Optimization of imidazole 5-lipoxygenase inhibitors and selection and synthesis of a development candidate

Article abstract of DOI:10.1248/cpb.53.965

Structural modification of imidazole 5-lipoxygenase (5-LO) inhibitors for optimizing inhibitory potency, pharmacokinetic behavior and toxicity (ocular) profile led to 4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]}phenyl-3,4,5,6- tetrahydro-2H-pyran-4-car

Full text of DOI:10.1248/cpb.53.965

August 2005
Chem. Pharm. Bull. 53(8) 965—973 (2005)
965
Optimization of Imidazole 5-Lipoxygenase Inhibitors and Selection and
Synthesis of a Development Candidate
Takashi MANO,* Rodney W. STEVENS, Kazuo ANDO, Makoto KAWAI, Kiyoshi KAWAMURA,
Kazunari NAKAO, Yoshiyuki OKUMURA, Takako OKUMURA, Minoru SAKAKIBARA,
Kimitaka MIYAMOTO, and Tetsuya TAMURA
Pfizer Global Research & Development, Nagoya Laboratories; 5–2 Taketoyo, Aichi 470–2393, Japan.
Received March 13, 2005; accepted May 16, 2005
Structural modification of imidazole 5-lipoxygenase (5-LO) inhibitors for optimizing inhibitory potency,
pharmacokinetic behavior and toxicity (ocular) profile led to 4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenyl-
thio]}phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (6) with no observable ocular toxicity. The orally active
and safe imidazole 5-LO inhibitor 6 was selected as a clinical candidate and advanced to clinical studies. An im-
proved synthesis of 6 is also discussed.
Key words lipoxygenase; inhibitor; structure–activity relationship; leukotriene; unsymmetric thioether
The leukotrienes (LTs) are endogenous mediators with po- ships (SARs) identified novel imidazole lead-compound 2
tent biological activity. It is known that leukotriene B4 (LTB4) with modest oral pharmacology and improved pharmacoki-
is a potent chemotactic agent for leukocytes while peptide netic profile.8,9) Importantly, compared with 1, ocular toxicity
leukotrienes (i.e., LTC4, LTD4 and LTE4) are powerful bron- of 2 was significantly reduced. In this paper, we disclose our
choconstrictor agents. 5-Lipoxygenase (5-LO) is the key en- efforts focused on optimization of 2 leading to the discovery
zyme in LT biosynthesis and catalyzes the initial steps in of clinical candidate, a novel 5-LO inhibitor void of ocular
conversion of arachidonic acid to LTs.1,2) Accordingly, in- toxicity as assessed in preclinical models.
hibiting the action of 5-LO and antagonizing the action of
LTs are expected to be valuable for the treatment of acute Chemistry
and chronic diseases such as asthma, allergic rhinitis and
psoriasis. It has been shown that 5-LO inhibitors and LTD4 study. Compounds 3 and 8 were synthesized as shown in
antagonists are efficacious in asthmatics.3—7)
Chart 2. Phenol 10, which was obtained by demethylation of
Imidazole compounds 3—8 were synthesized for this
We have disclosed on imidazole compound 1 as a novel known 3,4,5,6-tetrahydro-2H-pyran (THP) compound 9,10)
orally active 5-LO inhibitor (Chart 1). Shortcomings of 1 was treated with benzyl chloride 11 in the presence of K2CO3
were unsatisfactory pharmacokinetic profile and unwanted to give ether 12.8) Selective hydrolysis of nitrile 12 gave
side effects (ocular). Preliminary structure–activity relation- amide 3 (approximately 4 equivalents of powdered KOH in t-
BuOH at 80 °C).11) Similarly, nitrile 15, which was obtained
by coupling of 10 with iodide 14 in the presence of cupric
oxide, was converted to amide 8.
Chart 3 illustrates the synthesis of 4. Aldehyde group was
selectively introduced to commercially available 2,5-difluo-
rophenol 16 to give 19, which was converted to methyl a-
phenyl acetate derivative 22 in a stepwise manner. THP ring
was constructed by the method reported for the preparation
of 2.9) The THP 23 was demethylated to phenol 24, which
was treated with benzyl chloride 11 to give imidazole ester
25. The ester 25 was converted to amide 4 by standard proce-
dure.9)
Synthesis of 5 is depicted in Chart 4. Difluorobenzene
2611) was converted to the monomethylthioether 27. Oxida-
tion of 27 to the corresponding sulfoxide 28 followed by
Pummerer rearrangement yielded thiophenol 29. Palladium-
catalyzed coupling of 29 with iodide 14 gave nitrile 30,
which was selectively hydrolyzed to yield amide 5.
Chart 5 shows the syntheses of 6 and 7. Ester 32, synthe-
sized from ethyl (3-bromophenyl)acetate, was converted to
intermediate methyl thioether by lithium–bromine exchange
of carboxylic acid 33 with n-buthyl lithium followed by treat-
ment with dimethyl disulfide. The intermediate methyl
thioether was converted to 35 via sulfoxide 34. Palladium-
catalyzed coupling of 35 with iodide 14 gave thioether 36,
which was transformed to amide 6 via carboxylic acid 37.
Chart 1. Structures of Representative Imidazole 5-LO Inhibitors and Their
Improvement
∗ To whom correspondence should be addressed. e-mail: Takashi.Mano@pfizer.com
© 2005 Pharmaceutical Society of Japan

966
Vol. 53, No. 8
(i) BBr3, CH2Cl2; (ii) K2CO3, DMF; (iii) KOH, t-BuOH; (iv) NaH, 4-fluoro-1-iodobenzene, DMF; (v) CuO, K2CO3, pyridine.
Chart 2. Syntheses of 3 and 8
(i) NaH, TBDMSCl, DMF; (ii) sec-BuLi, THF, then DMF; (iii) KF, MeI, DMF; (vi) NaBH4, EtOH; (v) p-toluenesulfonyl chloride, triethylamine, then NaCN, DMSO; (vi) KOH,
ethylene glycol, then MeOH, H2SO4; (vii) NaH, 15-Crown-5, (ClCH2CH2)2O, DMF; (viii) BBr3, CH2Cl2; (ix) 11, K2CO3, DMF; (x) LiOH, THF, MeOH, H2O; (xi) (COCl)2,
CH2Cl2, then aqueous NH3.
Chart 3. Synthesis of 4
Oxidation of 6 with hydrogen peroxide gave sulfone 7.
The improved synthesis of 6 is shown in Chart 6. Several
yield.
Then, triisopropylsilylthiol was efficiently introduced to 39
conditions were examined to prepare 39 from 38. Reactions under the presence of palladium catalyst to afford 40. Triiso-
were carried out in a 1-mmol scale (i.e., 0.24 g of 38) and the propylsilylthioether 40 was coupled with iodide 14 to give
results are summarized in Table 1. The best result was ob- the desired thioether 41 with 75% yield from 39. The nitrile
tained when sodium hydride was used as base in DMSO (run of 41 was efficiently hydrolyzed to give 1 selectively, accord-
4: 78%). Phase-transfer catalyst (PTC) also yielded 39 (runs ing to the procedure developed for the large scale synthesis
5 and 6). Especially use of hexadecyltri-n-butylphosphonium of 2.11) Thus, 24 g of 6 was obtained with 98% purity by
bromide afforded 39 with 74% yield. However, in a 35-g HPLC.
scale synthesis, several impurities contaminated in the prod-
Biological Testing The 5-LO inhibitory activity of the
uct, and further purification was required.11) Thus, the condi- compounds was routinely evaluated in vitro using he-
tion of run 4 was chosen for a large scale synthesis and the parinized human whole blood (HWB) quantitating LTB4.12)
reaction was achieved to provide 39 in a 35-g scale with 75% The in vivo potency after oral administration of compounds

August 2005
967
to mice was determined by PAF (platelet activating factor)- methoxy group of 1 with aminocarbonyl (2) is well tolerated,
induced thrombosis assay.13—15)
and that metabolic stability was substantially enhanced, re-
sulting in reduced ocular toxicity and improved pharmacoki-
netic profile. In this paper we disclose SAR leading to devel-
Results and Discussion
We have already demonstrated that replacement of the opment candidate 6. We have examined both the connection
between the left handle and the central phenyl (viz., X in
Table 2) and the effect of fluorine atom(s) (viz., Y and Z in
Table 2) on the central phenyl ring (Table 2). Removal of the
fluorine atom of 2 reduced in vitro potency (3). Adding a flu-
orine atom at the 2 position of the central phenyl ring of 2,
exemplified by 4, slightly reduced in vitro and in vivo po-
Table 1. THP Ring Construction on 39
Run
Base
Solvent
Additive
Yield %
1a)
2a)
3a)
4a)
5b)
6b)
t-BuOK
NaOEt
NaNH2
NaH
NaOH
NaOH
DMF
None
None
None
None
20
ꢀ10
50
78
74
EtOH
DMSO
DMSO
Water
Water
CH3(CH2)15P(n-Bu)3Br
PhCH2N(Et)3Cl
35
(i) MeSNa, DMF; (ii) NaIO4, MeOH, H2O; (iii) (CF3CO)2O, then triethylamine,
MeOH; (iv) 14, Pd(PPh)4, t-BuONa, EtOH; (v) KOH, t-BuOH.
a) The reaction was conducted under a nitrogen atmosphere. b) 50% aqueous
NaOH.
