Discovery of 2-(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile (Perampanel): A novel, noncompetitive α-amino-3-hydroxy-5- methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist

Article abstract of DOI:10.1021/jm301268u

Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis of epilepsy and numerous other neurological diseases. Here we describe the discovery of a series of 1,3,5-triaryl-1H-pyridin-2-one derivatives as noncompetitive antagonists of AMPA-type ionotropic glutamate receptors. The structure-activity relationships for this series of compounds were investigated by manipulating individual aromatic rings located at positions 1, 3, and 5 of the pyridone ring. This culminated in the discovery of 2-(2-oxo-1-phenyl-5- pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel, 6), a novel, noncompetitive AMPA receptor antagonist that showed potent activity in an in vitro AMPA-induced Ca²⁺ influx assay (IC₅₀ = 60 nM) and in an in vivo AMPA-induced seizure model (minimum effective dose of 2 mg/kg po). Perampanel is currently in regulatory submission for partial-onset seizures associated with epilepsy.

Full text of DOI:10.1021/jm301268u

Article
pubs.acs.org/jmc
Discovery of 2‑(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-
yl)benzonitrile (Perampanel): A Novel, Noncompetitive α‑Amino-3-
hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor
Antagonist
Shigeki Hibi,*,† Koshi Ueno,† Satoshi Nagato,† Koki Kawano,† Koichi Ito,† Yoshihiko Norimine,†
Osamu Takenaka,§ Takahisa Hanada,‡ and Masahiro Yonaga†
‡
§
†Medicinal Chemistry, Biopharmacology, and Drug Metabolism and Pharmacokinetics, Tsukuba Research Laboratories, Eisai Co.,
Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
S
* Supporting Information
ABSTRACT: Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis
of epilepsy and numerous other neurological diseases. Here we describe the discovery of a series of
1,3,5-triaryl-1H-pyridin-2-one derivatives as noncompetitive antagonists of AMPA-type ionotropic
glutamate receptors. The structure−activity relationships for this series of compounds were investigated
by manipulating individual aromatic rings located at positions 1, 3, and 5 of the pyridone ring. This
culminated in the discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile
(perampanel, 6), a novel, noncompetitive AMPA receptor antagonist that showed potent activity in an
in vitro AMPA-induced Ca2+ influx assay (IC50 = 60 nM) and in an in vivo AMPA-induced seizure
model (minimum effective dose of 2 mg/kg po). Perampanel is currently in regulatory submission for
partial-onset seizures associated with epilepsy.
competitive AMPA receptor antagonists, including ZK-200775
(2) and tezampanel (3), have not yet reached the clinic (Figure
1).8,9
Meanwhile, noncompetitive AMPA receptor antagonists
have actively been explored, driven by the belief that such
drugs would exercise effectiveness independent of glutamate
levels and the synaptic membrane polarization state, with minor
influence on normal glutamatergic activity compared with
competitive antagonists.10
Piriqualone (4) and talampanel (5) are categorized as
noncompetitive AMPA receptor antagonists (Figure 1).11,12
The latter compound was assessed in clinical trials against
refractory epilepsy (last reported in 2002)13 and is currently
under investigation for the treatment of amyotrophic lateral
sclerosis.14 Overall, this early research suggested that AMPA
receptor antagonists could be viable treatments for certain
neurologic disorders without psychotomimetic adverse events.
Here we summarize our efforts to identify a selective,
noncompetitive AMPA receptor antagonist that exhibits potent
in vitro and in vivo efficacy with a pharmacokinetic profile
compatible with oral administration. Systematic investigations
of SARs for the series of 1,3,5-triaryl-1H-pyridin-2-one
derivatives led to the discovery of 2-(2-oxo-1-phenyl-5-
pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel,
6) (Figure 1), a potent noncompetitive AMPA receptor
antagonist currently in regulatory submission for partial-onset
seizures associated with epilepsy.
INTRODUCTION
■
The amino acid glutamate is the primary excitatory neuro-
transmitter in the human brain.1 Glutamate exerts its
physiologic effects via interaction with two major families of
receptor proteins: metabotropic glutamate receptors (mGluRs)
and ionotropic glutamate receptors (iGluRs). mGluRs allow
glutamate to modulate cell excitability and synaptic trans-
mission via second messenger signaling pathways, while iGluRs
are ligand-gated tetrameric ion channels that mediate fast
synaptic responses to glutamate.2−4 Three classes of iGluRs
have been identified and are named according to their selective
agonists: AMPA, kainate, and NMDA.3
Dysfunction of glutamatergic neurotransmission has long
been implicated in the pathogenesis of neurological diseases
such as epilepsy, Parkinson’s disease, neuropathic pain, and
stroke.1 In the case of epilepsy, it is more than 50 years since an
increase of glutamate concentrations in the brain above a
critical level was proposed to be the trigger for seizure activity.5
Moreover, the discovery and characterization of mGluRs and
iGluRs led to intensive efforts over the past 2 decades to
generate novel drugs that inhibit the activity of these receptors.
Nevertheless, no specific glutamate receptor antagonists have
been approved for clinical use. Indeed, many putative NMDA
receptor antagonists failed to reach the clinic because of the
occurrence of severe psychotomimetic adverse events.6 The
first reported selective AMPA receptor antagonists were
quinoxalinedione derivatives such as NBQX (1) (Figure 1)
whose therapeutic usefulness was hampered by poor solubility
and low blood−brain barrier penetration.7 These quinoxaline-
dione derivatives competitively block glutamate gating. Other
Received: September 3, 2012
© XXXX American Chemical Society
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Figure 1. Known AMPA receptor antagonists including 6 (perampanel).
diminished but still maintained weak in vitro activity in the Ca2+
influx assay. From a comparison of metabolic stability between
pyridone derivatives 13 and 16, acidic hydrogen seemed to
affect metabolic stability in human (H), mouse (M), and rat
(R) liver microsomes. To mask the acidic hydrogen in 16,
another phenyl group was added to the pyridone template
(17). Surprisingly, compound 17 showed both good Ca2+ influx
activity (IC50 = 1.08 μM) and good metabolic stability and was
chosen for further optimization.
Optimization of 1,3,5-Triaryl-1H-pyridin-2-one Deriv-
atives. Additional optimization of the 1,3,5-triaryl-1H-pyridin-
2-one template was conducted by focusing on manipulation of
the individual aromatic rings located at positions 1, 3, and 5 of
the pyridone ring to yield a series of potent and selective
noncompetitive AMPA receptor antagonists. First, the
introduction of basicity via a 2-pyridine ring was assessed
(Table 3). In comparison with 17 (IC50 = 1.08 μM), both 24a
(IC50 = 0.32 μM) and 28a (IC50 = 0.44 μM) improved the
activity to submicromolar level, resulting in the selection of a 2-
pyridyl substituent at position 5 on the pyridone ring (Ar1) for
further optimization. Moreover, 28a indicated the possibility of
modifying the aromatic ring at position 1.
RESULTS AND DISCUSSION
■
Hit Identification by HTS. To identify a starting
compound for our discovery efforts, we first screened our
compound library using two HTS (high throughput screening)
assays. The rat cortical neuron AMPA-induced cell-death assay
identified compounds with AMPA antagonist activity, while the
tritiated-AMPA binding assay allowed the detection and
elimination of compounds acting as competitive AMPA
receptor antagonists. Subsequently, a confirmatory AMPA-
induced Ca2+ influx assay was used to characterize the potency
of hit compounds and to enable identification of false-positive
hits arising during HTS. After completion of these assays,
commercially available 2,4-diphenyl-4H-[1,3,4]oxadiazin-5-one
(8a) (AMPA-induced Ca2+ influx assay IC50 = 9.17 μM, Figure
2) was selected as a suitable starting compound with a novel
structure versus other HTS hit compounds and known AMPA
antagonists.
To investigate whether steric or electrical effects of the
carbonyl group at position 2 on the pyridone ring affect in vitro
activity, several substituents were introduced to the aromatic
ring at position 3 on the pyridone ring (Ar2). A cyano group
was selected as a representative substituent because of its steric
interactions with the carbonyl group and its electron-with-
drawing force.
Figure 2. Structure of the starting compound 8a.
To clarify the substituent effect of the cyano group on the
phenyl group, we synthesized ortho, meta, and para position
substituted compounds 6, 24b, and 24c, respectively (Table 4).
The ortho substituent was shown to be the most appropriate
from an activity aspect. Next, bulkiness and electron density
were investigated. Among cyano, halogen, alkyl, and alkoxy
substituents in the ortho position, the cyano group was most
effective, suggesting that both electron-withdrawing properties
and steric hindrance, which induces a certain twist angle
between the pyridone core and 3-aryl ring, are essential to
improve the activity. In addition, the possibility of pyridyl
substituent at position 3 (24h, 24i, and 24j) was assessed, but
the phenyl group was found to be stronger than the pyridine.
Discovery of 1,3,5-Triaryl-1H-pyridin-2-one Template.
As our first effort to grasp the SARs for the oxadiazinone
derivatives, introduction of an aliphatic substituent at either R1
or R2 (8b−f) was investigated in the AMPA-induced Ca2+
influx assay. The replacement with aliphatic substituent reduced
activity, suggesting that conjugated aromaticity would be
required to maintain AMPA antagonism in these oxadiazinone
derivatives (Table 1).
Next, the oxadiazinone core structures were modified to
improve both chemical and metabolic stability (Table 2).
Replacement of the oxadiazinone (8a, IC50 = 9.17 μM) with the
diazinone (9) (IC50 = 28.10 μM) or the pyridone derivatives
(13) (IC50 = 69.54 μM) and (16) (IC50 = 57.72 μM)
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a
Table 1. SARs for the Oxadiazinone Derivatives (8a−f)
a
All values are from three measurements and are expressed as the mean SEM.
Table 2. Effects on in Vitro Potency and Metabolic Stability of Replacement of 4H-[1,3,4]Oxadizin-5(6H)-one Ring with 4,5-
Dihydro-3(2H)pyridinone or 1H-Pyridin-2-one Derivatives (8a vs 9, 13, 16, 17)
a
b
All values are from three measurements and are expressed as the mean SEM. Rate of human (H), mouse (M), and rat (R) intrisic clearance in
vitro.
When the phenyl group was substituted with an ortho electron-
withdrawing group, the cyano group in particular had a positive
effect on the in vitro activity (Table 4). Similar SARs were
observed in 1,5-dipyridylpyridone derivatives (Table 5). In the
series, 28b and 28e exhibited promising activity.
To confirm whether 2-pyridine at position 5 is optimized
even in derivatives with a 2-cyanophenyl substituent at position
3 of the pyridone, several aryl rings were introduced at position
5 (Table 6). From a comparison of the substituent patterns of
the pyridine rings, a 2-pyridyl derivative (6) showed greater in
vitro activity than the other pyridine region isomers (33a and
33b). Phenyl and thiophene (33c, 33e, and 33h) or ortho-
substituted phenyl groups (33d, 33f, and 33g) decreased in
vitro activity. In conclusion, the 2-pyridyl group was shown to
confer the greatest in vitro potency. A final optimization at
position 1 was executed by introduction of any substituted
(methoxy, cyano, and fluorine) phenyl or pyridine ring,
demonstrating that nonsubstituted phenyl (6) was best for in
vitro activity (Table 7). Subsequently, some of the most potent
compounds in Tables 4−7 were chosen to evaluate in vivo
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Data from the AMPA-induced seizure model (minimum
effective dose of 2 mg/kg po) and the pharmacokinetic profile,
which demonstrated good oral bioavailability, rapid absorption,
and extensive distribution into body tissues (Tables 8 and 9),
indicated that 6 was the most promising compound.
Compound 6 was thus selected for advancement to clinical
development.
Table 3. In Vitro Potency of Potential Template 1,3,5-
Triaryl-1H-pyridin-2-ones (17, 24a, and 28a)
a
The pharmacokinetic properties of 6 were evaluated in rats
after iv (n = 3) and po (n = 3) administration at a dose of 1
mg/kg (Table 9). The results indicated a time to reach maximal
plasma concentration of 0.50 h, a half-life of 2.37 h, a plasma
clearance (CL) of 1.82 L h−1 kg−1, and an oral bioavailability of
64.3%. The CL was investigated by in vitro metabolic stability
(CLint) with in vitro−in vivo extrapolation (IVIVE), which
indicated that the main elimination route of 6 is hepatic
metabolism. As the CLint of 6 in human liver microsomes was
low (0.009 μL/min/mg protein), it was predicted by IVIVE to
have good oral availability in humans.
In order to assess CNS penetration of compound 6, brain-to-
plasma concentration ratios were evaluated in mice and rats.
