkeys following oral administration (5 mgA/kg).
Cmax (mgA/mL)
AUC0À7 (mgAh/mL)
BA (%)b
1g HCl
ZD2138
0.22Æ0.12
0.12Æ0.00
0.84Æ0.29
0.56Æ0.05
13.0Æ4.1
enough to the experimental data the authors obtained
as shown in Table 4.3 ZD2138, a neutral compound,
was expected to show identical solubility throughout the
physiologic pH range. In contrast, the solubilities of 1g
HCl were measured to be 4.2 mgA/mL and 1.8 mgA/mL
in USP simulated gastric fluid without enzyme (pH 1.2)
and in phosphate buffered saline (PBS) at pH 6.5,
respectively. Since 1g was basic enough with a pKa of
6.9 to form hydrochloride salt, its solubility is suppose
to be enhanced.18 Furthermore, in order to assess the
solubilization effects of bile salts and phospholilids, the
solubility of 1g HCl in sodium taurocholate (3 mM)/
1-palmitoyl-2-oleoyl-l-a-phosphatidylcholine (0.75 mM)
in PBS at pH 6.5 was measured to be 6.6 mgA/mL and
found to be higher than that of ZD2138 (4.2 mgA/mL).
Thus, our approach for improving solubility by incor-
8.60Æ1.20
aMeanÆSD (n=3).
b5 mgA/kg po versus 3 mgA/kg iv.
porating an ionizable group was successful and was
supposed to increase in vivo solubility of the series of
compounds. The oral bioavailability in male cyno-
molgus monkeys of 1g HCl was determined to be
13.0Æ4.1% (n=3, ÆSD) from oral and iv studies at 5
mgA/kg po and 3 mgA/kg iv, compared to 8.60Æ1.20%
for ZD2138 (Fig. 3 and Table 5).
Conclusion
Aiming improvement of oral absorption, incorporation
of ionizable group into the known 5-LO inhibitor
ZD2138 led to a novel series of imidazole compounds.
From the series, CJ-12,918 (1g HCl) was discovered as
an orally active 5-LO inhibitor, selective over 12-LO
and cyclooxygenase and which was more soluble in the
physiologic pH range than ZD2138. Compared to
ZD2138, CJ-12,918 elicited comparable inhibitory
potency in the in vitro HWB assay, and demonstrated
improved activity in the in vivo rat foot edema test and
superior pharmacokinetic parameters (bioavailability,
Cmax) in monkeys. CJ-12,918 was selected for develop-
ment into clinical trials, however, was discontinued due
to preclinical animal test, 1g HCl toxicology findings.19
SAR developed to circumvent these findings is the topic
of a separate publication.20
Table 3. Substitution effect of imidazole ring on 5-LO inhibitory
activity
b
no.
Ra
X
HWB IC50 (mM) LTB4 PAF ED50 (mg/kg)b
1e
1f
1g
2-Me
4-Me
2-Me
H
H
F
F
F
H
F
F
0.13Æ0.02 (6)
41% inh. at 10 mM
0.068Æ0.019 (5)
0.060Æ0.017 (3)
0.83, 0.13
0.12
0.050
0.085
0.12
0.12
7
>30
4.5Æ1.5 (4)
1g HCl 2-Me
1h
1i
1j HCl 2-Et
1k HCl 2-(1-Pr)
1l HCl 2-(2-Pr)
1m
1n
1o
2.0Æ1.0 (3)
2-CF3
2-Et
13
5
5
9
10
>30
>30
>30
Experimental
F
2-Ph
2-Bn
2-(2-Py)
H
H
H
Biology. In vitro assay using heparinised human whole
blood (HWB)
0.11
0.40
aNumbers hyphened to acronyms for R indicate substitution position
on imidazole.
bIC50’s and ED50’s are shown withÆSD (number of determinations),
where more than three determinations were made. Otherwise results
based on single or two determinations are given.
Inhibition has been demonstrated in vitro using hepar-
inized human whole blood, which determines the inhi-
bitory effect of compounds on 5-LO metabolism of
arachidonic acid. Aliquots of heparinized human whole

T. Mano et al. / Bioorg. Med. Chem. 11 (2003) 3879–3887
3883
blood (1 mL) from healthy donors were preincubated
with drugs dissolved in DMSO (final concentration,
0.1%) for 10 min at 37 ꢀC, then calcium ionophore
A23187 (60 mL) and Heparapid (2.5%, Sekisui Chemi-
cal Co. LTD., Japan) were added. Incubation was then
continued for a further 30 min. Reactions were termi-
nated by rapid cooling in an ice bath. Blood-clots
induced by the Heparapid were removed by centrifuga-
tion. CH3CN (1.5 mL) and PGB2 (500 ng, as an internal
standard) were added to the supernatants. Samples were
mixed by a Vortex mixer, and precipitated proteins were
removed by centrifugation. Supernatants were diluted
with water (7 mL) and were loaded onto a pre-washed
Sep-Pak C18 cartridge (Waters Associates, Milford, MS,
USA) and arachidonate metabolites were eluted with
70% methanol (4mL). Methanolic extract was evapo-
rated and the residue was then reconstituted in 100 mL
of 50% aqueous ethanol.
suspended in 0.1% methylcellulose was administered
perorally at a volume of 2.5 mL per 100-g body weight 1
h prior to the yeast injection. The ED40 value was calcu-
lated from the equation for the log-linear regression line of
dose versus percent inhibition by the least squares
method.