Chart 4. Synthesis of 5
(i) NaH, 15-Crown-5, (ClCH2CH2)2O, DMF; (ii) LiOH, THF, MeOH, H2O; (iii) n-BuLi, MeSSMe, THF; (iv) HCl, MeOH; (v) NaIO4, MeOH, H2O; (vi) (CF3CO)2O, then triethy-
lamine, MeOH; (vii) 14, Pd(PPh)4, t-BuONa, EtOH; (viii) LiOH, THF, MeOH, H2O; (ix) (COCl)2, CH2Cl2, then aqueous NH3; (x) H2O2, AcOH.
Chart 5. Syntheses of 6 and 7
(i) NaH, (ClCH2CH2)2O, DMSO (75%); (ii) NaH, triisopropylsilylthiol, Pd(PPh3)4, THF; (iii) t-BuOK, Pd(PPh3)4, EtOH (75% by two steps); (iv) KOH, t-BuOH (77%) (44%
total yield).
Chaet 6. Improved Symthesis of 6

968
Vol. 53, No. 8
Table 2. Effects of Structural Modification of 1
Compd.
X
Y
Z
W
HWB IC50 (mM)a)
PAF-thrombosis ED50 (mg/kg)a)
1·HCl
2
3
4
5
6
6·HCl
7
8
CH2O
CH2O
CH2O
CH2O
S
F
F
H
F
F
H
H
H
H
H
H
H
F
H
H
H
H
H
OMe
0.060ꢂ0.008 (6)
0.34ꢂ0.11 (4)
1.14
4.5ꢂ1.5 (4)
CONH2
CONH2
CONH2
CONH2
CONH2
CONH2
CONH2
CONH2
4, 9b)
5
8
3
0.47
0.75
S
S
0.20, 0.33b)
0.23ꢂ0.05 (15)
ꢃ1
3.7ꢂ0.3 (3)
3.4ꢂ0.4 (3)
N.D.c)
S(O)2
O
ꢃ1
N.D.c)
a) IC50’s and ED50’s are shown withꢂS.D. (number of determinations), where three or more determinations were made. b) nꢁ2. c) Not determined.
tency. Replacement with sulfur (XꢁS) provided 5 with com-
parable oral in vivo potency but marginally reduced in vitro
inhibitory activity. However, des-fluoro analog 6 essentially
had comparable pharmacology with 1. The effect of fluorine
atom was found to be dependent upon the rest part of the
linkage and was not clearly understood at the moment. On
the other hand, substitution of sulfur with sulfone (XꢁS(O)2:
7) or oxygen (XꢁO: 8) was not tolerated. Thus, connection
between two phenyl rings was found to be critical for po-
tency and sulfur atom was the best as X in the present series
of compounds. Accordingly, 6 was selected for further char-
acterization.
The original discovery route of 6 was, however, a ten-step
synthesis with 14% total yield. In order to provide large
quantity of 6 for further studies including preclinical toxicol-
ogy studies, synthesis of 6 needed to be improved. Firstly, the
original route was not amenable for scaling because of the
low yield Pummerer reaction and instability of 35. Further-
more, carboxylic acid 37 contaminated 6 in a gram-scale
preparation. Consequently, an alternative route was required
for larger-scale synthesis. We have reported the improved
synthesis of 2, which is structurally similar to 6, and it was
anticipated that some of approaches to the improvement in
synthesis of 2 could be adapted to that of 1, that is, the facile
construction of the THP ring and carboxamide moiety.11) Chart 7. Revised Retro-Synthesis of 1
Also as shown in Chart 5, the unsymmetric thioether of 36
was constructed by six-step synthesis from bromide 32 via
unstable thiol 35 with 31% yield. Therefore, a convenient
method of construction the unsymmetric thioether without
isolating an unstable thiol was envisaged. On the base of the
above consideration, the retro-synthesis of 6 was revised as
illustrated in Chart 7, where commercially available 3-
iodophenylacetonitrile 38 was chosen as the starting mater-
ial.
Several methodologies to prepare unsymmetric thiols have
been reported16—18) and the method reported by Miranda and
Soderquist was chosen, since it allows to prevent isolation of
unstable arylthiol by protecting the thiol function with triiso-
propylsilyl group.19,20) This method composed two steps: (i)
introduction of triisopropylsilylthiol to one of the aryl io-
dides under the presence of palladium catalysis to produce
the corresponding protected thiol, (ii) reaction of the product
with the other aryl iodide under the presence of palladium
catalysis to give the desired unsymmetry thioether, without
deprotection step. As shown in Chart 6, the thioether con-
struction was improved by reducing synthetic steps from six
to two and enhancing yield from 31 to 75%. Nitrile 41 was
efficiently hydrolyzed to give 1 selectively, according to the
procedure developed for the large scale synthesis of 2.11)
Thus 24 g of 6 was obtained with 98% purity by HPLC. For
preclinical studies, 6 was converted to the hydrochloride salt
(6·HCl).
It was shown that 6 inhibited LTB4 synthesis in HWB with
an IC50 of 0.23ꢂ0.05 mM (meanꢂS.D., nꢁ15 (Fig. 1). Also 6
provides dose-dependent protection against PAF induced
thrombosis with an ED50 of 3.4ꢂ0.4 mg/kg p.o. (meanꢂS.D.,
nꢁ3, Fig. 2). Pharmacokinetic profiles of 1, 2 and 6 in rats
are illustrated in Fig. 3. In rats, 6 showed improved exposure

August 2005
969
Conclusion
Structure modification of 2 identified clinical candidate 6.
Furthermore a facile synthesis of 6 was developed, applying
the approach developed for 2. This method has advantages,
such as (i) no isolation of unstable thiol, (ii) short synthesis
(i.e., four steps), (iii) higher total yield (44%), (iv) no chro-
matographic purification, (v) 98% purity of the final com-
pound. The new method enabled to provide large quantity of
6, which was used for preclinical toxicology studies. In
rat toxicology studies, no overt ocular toxicity was observ-
ed.21—23) There have been several reports of a role of not only
LTD4 but also LTB4 in the antigen-induced pulmonary reac-
tion. While CycLT1 receptor antagonists, such as pranlukast,
reduce the asthmatic response, protection is incomplete. Fur-
thermore, synergetic effects on inhibitory activity in an
asthma model by pranlukast and an LTB4 antagonist were
also reported.25) The ability of 5-LO inhibitors to inhibit the
biosynthesis of both peptido-leukotrienes and LTB4 may sug-
gest that these drugs could offer distinct advantages over re-
ceptor antagonists in the chronic treatment of inflammatory
disease states.
Fig. 1. In Vitro Potency of 6·HCl on Production of 5-LO Metabolites,
LTB4 in Human Whole Blood Stimulated with A23187
Each point represents the meanꢂS.E.M. (nꢁ15).
Experimental
General Procedures Proton magnetic resonance (1H-NMR) spectra
were measured on a Joel FX270 spectrophotometer at 270 MHz and proton
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), 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 were recorded on a Shi-
madzu IR-440 spectrometer. Low-resolution mass spectra were recorded on
an Automass spectrometer and a Micromass Quattro II spectrometer for DI-
EI and ESI, respectively. High-resolution mass spectra (EI) were recorded on
a JOEL JMS-700 spectrometer (MStation) with direct inlet mode, and re-
ported in m/z. Microanalyses (C, H, N, Cl, S) were performed by Analytical
R&D, Pfizer Global Research & Development Nagoya Laboratories.
4-{3-[4-(2-Methy-1H-limidazol-1-yl)phenyl]thiophenyl}-3,4,5,6-tet-
rahydro-2H-pyran-4-carboxamide Hydrochloride (1·HCl). 4-(2-Meth-
yl-1H-imidazol-1-yl)phenyliodide (14) To a stirred solution of 2-methyl-
imidazole (13.6 g, 165 mmol) in DMF (500 ml) was added sodium hydride
(60% w/w dispersion in mineral oil, 6.60 g, 165 mmol) in portions over
10 min. The resulting white suspension was stirred at room temperature for
30 min, 4-fluoro-1-iodobenzene (33.3 g, 150 mmol) added and the mixture
heated at 100 °C for 16 h. After the bulk of DMF was removed by evapora-
tion, the resulting residue was partitioned between a mixture of ethyl ac-
etate–toluene (2 : 1, 500 ml) and water (250 ml). The organic layer was sepa-
rated and washed with water (250 ml). Product was extracted with 10%
aqueous HCl (2ꢄ200 ml) and the combined aqueous extracts neutralized
with 30% aqueous KOH solution. The resulting suspension was extracted
with a mixture of ethyl acetate–toluene (2 : 1, 3ꢄ250 ml) and the combined
organic extracts washed with water (2ꢄ250 ml), brine (250 ml), dried
(MgSO4) and concentrated to dryness. The residue was recrystallized from
toluene to afford the titled compound as off-white solids (21.9 g, 51%). mp:
136—138 °C; 1H-NMR (CDCl3) d: 7.65—7.61 (2H, m), 7.32—7.26 (2H,
m), 7.33 (1H, d, Jꢁ1.5 Hz), 6.98 (1H, d, Jꢁ1.5 Hz), 2.83 (3H, s); Anal.