The ratios of 6 were 1.06 and 1.14 in mice and rats, respectively
(Table 10). Furthermore, the cerebrospinal fluid (CSF)
concentration of 6 was measured in mice, and the CSF
concentration to unbound plasma concentration ratio was
calculated to be 1.14. These results indicated a good CNS
penetration of 6 in preclinical animal models, which is expected
to be maintained in humans.
a
All values are from three measurements and are expressed as the
mean SEM.
effects using a mouse AMPA-induced seizure model: 6, 24h,
24j, 28b, 28d, 28e, 28g, and 33c.
6, 28b, 24h, and 24j showed strong effects in the mouse
seizure model (as shown by the minimum effective dose) and
sufficient stability in liver microsomes derived from three
species (including human) (Table 8). The selected compounds
were subjected to further preclinical pharmacokinetic studies.
Chemistry. 2,4-Disubstituted-4H-1,3,4-oxadiazin-5(6H)-
ones derivatives (8a−f) were synthesized by cyclization of
intermediate 7 (Scheme 1).15−17
a
Table 4. SARs for the Aryl Group at Position 3 of the Pyridone Ring (i) (6, 24a−j)
a
All values are from three measurements and are expressed as the mean SEM.
D
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a
Table 5. SARs for the Aryl Group at Position 3 of the Pyridone Ring (ii) (28a−g)
a
All values are from three measurements and are expressed as the mean SEM.
a
Table 6. SARs for the Aryl Group at Position 5 of the Pyridone Ring (6, 33a−h)
a
All values are from three measurements and are expressed as the mean SEM.
The 4,5-dihydro-2,6-diphenyl-3(2H)pyridinone (9) was
obtained by condensation of ethyl benzoylacetate and phenyl-
hydrazine in EtOH.18 The 1,5-diphenyl-1,2-dihydropyridin-2-
one (13) was afforded by Ullmann-type reaction of a pyridone
derivative (12), prepared from 2-methoxy-5-bromopyridine
(10) in two steps in the usual manner with phenylboronic acid
(Scheme 2).
The 3,5-diarylsubstituted-pyridone derivative (16) was
produced by Suzuki−Miyaura coupling of 3,5-dibromo-2-
methoxypyridine (14) and phenylboronic acid followed by
acidic deprotection.
was synthesized by Ullmann-type reaction19−21 of compound
16 using phenylboronic acid (Scheme 3).
1,3,5-Triaryl-2(1H)-pyridone derivatives 6, 24a, 24f, 24h−j
were synthesized according to Scheme 4. 5-Ar-2(1H)-pyridone
21 was prepared by Suzuki−Miyaura coupling of 19, followed
by deprotection under acidic conditions. Modified Ullmann
reaction of compound 21 with Ar3-B(OH)2 gave compound 22,
which was subjected to halogenation by NBS or NIS and then
Suzuki−Miyaura coupling with the Ar2 moiety to deliver the
final compounds (6, 24a, 24f, 24h−j) (Scheme 4).
1-Aryl-5-(2-pyridyl)-3-aryl-2(1H)-pyridone derivatives 28a−
g, 38a, 38c−g were synthesized by bromination of intermediate
The preparation of trisubstituted derivatives is described in
Schemes 3−7. 1,3,5-Triaryl-substituted-pyridone derivative 17
E
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a
Table 7. SARs for the Aryl Group at Position 1 of the Pyridone Ring (6, 28b, 38a−g)
a
All values are from three measurements and are expressed as the mean SEM.
21 followed by sequential couplings under modified Ullmann
conditions and Suzuki−Miyaura/Stille conditions (Scheme 5).
The compounds 33a−h and 24b−d were afforded by
selective arylation of 3-iodo-5-bromo-2(1H)-pyridone (30) as
outlined in Scheme 6. Reaction of 30 with phenylboronic acid
in the presence of copper acetate provided 5-bromo-3-iodo-1-
phenyl-2(1H)-pyridone (31) in 52% yield. Coupling reaction of
31 with 2-aryl-1,3,2-dioxanorinate or arylboronic acid with
tetrakis(triphenylphosphine)palladium as a catalyst in DMF
furnished 5-bromo-3-aryl-1-phenyl-2(1H)-pyridone derivatives
32a−d in 28−52% yield. These compound were reacted with
various arylboronic acid derivatives or aryltributylstannane
derivatives in the presence of a palladium catalyst to afford
compounds 33a−h and 24b−d in 20−70% yields.
Finally, Scheme 7 demonstrated the introduction of a 1-aryl
substitute on the pyridone ring (Ar3) in the final step. Reaction
of 5-bromo-2-methoxypyridine (18) with 2-pyridyltributylstan-
nane in the presence of tetrakis(triphenylphosphine)palladium
provided 2-methoxy-5-(2-pyridyl)pyridine (34). Then bromi-
nation of 34 was carried out by using stoichiometric amounts of
silver acetate in acetic acid to afford 3-bromo-2-methoxy-5-(2-
pyridyl)pyridine (35), which was coupled with phenyl[1,3,2]-
dioxaborinate or arylboronic acid in the presence of palladium
catalyst to give a 3,5-diaryl-2-methoxypyridine derivative (36a−
c). 36 was treated with chlorotrimethylsilane and sodium iodide
in acetonitrile to afford the 3,5-diaryl-2(1H)-pyridone deriva-
tive (37a−c). The coupling reaction of pyridine with various
arylboronic acids in the presence of a copper(II) catalyst
provided derivatives 24e, 24g, and 38b.
assay; MED = 2 mg/kg po in the AMPA-induced seizure
model) and had a preclinical pharmacokinetic profile favorable
for clinical use due to its greater stability in humans (CLint
=
0.009 μL min−1 mg−1) than in rats (CLint = 0.108 μL min−1
mg−1). The binding assay results22 indicated that the binding
site for 6 is similar to those of other known noncompetitive
AMPA receptor antagonists. Moreover, pyridone derivative 6
was proven to be highly selective against the AMPA receptor
using radioligand binding assays that included 63 physiologi-
cally relevant enzymes, ion channels, and neurotransmitter
transporters (see Supporting Information).23
The potent in vivo activity of pyridone derivative 6 was
confirmed in a number of preclinical seizure models, such as
audiogenic seizures (ED50 = 0.47 mg/kg), maximal electro-
shock seizures (ED50 = 1.6 mg/kg), and pentylenetetrazole-
induced seizures (ED50 = 0.94 mg/kg),22 in addition to the
mouse AMPA-induced seizure model.
In early clinical studies involving healthy subjects, 6 was well
tolerated and displayed favorable pharmacokinetic character-
istics, including good oral availability and a long half-life
(approximately 70−100 h).24
We believe that the discovery of pyridone derivative 6 and its
passage through phases I−III of clinical development25,26 have
validated the clinical utility of an orally active, highly selective,
and noncompetitive AMPA receptor antagonist.
EXPERIMENTAL SECTION
Chemistry. H NMR spectra were recorded on a Bruker Avance
■
1
spectrometer (600, 400, 300 MHz) or Varian Mercury 400
spectrometer (400 MHz). 13C NMR spectra were recorded on a
Bruker Avance spectrometer (150 MHz) or JEOL JNM α400
spectrometer (100 MHz). Chemical shifts were expressed in ppm
(δ) from the residual CHCl3 signal at (δH) 7.26 ppm and (δC) 77.0
ppm in CDCl3 and the residual C5HD4N signal at (δH) 8.71 ppm and
(δC) 149.2 ppm in C5D5N. High-resolution mass spectra were
recorded on a ThermoFisher LTQ-Orbitrap XL spectrometer (using
ESI). The melting point of pyridone derivative 6 was determined by
visual inspection according to the Japanese pharmacopeia. The
elemental carbon, hydrogen, and nitrogen content was measured by
CONCLUSIONS
■
We have described the entire discovery process from HTS to
identification of our compound 6 by comprehensive manipu-
lation of the three aromatic rings of a novel 1,3,5-triaryl-1H-
pyridin-2-one template.
Pyridone derivative 6 exhibited extremely potent in vitro/in
vivo effects (IC50 = 60 nM in the AMPA-induced Ca2+ influx
F
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Table 8. In Vitro and in Vivo Efficacy of Selected 1,3,5-Triaryl-1H-pyridin-2-one Derivatives
a
b
All values are from three measurements and are expressed as the mean SEM. Rate of human (H), mouse (M), and rat (R) intrisic clearance in
vitro.
Table 9. Pharmacokinetic Parameters for 6 (iv and po) in
Male Rats
Table 10. Brain/Plasma or CSF/Unbound Plasma
a
a
Concentration Ratios for 6 in Male Mice or Rats
iv (1 mg/kg)
parameter
po (1 mg/kg)
parameter
dose
sampling
brain/plasma
concn ratio
CSF/unbound
species (mg/kg)
time (min)
plasma concn ratio
mice
mice
rats
3, po
60
20
30
1.06
NT
NT
1.14
NT
CL (L h−1 kg−1
)
1.82
4.56
0.56
2.37
Cmax (μg/mL)
Tmax (h)
0.17
0.50
0.36
64.3
0.5, ip
10, po
Vdss (L/kg)
1.14
AUC (μg mL−1 h−1
)
AUC (μg mL−1 h−1
)
a
Each value represents the mean of two or three animals. NT: not
T1/2 (h)
F (%)
tested.
a
Each parameter is calculated from the mean of plasma concentration
of three animals. F is the ratio of AUC(0−inf) values after oral and
intravenous administrations.
greater than or equal to 95% unless specified otherwise. The
parameters of the HPLC method were as follows: Accucore RP-MS
column (2.1 mm × 50 mm, 2.6 μm); mobile phase A = H2O with 0.1%
HCO2H, B = acetonitrile with 0.1% HCO2H; 0−1 min, 0% B; 1−4
a thermal-conductivity method using a CHN Corder MT5 analyzer
(Yanaco, Japan). The purity of the biological tested compounds was
determined by an analytical HPLC method and was found to be
G
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a
evaporated. The residue solidified after the addition of toluene. The
resulting precipitate was collected by filtration to give 2-phenyl-4H-
1,3,4-oxadiazin-5(6H)-one (2.2 g). The filtrate was evaporated and the
residue was purified by silica gel column chromatography (heptane/
EtOAc = 20:1 to 2:1) to afford 2-phenyl-4H-1,3,4-oxadiazin-5(6H)-
one (3.3 g). In total, 5.5 g (0.0312 mol) of 2-phenyl-4H-1,3,4-
oxadiazin-5(6H)-one was obtained.
Scheme 1
2-Phenyl-4H-1,3,4-oxadiazin-5(6H)-one (151.8 mg, 0.862 mmol)
was dissolved in DMF (1 mL). The solution was cooled to 0 °C, and
NaH (41.4 mg, 1.034 mmol) was added to the solution. The resulting
solution was stirred at room temperature for 10 min. The solution was
cooled to 0 °C, and benzyl bromide was added (0.113 mL, 0.948
mmol). The mixture was stirred at room temperature overnight. H2O
and EtOAc were added to the reaction mixture. The organic layer was
separated, and the water layer was extracted with EtOAc. The
combined organic layer was washed with H2O and dried over MgSO4,
filtered, and evaporated. The residue was purified by silica gel column
chromatography (heptane/EtOAc = 0:1 to 1:1) to afford 8b (196 mg,
a
Reagents and conditions: (a) chloroacetyl chloride, base, solvent. For
8b, (a) also requires BnBr, NaH, DMF.
min, 0% B → 100% B; 4−8 min, 100% B; 8−11 min, 0% B; flow rate
of 0.4 mL/min; detector, UV 254 nm; run time of 11 min.
Reagents were purchased from commercial sources. Chromatog-
raphy was performed on silica gel using the solvent systems indicated
below. For mixed solvent systems, the volume ratios are given.
2,4-Diphenyl-4H-1,3,4-oxadiazin-5(6H)-one (8a). Benzoyl
chloride (14.0 g, 100 mmol) was added dropwise at room temperature
to a stirred solution of phenylhydrazine (10.8 g, 100 mmol) in pyridine
(100 mL). After this addition, the reaction mixture was stirred at
ambient temperature for 2 h. The mixture was then poured into ice−
water (500 mL). The precipitates were collected by filtration and
dissolved in EtOAc (500 mL). The organic layer was washed with 1 N
HCl and brine and then dried over MgSO4. After the drying agent was
filtered off, the reaction solution was evaporated to give 7a (10.1g, 47.6
mmol, 48%) without further purification.