Chemistry
Proton magnetic resonance (1H NMR) spectra were
measured on a Joel FX270 spectrophotometer and pro-
ton chemical shifts are reported as d values in parts per
million (ppm) relative to tetramethylsilane as an internal
standard. Spin multiplicities are given as s (singlet), d
(doublet), t (triplet), q (quartet), dd (doublet of doub-
let), ddd (doublet of doublet of doublet), m (multiplet)
and br (broad). Melting points were determined on
either a Buchi 535 or on a Yanagimoto micro-melting-
point apparatus and were uncorrected. IR spectra and
mass spectra were recorded on a Shimadzu IR-440
spectrometer and a Micromass Quattro II specrtometer,
respectively. The results of elemental analyses were
within 0.4% of the theoretical values, and are reported
only with symbols. Chromatography was performed on
silica gel (E. Merck, 70–230 mesh).
Preconstituents (40 mL) were injected onto a reversed
phase C18 column (Wakosil 5C18, 4 .6Â150 mm, Wako
Pure Chemical Industries LTD, Japan). The column
temperature was 40 ꢀC. HPLC analysis was performed
by Hewlett Packard model 1090HPLC. The chromato-
graphy was achieved using two different mobile phases
as a gradient program (mobile A consisted of 10% ace-
tonitrile, 0.1% trifluoroacetic acid and 0.5% triethyl-
amine; mobile B consisted of 80% acetonitrile, 0.1%
trifluoroacetic acid and 0.5% triethylamine). Each
mobile phase was continuously sparged with helium.
The HPLC gradient was programmed as follows:
mobile phase A increased linearly from 35 to 100%
at a flow rate of 1 mL/min over 9.7 min (where
A+B=100%). Peaks of eluting products were quanti-
tated by UV absorbance (LTB4 and PGB2 at 275 nm;
HHT and 5-HETE at 235 nm) and were corrected by
PGB2 recovery. Sigmoid regression was used to estimate
IC50 values.
4-[3-[4-(1H-Imidazol-1-yl)benzyloxy]phenyl]-4-methoxy-
3,4,5,6-tetrahydro-2H-pyran (1a). To a stirred solution
of 4-(1H-imidazol-1-yl)benzyloxy alcohol (2a, 0.87 g,
5.0 mmol), 4-(3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetra-
hydro-2H-pyran (3a, 1.03 g, 4.9 mmol) and triphenyl-
phosphine (1.55 g, 5.9 mmol) in THF (30 mL) cooled to
0 ꢀC was added dropwise a solution of diethyl azodi-
carboxylate (DEAD) (1.03 g, 12.0 mmol) in THF (10
mL) over 20 min under a nitrogen atmosphere. After
completion of addition, the mixture was stirred at
0 ꢀC for 30 min and allowed to warm to room tem-
perature, and then volatiles were removed under
reduced pressure. Chromatographic purification of the
residue (gradient elution, 15–30% acetone in di-
chloromethane) provided 0.27 g of the title com-
pound as a gum, which solidified on standing at
room temperature. Fractions contaminated with tri-
phenylphosphine oxide were combined, concentrated to
dryness, solidified by triturating with diisopropyl ether/
ethyl acetate to provide 0.16 g of the title compound.
Combined solids were further purified by recrystalliza-
tion from diisopropyl ether–ethyl acetate afforded the
title compound as tiny colorless needles (0.30 g, 17%):
In vivo platelet activating factor (PAF) thrombosis assay
in mice
The in vivo potency after oral administration of com-
pounds to IRC mice (male) was determined using a
PAF thrombosis assay in a manner similar to that
described by J. M. Young et al.13 PAF was dissolved at
a concentration of 1.2 in 0.05 mg/mL propranolol-saline
containing 0.25% bovine serum albumin (BSA) and
injected intravenously into mice at a dose of 12 mg/kg.
The mortality rate was determined 1 h after PAF injec-
tion. To investigate the effect(s) of LO inhibitors, com-
pounds were dissolved in 5% Tween 80, 5%
EtOH-saline, and the solutions were administered orally
(10 mL/kg) 45 min prior to PAF injection.
mp=129–131 ꢀC; H NMR (CDCl3) 7.78 (t, 1H, J=1
1
Hz), 7.56 (d, 2H, J=8 Hz), 7.43 (d, 2H, J=8 Hz), 7.32
(t, 1H, J=8 Hz), 7.28 (dd, 1H, J=8, 1 Hz), 7.22 (t, 1H,
J=1 Hz), 7.08–6.98 (m, 2H), 6.94–6.88 (m, 1H), 5.12 (s,
2H), 3.92–3.81 (m, 4H), 2.98 (s, 3H), 2.10–1.92 (m, 4H);
MS (ESI+) m/e 365 (M+H)+. Anal. (C22H24N2O3) C,
H, N.
In vivo yeast-induced foot edema assay in rats
Female rats (5 weeks old), weighting 100–130 g body
weight, were fasted overnight. Food edema was induced
by subplantar injection of 0.1 mL of 3% Brewer’s yeast
(Sigma) suspended in saline. Foot volume was measured
by water displacement using a plenthysmometer before
and 1.5 h after the yeast injection. The compound
The following compounds were prepared from appro-
priate alcohols and phenols according to a similar pro-
cedure to that of 1a (method A).