Cacl. for C10H9N2I: C, 42.28, H, 3.19; N, 9.86. Found: C, 42.51; H, 3.19; N,
9.70.
Fig. 2. The Effect of 6·HCl Inhibition on PAF-Induced Thrombosis in
Mice
The compound was perorally administered 45 min prior to PAF challenge. Each point
represents the meanꢂS.E.M. (nꢁ3).
Fig. 3. Mean Plasma Concentration of 6, 2, and 1
Drugs were dosed perorally to three female Sprague-Dawley rats (10 mg/kg). Each
point represents the meanꢂS.E.M.
and extended half-life over 1 and 2. Furthermore, no overt
ocular toxicity was observed with 6, and consequently 6 was
advanced to clinical development.21—24) As already discussed,
the ocular toxicity was speculated due to metabolite(s), and
one of the potential explanations was that even though the
systemic exposure of 2 in rats was much higher than that of
1, the incident of cataract formation with 2 was much lower
than that of 1.9) Therefore, it is likely that the structural mod-
4-Cyano-4-(3-iodophenyl)-3,4,5,6-tetrahydro-2H-pyran (39) To a so-
lution of 3-iodophenylacetonitrile (38) (36.7 g, 151 mmol) in DMSO
(250 ml) cooled to 0 °C was added sodium hydride (60% w/w dispersion in
mineral oil, 13.3 g, 332 mmol) portionwise over 10 min. The reaction mix-
ture was stirred for 30 min at room temperature and then bis(2-
chloroethyl)ether (23.0 g, 161 mmol) was added slowly and stirring contin-
ued for an additional 1 h. The reaction mixture was poured into water
(500 ml) and the mixture was extracted with an ethyl acetate–toluene mix-
ture (2 : 1 v/v, 400 mlꢄ3). The combined extracts were washed with 2 N
ification leading to 6 retarded the metabolism that might pro- aqueous HCl (300 ml), water (300 ml) and brine (300 ml), dried (MgSO4)
and concentrated to 100 ml. The precipitated solids were collected and
washed with cold Et2O (50 ml) to afford 35.5 g (75%) of the titled compound
duce toxic metabolite(s) and improved the oral exposure
(Chart 1).

970
Vol. 53, No. 8
as off white solids. mp: 106.6—107.3 °C (recrystallized from diisopropyl stirring. To the resulting mixture, which was nearly homogeneous, was
ether); 1H-NMR (CDCl3) d: 7.83—7.80 (m, 1H), 7.73—7.67 (m, 1H), added 1.35 g of active charcoal. After stirring at reflux for 5 min, the mixture
7.50—7.44 (m, 1H), 7.16 (dd, 1H, Jꢁ8.1, 7.7 Hz), 4.14—4.02 (m, 2H),
was filtered while hot. The yellow filtrate was cooled to 0 °C over 30 min
3.98—3.81 (m, 2H), 2.20—1.99 (m, 2H); IR (KBr) cmꢅ1: 2240; MS (DI-EI) with gentle stirring and maintained to 0 °C for a further 30 min. Precipitates
m/z: 313 (Mꢆ); Anal. Calcd for C12H12NOI: C, 46.03, H, 3.86, N, 4.47. were collected by suction filtration, washed with cold ethanol (4 mlꢄ2) and
Found: C, 46.30; H, 3.68; N, 4.13.
n-hexane (10 ml) and dried under vacuum at 80 °C overnight to give 20.45 g
4-Cyano-4-{3-[tri-(1-methylethyl)]silylthiophenyl}-3,4,5,6-tetrahydro- of the titled compound as white solids. mp: 218—224 °C (decomposition);
2H-pyran (40) To a solution of sodium hydride (60% w/w dispersion in 1H-NMR (DMSO-d6) d: 7.86 (d, 1H, Jꢁ2.2 Hz), 7.76 (d, 1H, Jꢁ2.2 Hz),
mineral oil, 4.66 g, 117 mmol) in THF (180 ml) was added triisopropylsi- 7.60 (d, 1H, Jꢁ8.4 Hz), 7.53—7.50 (m, 1H), 7.48—7.31 (m, 6H), 7.10 (br s,
lylthiol (20.14 g, 106 mmol) in portions at 0 °C under an atmosphere of ni-
trogen. After being stirred for 30 min, the resulting mixture was added in
one portion to a solution of 4-cyano-4-(3-iodophenyl)-3,4,5,6-tetrahydro-
2H-pyran 39 (33.12 g, 106 mmol) and tetrakis(triphenylphosphine)palladium
(7.35 g, 6.36 mmol) in toluene (180 ml) at room temperature. The mixture
was heated at reflux for 1 h and the resulting mixture was diluted with water
(100 ml), and extracted with ethyl acetate (500 mlꢄ2). The combined ex-
1H), 3.80—3.69 (m, 2H), 3.52—3.39 (m, 2H), 2.54 (s, 3H), 2.48—2.38 (m,
2H), 1.87—1.75 (m, 2H); IR (KBr) cmꢅ1: 1683, 1669; MS (DI-EI) m/z: 393
(Mꢆ); Anal. Calcd for C22H23N3O2S·HCl: C, 59.71; H, 5.79; N, 9.49, Cl,
8.01; S, 7.25. Found: C, 59.44; H, 5.63; N, 9.29, Cl, 7.82; S, 7.13.
4-{3-[4-(2-Methy-1H-limidazol-1-yl)phenyl]thiophenyl}-3,4,5,6-
tetrahydro-2H-pyran-4-carboxamide (6): Discovery Route. Ethyl 4-(3-
Bromophenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (32) To
a
tracts were washed with brine (150 ml), dried (MgSO4) and concentrated in stirred solution of ethyl 3-bromophenylacetate (31) (41.3 g, 170 mmol) and
vacuo. The titled compound (45.1 g), contaminated with a small amount of
triphenylphosphine, obtained as a brownish oil was used in the next step
without further purification. A sample was purified by column chromatogra-
15-crown-5 (3.74 g, 17 mmol) in DMF (1 l) at room temperature was added
sodium hydride (14.8 g, 370 mmol, 60% dispersion in mineral oil) in por-
tions. After stirring at room temperature for 40 min, sodium iodide (25.5 g,
phy for microanalysis solidified on standing. mp: 52—53 °C; 1H-NMR 170 mmol) and bis(2-chloroethyl)ether (30.4 g, 210 mmol) were added. After
(CDCl3) d: 7.62 (t, 1H, Jꢁ1.5 Hz), 7.48 (dt, 1H, Jꢁ7.0, 1.5 Hz), 7.34 (dt,
10.5 h the bulk of DMF was removed under reduced pressure. The residue
1H, Jꢁ7.0, 1.5 Hz)), 7.28 (t, 1H, Jꢁ7.0 Hz), 4.13—4.02 (m, 2H), 3.96— was covered with a mixture of ethyl acetate and toluene (1 : 1, 500 ml) and
3.83 (m, 2H), 2.18—1.97 (m, 4H), 1.33—1.16 (m, 1H) , 1.07 (d, 18H,
Jꢁ6.6 Hz); IR (KBr) cmꢅ1: 2230; Anal. Calcd for C21H33NOSSi: C, 67.15;
H, 8.85; N, 3.73. Found: C, 67.23; H, 8.98; N, 3.52.