Compound 7a (10.1 g, 47.6 mmol) was dissolved in methyl ethyl
ketone (250 mL). Chloroacetyl chloride (3.77 mL, 47.4 mmol) was
added, followed by heating under reflux for 1 h. The solution was left
and cooled to room temperature, after which potassium carbonate
(39.4 g, 285.1 mmol) was added and the mixture was refluxed for 3 h
under heating. The reaction solution was left and cooled to room
temperature, evaporated, diluted with EtOAc, washed with water and
brine, and then dried over MgSO4. After the drying agent was filtered
off, the product was evaporated and the resulting crystalline residues
were recrystallized from n-hexane and EtOAc and then from
methanol/hexane to give 8a (6.80 g, 27.0 mmol, 56.6%) as a pinkish
1
0.734 mmol, 85%) as white powder. H NMR (400 MHz, CDCl3) δ
4.76 (s, 2H), 4.96 (s, 2H), 7.29−7.33 (m, 1H), 7.34−7.42 (m, 4H),
7.43−7.48 (m, 3H), 7.80−7.91 (m, 2H). 13C NMR (150 MHz,
CDCl3) δ 51.5, 65.0, 126.6 2*C, 127.7, 128.3 2*C, 128.5 2*C, 128.6
2*C, 129.5, 130.9, 136.4, 148.5, 158.7. HRMS calculated for
(C16H14N2O2) [M + H]+ 267.1128; found 267.1119.
2-Phenyl-4-cyclohexyl-4H-1,3,4-oxadiazin-5(6H)-one (8c).
Compound 8c was prepared according to the procedure described
for the synthesis of 8a using N′-cyclohexylbenzohydrazide 7c (1.0 g,
4.58 mmol). The product was purified by column chromatography on
silica gel (n-hexane/EtOAc = 10:1) to give 8c (150 mg, 0.58 mmol,
1
13%) as a white solid. H NMR (400 MHz, CDCl3) δ 1.13−1.27 (m,
1H), 1.33−1.47 (m, 2H), 1.65−1.89 (m, 7H), 4.46−4.56 (m, 1H),
4.69 (s, 2H), 7.36−7.47 (m, 3H), 7.87 (dd, J = 1.6, 7.6 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ 25.3, 25.4 2*C, 29.9 2*C, 53.9, 65.0,
126.5 2*C, 128.3 2*C, 130.0, 130.7, 148.1, 158.1. HRMS calculated
for (C15H18N2O2) [M + H]+ 259.1441; found 259.1434.
2-Cyclohexyl-4-phenyl-4H-1,3,4-oxadiazin-5(6H)-one (8d).
Compound 8d was prepared according to the procedure described
for the synthesis of 8a using N′-phenylcyclohexanecarbohydrazide 7d
(1.0g, 4.58 mmol). The product was purified by column chromatog-
raphy on silica gel (n-hexane/EtOAc = 10:1) to give 8d (962 mg, 3.72
1
white solid. H NMR (400 MHz, CDCl3) δ 4.90 (s, 2H), 7.29−7.34
(m, 1H), 7.42−7.52 (m, 5H), 7.73−7.78 (m, 2H), 7.94−7.98 (m, 2H).
13C NMR (150 MHz, CDCl3) δ 65.4, 123.5 2*C, 126.8 3*C, 128.5
2*C, 128.7 2*C, 129.4, 131.2, 139.6, 149.1, 158.7. HRMS calculated
for (C15H12N2O2) [M + H]+ 253.0972; found 253.0962.
1
mmol, 81%) as a pale yellow solid. H NMR (600 MHz, CDCl3) δ
1.18−1.38 (m, 3H), 1.48 (dq, J = 3.4, 12.3 Hz, 2H), 1.67−1.74 (m,
1H), 1.82 (td, J = 3.3, 13.0 Hz, 2H), 1.96 (dd, J = 2.3, 13.6 Hz, 2H),
2.36 (tt, J = 3.4, 11.5 Hz, 1H), 4.67 (s, 2H), 7.24−7.27 (m, 1H), 7.38−
7.44 (m, 2H), 7.65−7.69 (m, 2H). 13C NMR (150 MHz, CDCl3) δ
25.6 2*C, 25.8, 29.5 2*C, 41.1, 65.0, 123.2 2*C, 126.5, 128.6 2*C,
139.6, 156.4, 158.5. HRMS calculated for (C15H18N2O2) [M + H]+
259.1441; found 259.1433.
2-n-Propyl-4-phenyl-4H-1,3,4-oxadiazin-5(6H)-one (8e).
Compound 8e was prepared according to the procedure described
for the synthesis of 8a using N′-phenylbutanehydrazide 7e (500 mg,
2.81 mmol). The product was purified by column chromatography on
silica gel (n-hexane/EtOAc = 10:1) to give 8e (60 mg, 0.27 mmol,
10%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.64 (s, 2H), 4.63
(s, 2H), 7.25−7.45 (m, 8H), 7.63 (m, 2H). HRMS calculated for
(C12H14N2O2) [M + H]+ 219.1128; found 219.1127.
2-Phenyl-4-benzyl-4H-1,3,4-oxadiazin-5(6H)-one (8b). Ben-
zoylhydrazine (25 g, 0.18 mol) was dissolved in acetone (500 mL).
Et3N (21.8 g, 0.12 mol) was added to the solution. The resulting
solution was cooled to 0 °C, and chloroacetyl chloride was added
(17.2 mL, 0.216 mol). The mixture was stirred at room temperature
overnight. H2O was added to the reaction mixture, and then the
mixture was extracted with EtOAc. The organic layer was dried over
MgSO4, filtered, and evaporated. A small amount of ether and heptane
was added to the residue. The resulting precipitate was collected by
filtration. The solid was dried at 50 °C and used for the next reaction
without further purification. The solid was dissolved in DMF (190
mL), and K2CO3 (55 g, 0.401 mol) and NaI (4.2 g, 0.0268 mol) were
added to the solution. The mixture was heated to 60 °C for 2 h.
The reaction mixture was filtered through Celite. The filtrate was
evaporated, and EtOAc and H2O were added to the residue. The
mixture was acidified with 2 N aqueous HCl and then extracted with
EtOAc. The organic layer was dried over MgSO4, filtered, and
2-Benzyl-4-phenyl-4H-1,3,4-oxadiazin-5(6H)-one (8f). Com-
pound 8f was prepared according to the procedure described for the
synthesis of 8a using N′,2-diphenylacetohydrazide 7f (500 mg, 2.21
a
Scheme 2
a
Reagents and conditions: (a) phenylboronic acid, Pd(PPh3)4, sodium carbonate, xylene; (b) HBr, H2O; (c) bromobenzene, KOAc, copper powder.
H
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a
Scheme 3
a
Reagents and conditions: (a) phenylboronic acid, Pd(PPh3)4, potassium phosphate, toluene−water−EtOH; (b) HBr, H2O; (c) phenylboronic acid,
copper(II) acetate, pyridine, DMF.
a
Scheme 4
a
Reagents and conditions: (a) n-BuLi, B(OMe)3; (b) Ar1-Br, Pd(OAc)2, PPh3, K2CO3, 1,2-dimethoxyethane−H2O; (c) 4 N HCl; (d) Ar3-B(OH)2,
Cu(OAc)2, pyridine, DMF. (e) X = Br: NBS, DMF. X = I: NIS, DMF. (f) Ar2[1,3,2]dioxaborinane, PdCl2, PPh3 polymer or Ar2-B(OH)2, Pd(PPh3)4,
Cs2CO3, DMF . For 24j, (f) (SnBu3)2, Pd(PPh3)4, xylene, then Ar2Br, CuI, Pd(PPh3)4, xylene.
a
a
Scheme 5
Scheme 6
a
Reagents and conditions: (a) (i) HIO4, I2, AcOH, H2O, (ii) NaNO2,
H2SO4; (b) Ar3-B(OH)2, Cu(OAc)2, Et3N, CH2Cl2; (c) Ar2[1,3,2]-
dioxaborinate or Ar2-B(OH)2, Pd(PPh3)4, Cs2CO3, DMF; (d) Ar1-
B(OH)2, Pd(PPh3)4, Cs2CO3, DMF or Ar1-SnBu3, Pd(PPh3)4, DMF.
a
Reagents and conditions: (a) (i) NaOMe, MeOH, (ii) Ar1-SnBu3,
Pd(PPh3)4, DMF, (iii) 48% HBr; (b) NBS, DMF; (c) Ar3-B(OH)2,
Cu(II) catalyst, base, solvent; (d) Ar2-B(OH)2 or Ar2-SnBu3 or Ar2-
1,3-dioxaborinane, Pd(PPh3)4, base, DMF.
mL) was added to the extract. The organic layer was washed with 10%
aqueous solution of ammonium chloride (60 mL), 10% aqueous
ammonia (60 mL), and 10% saline (100 mL). The organic layer was
dried over MgSO4 and then evaporated to give 11 (1.86 g, 10.0 mmol,
1
>99%) without further purification. H NMR (400 MHz, CDCl3) δ
3.98 (s, 3H), 6.81 (d, J = 8.4 Hz, 1H), 7.32−7.38 (m, 1H), 7.42−7.47
(m, 2H), 7.50−7.54 (m, 2H), 7.78 (dd, J = 2.4, 8.4 Hz, 1H), 8.39 (d, J
= 2.4 Hz, 1H).
mmol). The product was purified by column chromatography on silica
gel (n-hexane/EtOAc = 10:1) to give 8f (70 mg, 0.263 mmol, 12%) as
a brown oil. 1H NMR (400 MHz, CDCl3) δ 1.03 (t, J = 7.6 Hz, 3H),
1.71 (sxt, J = 7.6 Hz, 2H), 2.36 (t, J = 7.6 Hz, 2H), 4.70 (s, 2H), 7.25−
7.31 (m, 1H), 7.43 (dd, J = 2.0, 7.6 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ 13.6, 19.3, 33.8, 64.8, 123.5 2*C,
126.7, 128.7 2*C, 139.4, 153.6, 158.4. HRMS calculated for
(C16H14N2O2) [M + H]+ 267.1128; found 267.1124. HPLC purity,
84.5%.
2-Methoxy-5-(pyridin-2-yl)pyridine (11). Phenylboronic acid
(1.83 g, 15.0 mmol), 5-bromo-2-methoxypyridine 10 (1.90 g, 10.1
mmol), Pd(PPh3)4 (0.20 g, 0.17 mmol), 10% sodium carbonate
solution (20 mL), and xylene (40 mL) were heated under reflux for 5
h with stirring. After the reaction solution was cooled, EtOAc (100
5-Phenyl-2(1H)-pyridone (12). A mixture of 2-methoxy-5-
phenylpyridine 11 (1.86 g, 10.0 mmol) and 48% aqueous solution
of HBr (10 mL) was heated at 130 °C for 1.5 h. After the reaction
solution was cooled, EtOAc (100 mL) and water (50 mL) were added.
The organic layer was separated and washed with saturated sodium
bicarbonate solution (30 mL) and saturated sodium chloride solution.
The organic layer was dried over MgSO4 and evaporated. The residue
was purified by silica gel column chromatography (EtOA/cyclohexane
= 1:1) to give 12 (1.14 g, 6.66 mmol, 67%) as a white solid. 1H NMR
(400 MHz, DMSO-d6) δ 6.43 (d, J = 9.6 Hz, 1H), 7.28 (dt, J = 1.2, 7.8
Hz, 1H), 7.37−7.43 (m, 2H), 7.53−7.57 (m, 2H), 7.69 (d, J = 2.8 Hz,
1H), 8.39 (dd, J = 2.8, 9.6 Hz, 1H), 11.78 (br s, 1H).
I
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a
Scheme 7
a
Reagents and conditions: (a) Ar1-SnBu3, Pd(PPh3)4, DMF; (b) Br2, CH3CO2Ag, AcOH, DMF; (c) phenyl[1,3,2]dioxaborinate or Ar2-B(OH)2,
Pd(PPh3)4, Cs2CO3 or Et3N, DMF; (d) for 37a and 37b, HBr; or for 37c, chlorotrimethylsilane, NaI, CH3CN; (e) Ar3-B(OH)2, Cu(OAc)2, Et3N,
CH2Cl2.
1,5-Diphenyl-1,2-dihydropyridin-2-one (13). A mixture of 5-
phenyl-1,2-dihydropyridin-2-one 12 (500 mg, 2.92 mmol), copper
powder (560 mg, 8.8 mmol), potassium acetate (800 mg, 8.2 mmol),
and bromobenzene (5.0 mL, 47.6 mmol) was stirred at 160 °C
overnight. After the reaction mixture was cooled to room temperature,
it was directly purified by silica gel column chromatography (EtOA/
cyclohexane = 1:1). The solvent was evaporated in vacuo to give 13
under reduced pressure and air-dried at 60 °C to give 16 (500 mg,
2.02 mmol, 78%) as a white solid. H NMR (400 MHz, DMSO-d6) δ
1
7.28−7.37 (m, 2H), 7.38−7.45 (m, 4H), 7.65 (d, J = 8.0 Hz, 2H), 7.72
(d, J = 2.4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 2.4 Hz, 1H),
11.95−12.22 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ 118.8, 126.0
2*C, 127.2, 127.9, 128.4 2*C, 128.9 2*C, 129.4 2*C, 130.4, 132.2,
136.7, 137.1, 138.1, 161.1. HRMS calculated for (C17H13NO) [M +
H]+ 248.107; found 248.1065.