4-Methoxy-4-[3-[4-(1H-pyrrol-1-yl)benzyloxy]phenyl]-
3,4,5,6-tetrahydro-2H-pyran (1b). Mp=112.5–113 ꢀC;

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T. Mano et al. / Bioorg. Med. Chem. 11 (2003) 3879–3887
1H NMR (CDCl3) 7.50 (d, 2H, J=9 Hz), 7.42 (d, 2H,
J=9 Hz), 7.40–7.30 (m, 1H), 7.10 (t, 2H, J=2 Hz),
7.06–6.89 (m, 2H), 6.94–6.88 (m, 1H), 6.36 (t, 2H, J=2
Hz), 5.09 (s, 2H), 3.92–3.80 (m, 4H), 3.00 (s, 3H),
2.09–1.91 (m, 4H); MS (ESI+) m/e 332 (M–OCH3)+.
Anal. (C23H25NO3) C, H, N.
4-[3-[4-(2-Benzyl-1H-imidazol-1-yl)benzyloxy]phenyl]-4-
methoxy-3,4,5,6-tetrahydro-2H-pyran (1n). Oil; 1H
NMR (CDCl3) 7.74–6.85 (m, 15H), 5.12 (s, 2H), 4.03 (s,
2H), 3.94–3.76 (m, 4H), 2.98 (s, 3H), 2.10–1.89 (m, 4H);
MS (ESI+) m/e 455 (M+H) . Anal. (C29H30N2O3
0.9H2O) C, H; N, calcd, 5.95; found 5.41.
+
.
4-Methoxy-4-[3-[4-(1H-pyrazol-1-yl)benzyloxy]phenyl]-
3,4,5,6-tetrahydro-2H-pyran (1c). Mp=91–92 ꢀC; 1H
NMR (CDCl3) 7.94(dd, 1H, J=2, 1 Hz), 7.75–7.23 (m,
4-Methoxy-4-[3-[4-[2-(pyridin-2-yl)-1H-imidazol-1-yl]-
(1o).
benzyloxꢀy]phenyl]-3,4,5,6-tetrahydro-2H-pyran
1
103–105 C; H NMR (CDCl3) 8.32 (d, 1H, J=4Hz),
7.92 (d, 1H, J=8 Hz), 7.70 (dd, 1H, J=8, 2 Hz), 7.47
(d, 2H, J=8 Hz), 7.39–7.24(m, 4H), 7.21–7.11 (m, 2H),
7.08–6.98 (m, 2H), 6.96–6.87 (m, 1H), 5.12 (s, 2H),
3.94–3.77 (m, 4H), 2.98 (s, 3H), 2.10–1.90 (m, 4H); MS
3H), 7.54(d, 2H,
J=8 Hz), 7.34–7.27 (m, 1H),
7.07–6.98 (m, 2H), 6.94–6.89 (m, 1H), 6.48 (dd, 1H,
J=3, 2 Hz), 5.11 (s, 2H), 3.92–3.77 (m, 4H), 2.98 (s,
3H), 2.10–1.92 (m, 4H); MS (ESI+) m/e 333
(M–OCH3)+. Anal. (C22H24N2O3) C, H, N.
+
.
(ESI+) m/e 442 (M + H) . Anal. (C27H27N3O3 H2O)
C, H, N.
4-Methoxy-4-[3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]-
phenyl]-3,4,5,6-tetrahydro-2H-pyran (1e). Mp=135–
137 ꢀC; 1H NMR (CDCl3) 7.57 (d, 2H, J=8 Hz),
7.36–7.30 (m, 3H), 7.07–7.00 (m, 4H), 6.93 (ddd, 1H,
J=8, 3, 1 Hz), 5.14(s, 2H), 3.91–3.82 (m, 4H), 2.98 (s,
4-[5-Fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]-
phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1g) and
the hydrochloride salt (1g HCl). Step 1: 4-[5-Fluoro-3-[4-
(2-methyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-4-meth-
oxy-3,4,5,6-tetrahydro-2H-pyran (1g). 4-(2-Methyl-1H-
imidazol-1-yl)benzyl alcohol (2e, 1.28 g, 6.8 mmol) in
thionyl chloride (5 mL) was stirred at the ambient tem-
perature for 30 min and then volatiles were removed
under reduced pressure. The resultant crude product was
washed with minimal dry Et2O and dried in vacuo to
afford 4-(2-methylimidazol-1-yl)benzylchloride hydro-
chloride (1.65 g) as white solids.
3H), 2.38 (s, 3H), 2.09–1.92 (m, 4H); MS (ESI+) m/e
+
.
379 (M+H) . Anal. (C23H26N2O3 0.1H2O) C, H, N.
4-Methoxy-4-[3-[4-(4-methyl-1H-imidazol-1-yl)benzyloxy]-
phenyl]-3,4,5,6-tetrahydro-2H-pyran (1f). Mp=120–
121 ꢀC; H NMR (CDCl3) 7.76 (d, 1H, J=1 Hz), 7.55
1
(d, 2H, J=9 Hz), 7.39 (d, 2H, J=9 Hz), 7.32 (t, 1H,
J=8 Hz), 7.26–7.00 (m, 3H), 6.91 (dd, 1H, J=8 and 2
Hz), 5.11 (s, 2H), 3.87–3.82 (m, 4H), 2.98 (s, 3H), 2.31
(s, 3H), 2.04–1.92 (m, 4H); MS (ESI+) m/e 379
(M+H)+. Anal. (C23H26N2O3) C, H, N.