washed with 0.5 N hydrogen chloride (500 ml). The aqueous layer was ex-
tracted with a mixture of ethyl acetate–toluene (1 : 1, 2ꢄ500 ml) and the
combined extracts were washed with water (250 ml), saturated sodium bicar-
4-Cyano-4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]phenyl}- bonate (250 ml), water (2ꢄ250 ml) and brine (250 ml), dried (MgSO4) and
3,4,5,6-tetrahydro-2H-pyran (41) To a stirred solution of 4-cyano-4-{3-
[tri-(1-methylethyl)]silylthiophenyl}-3,4,5,6-tetrahydro-2H-pyran 10 (39.82 g,
106 mmol), tetrakis(triphenylphosphine)palladium (3.67 g, 3.18 mmol) and
14 (29.81 g, 105 mmol) in ethanol (450 ml) was added potassium tert-butox-
ide (14.27 g, 127 mmol) at room temperature under an atmosphere of nitro-
gen. The mixture was heated to 80 °C overnight, then cooled and solvent re-
concentrated under reduced pressure to give 56.8 g of crude product as an
orange liquid. Purification by column chromatography (15% then 20% ethyl
acetate in n-hexane) gave the titled compound as a yellow liquid (36.5 g,
69%). H-NMR (CDCl3) d: 7.52 (1H, dd, Jꢁ1.8, 1.8 Hz), 7.40 (1H, ddd,
Jꢁ7.7, 1.8, 1.8 Hz), 7.31 (1H, ddd, Jꢁ1.8, 1.8, 8.1 Hz), 7.22 (1H, dd, Jꢁ8.1,
7.7 Hz), 4.16 (2H, q, Jꢁ7.3 Hz), 3.94 (2H, ddd, Jꢁ11.7, 4.0, 3.3 Hz), 3.56
1
moved under reduced pressure. The residual oil was poured into water (2H, ddd, Jꢁ13.6, 11.7, 2.2 Hz), 2.50 (2H, ddd, Jꢁ11.4, 3.3, 2.2 Hz), 1.94
(100 ml) and extracted with ethyl acetate (700 mlꢄ2). The combined organic (2H, ddd, Jꢁ13.6, 11.4, 4.0 Hz), 1.20 (3H, t, Jꢁ7.3 Hz).
extracts were washed with 2 N aqueous HCl (75 mlꢄ2) and discarded. The
combined acidic aqueous extracts were neutralized with 3 N aqueous NaOH
solution and than extracted with ethyl acetate (700 mlꢄ2). The combined or-
ganic extracts were washed with brine (200 ml), dried (MgSO4) and concen-
4-(3-Bromophenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylic
Acid
(33) A stirred mixture of ethyl 4-(3-bromophenyl)-3,4,5,6-2H-tetrahydro-
2H-pyran-4-carboxylate (32) (36.5 g, 117 mmol), an aqueous solution of
lithium hydroxide (6.14 g, 146 mmol, 50 ml), methanol (150 ml) and THF
trated in vacuo to afford 30.04 g (75%) of the titled compound as a brownish (150 ml) was refluxed for 1 d. The reaction mixture was partitioned between
oil contaminated with a small quantity of 6, which was used in the next step ether (100 ml) and 10% aqueous potasium hydroxide solution (300 ml). The
without further purification. 1H-NMR (CDCl3) d: 7.54—7.57 (m, 1H), ethereal layer was separated, extracted with 10% aqueous potassium hydrox-
7.48—7.35 (m, 5H), 7.28—7.22 (m, 2H), 7.02 (d, 1H, Jꢁ1.5 Hz), 7.00 (d,
ide solution (2ꢄ100 ml) and discarded. The combined aqueous extracts were
1H, Jꢁ1.5 Hz), 4.21—4.05 (m, 2H), 3.99—3.80 (m, 2H), 2.40 (s, 3H), acidified with concentrated hydrogen chloride and the resulting white pre-
2.19—2.02 (m, 4H); MS (DI-EI) m/z: 375 (Mꢆ). Further characterization
was not performed due to the contamination of 6.
cipitate were collected by filtration, washed with water and dried to constant
weight under vacuum at 80 °C to give the titled compound as white solids
4-{3-[4-(2-Methyl-1H-imidazol-1-yl)phenylthio]}phenyl-3,4,5,6- (26.4 g, 79%). 1H-NMR (CDCl3) d: 7.55 (1H, dd, Jꢁ1.8, 1.8 Hz), 7.43 (1H,
tetrahydro-2H-pyran-4-carboxamide (6) To a solution of 4-cyano-4-{3-
ddd, Jꢁ8.1, 1.8, 1.5 Hz), 7.35 (1H, ddd, Jꢁ8.1, 1.8, 1.5 Hz), 7.24 (1H, dd,
[4-(2-methyl-1H-imidazol-1-yl)phenylthio]}phenyl-3,4,5,6-tetrahydro-2H- Jꢁ8.1, 8.1 Hz), 3.94 (2H, ddd, Jꢁ12.1, 4.0, 3.7 Hz), 3.62 (2H, ddd, Jꢁ12.1,
pyran 41 (30.04 g, 80 mmol) in tert-butanol (300 ml) was added powdered
potassium hydroxide (85%, 15.8 g, 239 mmol) at 50 °C. The mixture was
then heated at reflux with stirring for 6 h. The reaction mixture was cooled
and volatiles removed under reduced pressure. To the residue was added
11.7, 1.8 Hz), 2.50 (2H, m), 1.97 (2H, ddd, Jꢁ13.9, 11.7, 4.0 Hz) (A peak
due to the exchangeable carboxylic acid proton was not observed).
Methyl
4-(3-Methylsulfinylphenyl)-3,4,5,6-tetrahydro-2H-pyran-4-
carboxylate (34) To a stirred solution of 4-(3-bromophenyl)-3,4,5,6-tet-
water (200 ml) and the resulting pale pink precipitates were collected by suc- rahydro-2H-pyran-4-carboxylic acid (33) (19.1 g, 67 mmol) in THF (650 ml)
tion filtration and washed with water (100 mlꢄ2) and then ethyl acetate
(100 mlꢄ2) to afford 13.5 g (43%) of the titled compound as a pale pink
at ꢅ78 °C under a nitrogen atmosphere was added a solution of n-butyl-
lithium (1.60 M in n-hexane solution, 100 ml, 160 mmol) below ꢅ70 °C.
After 45 min a solution of dimethyl disulfide (8.84 g, 94 mmol) in THF
powder. Further product crystallized out of the filtrate: second crop, 7.5 g
1
(24%) and third crop, 3.0 g (10%). mp: 208—210 °C; H-NMR (DMSO-d6) (50 ml) was added slowly over 30 min and the mixture was stirred at ꢅ78 °C
d: 7.48—7.33 (m, 8H), 7.30 (br s, 1H), 7.28 (d, 1H, Jꢁ1.5 Hz), 7.09 (br s,
1H), 6.91 (d, 1H, Jꢁ1.5 Hz), 3.83—3.68 (m, 2H), 3.53—3.40 (m, 2H),
for 70 min and then at ambient temperature for 3 h. To the resulting suspen-
sion was added 2 N hydrogen chloride (500 ml) and the layers were sepa-
rated. The aqueous layer was extracted with ethyl acetate (2ꢄ250 ml) and
the combined organic layers washed with water (4ꢄ100 ml) and brine
(100 ml), dried (MgSO4) and concentrated to dryness. The residue (21.5 g)
2.48—2.38 (m, 2H), 2.30 (s, 3H), 1.90—1.73 (m, 2H); IR (KBr) cmꢅ1
:
1682, 1664; MS (ESIꢆ) m/z: 394 (Mꢆ1)ꢆ; Anal. Calcd for C22H23N3O2S:
C, 67.15; H, 5.89; N, 10.68. Found: C, 67.23; H, 5.96; N, 10.64.
4-{3-[4-(2-Methy-1H-limidazol-1-yl)phenyl]thiophenyl}-3,4,5,6- was dissolved in methanol (100 ml) and 10% methanolic hydrogen chloride
tetrahydro-2H-pyran-4-carboxamide Hydrochloride (6·HCl) Free base (100 ml) was added. The mixture was heated to reflux with stirring for 13 h.
4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]phenyl}-3,4,5,6-tetrahydro- Another portion of 10% methanolic hydrogen chloride (100 ml) was added
2H-pyran-4-carboxamide 1 (24.15 g, 61 mmol) was suspended into methanol
(200 ml) and the suspension was heated to reflux. Thirty milliliters of 10%
hydrogen chloride in methanol was then added. The suspension turned into a
pale orange solution. The resulting solution was concentrated to dryness to
and heating was continued for another 7 h. Volatiles were removed by evapo-
ration and the residue was dissolved in ethyl acetate (500 ml), and washed
with water (2ꢄ250 ml), saturated aqueous sodium bicarbonate (250 ml),
water (250 ml) and brine (250 ml). The aqueous layers were combined and
give pale yellow solids. Toluene (200 ml) was added and evaporated under extracted with ethyl acetate (2ꢄ250 ml). The combined organic layers were
reduced pressure to eliminate remaining hydrogen chloride and methanol. dried (MgSO4) and concentrated to dryness. This product (17.9 g) was dis-
The resulting pale orange solids (35.75 g) were dried to constant weight in
vacuo. Ethanol (200 ml) was added and the mixture heated to reflux with
solved in methyl alcohol (200 ml) and cooled to 0 °C. A solution of sodium
periodate (16.0 g, 75 mmol) in water (200 ml) was added and the resulting

August 2005
971
pyran (26)11) (1.65 g, 7.4 mmol) was added and the resulting mixture was
heated at 100 °C for 22 h, cooled and poured into water (100 ml). The mix-
ture was extracted with diethyl ether (100 ml) and extract washed with water
(100 ml), brine (100 ml) and dried (MgSO4). Removal of solvent gave 1.87 g
suspension was stirred at 0 °C for 1 h. The reaction mixture was diluted with
water (500 ml) and extracted with dichloromethane (200 ml) and 10%
methyl alcohol in dichloromethane (3ꢄ200 ml). The combined extracts were
washed with brine (200 ml), dried (MgSO4) and concentrated to dryness. Pu-
rification by column chromatography (ethyl acetate) gave the titled com-
of
4-cyano-4-(5-fluoro-3-methylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran
1
pound as a colorless liquid (12.2 g, 64%), which solidified on standing. H-
(27) as a tan oil, which was used for the next step without further purifica-
tion.