1
(140 mg, 0.566 mmol, 19%) as a white solid. H NMR (300 MHz,
DMSO-d6) δ 6.57 (dd, J = 1.8, 8.4 Hz, 1H), 7.23−7.30 (m, 1H), 7.31−
7.55 (m, 7H), 7.60 (dd, J = 2.0, 7.2 Hz, 2H), 7.85−7.95 (m, 1H), 7.92
(s, 1H). 13C NMR (100 MHz, CDCl3) δ 118.8, 121.1, 126.0 2*C,
127.4 2*C, 127.5, 128.7, 129.4 2*C, 129.5 2*C, 136.2, 136.5, 140.3,
141.3, 161.0. HRMS calculated for (C17H13NO) [M + H]+ 248.107;
found 248.1071.
3,5-Dibromo-2-methoxypyridine (14). Sodium methoxide
methanol solution (28%, 80 mL) was incorporated with 2,3,5-
tribromopyridine (30 g, 95.0 mmol) under ice-cooling, followed by
stirring at 50 °C for 2 h. The reaction solution was diluted with water
and extracted with diethyl ether. The organic layer was washed with
brine and then dried over MgSO4. The solvent was evaporated, and
the residue was purified by silica gel chromatography (n-hexane/
EtOAc = 20:1) to give 14 (18.5g, 69.3 mmol, 73%) as a greyish solid.
1H NMR (300 MHz, DMSO-d6) δ 3.88 (s, 3H), 8.27 (d, J = 2.4 Hz,
1H), 8.30 (d, J = 2.1 Hz, 1H).
1,3,5-Triphenyl-1,2-dihydropyridin-2-one (17). A mixture of
3,5-diphenyl-1,2-dihydropyridin-2-one 16 (400 mg, 1.62 mmol),
phenylboronic acid (260 mg, 2.13 mmol), copper(II) acetate (42
mg, 0.23 mmol), pyridine (0.37 mL), and DMF (5 mL) was stirred at
room temperature overnight under an oxygen atmosphere. The
reaction solution was poured into ice-cooled 10% aqueous ammonia
and extracted with EtOAc. The organic layer was washed with water
and brine. The organic layer was concentrated under reduced pressure
and the residue was purified by silica gel column chromatography to
1
give 17 (170 mg, 0.525 mmol, 32%) as a white solid. H NMR (400
MHz, CDCl3) δ 7.32−7.55 (m, 13H), 7.62 (d, J = 2.8 Hz, 1H), 7.81
(d, J = 7.6 Hz, 2H), 7.90 (d, J = 2.8 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 120.1, 125.9 2*C, 126.8 2*C, 127.5, 128.0, 128.2 2*C,
128.6, 128.8 2*C, 129.1 2*C, 129.4 2*C, 132.4, 134.3, 136.5, 136.6,
137.9, 141.4, 160.8. HRMS calculated for (C23H17NO) [M + H]+
324.1383; found 324.1368.
3,5-Diphenyl-2-methoxypyridine (15). A mixture of 3,5-
dibromo-2-methoxypyridine 14 (780 mg, 2.92 mmol) and phenyl-
boronic acid (712 mg, 5.84 mmol) was incorporated with Pd(PPh3)4
(1.0 g, 0.87 mmol) and potassium phosphate in toluene−water−
EtOH. This was heated with stirring under reflux overnight in a
nitrogen atmosphere. After the mixture was cooled to room
temperature, the solvent was evaporated and the residue was extracted
with EtOAc. The organic layer was washed with water and brine and
then dried over MgSO4. The solvent was evaporated and the residue
was purified by silica gel chromatography (n-hexane/EtOAc = 3:1) to
5-Bromo-2-methoxypyridine (18). 2,5-Dibromopyridine (200 g,
0.84 mol) and 28% NaOMe methanol solution (1535 g) were heated
under reflux for 30 min followed by cooling to room temperature. The
mixture was partitioned between water (1.6 L) and tert-butyl methyl
ether (1.6 L). The resulting organic layer was washed with brine (1 L)
three times and then dried over MgSO4 overnight. The dried organic
layer was evaporated at 65 °C to give 18 (159 g, 0.84 mol, >99%) as a
1
brown oil. H NMR (400 MHz, CDCl3) δ 3.91 (s, 3H), 6.66 (d, J =
8.8 Hz, 1H), 7.64 (dd, J = 2.2, 8.8 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H).
2-Methoxy-5-pyridylboronic Acid (19). 5-Bromo-2-methoxy-
pyridine 18 (152 g, 0.81 mol) was dissolved in THF (1520 mL) under
a nitrogen atmosphere, followed by cooling to −75.1 °C. Under
cooling and stirring, a 2.46 mol/L n-butyl lithium solution (380 mL,
0.935 mol) was added dropwise, followed by the dropwise addition of
trimethoxyborane (192 mL, 1.718 mol). The cooling bath was
removed 30 min after completion of the dropwise addition, and the
mixture was stirred at room temperature overnight. A 2 mol/L
aqueous solution of HCl (1.5 L) was then added, followed by stirring
for 1.5 h. The mixture was neutralized with a 5 mol/L aqueous
solution of NaOH (460 mL) and then extracted with EtOAc (1 L ×
2). The combined organic layer was washed twice with 10% saline
water (1 L), dried over MgSO4, and evaporated to give 19 (105 g,
1
give 15 (680 mg, 2.60 mmol, 89%) as a an off-white solid. H NMR
(300 MHz, DMSO-d6) δ 3.94 (s, 3H), 7.37−7.41 (m, 2H), 7.45−7.50
(m, 4H), 7.66 (br d, J = 5.4 Hz, 1H), 7.76 (br d, J = 5.4 Hz, 1H), 8.01
(d, J = 1.8 Hz, 1H), 8.50 (d, J = 1.8 Hz, 1H).
3,5-Diphenyl-1,2-dihydropyridin-2-one (16). A mixture of 3,5-
diphenyl-2-methoxypyridine 15 (680 mg, 2.60 mmol) and a 48%
aqueous solution of HBr in EtOH was heated under reflux for 3 h.
After the reaction solution was cooled, it was washed with tert-butyl
methyl ether. An 8 mol/L aqueous solution of NaOH was added to
the aqueous layer under cooling with ice−water, and then the mixture
was washed twice with tert-butyl methyl ether. Then it was adjusted to
pH 8 with concentrated HCl and an 8 mol/L aqueous solution of
NaOH, followed by partitioning between EtOAc and brine. The
aqueous layer was extracted again with EtOAc, and the combined
organic layer was evaporated. tert-Butyl methyl ether was added to the
resulting residue. The resulting precipitate was collected by filtration
1
85%, 0.69 mol) as a slightly yellowish white solid. H NMR (400
MHz, CDCl3) δ 3.83 (s, 3H), 6.74 (d, J = 8.4 Hz, 1H), 7.98 (dd, J =
2.0, 8.4 Hz, 1H), 8.10 (s, 2H), 8.50 (d, J = 2.0 Hz, 1H).
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2-Methoxy-5-(pyridin-2-yl)pyridine (20). 2-Methoxy-5-pyridyl-
boronic acid 19 (105 g, 0.69 mol), 2-bromopyridine (90 g, 0.57 mol),
palladium(II) acetate (3.21 g, 0.014 mol), triphenylphosphine (15 g,
0.057 mol), potassium carbonate (237 g, 1.72 mol), 1,2-dimethoxy-
ethane (900 mL), and water (900 mL) were heated under reflux for 5
h and under stirring for 40 min. After the reaction solution was cooled,
EtOAc (1 L) was added. The organic layer was washed with 10%
aqueous solution of ammonium chloride (1 L), 10% aqueous ammonia
(1 L), and 10% saline (1 L) and then evaporated to give 20 (126 g,
dihydropyridin-2-one 23a (50 mg, 0.152 mmol), 2-(1,3,2-dioxabor-
inan-2-yl)benzonitrile (40 mg, 0.213 mmol), palladium chloride (2.7
mg, 0.015 mmol), triphenylphosphine polymer (20 mg), Cs2CO3 (100
mg, 0.307 mmol), and DMF (1.5 mL) was stirred at 80 °C under a
nitrogen atmosphere for 6 h. Subsequently, EtOAc (50 mL) was added
to the reaction mixture and the mixture was filtered and washed with
12.5% aqueous ammonia, water, and brine. The organic layer was dried
over MgSO4 and concentrated under reduced pressure. Acetone (4
mL) was added, followed by concentration under reduced pressure.
The residue was purified by silica gel chromatography (EtOAc/n-
hexane = 1:2) to give 6 (39 mg, 0.111 mmol, 73%) as a yellowish
white solid (mp 180 °C). 1H NMR (400 MHz, DMSO-d6) δ 7.31 (dd,
J = 4.8, 7.6 Hz, 1H), 7.48−7.63 (m, 6H), 7.73 (dd, J = 8.4 Hz, 1H),
7.79 (ddd, J = 1.2, 6.4, 8.0 Hz, 1H), 7.85 (ddd, J = 2.0, 6.4, 8.0 Hz,
1H), 7.94 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 2.8
Hz, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.59 (ddd, J = 0.8, 1.2, 4.8 Hz, 1H).
13C NMR (150 MHz, CDCl3) δ 112.5, 118.3, 118.6, 118.8, 122.1,
1
0.68 mol, 98%) as a colorless oil. H NMR (300 MHz, DMSO-d6) δ
3.86 (s, 3H), 6.87 (dd, J = 0.6, 8.1 Hz, 1H), 7.25−7.30 (m, 1H), 7.77−
7.90 (m, 2H), 8.31 (dd, J = 2.4, 8.7 Hz, 1H), 8.59−8.61 (m, 1H),
8.78−8.85 (m, 1H).
5-(Pyridin-2-yl)-2(1H)-pyridone (21). A mixture of 2-methoxy-5-
(pyridin-2-yl)pyridine 20 (308 g, 1.65 mol) and a 4 mol/L aqueous
solution of HCl (2.4 L) was heated under reflux for 3 h. After the
reaction solution was cooled, it was washed with tert-butyl methyl
ether (2.2 L). An 8 mol/L aqueous solution of NaOH (1.1 L) was
added to the aqueous layer under cooling with ice−water, and then the
mixture was washed twice with tert-butyl methyl ether (2.2 L). Then it
was adjusted to pH 8 with concentrated HCl (310 mL) and an 8 mol/
L aqueous solution of NaOH (100 mL), followed by partitioning
between 1-butanol (4.5 L) and brine (1.8 L). The aqueous layer was
extracted again with 1-butanol (4.5 L), and the combined organic layer
was evaporated at 45−50 °C. tert-Butyl methyl ether (2.2 L) was
added to the resulting residue. The resulting precipitate was collected
by filtration. Water (1.6 L) was then added to dissolve the residue
under heating. The mixture was water-cooled, recrystallized, and the
resulting precipitate was collected by filtration to give 21 (188 g, 1.09
mol, 66%) as a grayish white solid. 1H NMR (400 MHz, DMSO-d6) δ
6.42 (d, J = 9.6 Hz, 1H), 7.19−7.26 (m, 1H). 7.74−7.81 (m, 2H), 8.11
(d, J = 2.8 Hz, 1H), 8.17 (dd, J = 2.8, 9.6 Hz, 1H), 8.52−8.55 (m, 1H).
1-Phenyl-5-(pyridin-2-yl)-2(1H)-pyridone (22). While 5-(pyr-
idin-2-yl)-2(1H)-pyridone 21 (185 g, 1.07 mol), phenylboronic acid
(261 g, 2.14 mol), copper(II) acetate (19.4 g, 0.107 mol), pyridine
(173 mL), and DMF (1480 mL) were stirred at room temperature, air
was blown in at 2.0 L/min to initiate the reaction. Since 26% of the
reactant remained unreacted 7 h after the initiation of the reaction, the
flow of air was stopped to suspend the reactions. On the next day, air
was blown into the solution to restart the reaction, and the reactant
was consumed to 0.57% of the initial weight in 5.5 h. The reaction
solution was poured into ice-cooled 10% aqueous ammonia (7.5 L).
The resulting precipitate was collected by filtration under reduced
pressure and washed with water (3 L). The resulting crystals were
suspended into 10% aqueous ammonia (3.6 L) under stirring at room
temperature for 1 h. Then the crystals were collected by filtration
under reduced pressure and washed with water (2 L). The resulting
crystals were air-dried overnight to give 22 (187 g, 70%, 0.753 mol) as
126.7 2*C, 128.2, 128.8, 129.0, 129.4 2*C, 131.1, 132.3, 133.2, 137.1,
138.0, 138.9, 140.3, 140.9, 149.8, 153.1, 160.5. HRMS calculated for
(C23H15N3O) [M + H]+ 350.1288; found 350.1276.