A mixture of 4-(5-fluoro-3-hydroxyphenyl)-4-benzylxy-
3,4,5,6-terahydro-2H-pyran (3b, 1.4g, 6.8 mmol), 4-(2-
methyl-1H-imidazol-1-yl)benzylchloride hydrochloride
(1.65 g, 6.8 mmol) and potassium carbonate (7.2 g, 68
mmol) in dry DMF (10 mL) was stirred at 120 ꢀC for
2 h. The mixture was poured into water (100 mL) and
extracted with ethyl acetate–benzene (300 mL, 2:1 v/v).
The organic phase was washed with water (100 mL),
brine (100 mL), dried (MgSO4) and evaporated. Pur-
ification of the residual yellow solids by column chro-
matography on silica gel (100 g) eluting with
dichloromethane/methanol 10:1 and recrystallization
from ethyl acetate–n-hexane gave 4-[5-fluoro-3-[4-(2-
mthyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-4-methoxy-
3,4,5,6-tetrahydro-2H-pꢀyran as off-white solids (1.9 g,
4-[3-[4-(2-Ethyl-1H-imidazol-1-yl)benzyloxy]phenyl]-4-
methoxy-3,4,5,6-tetrahydro-2H-pyran (1i). Oil; 1H
NMR (CDCl3) 7.57 (d, 2H, J=8 Hz), 7.33 (dd, 1H,
J=8, 8 Hz), 7.32 (d, 2H, J=8 Hz), 7.07 (d, 1H, J=1
Hz), 7.06 (d, 1H, J=3 Hz), 7.02 (d, 1H, J=8 Hz), 6.98
(d, 1H, J=1 Hz), 6.93 (ddd, 1H, J=8, 3, 1 Hz), 5.14(s,
2H), 3.88–3.82 (m, 4H), 2.98 (s, 3H), 2.67 (q, 2H, J=8
Hz), 2.09–1.92 (m, 4H), 1.26 (t, 3H, J=8 Hz); MS
+
.
(ESI+) m/e 393 (M+H) . Anal. (C24H28N2O3 0.2H2O)
C, H, N.
4-[3-[4-(2-Ethyl-1H-imidazol-1-yl)benzyloxy]-5-fluoro-
phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran hydro-
1
39%)): mp=168–168.5 C; H NMR (CDCl3) 7.56 (d,
chloride (1j). Mp=210–211 ꢀC; H NMR (CDCl3) 7.71
2H, J=8 Hz), 7.34(d, 2H, J=8 Hz), 7.04(d, 1H, J=1
Hz), 7.01 (d, 1H, J=1 Hz), 6.83 (br s, 1H), 7.75 (ddd,
1H, J=10, 2 and 2 Hz), 6.64(ddd, 1H, J=10, 2 and 2
Hz), 5.11 (s, 2H), 3.86–3.81 (m, 4H), 2.99 (s, 3H), 2.38
(s, 3H), 1.99–1.88 (m, 4H); MS (ESI+) m/e 397
(M+H)+. Anal. (C23H25FN2O3) C, H, N.
1
(d, 2H, J=8 Hz), 7.47 (d, 1H, J=2 Hz), 7.42 (d, 2H,
J=8 Hz), 7.15 (d, 1H, J=2 Hz), 6.85 (brs, 1H), 6.77
(ddd, 1H, J=10, 2, 2 Hz), 6.33 (ddd, 1H, J=10, 2, 2),
5.17 (s, 2H), 3.9–3.8 (m, 4H), 3.06 (q, 2H, J=8 Hz),
3.01 (s, 3H), 2.00–1.90 (m, 4H), 1.41 (t, 3H, J=8 Hz);
+
.
MS (ESI+) m/e 411 (M+H) . Anal. (C24H27FN2O3 HCl)
C, H, N.
Step 2: 4-[5-Fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)ben-
zyloxy]-phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran
hydrochloride (1g HCl). To a stirred solution of 4-[5-
fluoro-3-[4-(2-mthyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-
4-methoxy-3,4,5,6-tetrahydro-2H-pyran (0.5 g, 1.3
mmol) in dry dichloromethane (5 mL) was added
‘Hydrogen Chloride; Methanol Reagent 10’ (4mL,
Tokyo Chemical Industries) at ambient temperature.
After being stirred for 10 min, volatiles were removed
under reduced pressure. The crude product was recrys-
4-Methoxy-4-[3-[4-(4-phenyl-1H-imidazol-1-yl)benzyloxy]-
phenyl]-3,4,5,6-tetrahydro-2H-pyran (1m). Mp=117–
117.5 ꢀC; 1H NMR (CDCl3) 7.49 (d, 2H, J=9 Hz),
7.42–7.38 (m, 2H), 7.32 (t, 1H, J=8 Hz), 7.30–7.23 (m,
6H), 7.16 (d, 1H, J=1 Hz), 7.05–7.00 (m, 2H), 6.91 (dd,
1H, J=9, 2 Hz), 5.21 (s, 2H), 3.91–3.82 (m, 4H), 2.98 (s,
3H), 2.09–1.92 (m, 4H); MS (ESI+) m/e 441 (M+H)+.
Anal. (C28H28N2O3) C, H, N.