NMR (CDCl3) d: 7.71—7.68 (1H, m), 7.55—7.50 (3H, m), 4.02—3.92 (2H,
m), 3.69 (3H, s), 3.62—3.50 (2H, m), 2.73 (3H, s), 2.62—2.52 (2H, m),
2.06—1.59 (2H, m).
To a solution of the product in methyl alcohol (200 ml) stirred at 0 °C a
solution of sodium periodate (16.0 g, 75 mmol) in water (200 ml) was added
and the resulting suspension was stirred at 0 °C for 1 h. The reaction mixture
was diluted with water (500 ml) and extracted with dichloromethane
(200 ml) and methyl alcohol–dichloromethane (1 : 9, 2ꢄ200 ml). The com-
bined extracts were washed with brine (200 ml), dried (MgSO4) and concen-
trated to dryness. Purification by chromatography using ethyl acetate as an
eluent gave the titled compound as a colorless liquid (12.2 g, 64%) , which
solidified on standing. 1H-NMR (CDCl3) d: 7.60—7.54 (1H, m), 7.41—7.30
(2H, m), 4.20—4.15 (2H, m), 3.98—3.81 (2H, m), 2.78 (3H, s), 2.25—2.01
(4H, m).
Methyl
4-(3-Mercaptophenyl)-3,4,5,6-tetrahydro-2H-pyran-4-car-
boxylate (35) Methyl 4-(3-methylsulfinylphenyl)-3,4,5,6-tetrahydro-2H-
pyran-4-carboxylate (34) (12.2 g, 43 mmol) was dissolved in trifluoroacetic
anhydride (50 ml) and heated at reflux for 30 min. Volatiles were removed by
evaporation and the residue was dissolved into methyl alcohol (100 ml). Tri-
ethylamine (100 ml) was added over 5 min and the mixture concentrated to
dryness. The residue was dissolved in ethyl acetate (500 ml), washed with
saturated aqueous ammonium chloride (200 ml) and brine (200 ml), dried
(MgSO4) and concentrated to dryness to provide crude titled compound as a
pale black liquid which was used as such without further purification.
Ethyl 4-{3-[4-(2-Methyl-1H-imidazol-1-yl)phenylthio]phenyl}-3,4,5,6-
tetrahydro-2H-pyran-4-carboxylate (36) A solution of methyl 4-(3-mer-
4-Cyano-4-(5-fluoro-3-mercaptophenyl)-3,4,5,6-tetrahydro-2H-pyran
(29) 4-Cyano-4-(5-fluoro-3-methylsulfinylphenyl)-3,4,5,6-tetrahydro-2H-
pyran (28) (1.24 g, 4.66 mmol) was dissolved in trifluoroacetic anhydride
(10 ml) and heated at reflux for 30 min. Volatiles were removed by evapora-
tion, to the residue added 1 : 1 methyl alcohol–triethylamine (100 ml) with
stirring, and the mixture concentrated to dryness. The residue was dissolved
in methylene chloride (200 ml), washed with saturated aqueous ammonium
chloride (100 ml), dried (MgSO4) and concentrated to dryness to provide
crude titled compound as a yellow liquid which was used without further pu-
captophenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate
(35)
(1.04 g,
3.5 mmol), 4-(2-methylimidazol-1-yl)phenyliodide (14) (0.89 g, 3.5 mmol),
sodium tert-butoxide (673 mg, 7 mmol) and tetrakis(triphenylphosphine)pal-
ladium 162 mg, 0.14 mmol) in dry ethanol (20 ml) was heated to reflux with
stirring overnight. Volatiles were removed by evaporation and the residue
was partitioned between ethyl acetate (100 ml) and water (100 ml). The
aqueous layer was extracted with ethyl acetate (100 ml). The combined or-
ganic layers were washed with brine (100 ml), dried (MgSO4) and concen-
trated to dryness to give 1.09 g of crude product as a brown liquid. Purifica-
tion by column chromatography (methyl alcohol in dichloromethane, in-
creasing the ratio of methyl alcohol from 0 to 4%) afforded the titled com-
1
rification. H-NMR (CDCl3) d: 7.46—6.89 (3H, m), 4.18—4.00 (2H, m),
3.96—3.78 (2H, m), 2.20—1.92 (4H, m) (A peak due to the exchangeable
thiol proton was not observed).
4-Cyano-4-{5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)phenyl-
thio]phenyl}-3,4,5,6-tetrahydro-2H-pyran (30) A solution of 4-cyano-4-
(5-fluoro-3-mercaptophenyl)-3,4,5,6-tetrahydro-2H-pyran (29) (1.30 g,
5.5 mmol), 4-(2-methylimidazol-1-yl)phenyliodide (14) (1.56 g, 5.5 mmol),
sodium tert-butoxide (1.06 g, 11 mmol) and tetrakis(triphenylphosphine)pal-
ladium (578 mg, 0.5 mmol) in dry ethyl alcohol (80 ml) was heated to reflux
with stirring for 4.5 h. Volatiles were removed by evaporation and the
residue was dissolved into diethyl ether (200 ml), washed with water
(100 ml) and brine (100 ml), dried (MgSO4) and concentrated to dryness to
give 2.96 g of crude product as a tar oil. Purification by chromatography
(1 : 20 methyl alcohol–dichloromethane) afforded the titled compound
(1.82 g) as a brown oil, which was contaminated with 4-(2-methylimidazol-
1-yl)phenyliodide (14). 1H-NMR (CDCl3) d: 7.75—6.89 (9H, m), 4.15—
4.04 (2H, m), 3.96—3.81 (2H, m), 2.40 (3H, s), 2.18—1.98 (4H, m).
4-{5-Fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]phenyl}-
3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (5) To a solution of 4-
cyano-4-{5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]phenyl}-
3,4,5,6-tetrahydro-2H-pyran (30) (1.71 g, 4.36 mmol) in tert-butyl alcohol
(20 ml) was added powdered potassium hydroxide (85%, 860 mg, 13 mmol).
The resulting mixture was heated at reflux temperature for 4 h, cooled and
concentrated in vacuo. Water (50 ml) was added and the precipitates were
collected by filtration and washed with 50 ml of ethyl acetate. After drying
under vacuum, 560 mg (31%) of the titled compound was obtained as a yel-
low powder. mp: 203—206 °C; 1H-NMR (CDCl3) d: 7.50 (4H, s), 7.32 (2H,
s), 7.21 (1H, s), 7.20—6.98 (3H, m), 6.92 (1H, s), 3.80—3.62 (2H, m),
3.52—3.26 (2H, m), 2.47—2.20 (5H, m), 1.88—1.67 (2H, m); IR (KBr)
1
pound (0.90 g, 61%). H-NMR (CDCl3) d: 7.51—6.98 (10H, m), 4.15 (2H,
d, Jꢁ7.0 Hz), 3.98—3.88 (2H, m), 3.61—3.50 (2H, m), 2.55—2.45 (2H, m),
2.37 (3H, s), 2.01—1.90 (2H, m), 1.18 (3H, t, Jꢁ7.0 Hz).
4-{3-[4-(2-Methylimidazol-1-yl)phenylthio]phenyl}-3,4,5,6-tetrahydro-
2H-pyran-4-carboxylic Acid (37) To a solution of ethyl 4-{3-[4-(2-
methyl-1H-imidazol-1-yl)phenylthio]phenyl}-3,4,5,6-tetrahydro-2H-pyran-
4-carboxylate (36) obtained as above in a mixture of tetrahydrofuran (20 ml)
and methyl alcohol (20 ml) was added an aqueous solution of lithium hy-
droxide (0.42 g, 10 mmol) and the mixture heated at reflux with stirring for
11 h. Volatiles were then removed under reduced pressure. The residue was
partitioned between ether (100 ml) and water (100 ml) and the ethereal layer
was extracted with 1 N aqueous potassium hydroxide (2ꢄ50 ml). The com-
bined aqueous layers were neutralized with 1 N aqueous hydrogen chloride
and saturated aqueous sodium bicarbonate. Precipitates were collected by
filtration, washed with water and dried under vacuum at 80 °C to give the ti-
tled compound (488 mg, 35% from methyl 4-(3-methylsulfinylphenyl)-
1
3,4,5,6-2H-tetrahydropyran-4-carboxylate. H-NMR (CDCl3) d: 7.49—7.37
(7H, m), 7.34—7.29 (1H, m), 7.30 (1H, d, Jꢁ1.1 Hz), 6.91 (1H, d,
Jꢁ1.1 Hz), 3.90—3.78 (2H, m), 3.49—3.36 (2H, m), 2.38—2.28 (2H, m),
2.28 (3H, s), 1.88—1.76 (2H, m) (A peak due to the exchangeable car-
boxylic acid proton was not observed).