3-Phenyl-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one
(24a). Compound 24a was prepared according to the procedure
described for the synthesis of 6 using 23a (1.6 g, 4.9 mmol) and
phenylboronic acid to give 24a (440 mg, 1.36 mmol, 28%) as a yellow
1
solid. H NMR (400 MHz, DMSO-d6) δ 7.30 (ddd, J = 0.8, 4.8, 8.4
Hz, 1H), 7.35−7.40 (m, 1H), 7.41−7.47 (m, 2H), 7.49−7.54 (m, 2H),
7.56−7.60 (m, 3H), 7.83 (ddd, J = 1.6, 6.0, 8.4 Hz, 3H), 8.02 (dd, J =
0.8, 8.4 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 2.8 Hz, 1H),
8.59 (ddd, J = 0.8, 1.6, 4.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ
118.4, 118.5, 121.9, 126.8 2*C, 128.0, 128.1 2*C, 128.6, 128.9 2*C,
129.3 2*C, 132.0, 136.3 2*C, 136.6, 137.0, 141.3, 149.8, 153.5, 161.1.
HRMS calculated for (C22H16N2O) [M + H]+ 325.1336; found
325.1347.
3-(3-Cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyri-
din-2-one (24b). Compound 24b was prepared according to the
procedure described for the synthesis of 33c using 32 (114 mg, 0.32
mmol) and 2-(tributylstannyl)pyridine to give 24b (42 mg, 0.12
1
mmol, 38%) as a white solid. H NMR (400 MHz, CDCl3) δ 7.24
(ddd, J = 0.8, 4.8, 7.6 Hz, 1H), 7.46−7.66 (m, 8H), 7.78 (td, J = 1.6,
7.6 Hz, 1H), 8.10 (dt, J = 1.2, 8.0 Hz, 1H), 8.16 (t, J = 8.0 Hz, 1H),
8.25 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.61−8.63 (m,1H).
13C NMR (100 MHz, DMSO-d6) δ 111.6, 117.9, 119.3, 119.7, 122.6
2*C, 127.5, 128.4, 129.1 2*C, 129.6, 129.7, 131.7, 132.7, 133.8, 137.7,
137.7, 138.1, 138.3, 141.5, 149.8, 152.9, 160.3. HRMS calculated for
(C23H15N3O) [M + H]+ 350.1288; found 350.1301.
3-(4-Cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyri-
din-2-one (24c). Compound 24c was prepared according to the
procedure described for the synthesis of 33c using 32 (55 mg, 0.16
mmol) and 2-(tributylstannyl)pyridine to give 24c (23 mg, 0.066
1
a brown solid. H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 9.5 Hz,
1
mmol, 41%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 7.22−
1H), 7.19 (dd, J = 4.9, 7.3 Hz, 1H), 7.42−7.48 (m, 3H), 7.49−7.55
(m, 3H), 7.72 (dt, J = 1.7, 7.8 Hz, 1H), 8.04 (dd, J = 2.7, 9.5 Hz, 1H),
8.21 (d, J = 2.7 Hz, 1H), 8.57−8.59 (m, 1H).
7.26 (m, 1H), 7.47−7.60 (m, 6H), 7.70−7.78 (m, 3H), 7.95−7.98 (m,
2H), 8.26 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 2.4 Hz,1H), 8.61−8.63
(m,1H). 13C NMR (100 MHz, CDCl3) δ 111.4, 118.5, 118.6, 119.0,
122.2*C, 126.7, 129.0*C, 129.4, 129.5*C, 129.8, 131.9*C, 137.1,
137.4, 137.4, 140.9, 141.2, 149.8, 152.9, 160.6. HRMS calculated for
(C23H15N3O) [M + H]+ 350.1288; found 350.1282.
3-Bromo-1-phenyl-5-(pyridin-2-yl)-2(1H)-pyridone (23a). 1-
Phenyl-5-(pyridin-2-yl)-2(1H)-pyridone 22 (186 g, 0.749 mol), NBS
(141.7 g, 0.796 mol), and DMF (900 mL) were stirred at room
temperature. After 2.5 h, NBS (6.45 g, 0.036 mol) was added. After
depletion of the reactant was confirmed, the reaction solution was
poured into water (4.5 L) under ice cooling, followed by stirring in a
cold room (approximately 4 °C) overnight. The resulting crystals were
collected by filtration under reduced pressure, followed by dissolving
in IPA (3.25 L) and H2O (650 mL) under heating. After complete
dissolution was confirmed, the solution was left to cool gradually and
then ice cooled. Then the mixture was stirred in a cold room
overnight. The resulting solid was collected by filtration to give 23a
(191 g, 0.583 mol, 78%) as a white solid. 1H NMR (400 MHz,
DMSO-d6) δ 7.29−7.34 (m,1H), 7.50−7.60 (m, 6H), 7.81−7.88 (m,
1H), 8.46 (d, J = 1.8 Hz, 1H), 8.55−8.62 (m, 1H), 8.77−8.80 (m,
1H).
3-(2-Fluorophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyri-
din-2-one (24d). Compound 24d was prepared according to the
procedure described for the synthesis of 33c using 32 (75 mg, 0.22
mmol) and 2-(tributylstannyl)pyridine to give 24d (19 mg, 0.006
1
mmol, 27%) as a white solid. H NMR (400 MHz, CDCl3) δ 7.13−
7.22 (m, 3H), 7.31−7.59 (m, 7H), 7.66 (td, J = 1.6, 7.6 Hz, 1H), 7.74
(td, J = 1.6, 7.6 Hz, 1H), 8.22 (dd, J = 1.2, 2.8 Hz, 1H), 8.29 (d, J = 2.8
Hz, 1H), 8.58−8.60 (m, 1H). 13C NMR (150 MHz, CDCl3) δ
115.7(d, J(c,f) = 22.4 Hz), 118.1, 118.6, 121.9, 123.8 (d, J(c,f) = 3.4
Hz), 124.3 (d, J(c,f) = 14.4 Hz), 126.8, 127.1, 128.6, 129.3, 129.7 (d,
J(c,f) = 8.5 Hz), 131.7 (d, J(c,f) = 2.7 Hz), 137.0, 136.7*2, 138.5 (d,
J(c,f) = 3 Hz), 141.2, 149.7, 153.4, 160.2 (d, J(c,f) = 246 Hz), 160.5.
HRMS calculated for (C22H15N2O) [M + H]+ 343.1241; found
343.1257.
2-(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)-
benzonitrile (6). A mixture of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-
K
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3-(2-Chlorophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyri-
din-2-one (24e). A suspension of 3-(2-chlorophenyl)-5-(2-pyridyl)-
2(1H)-pyridone 37a (430 mg, 1.52 mmol), phenylboronic acid (570
mg, 4.67 mmol), copper(II) acetate (840 mg, 4.62 mmol), and Et3N
(0.8 mL, 5.74 mmol) in methylene chloride (15 mL) was stirred at
room temperature overnight. Concentrated aqueous ammonia (10
mL), water (20 mL), and EtOAc (100 mL) were added, and the
organic layer was separated, washed with water and a saturated saline
solution, and dried over MgSO4. The solvent was concentrated in
vacuo and the residue was purified by a silica gel column
chromatography (n-hexane/EtOAc = 2:1) to give 24e (120 mg, 0.33
acid (130 mg, 0.826 mmol) and Cs2CO3 (250 mg, 0.767 mmol) were
suspended in DMF (10 mL). Pd(PPh3)4 (40 mg, 0.035 mmol) was
added, and the mixture was stirred at 100 °C in a nitrogen atmosphere
for 3 h. After it had cooled, the reaction solution was poured into
water, the mixture was extracted with EtOAc, the extract was dried
over MgSO4, the solvent was evaporated in vacuo, and the residue was
purified by a silica gel column chromatography (n-hexane/EtOAc =
1:1) to give 24i (143 mg, 0.397 mmol, 75%) as a white solid. 1H NMR
(400 MHz, CDCl3) δ 7.20−7.24 (m, 1H), 7.31 (dd, J = 4.7, 7.6 Hz,
1H), 7.44−7.59 (m, 6H), 7.75 (dt, J = 1.6, 7.9 Hz, 1H), 7.91 (dd, J =
1.6, 7.9 Hz, 1H), 8.25 (d, J = 3.2 Hz, 1H), 8.33 (d, J = 3.2 Hz, 1H),
8.41 (dd, J = 1.6, 4.7 Hz, 1H), 8.59−9.62 (m, 1H). 13C NMR (100
MHz, CDCl3) δ 118.1, 118.6, 122.1, 122.2, 126.7 2*C, 128.5, 128.9,
129.4 2*C, 132.0, 137.1, 137.7, 139.1, 140.6, 140.8, 149.0, 149.8,
150.4, 153.0, 160.3. HRMS calculated for (C21H14ClN3O) [M + H]+
360.0898; found 360.0883.
1
mmol, 22%) as a brown solid. H NMR (400 MHz, CDCl3) δ 6.76−
6.81 (m, 2H), 6.86−6.91 (m, 1H), 7.17−7.22 (m, 2H), 7.26−7.75 (m,
5H), 7.61 (d, J = 8.0 Hz, 1H), 7.78−7.86 (m, 1H), 8.11 (d, J = 2.0 Hz,
1H), 8.41 (br s, 1H), 8.62 (d, J = 5.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 117.9, 118.6, 121.9, 126.5, 126.7 2*C, 128.6, 129.2 2*C,
129.3, 129.7, 130.9, 131.8, 133.7, 135.6, 137.0, 137.1, 138.4, 141.1,
149.7, 153.4, 160.4. HRMS calculated for (C22H15ClN2O) [M + H]+
359.0946; found 359.0936.
3-(2-Cyano-3-pyridyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydro-
pyridin-2-one (24j). 3-Bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydro-
pyridin-2-one 23a (2.9 g, 8.86 mmol) was dissolved in xylene (200
mL). Bis(tributyltin) (5 mL, 0.01 mmol) and Pd(PPh3)4 (400 mg,
0.346 mmol) were added, and the mixture was stirred at 140 °C for 2
h. 3-Bromo-2-cyanopyridine (3.2 g, 17.4 mmol) and Pd(PPh3)4 (100
mg, 0.087 mmol) were added, and the mixture was stirred at 140 °C
for 2 h. Pd(PPh3)4 (1.0 g, 0.865 mmol) and copper iodide (800 mg)
were divided into four and added every 1 h. Then 3-bromo-2-
cyanopyridine (2.0 g, 10.92 mmol) was added and the mixture was
stirred at 140 °C overnight. The reaction solution was cooled to room
temperature, water and EtOAc were added, the organic layer was
partitioned, washed with water, and dried over anhydrous sodium
sulfate, the drying agent was filtered off, the filtrate was concentrated
in vacuo, and the residue was purified by a silica gel column
chromatography (n-hexane/EtOAc system) to give 24j (1.5 g, 4.28
3-(2-Tolyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one
(24f). Compound 24f was prepared according to the procedure
described for the synthesis of 6 using 23a (108 mg, 0.33 mmol) and 2-
tolylboronic acid to give 24f (76 mg, 0.225 mmol, 68%) as a white
solid. 1H NMR (400 MHz, DMSO-d6) δ 2.24 (s, 3H), 7.22−7.34 (m,
5H), 7.47−7.60 (m, 5H), 7.78−7.84 (td, J = 2.4, 8.0 Hz, 1H), 7.99 (d,
J = 8.0 Hz, 1H), 8.22 (d, J = 3.2 Hz, 1H), 8.45 (d, J = 3.2 Hz, 1H),
8.56 (d, J = 4.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 20.2, 117.5,
119.5, 122.4, 126.0, 127.5 2*C, 128.3, 128.9, 129.6 2*C, 130.1, 130.5,
133.0, 137.1, 137.4, 137.6, 137.7, 138.0, 141.7, 149.8, 153.1, 160.1.
HRMS calculated for (C23H18N2O) [M + H]+ 339.1492; found
339.1506.
3-(2-Methoxyphenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydro-
pyridin-2-one (24g). A suspension of 3-(2-methoxyphenyl)-5-(2-
pyridyl)-2(1H)-pyridone 37b (150 mg, 0.54 mmol), phenylboronic
acid (120 mg, 0.98 mmol), copper(II) acetate (160 mg, 0.88 mmol),
and Et3N (0.5 mL, 3.59 mmol) in methylene chloride (5 mL) was
stirred at room temperature overnight. Concentrated aqueous
ammonia (5 mL), water (10 mL), and EtOAc (50 mL) were added
to this, and the organic layer was separated, washed with water and a
saturated saline solution, and dried over MgSO4. The solvent was
concentrated in vacuo and the residue was purified by silica gel column
chromatography (n-hexane/EtOAc = 2:1) to give compound 24g (45
mg, 0.127 mmol, 23.6%) as a yellow solid. 1H NMR (400 MHz,
DMSO-d6) δ 3.76 (s, 3H), 7.00 (td, J = 0.8, 7.6 Hz, 1H), 7.09 (d, J =
8.0 Hz, 1H), 7.27 (ddd, J = 0.8, 4.8, 7.2 Hz, 1H), 7.30−7.40 (m, 1H),
7.46−7.52 (m, 1H), 7.53−7.59 (m, 3H), 7.76−7.84 (m, 3H), 7.94 (d, J
= 8.0 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H),
8.55−8.58 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 55.9, 111.2,
117.9, 118.5, 120.4, 121.7, 125.9, 126.8 2*C, 128.4, 129.2 2*C, 129.4,
130.3, 131.3, 136.4, 136.9, 137.9, 141.5, 149.7, 153.8, 157.3, 160.8.