T. Mano et al. / Bioorg. Med. Chem. 11 (2003) 3879–3887
3885
tallized from isopropyl alcohol/ethanol (4:3) to give the
title compound 1i (0.3 g, 55%) as white solids:
mp=233–234 ꢀC (decomposition); 1H NMR (CDCl3)
7.71 (d, 2H, J=8 Hz), 7.43 (d, 2H, J=2 Hz), 7.72 (d,
2H, J=8 Hz), 7.19 (d, 1H, J=2 Hz), 6.84(br s, 1H),
6.77 (ddd, 1H, J=10, 2 and 2 Hz), 6.62 (ddd, 1H,
J=10, 2 and 2 Hz), 5.16 (s, 2H), 3.9–3.8 (m, 4H), 3.00
(s, 3H), 2.77 (s, 3H), 2.0–1.8 (m, 4H). Anal.
pereture. 4-Fluorobenzaldehyde (2.54 g, 20.5 mmol) was
added to the reaction mixture, and the resulting solution
was stirred for 60 h. The reaction mixture was poured
into an ice-cooled saturated NH4Cl solution and
extracted with ethyl acetate. The organic layer was
washed with water and brine, dried (MgSO4) and the
solvent removed under reduced pressure. The resultant
residue was purified by column chromatography (5%
methanol in ethyl acetate) to give crude 4-(4-methyl-1H-
imidazol-1-yl)benzaldehyde (3.0 g) as oil, which was
contaminated with unknown impurities and used with-
out further purification.
.
(C23H25FN2O3 HCl) C, H, Cl, F, N.
The following compounds were prepared from appro-
priate benzyl alcohols and phenol 3b according to a
similar procedure to that of 1g and 1g HCl.
To a stirred solution of the crude 4-(4-methyl-1H-imi-
dazol-1-yl)benzaldehyde (3.0 g) in methanol (20 mL)
cooled to 0 ꢀC was added NaBH4 (0.352 g, 8.7 mmol) in
portions over 15 min and the whole stirred for 1 h. A
saturated aqueous NH4Cl solution (50 mL) was added
to the reaction mixture and methanol was evaporated
off. The resultant aqueous mixture was extracted with
ethyl acetate. The organic layer was washed with water,
brine, dried (MgSO4), and solvent removed under
reduced pressure. The crude product was recrystallized
from isopropyl alcohol–isopropyl ether to give 2f (0.51 g,
21% byꢀ 2 steps) as a white amorphous solid: mp
138–141 C; 1H NMR (CDCl3) 7.65 (br, 1H), 7.5–7.3 (m,
4H), 7.0 (br, 1H), 4.8 (s, 2H), 2.3 (s, 3H); MS (ESI+) m/e
189 (M + H)+. Anal. (C11H12N2O) C, H, N.
4-[5-Fluoro-3-[4-(1-methyl-1H-imidazol-2-yl)benzyloxy]-
phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1d).
Mp=160–161 ꢀC; H NMR (CDCl3) 7.68 (d, 2H, J=8
1
Hz), 7.52 (d, 2H, J=8 Hz), 7.13 (d, 1H, J=1 Hz), 6.98
(d, 1H, J=1 Hz), 6.86–6.81 (m, 1H), 6.73 (ddd,
1H, J=10, 2 and 1 Hz), 6.64(ddd, 1H, J=10, 3 and
2 Hz), 5.11 (s, 2H), 3.91–3.78 (m, 4H), 3.77 (s, 3H),
2.98 (s, 3H), 2.08–1.83 (m, 4H); MS (ESI+) m/e 397
+
.
(M+H) . Anal. (C23H25FN2O3 0.4H2O) C, H, N.
4-[3-Fluoro-5-[4-(2-trifluoromethyl-1H-imidazol-1-yl)ben-
zyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran
(1h). Mp=96–98 ꢀC; 1H NMR (CDCl3) 7.57 (d, 2H,
J=8 Hz), 7.41 (d, 2H, J=8 Hz), 7.24(d, 1H, J=2 Hz),
7.16 (d, 1H, J=1 Hz), 6.85–6.60 (m, 3H), 5.14(s, 2H),
3.90–3.80 (m, 4H), 2.98 (s, 3H), 2.05–1.85 (m, 4H); MS
(ESI+) m/e 451 (M+H)+. Anal. (C23H22F4N2O3) C,
H, N.
4-(2-Methyl-1H-imidazol-1-yl)benzyl alcohol (2e). Step
1: Ethyl 4-(2-methyl-1H-imidazol-1-yl)benzoate. A mix-
ture of 2-methyl-1H-imidazole (50 g, 0.6 mol), ethyl
4-fluorobenzoate (100 g, 0.6 mol) and potassium car-
bonate (415 g, 3 mol) in dry DMSO (1.5 L) was heated
at 120 ꢀC for 66 h under a nitrogen atmosphere. After
cooling to room temperature, the mixture was poured
into ice water (1 L), and extracted with Et2O (2Â750
mL). The combined organic phases were washed with
water (500 mL) and then with brine (500 mL), dried
(MgSO4) and evaporated. The residual solid was recrys-
tallized from ethyl acetate–n-hexane to give ethyl 4-(2-
methyl-1H-imidazol-1-yl)benzoate (47 g, 33%) as yellow
The following hydrochloride salt compounds were pre-
pared from appropriate benzyl alcohols and phenol 3b
according to a similar procedure to that of 1g HCl.