4-{3-[4-(2-Methyl-1H-imidazol-1-yl)phenylthio]phenyl}-3,4,5,6-
tetrahydro-2H-pyran-4-carboxamide (6) To a stirred suspension of 4-{3-
[4-(2-methyl-1H-imidazol-1-yl)phenylthio]phenyl}-3,4,5,6-tetrahydro-2H-
pyran-4-carboxylic acid (37) (217 mg, 0.55 mmol) in CH2Cl2 (20 ml) at 0 °C
was added oxalyl chloride (254 mg, 2.0 mmol). The resulting solution was
stirred at 0 °C for 30 min and then at room temperature for 20 min. Volatiles
were then removed by evaporation. The residue was added to a stirred aque-
ous ammonia solution (30 ml) and stirred for 1 h. After cooling to 0 °C, pre-
cipitates were collected by filtration, washed with water and dried to con-
stant under vacuum at 80 °C to give the titled compound (207 mg, 96%). mp:
208—210 °C; 1H-NMR (DMSO-d6) d: 7.49—7.26 (10H, m), 7.10 (1H, br s),
6.90 (1H, d, Jꢁ1.1 Hz), 3.78—3.68 (2H, m), 3.52—3.40 (2H, m), 2.46—
2.36 (2H, m), 2.28 (3H, s), 1.86—1.64 (2H, m); IR (KBr) cmꢅ1: 1682, 1664;
MS (ESI+) m/z: 394 (Mꢆ1)ꢆ; Anal. Calcd for C22H23N3O2S: C, 67.15; H,
5.89; N, 10.68; Cl, 8.15. Found: C, 66.82; H, 5.83; N, 10.39, Cl, 8.22.
4-{5-Fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]phenyl}-
3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (5). 4-Cyano-4-(5-fluoro-
3-methylsulfinylphenyl)-3,4,5,6-tetrahydro-2H-pyran (28) Methane thi-
ol was bubbled into a stirred suspension of sodium hydride (65% w/w dis-
persion in mineral oil, 273 mg, 7.4 mmol) in DMF (10 ml) until a clear solu-
tion was obtained. 4-Cyano-4-(3,5-difluorophenyl)-3,4,5,6-tetrahydro-2H-
cmꢅ1
:
1683; MS (ESI+) m/z: 411 (Mꢆ1)ꢆ; Anal. Calcd for
C22H22FN3O2S·H2O: C, 61.52; H, 5.63; N, 9.78. Found: C, 61.92; H, 5.27;
N, 9.51.
4-{3-[4-(2-Methyl-1H-imidazol-1-yl)phenoxy]phenyl}-3,4,5,6-tetra-
hydro-2H-pyran-4-carboxamide
(8). 4-Cyano-4-(3-hydroxyphenyl)-
3,4,5,6-tetrahydro-2H-pyran (10) To a dichloromethane (80 ml) solution
of 4-cyano-4-(3-methoxyphenyl)-3,4,5,6-tetrahydro-2H-pyran (9) (2.32 g,
10.35 mmol)10) cooled to 0 °C was added boron tribromide (3.15 ml,
33.3 mmol) dropwise over 10 min. The ice-bath was removed and the reac-
tion mixture stirred at ambient temperature for 19 h, and then at reflux for
4 h. The reaction mixture was cooled and poured into water (150 ml). The
organic layer was separated and the aqueous layer was extracted with ethyl
acetate (50 mlꢄ3). The combined organic extracts were washed with brine
(50 ml), dried (magnesium sulfate) and concentrated in vacuo. The crude
product was crystallized from isopropyl ether to afford titled compound as
off-white solids (1.43 g, 66%). 1H-NMR (CDCl3) d: 7.29 (1H, t, Jꢁ8.1 Hz),
7.04 (1H, dd, Jꢁ8.1, 2.2 Hz), 6.98 (1H, dd, Jꢁ4.0, 2.2 Hz), 6.83 (1H, dd,
Jꢁ8.1, 4.0 Hz), 5.14 (1H, br s), 4.09 (2H, ddd, Jꢁ11.7, 4.0, 3.3 Hz), 3.90

972
Vol. 53, No. 8
(2H, ddd, Jꢁ12.1, 11.7, 2.2 Hz), 2.14—2.01 (4H, m); Anal. Calcd for
C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.80; H, 6.44; N, 6.86.
4-Cyano-4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenoxy]phenyl}-3,4,5,6-
tetrahydro-2H-pyran (15) A mixture of 4-(2-methylimidazol-1-yl)phenyl
iodide (14) (1.28 g, 4.5 mmol), 4-cyano-4-(3-hydroxyphenyl)-3,4,5,6-
tetrahydro-2H-pyran (10) (1.20 g, 5.9 mmol) and K2CO3 (4.15 g, 30 mmol)
in pyridine (50 ml) was heated at 130 °C, cupric oxide (636 mg, 8.0 mmol)
added and the reaction mixture was heated under reflux for 2 d. The reaction
mixture was cooled and filtered through a celite pad and the solids were
washed with ethyl acetate (100 ml). The filtrate was concentrated under re-
duced pressure, and the resulting residue was diluted with water (100 ml)
and extracted with ethyl acetate (50 mlꢄ3). The combined organic extracts
were washed with 1 N aqueous NaOH (100 ml), water (100 ml) and brine
(100 ml), dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by column chromatography (E. Merck LiChroprep
NH2, 100 g; eluted with hexane–ethyl acetate (1 : 1)) to afford 620 mg (38%)
(200 ml). The extract was washed with water (100 ml), brine (100 ml), dried
(MgSO4), and concentrated under reduced pressure. The residue was puri-
fied by column chromatography eluting with ethyl acetate/n-hexane (1/10) to
give 8.58 g (74%) of the titled compound as a white solid. 1H-NMR (CDCl3)
d: 10.35 (1H, d, Jꢁ2.9 Hz), 7.08 (1H, ddd, Jꢁ7.3, 4.0, 2.9 Hz), 6.94 (1H,
ddd, Jꢁ9.5, 6.6, 2.9 Hz), 3.94 (3H, s).
2,5-Difluoro-3-methoxybenzyl alcohol (20) Sodium borohydride
(2.83 g, 74.7 mmol) was added to a stirred solution of 2,5-difluoro-3-
methoxybenzaldehyde (19) (8.57 g, 49.8 mmol) in ethanol (100 ml) at room
temperature. After 30 min, the mixture was concentrated, the residue was di-
luted with ether (300 ml) and successively washed with water (200 ml), 10%
citric acid (200 ml), water (200 ml), brine (200 ml), and dried (MgSO4). Re-
moval of solvent gave 8.26 g (95%) of the titled compound as a white solid.
1H-NMR (CDCl3) d: 6.80—6.69 (2H, m), 4.74 (2H, s), 3.86 (3H, s), 2.14
(1H, br s).
2,5-Difluoro-3-methoxyphenylacetonitrile (21) To a stirred solution
of 2,5-difluoro-3-methoxybenzyl alcohol (20) (8.26 g, 47.4 mmol) in
dichloromethane was added p-toluenesulfonyl chloride (9.95 g, 52.2 mmol)
and triethylamine (7.30 ml, 52.2 mmol) at room temperature. After 3.5 h, the
mixture was poured into water (200 ml) and extracted with ether (200 ml).
The extract was washed with brine (200 ml), dried (MgSO4) and concen-
trated consecutively. To the residue was added DMSO (200 ml) and sodium
cyanide (3.48 g, 71 mmol). The resulting mixture was stirred for 2 h and then
poured into water (200 ml) and extracted with ether (300 ml). The extract
was washed with water (100 ml), brine (100 ml) and dried (MgSO4). Re-
1
of the titled compound as a yellow oil. H-NMR (CDCl3) d: 7.44 (1H, dd,
Jꢁ8.1, 7.7 Hz), 7.33—7.21 (4H, m), 7.12—6.98 (5H, m), 4.15—4.04 (2H,
m), 3.99—3.82 (2H, m), 2.37 (3H, s), 2.22—2.00 (4H, m).