HRMS calculated for (C23H18N2O2) [M + H]+ 355.1441; found
355.1432.
1
mmol, 48%) as a white solid. H NMR (400 MHz, CDCl3) δ 7.24
(ddd, J = 0.8, 4.8, 7.4 Hz, 1H), 7.47−7.57 (m, 6H), 7.63 (d, J = 8.0 Hz,
1H), 7.77 (td, J = 1.6, 6.0 Hz, 1H), 8.22 (dd, J = 1.6, 8.4 Hz, 1H), 8.37
(d, J = 2.6 Hz, 1H), 8.43 (d, J = 2.6 Hz, 1H), 8.59−8.61 (m, 1H), 8.69
(dd, J = 1.6, 4.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 117.0,
118.5, 118.9, 122.3, 125.8, 125.9, 126.6 2*C, 129.1, 129.5 2*C, 132.9,
137.3, 137.4, 138.8, 138.9, 139.5, 140.7, 149.8, 149.9, 152.7, 160.4.
HRMS calculated for (C22H14N4O) [M + H]+ 351.1241; found
351.1229.
3-Bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one (26). 5-(2-
Pyridyl)-1,2-dihydropyridin-2-one (21) (201.5 g, 1.17 mol) was
dissolved in DMF (1300 mL). NBS (208.3 g, 1.17 mol) was added,
and the mixture was stirred at room temperature for 2 h. The reaction
mixture was poured into 4 L of ice−water and the precipitate was
filtered and dried with warm air at 50 °C for 2 days and nights to give
1
26 (230 g, 0.916 mL, 78%) as a brown solid. H NMR (400 MHz,
CDCl3) δ 7.21−7.26 (m, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.75 (dt, J =
2.0, 7.8 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.61−8.64 (m, 1H), 8.67 (d,
J = 2.4 Hz, 1H).
3-Bromo-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-
one (27a). Dichloromethane (300 mL) was added to 3-bromo-5-(2-
pyridyl)-1,2-dihydropyridin-2-one 26 (18.75 g, 74.7 mmol) and
(pyridin-3-yl)boronic acid (18.36 g, 0.15 mol). Then di-μ-hydroxo-
bis[(N,N,N′,N′-tetramethylethylenediamine)copper(II)] chloride
(3.47 g, 7.47 mmol) was added, and the mixture was stirred in an
oxygen atmosphere for 4 days and nights. The reaction solution was
purified by an NH silica gel short column (eluted by EtOAc), the
solvent was evaporated in vacuo, and the resulting crude crystals were
washed with diethyl ether to give 27a (24.3 g, 74.09 mmol, 99%) as a
white solid. 1H NMR (400 MHz, CDCl3) δ 7.23−7.26 (m,1H), 7.47−
7.51 (m,1H), 7.52−7.56 (m,1H), 7.77 (dt, J = 2.0, 7.8 Hz, 1H), 7.87−
7.91 (m, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.59−
8.62 (m, 1H), 8.71−8.75 (m, 2H).
3-(2-Fluoro-3-pyridyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydro-
pyridin-2-one (24h). Compound 24h was prepared according to the
procedure described for the synthesis of 6 using 23a (66 mg, 0.20
mmol) and 2-fluoro-3-pyridylboronic acid to give 24h (40 mg, 0.116
1
mmol, 58%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 7.20−
7.28 (m, 2H), 7.44−7.56 (m, 5H), 7.56−7.60 (m, 1H), 7.75 (td, J =
1.6, 7.8 Hz, 1H), 8.19−8.21 (m, 1H), 8.26 (ddd, J = 0.9, 7.4, 9.4 Hz,
1H), 8.30 (d, J = 2.8 Hz, 1H), 8.34 (t, J = 2.2 Hz, 1H), 8.59−8.61 (m,
1H). 13C NMR (150 MHz, CDCl3) δ 118.3, 118.6, 119.0 (d, J(c,f) =
28.0 Hz), 121.1 (d, J(c,f) = 4.1 Hz), 122.1, 124.5 (d, J(c,f) = 4.1 Hz),
126.7, 128.9, 129.4, 137.1, 137.6, 139.0 (d, J(c,f) = 4.6 Hz), 140.9,
142.3 (d, J(c,f) = 3.8 Hz), 146.9 (d, J(c,f) = 4.7 Hz), 149.8, 153.0,
160.5, 160.6 (d, J(c,f) = 239.3 Hz). HRMS calculated for
(C21H14FN3O) [M + H]+ 344.1194; found 344.1184.
3-Phenyl-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-
one (28a). Compound 28a was prepared according to the procedure
described for the synthesis of 28b using 27a (58 mg, 0.177 mmol) and
phenylboronic acid to give 28a (29 mg, 0.089 mmol, 50%) as a white
3-(2-Chloro-3-pyridyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydro-
nyridin-2-one (24i). 3-Iodo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyr-
idin-2-one 23b (200 mg, 0.53 mmol) was synthesized by the same
method as for the bromo derivative (23a). 2-Chloro-3-pyridylboronic
1
solid. H NMR (400 MHz, CDCl3) δ 7.23 (ddd, J = 1.0, 4.8, 7.4 Hz,
L
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1H), 7.36−7.50 (m, 4H), 7.60 (td, J = 1.0, 8.0 Hz, 1H), 7.75 (dd, J =
2.0, 7.6 Hz, 1H), 7.76−7.80 (m, 2H), 7.94 (ddd, J = 1.6, 2.6, 8.2 Hz,
1H), 8.22 (d, J = 2.8 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 8.62 (ddd, J =
0.8, 2.0, 4.8 Hz, 1H), 8.71 (dd, J = 1.4, 4.6 Hz, 1H), 8.75−8.79 (m,
1H). 13C NMR (150 MHz, CDCl3) δ 118.6, 119.1, 122.2, 123.6, 128.3
2*C, 128.8, 132.3, 134.7, 135.4, 136.2, 136.7, 137.1, 137.9, 147.5,
149.7, 149.8, 153.1, 161.0. HRMS calculated for (C21H15N3O) [M +
H]+ 326.1288; found 326.1287.
146.36, 147.37, 149.84, 150.05, 152.43, 159.95. HRMS calculated for
(C20H12N4OS) [M + H]+ 357.0805; found 357.0818.
3-(2-Trifluoromethylphenyl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-
dihydropyridin-2-one (28f). Compound 28f was prepared accord-
ing to the procedure described for the synthesis of 28b using 27a (58
mg, 0.158 mmol) and 2-trifluoromethylphenylboronic acid to give 28f
1
(24 mg, 0.061 mmol, 39%) as a brown solid. H NMR (400 MHz,
CDCl3) δ 7.22 (ddd, J = 0.8, 4.8, 7.2 Hz, 1H), 7.44−7.56 (m, 4H),
7.59−7.63 (m, 2H), 7.72−7.78 (m, 1H), 7.94 (ddd, J = 1.6, 2.4, 8.0
Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 8.59−8.61
(m, 1H), 8.69 (dd, J = 1.2, 4.8 Hz, 1H), 8.78−8.79 (m, 1H). 13C NMR
(100 MHz, CDCl3) δ 118.5, 118.7, 122.3, 122.8, 123.6, 125.6, 126,4
(q, J(c,f) = 50 Hz), 128.4, 129.3 (q, J(c,f) = 298 Hz), 131.4, 131.6,
132.1, 134.6, 135.0, 136.3, 137.2, 138.1, 147,3, 149.7, 149.8, 152.8,
160.8. HRMS calculated for (C22H14F3N3O) [M + H]+ 394.1162;
found 394.1155.
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydro-
pyridin-2-one (28b). 3-Bromo-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihy-
dropyridin-2-one 27a (5.39 g, 16.4 mmol) was dissolved in DMF (200
mL). Cs2CO3 (6.42 g, 19.70 mmol), 2-(1,3,2-dioxaborinan-2-yl)-
benzonitrile (3.69 g, 19.7 mmol), and Pd(PPh3)4 (949 mg, 0.82
mmol) were added, and the mixture was stirred at 120 °C for 1 h. The
reaction solution was cooled to room temperature, water and EtOAc
were added, the organic layer was partitioned, washed with water, and
dried over MgSO4, the drying agent was filtered off, the filtrate was
concentrated in vacuo, and the residue was purified by silica gel
column chromatography (n-hexane/EtOAc system) to give 28b (4.8 g,
3-(2-Fluoro-3-pyridyl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihy-
dropyridin-2-one (28g). Compound 28g was prepared according to
the procedure described for the synthesis of 28g using 27a (100 mg,
0.30 mmol) and 2-fluoro-3-pyridylboronic acid to give 28g (52 mg,
1
13.7 mmol, 84%) as a yellow solid. H NMR (400 MHz, CDCl3) δ
1
0.151 mmol, 50%) as a white solid. H NMR (400 MHz, CDCl3) δ
7.22−7.26 (m, 1H), 7.46−7.52 (m, 2H), 7.62 (dt, J = 1.0, 8.2 Hz, 1H),
7.66 (dt, J = 1.4, 7.7 Hz, 1H), 7.74−7.81 (m, 3H), 7.97 (ddd, J = 1.6,
2.5, 8.2 Hz, 1H), 8.32 (s, 2H), 8.61 (ddd, J = 1.0, 1.8, 4.8 Hz, 1H),
8.72 (dd, J = 1.5, 4.8 Hz, 1H), 8.80−8.81 (m, 1H). 13C NMR (150
MHz, CDCl3) δ 112.6, 118.5, 118.8, 118.9, 122.4, 123.7, 128.5, 129.3,
131.0, 132.5, 133.3, 134.7, 137.2, 137.2, 137.6, 139.3, 139.9, 147.3,
149.8, 149.9, 152.6, 160.3. HRMS calculated for (C22H14N4O) [M +
H]+ 351.1241; found 351.1232.
7.21−7.29 (m, 2H), 7.45−7.52 (m, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.78
(dt, J = 2.1, 8.1 Hz, 1H), 7.91−7.95 (m, 1H), 8.19−8.25 (m, 2H), 8.30
(d, J = 2.6 Hz, 1H), 8.35 (t, J = 2.1 Hz, 1H), 8.60−8.63 (m, 1H),
8.70−8.73 (m, 1H), 8.79 (d, J = 2.6 Hz, 1H). 13C NMR (150 MHz,
CDCl3) δ 118.6, 118.6 (d, J(c,f) = 28.6 Hz), 118.9, 121.2 (d, J(c,f) =
4.2 Hz), 122.4, 123.7, 124.9 (d, J(c,f) = 5.2 Hz), 134.6, 136.7, 137.2,
137.5, 139.4 (d, J(c,f) = 4.4 Hz), 142.2 (d, J(c,f) = 3.4 Hz), 147.1 (d,
J(c,f) = 14.9 Hz), 147.3, 149.9, 149.9, 152.5, 160.3, 160.3 (d, J(c,f) =
239.7 Hz). HRMS calculated for (C20H13FN4O) [M + H]+ 345.1146;
found 345.1136.
5-Bromo-3-iodo-1,2-dihydropyridin-2-one (30). 2-Amino-5-
bromopyridine 30 (300 g, 1.73 mol) was dissolved in a mixed solvent
consisting of acetic acid (1000 mL) and water (200 mL).
Concentrated H2SO4 (30 mL) was gradually dropped in under
stirring. Then acid hydrate (79.1 g, 0.347 mol) and iodine (176 g,
0.693 mol) were added periodically, followed by stirring at 80 °C for 4
h. Acid hydrate (40 g, 0.175 mol) and iodine (22 g, 0.086 mol) were
added periodically to the reaction mixture followed by further stirring
at 80 °C for 2 h. After cooling to room temperature, the reaction
mixture was poured onto ice (3 L) and neutralized to pH 7.0 with 5 N
aqueous NaOH. The resulting precipitate was collected by filtration,
dissolved in a mixed solvent of EtOAc/diethyl ether, successively
washed with aqueous sodium thiosulfate, water, 1 N aqueous NaOH,
and brine, and dried over MgSO4. The solvent was evaporated to give
2-amino-5-bromo-3-iodopyridine (392 g, 1.31 mol, 76%).