4-[3-Fluoro-5-[4-(2-propyl-1H-imidazol-1-yl)benzyloxy]-
phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran hydro-
chloride (1k HCl). Mp=142–146 ꢀC; 1H NMR
(DMSO-d6) 7.89 (d, 1H, J=2 Hz), 7.82 (d, 1H, J=2
Hz), 7.88–7.63 (m, 4H), 6.95–6.77 (m, 3H), 5.27 (s, 2H),
3.77–3.59 (m, 4H), 2.89 (s, 3H), 2.86 (t, 2H, J=8 Hz),
2.00–1.80 (m, 4H), 1.70–1.52(m, 2H), 0.79 (t, 3H, J=7.3
Hz); MS (ESI+) m/e 425 (M+H)+. Anal.
needles: mp 72–73 ꢀC; H NMR (CDCl3) 8.22–8.12 (m,
1
2H), 7.43–7.33 (m, 2H), 7.10–6.99 (m, 2H), 4.42 (q, 2H,
J=7 Hz), 2.42 (s, 3H), 1.43 (t, 3H, J=7 Hz); IR (KBr)
1720 cmÀ1. Anal. (C13H14N2O2) C, H, N.
.
.
(C25H29N2O3 HCl 0.5H2O) C, H, N.
4-[3-Fluoro-5-[4-(2-isopropyl-1H-imidazol-1-yl)benzyl-
oxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran hydro-
Step 2: 4-(2-Methyl-1H-imidazol-1-yl)benzyl alcohol
(2e). To a solution of ethyl 4-(2-methyl-1H-imidazol-1-yl)-
benzoate (46 g, 0.20 mol) in dry dichloromethane (1 L)
cooled to À75 ꢀC under a nitrogen atmosphere was
added di-iso-butylaluminum hydride in n-hexane
(0.93 M, 540 mL, 0.50 mol) carefully over 30 min and
then the mixture allowed to warm slowly to room tem-
perature. After stirring for 5 h, the reaction mixture was
cooled in an ice-bath, after which methanol (30 mL) was
carefully added. A 30% aqueous solution of Rochelle
salt (500 mL) was then added, and the mixture was
stirred at room temperature for 16 h. Insolubles were
collected by filtration, and the organic phase was sepa-
rated, washed with water (500 mL) and dried (MgSO4).
The solvents were evaporated to yield a second solid.
The combined solids were recrystallized from ethanol
chloride (1l HCl). Mp=140–143 ꢀC; H NMR (DMSO-
1
d6) 7.86 (d, 1H, J=2 Hz), 7.83 (d, 1H, J=2 Hz), 7.74(d,
2H, J=8 Hz), 7.68 (d, 2H, J=8 Hz), 6.95–6.77 (m, 3H),
5.28 (s, 2H), 3.78–3.59 (m, 4H), 3.15–3.00 (m, 1H), 2.89 (s,
3H), 2.00–1.80 (m, 4H), 1.31 (d, 6H, J=7 Hz); MS (ESI+)
+
.
m/e 425 (M+H) . Anal. (C25H29N2O3 HCl 0.3H2O) C,
.
H, N.
4-(4-Methyl-1H-imidazol-1-yl)benzyl alcohol (2f). To a
suspension of NaH (0.82 g, 20.5 mmol: 60% suspension
on mineral oil) in dry DMF (20 mL) cooled to 0 ꢀC was
added a solution of 4-methylimidazole (1.64 g, 20
mmol) in DMF (10 mL) under a nitrogen atmosphere,
and the mixture was stirred for 20 min at room tem-

3886
T. Mano et al. / Bioorg. Med. Chem. 11 (2003) 3879–3887
(ca. 300 mL) to afford 4-(2-methyl-1H-imidazol-1-yl)-
benzyl alcohol (35.6 g, 95%) as white needles: mp 167–
168 C; H NMR (DMSO-d6) 7.50–7.33 (m, 4H), 7.25
(d, 1H, J=2 Hz), 6.90 (d, 1H, J=2 Hz), 5.33 (t, 1H,
J=6 Hz), 4.56 (d, 2H, J=6 Hz), 2.27 (s, 3H); IR (KBr)
3200 cmÀ1. Anal. (C11H12N2O) C, H, N.
4-[2-(2-Pyridyl)-1H-imidazol-1-yl]benzyl alcohol (2o).
Benzyl alcohol 2o was prepared from 2-(2-pyridyl)-
1H-imidazole and 4-fluorobenzonitrile as a white
solid according to the procedure described as step 2
for 2m: mp=147–148 ꢀC; 1H NMR (CDCl3) 8.36–
8.27 (m, 1H), 7.89 (d, 1H, J=8 Hz), 7.70 (dd, 1H,
J=8 and 2 Hz), 7.39 (d, 2H, J=9 Hz), 7.30–7.07 (m,
5H), 4.76 (d, 2H, J=5 Hz), 2.07 (br s, 1H); MS
(ESI+) m/e 252 (M+H)+. Anal. (C15H13N3O) C, H,
N.
ꢀ
1
The following benzyl alcohols were synthesized from
appropriate imidazoles and the corresponding ethyl
4-fluorobenzoates in a similar manner to that described
for 2e.
4-(1-Methyl-1H-imidazol-2-yl)benzyl alcohol (2d).21 Step
1: Ethyl 4-(1H-imidazol-2-yl)benzoate. Ethyl 4-(1H-imi-
dazol-2-yl)benzoate was prepared from ethyl 4-(1H-4,5-
dihydroimidazol-2-yl)benzoate22 as a yellow solid (32%)
according to the literature procedure:23 1H NMR
(CDCl3) 8.19–7.61 (m, 4H), 7.16 (s, 2H), 5.31 (s, 1H),
4.39 (q, 2H, J=7 Hz), 1.41 (t, 3H, J=7 Hz).