4-{3-[4-(2-Methyl-1H-imidazol-1-yl)phenoxy]phenyl}-3,4,5,6-tetrahy-
dro-2H-pyran-4-carboxamide (8) The titled compound was prepared ac-
cording to the procedure described as the procedure for preparation of 4-{5-
fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]phenyl}-3,4,5,6-tetrahy-
dro-2H-pyran-4-carboxamide (5) except that 4-cyano-4-{3-[4-(2-methylimi-
dazol-1-yl)phenoxy]phenyl}-3,4,5,6-tetrahydro-2H-pyran (15) was used
in place of 4-cyano-4-{5-fluoro-3-[4-(2-methylimidazol-1-yl)phenylthio]-
phenyl}-3,4,5,6-tetrahydro-2H-pyran (30). mp: 186—186.5 °C; 1H-NMR
(CDCl3) d: 7.40 (1H, dd, Jꢁ8.1, 7.7 Hz), 7.29—7.13 (4H, m), 7.09—6.95
(5H, m), 5.32 (2H, br s), 3.89—3.70 (4H, m), 2.43—2.32 (2H, m), 2.40 (3H,
s), 2.16—2.02 (2H, m); IR (KBr) cmꢅ1: 1670; MS (ESI+) m/z: 378 (Mꢆ1)ꢆ;
Anal. Calcd for C22H23N3O3: C, 70.01; H, 6.14; N, 11.13. Found: C, 70.05;
H, 6.21; N, 10.99.
1
moval of solvent gave 5.91 g (63%) of the titled compound as a red oil. H-
NMR (CDCl3) d: 6.80—6.65 (2H, m), 3.89 (3H, s), 3.76 (2H, d, Jꢁ0.7 Hz).
Methyl 2,5-Difluoro-3-methoxyphenylacetate (22) To a stirred solu-
tion of 2,5-difluoro-3-methoxyphenylacetonitrile (21) (5.92 g, 30 mmol) in
ethylene glycol (150 ml) was added potassium hydroxide (85%; 3.0 g,
45 mmol). The mixture was heated at 120 °C for 1 h and then the mixture
was poured into water (100 ml) and washed with ether (100 ml). The aque-
ous layer was acidified with 6 N HCl (10 ml) and extracted with ether
(200 ml). The extract was washed with water (50 ml), brine (50 ml), dried
(MgSO4) and evaporated. The residual solid was dissolved in methanol
(200 ml) and to the solution was added concentrated sulfuric acid (2 ml). The
resulting mixture was heated at reflux for 1 h, cooled and concentrated in
vacuo. The residue was dissolved in ether (100 ml), washed with water
(100 ml), saturated aqueous sodium hydrogen carbonate (100 ml), brine
(100 ml) and dried (MgSO4). Removal of solvent gave 3.80 g (59%) of the ti-
4-{3-[4-(2-Methyl-1H-imidazol-1-yl)benzyloxy]phenyl}-3,4,5,6-
tetrahydro-2H-pyran-4-carboxamide (3) The titled compound was pre-
pared according to the procedure reported8) using 4-(2-methyl-1H-imidazol-
1-yl)benzyl chloride hydrochloride (11) and 4-cyano-4-(3-hydroxyphenyl)-
3,4,5,6-tetrahydro-2H-pyran (10) and then the one described as a proce-
dure for 4-{5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]phenyl}-
3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (5). mp: 183—186 °C; 1H-NMR
(CDCl3) d: d: 7.60—7.54 (2H, m), 7.41—7.32 (3H, m), 7.09—7.00 (4H, m),
6.98—6.91 (1H, m), 5.36—5.22 (2H, br s), 5.12 (2H, s), 3.89—3.76 (4H,
1
tled compound as a yellow oil. H-NMR (CDCl3) d: (CDCl3) 6.70—6.50
m), 2.39 (3H, s), 2.44—2.33 (2H, m) , 2.19—2.02 (2H, m); IR (KBr) cmꢅ1
:
(2H, m), 3.87 (3H, s), 3.72 (3H, s), 3.65 (2H, d, Jꢁ1.8 Hz).
1680; MS (ESI+) m/z: 392 (Mꢆ1)ꢆ; Anal. Calcd. for C23H25N3O3·0.1H2O:
C, 70.25; H, 6.46; N, 10.68. Found: C, 70.04; H, 6.44; N, 10.67.
Methyl 4-(2,5-Difluoro-3-methoxyphenyl)-3,4,5,6-tetrahydro-2H-py-
ran-4-carboxylate (23) The titled compound was prepared according to
the procedure described for preparation of ethyl 4-(3-bromophenyl)-3,4,5,6-
tetrahydro-2H-pyran-4-carboxylate (32) except that methyl 2,5-difluoro-3-
methoxyphenylacetate (22) was used in place of ethyl 3-bromophenylacetate
4-{2,5-Difluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl}-
3,4,5,6-tetrahydro-2H-pyran-4-caboxamide (4). 1-O-tert-Butyldimeth-
ylsilyloxy-2,5-difluorobenzene (17) To a stirred solution of 2,5-difluo-
rophenol (16) (15.1 g, 116 mmol) in DMF (100 ml) was added sodium hy-
dride (65% oil dispersion; 5.13 g, 139 mmol) with ice-cooling. After stirring
for 30 min, tert-butyldimethylsilyl chloride (17.5 g, 0.116 mmol) was added
and the stirring was continued for an additional 1 h. The mixture was poured
into water (200 ml) and extracted with ether (300 ml). The extract was
washed with brine (200 ml), dried (NaSO4) and solvent removal of by evapo-
1
(31). H-NMR (CDCl3) d: 6.71—6.59 (2H, m), 3.93—3.73 (4H, m), 3.86
(3H, s), 3.75 (3H, s), 2.45—2.32 (2H, m), 2.14—1.96 (2H, m).
Methyl 4-(2,5-Difluoro-3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-py-
ran-4-carboxylate (24) The titled compound was prepared according to
the procedure described for preparation of 4-cyano-4-(3-hydroxyphenyl)-
3,4,5,6-tetrahydro-2H-pyran (10) except that methyl 4-(2,5-difluoro-3-
methoxyphenyl)-3,4,5,6-tetrahydropyran-4-carboxylate (23) was used in
1
ration to give 26.65 g (94%) of the titled compound as a colorless oil. H-
1
NMR (CDCl3) d: 7.05—6.91 (1H, m), 6.70—6.52 (2H, m), 1.00 (9H, s),
0.201 (3H, s), 0.197 (3H, s).
place of 4-cyano-4-(3-methoxyphenyl)-3,4,5,6-tetrahydro-2H-pyran (9). H-
NMR (CDCl3) d: 6.80—6.50 (2H, m), 3.96—3.68 (7H, m), 2.49—2.32 (2H,
m), 2.16—1.95 (2H, m) (A peak due to the exchangeable phenol proton was
not observed).
3-tert-Butyldimethylsilyloxy-2,5-difluorobenzaldehyde (18) A 1.0 M
solution of sec-BuLi (21.5 ml, 21.5 mmol) was added dropwise to a stirred
solution of 1-O-tert-butyldimethylsilyloxy-2,5-difluorobenzene (17) (5.0 g,
20 mmol) in THF (20 ml) at ꢅ78 °C. After 0.5 h, DMF (1.9 ml, 24.6 mmol)
was added dropwise while the temperature was kept below ꢅ70 °C. After
30 min the mixture was allowed to warm to room temperature over 30 min.
To the mixture was added 3 N HCl (30 ml) and the stirring was continued for
30 min. The mixture was extracted with ether (100 ml) and the extract was
washed with water (100 ml), brine (100 ml), dried (NaSO4) and evaporated.
Column chromatography of the residue eluting with n-hexane gave 3.56 g
Methyl 4-{2,5-Difluoro-3-[4-(2-methyl-1H-imidazol-1-yl)]benzyloxy-
phenyl}-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (25) The titled
compound was obtained from methyl 4-(2,5-difluoro-3-hydroxyphenyl)-2H-
3,4,5,6-tetrahydropyran-4-carboxylate (24) and 4-(2-methyl-imidazol-1-
yl)benzyl chloride hydrochloride (11) as a yellow oil, according to the pro-
cedure reported.8) Yield was 49%. 1H-NMR (CDCl3) d: 7.57 (2H, d,
Jꢁ8.4 Hz), 7.34 (2H, d, Jꢁ8.4 Hz), 7.05 (1H, d, Jꢁ1.5 Hz), 7.01 (1H, d,
Jꢁ1.5 Hz), 6.90—6.45 (2H, m), 5.13 (2H, s), 3.95—3.62 (7H, m), 2.50—
2.30 (5H, m), 2.16—1.94 (2H, m).