3-(Thiophen-3-yl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyr-
idin-2-one (28c). Compound 28c was prepared according to the
procedure described for the synthesis of 28b using 27a (56 mg, 0.17
mmol) and thiophen-3-boronic acid to give 28c (36 mg, 0.109 mmol,
1
64%) as a white solid. H NMR (400 MHz, CDCl3) δ 7.24 (ddd, J =
0.8, 4.8, 7.4 Hz, 1H), 7.39 (dd, J = 2.8, 5.2 Hz, 1H), 7.50 (dd, J = 4.8.
8.0 Hz, 1H), 7.60−7.63 (m, 1H), 7.65 (dd, J = 1.2, 5.2 Hz, 1H), 7.77
(td, J = 2.0, 7.8 Hz, 1H), 7.93 (ddd, J = 1.6, 2.6, 8.4 Hz, 1H), 8.15 (d, J
= 2.8 Hz, 1H), 8.32 (dd, J = 1.2, 3.2 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H),
8.62−8.64 (m, 1H), 8.72−7.73 (m, 1H), 8.77 (d, J = 2.0 Hz, 1H). 13C
NMR (150 MHz, CDCl3) δ 118.7, 119.0, 122.2, 123.7, 125.1, 125.4,
126.6, 126.7, 134.4, 134.5, 134.7, 135.9, 137.1, 138.0, 147.5, 149.8,
149.8, 153.1, 160.59. HRMS calculated for (C19H13N3OS) [M + H]+
332.0852; found 332.0843.
3-(2-Chlorophenyl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydro-
pyridin-2-one (28d). Compound 28d was prepared according to the
procedure described for the synthesis of 28b using 27a (58 mg, 0.158
mmol) and 2-chlorophenylboronic acid to give 28d (26 mg, 0.072
1
2-Amino-5-bromo-3-iodopyridine (100 g, 0.34 mol) was gradually
added to concentrated sulfuric acid (300 mL) under ice cooling. After
the reaction mixture was stirred at room temperature for 2 h, it was ice
cooled again. Sodium nitrite (35 g, 0.51 mol) was gradually added,
followed by stirring at room temperature for 3 days and nights. The
reaction solution was poured onto ice (3 L) and neutralized to pH 4.0
with NaOH. The resulting precipitate was collected by filtration,
washed with water, and warm-air-dried at 60 °C for 1 day and night to
mmol, 46%) as a brown solid. H NMR (400 MHz, CDCl3) δ 7.23
(ddd, J = 1.2, 4.6, 7.4 Hz, 1H), 7.31−7.36 (m, 2H), 7.41−7.51 (m,
3H), 7.56−7.59 (m, 1H), 7.75 (td, J = 2.0, 8.0 Hz, 1H), 7.95 (ddd, J =
1.6, 2.6, 8.2 Hz, 1H), 8.15 (d, J = 2.8 Hz, 1H), 8.30 (d, J = 2.4 Hz,
1H), 8.60−8.62 (m, 1H), 8.69 (dd, J = 1.6, 4.8 Hz, 1H), 8.80 (d, J =
2.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 118.6 2*C, 122.2, 123.5,
126.7, 129.5, 129.8, 131.2, 131.6, 133.7, 134.6, 135.2, 136.3, 137.1,
137.7, 138.9, 147.3, 149.7, 149.8, 152.9, 160.2. HRMS calculated for
(C21H14ClN3O) [M + H]+ 360.0898; found 360.0889.
1
give 30 (102 g, 0.34 mol, >99%) as a brown solid. H NMR (400
MHz, CDCl3) δ 7.60 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H).
5-Bromo-1-phenyl-3-iodo-1,2-dihydropyridin-2-one (31). 5-
Bromo-3-iodo-1,2-dihydropyridin-2-one 30 (10.0 g, 33.3 mmol),
phenylboronic acid (10.0 g, 82.0 mmol), and copper acetate (8.1 g,
44.6 mmol) were suspended in dichloromethane (500 mL). Et3N (15
mL, 107.6 mmol) was added, followed by stirring at room temperature
for 5 days and nights. Water (200 mL) and aqueous ammonia (50
mL) were added to the reaction solution, and it was stirred vigorously.
Then the insoluble matter was filtered off through Celite, the filtrate
was extracted with dichloromethane, and the extract was dried over
MgSO4. The solvent was evaporated, and the residue was recrystallized
from EtOAc and n-hexane to give 31 (6.54 g, 17.4 mmol, 52%) as a
3-(2-Cyanothiophen-3-yl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-di-
hydropyridin-2-one (28e). Compound 28e was prepared according
to the procedure described for the synthesis of 28b using 27a (58 mg,
0.177 mmol) and 2-formyl-3-thienylboronic acid to give the 2-formyl-
3-thienyl derivative (42 mg, 38%). This formyl derivative (20 mg) was
treated with hydroxylamine hydrochloride in NaOAc and EtOH at 80
°C and then 1,1′-carbonyldiimidazole with Et3N in DMF at 60 °C to
give 28e (20 mg, 0.056 mmol, 67% in two steps) as a yellow solid. 1H
NMR (400 MHz, CDCl3) δ 7.23−7.26 (m, 1H), 7.50 (dd, J = 4.8, 8.0
Hz, 1H), 7.61−7.74 (m, 3H), 7.79 (td, J = 2.0, 7.6 Hz, 1H), 7.91−7.94
(m, 1H), 8.36 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 2.4 H, 1H), 8.60−8.61
(m, 1H), 8.74 (dd, J = 1.4, 5.0 Hz, 1H), 8.79 (d, J = 2.4 Hz, 1H). 13C
NMR (150 MHz, CDCl3) δ 106.72, 114.79, 118.96, 119.09, 122.49,
123.72, 124.39, 129.79, 131.19, 134.51, 137.39, 137.41, 137.44, 138.60,
1
yellow solid. H NMR (400 MHz, CDCl3) δ 7.34−7.38 (m, 2H),
7.44−7.52 (m, 3H), 7.53 (d, J = 2.6 Hz, 1H), 8.10 (d, J = 2.6 Hz, 1H).
M
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5-Bromo-3-(2-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-
one (32a). 5-Bromo-1-phenyl-3-iodo-1,2-dihydropyridin-2-one 31
(11.69 g, 31.1 mmol), 2-(1,3,2-dioxaborinan-2-yl)benzonitrile (8.0 g,
42.8 mmol), and Cs2CO3 (16.0 g, 49.1 mmol) were suspended in
DMF (150 mL). Pd(PPh3)4 (3.0 g, 2.6 mmol) was added, followed by
stirring at 80 °C in a nitrogen atmosphere for 2 h. The reaction
solution was poured into water. The mixture was extracted with
EtOAc. The extract was successively washed with water and brine and
dried over MgSO4. Then the solvent was evaporated, and the residue
was purified by silica gel column chromatography (n-hexane/EtOAc
system) followed by recrystallizing from EtOAc and n-hexane to give
10H), 7.63 (td, J = 1.6, 7.8 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.77−
7.82 (m, 2H), 7.98 (d, J = 2.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 112.4, 118.7, 120.1, 126.1 2*C, 126.7 2*C, 127.7, 128.3, 128.8, 129.2
2*C, 129.2, 129.5 2*C, 131.1, 132.3, 133.3, 136.0, 136.1, 140.3, 140.6,
141.0, 160.2. HRMS calculated for (C24H16N2O) [M + H]+ 349.1335;
found 349.1336.
3-(2-Cyanophenyl)-5-(2-fluorophenyl)-1-phenyl-1,2-dihy-
dropyridin-2-one (33d). Compound 33d was prepared according to
the procedure described for the synthesis of 33c using 32a (50 mg,
0.142 mmol) and 2-fluorophenyllboronic acid to give 33d (32 mg,
1
0.087 mmol, 62%) as a brown solid. H NMR (400 MHz, CDCl3) δ
1
7.16 (ddd, J = 1.4, 8.1, 11.1 Hz, 1H), 7.23 (dt, J = 1.4, 7.5 Hz, 1H),
7.29−7.36 (m, 1H), 7.42−7.54 (m, 6H), 7.60−7.67 (m, 2H), 7.74−
7.81 (m, 3H), 7.92 (dd, J = 1.3, 3.6 Hz, 1H). 13C NMR (150 MHz,
CDCl3) δ 112.4, 114.1, 116.3 (d, J(c,f) = 21.7 Hz), 118.6, 123.7 (d,
J(c,f) = 13.0 Hz), 124.9 (d, J(c,f) = 3.5 Hz), 126.6 2*C, 128.2, 128.8,
129.2, 129.4 2*C, 129.4 (d, J(c,f) = 12.7 Hz), 129.5, 131.1, 132.3,
133.3, 138.3 (d, J(c,f) = 4.6 Hz), 140.2, 140.9, 141.4, 159.6 (d, J(c,f) =
247.4 Hz), 160.0. HRMS calculated for (C24H15FN2O) [M + H]+
367.1241; found 367.1231. HPLC purity; 83.8%.
32a (5.67 g, 16.1 mmol, 52%) as a brown solid. H NMR (400 MHz,
CDCl3) δ 7.42−7.54 (m, 6H), 7.61−7.65 (m, 3H), 7.66 (d, J = 2.8 Hz,
1H), 7.74−7.77 (m, 1H).
5-Bromo-3-(3-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-
one (32b). Compound 32b was prepared according to the procedure
described for the synthesis of 32a using 31 (52 mg, 0.14 mmol) and 3-
cyanophenylboronic acid to give 32b (15 mg, 0.04 mmol, 28%) as a
1
brown solid. H NMR (400 MHz, CDCl3) δ 7.30−7.38 (m, 1H),
7.39−7.42 (m, 2H), 7.46−7.53 (m, 3H), 7.58 (d, J = 2.8 Hz, 1H),
7.62−7.65 (m, 1H), 7.65 (d, J = 2.8 Hz, 1H), 7.94−7.98 (m, 1H),
8.06−8.08 (m, 1H).
3-(2-Cyanophenyl)-5-(thiophen-2-yl)-1-phenyl-1,2-dihydro-
pyridin-2-one (33e). Compound 33e was prepared according to the
procedure described for the synthesis of 33c using 32a (50 mg, 0.142
mmol) and 2-thienylboronic acid to give 33e (14 mg, 0.040 mmol,
5-Bromo-3-(4-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-
one (32c). Compound 32c was prepared according to the procedure
described for the synthesis of 32a using 31 (150 mg, 0.40 mmol) and
3-cyanophenylboronic acid to give 32c (55 mg, 0.16 mmol, 40%) as a
1
28%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 7.07 (dd, J =
3.6, 5.1 Hz, 1H), 7.17 (dd, J = 1.3, 3.6 Hz, 1H), 7.25−7.28 (m, 1H),
7.43−7.56 (m, 6H), 7.64 (dt, J = 1.3, 7.6 Hz, 1H), 7.72 (d, J = 2.6 Hz,
1H), 7.74−7.80 (m, 2H), 7.93 (d, J = 2.6 Hz, 1H). 13C NMR (150
MHz, CDCl3) δ 112.6, 114.3, 118.4, 123.4, 124.6, 126.7 2*C, 128.2,
128.4, 128.9, 129.5 2*C, 129.6, 131.0, 132.3, 133.2, 135.0, 138.7,
139.7, 139.9, 140.7, 159.9. HRMS calculated for (C22H14N2OS) [M +
H]+ 355.0900; found 355.0888.
1
brown solid. H NMR (400 MHz, CDCl3) δ 7.26 (s, 2H), 7.39−7.42
(m, 2H), 7.47−7.56 (m, 2H), 7.60 (d, J = 2.8 Hz, 1H), 7.67(d, J = 2.8
Hz, 1H), 7.68−7.71 (m, 1H), 7.84−7.87 (m, 2H).
5-Bromo-3-(2-fluorophenyl)-1-phenyl-1,2-dihydropyridin-2-
one (32d). Compound 32d was prepared according to the procedure
described for the synthesis of 32a using 31 (300 mg, 0.80 mmol) and
3-cyanophenylboronic acid to give 32d (150 mg, 44 mmol, 55%) as a
3-(2-Cyanophenyl)-5-(2-cyanophenyl)-1-phenyl-1,2-dihy-
dropyridin-2-one (33f). A mixture of 31 (376 mg, 1.00 mmol), 2-
(1,3,2-dioxaborolan-2-yl)benzonitrile (573 mg, 3.06 mmol), Pd-
(PPh3)4 (80 mg, 0.069 mmol), and Cs2CO3 (652 mg, 2.00 mmol)
in DMF (8 mL) was stirred at 110−120 °C under a nitrogen
atmosphere for 4 h. The mixture was diluted with water and then
extracted with EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (PE/
EtOAc = 5:1) to give crude product, which was triturated with PE/
MTBE (5:1, 40 mL) to give 33f (110 mg, 0.295 mmol 30%) as light
1
brown solid. H NMR (400 MHz, CDCl3) δ 7.11−7.25 (m, 4H),
7.26−7.37 (m, 2H), 7.41−7.63 (m, 5H).