4 - (2 - Ethyl - 1H - imidazol - 1 - yl)benzyl alcohol (2i).
Mp=104–105 ꢀC; H NMR (CDCl3) 7.50 (d, 2H, J=8
Hz), 7.28 (d, 2H, J=8 Hz), 7.02 (d, 1H, J=1 Hz), 6.97
(d, 1H, J=1 Hz), 4.80 (s, 2H), 2.63 (dq, 2H, J=1 and 8
Hz), 1.23 (dt, 3H, J=3 and 8 Hz); MS (ESI+) m/e 203
(M+H)+. Anal. (C12H14N2O) C, H, N.
1
4 - (2 - Propyl - 1H - imidazol - 1 - yl)benzyl alcohol (2k).
Mp=78–79 ꢀC; H NMR (CDCl3) 7.60–6.80 (m, 6H),
4.80 (s, 2H), 2.70–2.45 (m, 2H), 2.00–1.50 (m, 3H),
1.00–0.70 (m, 3H); MS (ESI+) m/e 217 (M+H)+.
Anal. (C13H16N2O) C, H, N.
Step 2: Methyl 4-(1-methyl-1H-imidazol-2-yl)benzoate.
A mixture of ethyl 4-(-1H-imidazol-2-yl)benzoate (1.54
g, 7.1 mmol), potassium carbonate (1.13 g, 11 mmol),
18-crown-6 (26 mg, 0.1 mmol) and dimethyl carbonate
(2.45 g, 25 mmol) was heated at 100 ꢀC under a nitrogen
atmosphere. After 44 h, the mixture was concentrated to
dryness, the residue was covered with water and the
whole was extracted with dichloromethane. The organic
layer was washed with water (100 mL), dried (MgSO4)
and concentrated to dryness. Column chromatographic
purification (3% methanol in dichloromethane) yielded
methyl 4-(1-methyl-1H-imidazol-2-yl)benzoate (0.65 g,
42%).
1
4 - (2 - Isopropyl - 1H - imidazol - 1 - yl)benzyl alcohol (2l).
Mp=165–166 ꢀC; 1H NMR (CDCl3) 7.55–6.80 (m,
6H), 4.79 (s, 2H), 3.07–2.85 (m, 1H), 2.37 (br s, 1H),
1.24(d, 6H, J=6.9 Hz); MS (ESI+) m/e 217 (M+H)+.
Anal. (C13H16N2O) C, H, N.
4 - (2 - Benzyl - 1H - imidazol - 1 - yl)benzyl alcohol (2n).
Mp=131–132 ꢀC; 1H NMR (CDCl3) 7.45–7.37 (m,
2H), 7.28–7.10 (m, 8H), 7.00 (d, 1H, J=1 Hz), 4.77 (d,
2H, J=4Hz), .402 (s, 2H), 2.20–2.07 (br, 1H); MS
(ESI+) m/e 265 (M+H)+. Anal. (C17H16N2O) C, H.
Step 3: 4-(1-Methyl-1H-imidazol-2-yl)benzyl alcohol
(2d).21 Benzyl alcohol 2d was prepared from methyl
4-(1-methyl-1H-imidazol-2-yl)benzoate as a yellow oil
according to the procedure described as step 2 for 2e:
1H NMR (CDCl3) 7.53 (d, 2H, J=8 Hz), 7.37 (d, 2H,
J=8 Hz), 7.12 (d, 1H, J=1 Hz), 6.96 (d, 1H, J=1 Hz),
4.72 (s, 2H), 3.72 (s, 3H).
4-(2-Phenyl-1H-imidazol-1-yl)benzyl alcohol (2m). To a
solution of 4-(2-phenyl-1H-imidazol-1-yl)benzonitrile9
(3.2 g, 13 mmol) in dichloromethane (30 mL) and tolu-
ene (20 mL) cooled to À78 ꢀC was added dropwise dii-
sobutylalminum hydride in toluene (1.02 M, 13 mL, 13
mmol) under a nitrogen atmosphere and the whole stir-
red at this temperature for 1.5 h. Saturated aqueous
NH4Cl solution (20 mL) was then added carefully to the
reaction mixture, and the whole allowed to warm to
room temperature. The resulting gelatinous mixture was
washed with 0.3 N HCl solution (100 mL), water (200
mL) and brine (100 mL), and the organic layer dried
(MgSO4). Removal of solvent under reduced pressure
provided crude product (2.5 g), which was dissolved in
methanol (30 mL) and cooled to 0 ꢀC. NaBH4 (0.3 g, 8
mmol) was added in portions and the reaction mixture
and the whole extracted three times with ethyl acetate
(20 mL). The organic layer was washed with water (10
mL), brine (10 mL), dried (MgSO4) and solvent
removed under reduced pressure. The resultant crude
product was washed with ethyl acetate (35 mL) to give
2m (0.81 g, 25%) as a white powder: mp=176–178 ꢀC;
1H NMR (CDCl3) 7.41–7.34 (m, 4H), 7.29–7.18 (m,
6H), 7.15 (t, 1H, J=1 Hz), 4.75 (s, 2H), 2.6 (br, 1H);
MS (ESI+) m/e 251 (M+H)+. Anal. (C16H14N2O) C,
H, N.