4-{2,5-Difluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl}-
3,4,5,6-tetrahydro-2H-pyran-4-caboxamide (4) To a solution of methyl
4-{2,5-difluoro-3-[4-(2-methyl-1H-imidazol-1-yl)]benzyloxyphenyl}-
3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (25) in a mixture of tetrahydrofu-
ran (9 ml), methyl alcohol (3 ml) and water (1.5 ml) was added an aqueous
4 N solution of lithium hydroxide (1.5 ml) and the mixture heated at reflux
with stirring for 1.5 h. Volatiles were then removed under reduced pressure.
1
(64%) of the titled compound as a colorless oil. H-NMR (CDCl3) d: 10.31
(1H, d, Jꢁ2.9 Hz), 7.12 (1H, ddd, Jꢁ7.7, 4.4, 3.3 Hz), 6.89 (1H, ddd, Jꢁ9.2,
7.0, 3.3 Hz), 1.02 (9H, s), 0.245 (3H, s), 0.240 (3H, s).
2,5-Difluoro-3-methoxybenzaldehyde (19) Potassium fluoride (7.79 g,
134 mmol) and iodomethane (4.98 ml, 80 mmol) were added to a stirred
solution of 3-tert-butyldimethylsilyloxy-2,5-difluorobenzaldehyde (18)
(19.45 g, 67 mmol) in DMF (100 ml) at room temperature. After 5 h, the
mixture was poured into water (100 ml) and extracted with ethyl acetate

August 2005
973
To the residue was added water (100 ml) and extracted with CH2Cl2
(2ꢄ100 ml). The combined extracts were washed with brine (100 ml), dried
(MgSO4) and concentrated to dryness to give 469 mg of a off-white solid,
which was used for the next reaction without further purification.
To a stirred suspension of the product obtained above in CH2Cl2 (15 ml) at
room temperature was added thionyl chloride (15 ml). The resulting solution
was stirred and heated to reflux for 1 h. After cooling to room temperature,
volatiles were removed by evaporation. To the residue was added aqueous
ammonia solution (20 ml) and stirred for 0.5 h at room temperature. Precipi-
by Jucker E., Birkhauser Verlag, Basel, 1996, pp. 115—168.
5) Henderson W. R., Jr., J. Allergy Clin. Immunol., 79, 543—553 (1987).
6) Steinhilber D., Curr. Med. Chem., 6, 71—85 (1999).
7) Vianna E. O., Martin R. J., Drugs Today, 34, 341—351 (1998).
8) Mano T., Stevens R. W., Ando K., Nakao K., Okumura Y., Sakakibara
M., Okumura T., Tamura T., Miyamoto K., Bioorg. Med. Chem., 11,
3879—3887 (2003).
9) Mano T., Okumura Y., Sakakibara M., Okumura T., Tamura T.,
Miyamoto K., Stevens R. W., J. Med. Chem., 47, 720—725 (2004).
tates were collected by filtration and recrystallized from acetonitrile to give 10) Cuny G. D., Hauske J. R., Heffernan M. L., Holland J. M., Persons P.
the titled compound (180 mg, 39%). mp: 222—224 °C; 1H-NMR (CDCl3) d:
E., Radeke H., PCT Int. Appl. WO 02083863 A2, October 24, 2002.
7.56 (2H, d, Jꢁ8.4 Hz), 7.34 (2H, d, Jꢁ8.4 Hz), 7.04 (1H, d, Jꢁ1.1 Hz), 11) Mano T., Stevens R. W., Nakao K., Okumura Y., Kawamura K., Ando
7.01 (1H, d, Jꢁ1.5 Hz), 6.82—6.69 (2H, m), 5.40 (2H, br s), 5.15 (2H, s),
4.00—3.70 (4H, m), 2.50—2.30 (5H, m), 2.22—2.02 (2H, m); MS (ESI+)
m/z: 428 (Mꢆ1)ꢆ; Anal. Calcd for C23H23F2N3O3: C, 64.63; H, 5.42; N,
9.83. Found: C, 64.77; H, 5.78; N, 9.64.
A., Matsuoka Y., Synthesis, 16, 2625—2628 (2004).
12) Foster S. J., Bruneau P., Walker E. R. H., McMillan R. M., Br. J. Phar-
maco., 99, 113—118 (1990).
13) Young J. M., Maloney P. J., Jubb S. N., Clark J. S., Prostaglandines,
30, 545—551 (1985).
4-{3-[4-(2-Methylimidazol-1-yl)phenylsulfonyl]phenyl}-3,4,5,6-
tetrahydro-2H-pyran-4-carboxamide (7)
A mixture of 6 (1.62 g, 14) Criscuoli M., Subissi A., Br. J. Pharmaco., 90, 203—209 (1987).
4 mmol) and hydrogen peroxide (30% in water, 5 ml) in acetic acid (12 ml) 15) Tsunoda H., Abe S., Sakuma Y., Katayama S., Katayama K.,
was stirred at room temperature for 12 h, then heated at reflux for 2 h. The
reaction mixture was then poured into saturated NaHCO3 (50 ml) and ex-
Prostaglandins, Leukotrienes and Essential Fatty Acids, 39, 291—294
(1990).
tracted with ethyl acetate (300 mlꢄ2). The combined organic extracts were 16) Yin J., Pidgeon C., Tetrahedron Lett., 38, 5953—5954 (1997).
washed with brine (100 ml), dried (MgSO4) and concentrated under reduced 17) Ishiyama T., Mori M., Suzuki A., Miyaura N., J. Organometallic
pressure to afford 1.68 g (quant.) of the titled compound as pale yellow solid.
Further purification was performed by preparative thin-layer chromatogra- 18) Vijaikumar S., Pitchumani K., J. Mol. Catalysis, 217, 225—231
phy using CH2Cl2–MeOH (10 : 1) as an eluent and recrystallization from (2004).
EtOH–n-hexane. mp: 110—115 °C; H-NMR (CDCl3) d: 8.10—8.01 (3H, 19) Miranda E. I., Diaz M. J., Rosado I., Soderquist J. A., Tetrahedron
m), 7.88 (1H, d, Jꢁ7.0 Hz), 7.68 (1H, d, Jꢁ7.0 Hz), 7.57 (1H, dd, Jꢁ7.0, Lett., 35, 3221—3224 (1994).
7.0 Hz), 7.47 (2H, d, Jꢁ8.8 Hz), 7.05 (1H, d, Jꢁ1.5 Hz), 7.01 (1H, d, 20) Rane A. M., Miranda, E. I., Soderquist J. A., Tetrahedron Lett., 35,
Jꢁ1.5 Hz), 5.42 (1H, br s), 3.91—3.70 (4H, m), 2.39 (3H, s), 2.48—2.38 3225—3226 (1994).
(2H, m), 2.12—1.99 (2H, m); IR (KBr) cmꢅ1: 1300, 1150; HR-MS (EI) m/z: 21) Aleo M. D., Drupa C. A., Fritz C. A., Walsh C. M., Whitman-Sherman
Chem., 525, 225—231 (1996).
1
426.1513 (Calcd for C22H23N3O4S: 426.1488).
J. L., Fortner J. H., Toxicol. Sci. (Suppl.), 60, 101 (2001).
22) Baltrukonis D. J., Fritz C. A., Render J. A., Tengowski M. W., Costello
K., Jakowski A. B., Fortner J. H., Lawton M. P., Nelms L. F., Drupa C.
A., Verdugo-Gazdik M. E., Schnellmann R. G., Kajiji S., Aleo M. D.,
Toxicol. Sci. (Suppl.), 60, 101 (2001).
Acknowledgements We are grateful to Akemi Ando, Yoko Matauoka
and Shinichi Sakemi (Pfizer Global Research & Development, Nagoya Lab-
oratories) for elemental analysis and mass spectroscopy experiments.
23) Aleo M. D., Avery M. J., Beierschmitt W. P., Drupa C. A., Fortner J.
H., Kaplan A. H., Navetta K. A., Shepard R. M., Walsh C. M., “Annals
of the New York Academy of Sciences,” Vol. 919 (Toxicology for the
Next Millennium), ed. by Isfort R. J., Lederberg J., Academy of Sci-
ences, New York, 2000, pp. 171—187.
References
1) Masamune H., Melvin L. S., Jr., “Annual Reports in Medicinal Chem-
istry,” Vol. 24, ed. by Allen R. C., Academic Press, San Diego, 1989,
pp. 71—79.
2) Samuelsson B., Science, 220, 568—575 (1983).
3) Turner C. R., Breslow R., Conklyn M. J., Andrese C. J., Patterson D.
24) Fischer L., Steinhilber D., Werz O., Br. J. Pharmacol., 142, 861—868
(2004).
K., Lopez-Anaya A., Owens B., Lee P., Watson J. W., Showell H. J., J. 25) Sakurada T., Abe M., Kodani M., Sakata N., Katsuragi T., Eur. J.
Clin. Invest., 97, 381—387 (1996).
Pharmacol., 370, 153—159 (1999).
4) Jackson W. T., Fleisch J. H., “Progress in Drug Research,” Vol. 46, ed.