4-(2-Trifluoromethyl-1H-imidazol-1-yl)benzyl alcohol
(2h). Step 1: 4-(2-Iodo-1H-imidazol-1-yl)benzonitrile. To
a solution of 4-(1H-imidazol-1-yl)benzonitrile9b (5.08 g,
30 mmol) stirred at À78 ꢀC under a nitrogen atmo-
sphere was added a solution of n-butyllithium in n-hex-
ane (1.61 M, 20 mL, 33 mmol). After 30 min at À78 ꢀC,
iodine (9.1 g, 36 mmol) was added, the resultant mixture
allowed to warm to room temperature. After stirred at
room temperature for 2 h, the mixture was poured into
water (100 mL) and the whole extracted with ethyl acetate
(100 mL). The organic layer was washed with water (100
mL) and brine (100 mL) and dried (MgSO4). Removal of
solvent afforded 5.20 g of yellow solid, which was recrys-
tallized from n-hexane–ethyl acetate to yield 1.06 g of
4-(2-iodo-1H-imidazol-1-yl)benzonitrile as a yellow solid.
The filtrate was concentrated to dryness and purified by
column chromatography (methanol/dichloromethane) to
give another 1.66 g of 4-(2-iodo-1H-imidazol-1-yl)benzo-
nitrile (total, 35%): mp=194–198 ꢀC; 1H NMR (CDCl3)
7.84(d, 2H, J=9 Hz), 7.54(d, 2H, J=9 Hz), 7.30–7.20
(m, 2H); MS (ESI+) m/e 296 (M+H)+. Anal.
(C10H6N3I) C, H, N.

T. Mano et al. / Bioorg. Med. Chem. 11 (2003) 3879–3887
3887
Step 2: 4-(2-Trifluoromethyl-1H-imidazol-1-yl)benzoni-
trile. A stainless tube was charged with 4-(2-iodo-1H-
imidazol-1-yl)benzonitrile (2.74, 9.27 mmol), trimethyl-
silyltrifluoromethane (1.98 g, 13.9 mmol), cuprous
iodide (3.52 g, 13.9 mmol), potassium fluoride (0.807 g,
13.9 mmol), DMF (20 mL) and 1-methyl-2-pyrrolidone
(20 mL) was sealed and heated to 80 ꢀC. After 41 h, the
reaction mixture was poured into a mixture of ethyl
acetate/benzene (2:1, 300 mL) and water (200 mL).
Precipitates were filtered off and the organic layer was
separated, washed with water (100 mL) and brine (100
mL), dried (MgSO4) and concentrated to dryness.
Recrystallization of the residue from Et2O afforded 4-
(2-trifluoromethyl-1H-imidazol-1-yl)benzonitrile (0.820
5. Bird, T. G. C.; Olivier, A. Bioorg. Med. Chem. Lett. 1996,
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g, 37%) as a yellow solid: mp=123–124 ꢀC; H NMR
1
(CDCl3) 7.84(d, 2H, J=8 Hz), 7.53 (d, 2H, J=8 Hz),
7.29 (d, 1H, J=1 Hz), 7.19 (s, 1H, J=1 Hz); MS
(ESI+) m/e 238 (M+H)+. Anal. (C11H6N3F3) C, H, N.
Step 3: 4-(2-Trifluoromethyl-1H-imidazol-1-yl)benzyl al-
cohol (2h). Benzyl alcohol 2h was prepared as a white
solid from 4-(2-trifluoromethyl-1H-imidazol-1-yl)benzo-
nitrile according to the procedure described for 4-(2-phenyl-
1H-imidazol-1-yl)benzyl alcohol (2m): mp=112–114 ꢀC
1H NMR (CDCl3) 7.55–7.05 (m, 6H), 4.08 (d, 2H, J=2
Hz), 1.95 (t, 1H, J=2 Hz); MS (ESI+) m/e 243
(M+H)+. Anal. (C11H9N2F3O) C, H, N.
14. Rackham, Anita; Ford-Hutchinson, A. W. Pros-
taglandines 1983, 25, 193.
15. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney,
P. J. Adv. Drug Deliv. Rev. 1997, 23, 3.
Acknowledgements
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912.
17. Avdeef, A. Curr. Top. Med. Chem. 2001, 1, 277.
18. Solubility, log P and pKa data of 1g HCl were provided by
Fiese, E. E.; Campeta, A.; Biron, M. Pfizer Global Research &
Development, Groton Laboratories, Eastern Point Road,
Groton, CT 06340, USA.
The authors thank Mses. Yoko Matsuoka and Jinsong
Niu for their elemental analyses and mass measurement,
respectively.
19. (a) Aleo, M. D.; Drupa, C. A.; Fritz, C. A.; Walsh, C. M.;
Whitman-Sherman, J. L.; Fortner, J. H. Abstracts of Papers,
40th Annual Meeting of the Society of Toxicology, San Fran-
cisco CA, March 25–29, 2001, Society of Toxicology: VA.
Abstact #480. (b) Baltrukonis, D. J.; Fritz, C. A.; Jakowski,
A. B.; Boucher, G. G.; Costello, K. M.; Wolfgang, J. C.;
Render, M. W.; Tengowski, J. A.; Fortner, J. H.; Lawton, M.
P.; Nelms, C. A.; Drupa, C. A.; Verdugo, M. E.; Kajiji, S.;
Aleo, M. D. Abstracts of Papers, 40th Annual Meeting of the
Society of Toxicology, San Francisco CA, 25–29 March 2001,
Society of Toxicology: VA. Abstract #482.
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