3-(2-Cyanophenyl)-5-(3-pyridyl)-1-phenyl-1,2-dihydropyri-
din-2-one (33a). Compound 33a was prepared according to the
procedure described for the synthesis of 33c using 32a (90 mg, 0.256
mmol) and 3-pyridylboronic acid to give 33a (89 mg, 0.255 mmol,
1
99%) as a white solid. H NMR (600 MHz, CDCl3) δ 7.39 (dd, J =
4.7, 8.1 Hz, 1H), 7.46−7.51 (m, 2H), 7.52−7.60 (m, 4H), 7.66 (dt, J =
1.3, 7.7 Hz, 1H), 7.74 (d, J = 2.6 Hz, 1H), 7.78−7.88 (m, 3H), 7.96 (d,
J = 2.6 Hz, 1H), 8.62 (dd, J = 1.3, 4.7 Hz, 1H), 8.80 (d, J = 2.3 Hz,
1H). 13C NMR (150 MHz, CDCl3) δ 112.4, 116.7, 118.6, 123.8, 126.6
2*C, 128.5, 129.0, 129.5, 129.8 2*C, 131.1, 131.9, 132.3, 133.3, 133.5,
136.4, 139.9 2*C, 140.7, 147.1, 148.9, 160.1. HRMS calculated for
(C23H15N3O) [M + H]+ 350.1288; found 350.1277.
1
yellow solid. H NMR (400 MHz, CDCl3) δ 7.26−7.59 (m, 7H),
7.62−7.72 (m, 3H), 7.76−7.80 (m, 2H), 7.82−7.84 (m, 1H), 7.86−
7.88 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 110.6, 112.2, 116.3,
118.6, 118.7, 126.6, 126.6, 128.2, 128.5, 128.9, 129.5, 129.5 2*C,
129.5, 131.2, 132.4, 133.2, 133.6, 133.8, 138.7, 139.8, 140.0, 140.5,
141.0, 160.0. HRMS calculated for (C25H15N3O) [M + H]+ 374.1288;
found 374.1297.
3-(2-Cyanophenyl)-5-(4-pyridyl)-1-phenyl-1,2-dihydropyri-
din-2-one (33b). Compound 33b was prepared according to the
procedure described for the synthesis of 33c using 32a (90 mg, 0.256
mmol) and 4-pyridyllboronic acid to give 33b (89 mg, 0.255 mmol,
3-(2-Cyanophenyl)-5-(2-methoxyphenyl)-1-phenyl-1,2-dihy-
dropyridin-2-one (33g). Compound 33g was prepared according to
the procedure described for the synthesis of 33c using 32a (268 mg,
0.763 mmol) and 2-methoxyphenylboronic acid to give 33g (279 mg,
1
99%) as a white solid. H NMR (600 MHz, CDCl3) δ 7.43−7.46 (m,
2H), 7.47−7.54 (m, 4H), 7.55−7.59 (m, 2H), 7.66 (dt, J = 1.1, 7.7 Hz,
1H), 7.82 (dd, J = 1.7, 7.7 Hz, 2H), 7.84 (d, J = 2.6 Hz, 1H), 8.02 (d, J
= 2.6 Hz, 1H), 8.65−8.70 (m, 2H). 13C NMR (150 MHz, CDCl3) δ
112.4, 116.8, 118.6, 120.1 2*C, 126.6 2*C, 128.5, 129.1, 129.6 2*C,
129.8, 131.0, 132.4, 133.3, 137.1, 139.2, 139.8, 140.6, 143.4, 150.7
2*C, 160.2. HRMS calculated for (C23H15N3O) [M + H]+ 350.1288;
found 350.1277.
1
0.737 mmol, 97%) as a yellow solid. H NMR (400 MHz, CDCl3) δ
3.88 (s, 3H), 6.95−7.04 (m, 3H), 7.29−7.54 (m, 7H), 7.58−7.64 (m,
1H), 7.71 (d, J = 2.4 Hz, 1H), 7.74−7.79 (m, 2H), 7.95 (d, J = 2.4 Hz,
1H). 13C NMR (150 MHz, CDCl3) δ 55.6, 111.2, 112.4, 117.0, 118.6,
121.1, 124.9, 126.7 2*C, 128.0, 128.2, 128.6, 129.3,129.3 2*C, 129.7,
131.3, 132.1, 133.3, 138.2, 140.5, 141.1, 142.9, 156.5, 160.1. HRMS
calculated for (C25H18N2O2) [M + H]+ 379.1441; found 379.1430.
3-(2-Cyanophenyl)-5-(thiophen-3-yl)-1-phenyl-1,2-dihydro-
pyridin-2-one (33h). Compound 33h was prepared according to the
procedure described for the synthesis of 33c using 32a (50 mg, 0.142
mmol) and 3-thienylboronic acid to give 33h (20 mg, 0.056 mmol,
3-(2-Cyanophenyl)-1,5-diphenyl-1,2-dihydropyridin-2-one
(33c). A mixture of compound 32a (280 mg, 0.797 mmol),
phenylboronic acid (194 mg, 1.59 mmol), Pd(PPh3)4 (80 mg, 0.069
mmol), and Cs2CO3 (775 mg, 2.38 mmol) in DMF (8 mL) was stirred
at 110−120 °C under a nitrogen atmosphere for 6 h. The mixture was
diluted with water (50 mL) and then extracted with EtOAc (30 mL ×
3). The combined organic layers were washed with brine (50 mL × 3),
dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (n-hexane/
EtOAc = 5:1) to give 33c (90 mg, 0.258 mmol, 32%) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.32−7.37 (m, 1H), 7.41−7.56 (m,
1
40%) as a brown solid. H NMR (400 MHz, CDCl3) δ 7.24 (dd, J =
1.4, 6.0 Hz, 1H), 7.35 (dd, J = 1.4, 3.0 Hz, 1H), 7.41 (dd, J = 2.8, 5.2
Hz, 1H), 7.43−7.56 (m, 6H), 7.63 (dt, J = 1.4, 7.8 Hz, 1H), 7.70 (d, J
= 2.8 Hz, 1H), 7.76−7.81 (m, 2H), 7.96 (d, J = 2.8 Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 112.4, 115.5, 118.6, 119.9, 125.2, 126.7 2*C,
N
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Journal of Medicinal Chemistry
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127.2, 128.3, 128.8, 129.4, 129.4 2*C, 131.1, 132.3, 133.3, 135.3,
136.9, 140.1 2*C, 140.9, 160.0. HRMS calculated for (C22H14N2OS)
[M + H]+ 355.0900; found 355.0891.
0.70 mmol) and sodium iodide (0.12 g, 0.80 mmol) in acetonitrile (10
mL), and the mixture was stirred at room temperature for 3 h. A
saturated sodium bicarbonate solution was added to the mixture
followed by extraction with EtOAc. The EtOAc layer was washed with
water and a saturated saline solution and dried over MgSO4. The
solvent was concentrated in vacuo and the residue was purified by a
silica gel column chromatography (EtOAc/n-hexane =1:1) to give 37c
(110 mg, 0.40 mmol, 58%) as a pale yellow solid. 1H NMR (400 MHz,
DMSO-d6) δ 7.26−7.30 (ddd, J = 0.8, 4.8, 8.0 Hz, 1H), 7.55−7.60 (td,
J = 1.4, 8.0 Hz, 1H), 7.66 (dd, J = 0.8, 8.0 Hz, 1H), 7.74−7.79 (td, J =
1.4, 8.0 Hz, 1H), 7.80−7.86 (td, J = 1.4, 8.0 Hz, 1H), 7.89−7.94 (d, J =
8.0 Hz, 2H), 8.28 (d, J = 2.7 Hz, 1H), 8.37 (d, J = 2.7 Hz, 1H), 8.56−
8.5.9 (m, 1H).
3-(2-Cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine (36c).
Pd(PPh3)4 (0.15 g) was added to a mixed solution of 5-(2-pyridyl)-
3-bromo-2-methoxypyridine 35 (500 mg, 1.89 mmol), 2-(1,3,2-
dioxaborinan-2-yl)benzonitrile (0.42 g, 2.24 mmol), Cs2CO3 (0.82 g,
2.52 mmol), and DMF (20 mL), and the mixture was stirred at 140 °C
in a nitrogen atmosphere for 5 h. After the mixture was cooled to
room temperature, EtOAc was added, the mixture was washed with
water and a saturated saline solution, and it was dried over MgSO4.
The solvent was concentrated in vacuo and the residue was purified by
silica gel column chromatography (EtOAc/n-hexane = 1:3) to give 36
(0.36 g, 1.25 mmol, 66%) as a pale yellow solid. 1H NMR (400 MHz,
CDCl3) δ 4.03 (s, 3H), 7.24−7.28 (m, 1H), 7.46−7.51 (td, J = 1.6, 8.0
Hz, 1H), 7.57 (dd, J = 1.2, 8.0 Hz, 1H), 7.65−7.69 (td, J = 1.6, 8.0 Hz,
1H), 7.72−7.82 (m, 3H), 8.31 (d, J = 2.8 Hz, 1H), 8.66−8.69 (m,
1H), 8.83 (d, J = 2.8 Hz, 1H).
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(3-methoxyphenyl)-1,2-
dihydropyridin-2-one (38a). Compound 27b was prepared
according to the procedure described for the synthesis of 22 using
26 (500 mg, 2.0 mmol) and 3-methoxyphenylboronic acid to give 27b
(122 mg, 0.3 mmol, 15%).
3-(2-Chlorophenyl)-5-(2-pyridyl)-2(1H)-pyridone (37a). Pd-
(PPh3)4 (150 mg) was added to a mixed solution of 5-(2-pyridyl)-3-
bromo-2-methoxypyridine (35) (170 mg, 0.64 mmol), 2-chlorophe-
nylboronic acid (150 g, 0.96 mmol), Et3N (1 mL), and DMF (5 mL),
and the mixture was stirred at 140 °C in a nitrogen atmosphere
overnight. After the mixture was cooled to room temperature, EtOAc
was added and the mixture was washed with water and a saturated
saline solution and dried over MgSO4. The solvent was concentrated
in vacuo and the residue was passed through silica gel column
chromatography (EtOAc/n-hexane = 1:3) to give crude 3-(2-
chlorophenyl)-5-(2-pyridyl)-2-methoxypyridine 36a (170 mg) without
further purification.
Compound 38a was prepared according to the procedure described
for the synthesis of 38f using 27b (100 mg, 0.28 mmol) and 2-(1,3,2-
dioxaborinan-2-yl)benzonitrile to give 38a (33 mg, 0.087 mmol, 31%)
1
as a white solid. H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 6.95−
7.03 (m, 1H), 7.06−7.10 (m, 2H), 7.20−7.22 (m, 1H), 7.41−7.81 (m,
7H), 8.31 (s, 2H), 8.59−8.61 (m, 1H). 13C NMR (150 MHz, CDCl3)
δ 55.6, 112.3, 112.5, 115.2, 118.2, 118.6, 118.8 2*C, 122.1, 128.2,
128.9, 130.2, 131.1, 132.3, 133.2, 137.1, 138.0, 138.9, 140.3, 142.0,
149.8, 153.1, 160.3, 160.4. HRMS calculated for (C24H17N3O2) [M +
H]+ 380.1394; found 380.1406.
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(2-methoxyphenyl)-1,2-
dihydropyridin-2-one (38b). A suspension of 3-(2-cyanophenyl)-5-
(2-pyridyl)-2(1H)-pyridone 37c (250 mg, 0.914 mmol), 2-methox-
yphenylboronic acid (250 mg, 1.65 mmol), copper(II) acetate (300
mg, 1.65 mmol), and Et3N (1 mL, 7.17 mmol) in methylene chloride
(10 mL) was stirred at room temperature overnight. Concentrated
aqueous ammonia (5 mL), water (10 mL), and EtOAc (80 mL) were
added, and the organic layer was separated, washed with water and a
saturated saline solution, and dried over MgSO4. The solvent was
concentrated in vacuo and the residue was purified by silica gel column
chromatography (n-hexane/EtOAc = 2:1) to give 38b (45 mg, 0.12
A mixture of 3-(2-cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine
(170 mg, 0.70 mmol) and 48% HBr (2 mL) was stirred at 80 °C for 4
h. A saturated sodium bicarbonate solution was added to the mixture
followed by extraction with EtOAc. The EtOAc layer was washed with
water and a saturated saline solution and dried over MgSO4. The
solvent was concentrated in vacuo and the residue was purified by
silica gel column chromatography (EtOAc:n-hexane = 1:1) to give 37a
1
(105 mg, 0.37 mmol, 58% in two steps) as a pale yellow solid. H
NMR (400 MHz, DMSO-d6) δ 7.24 (t, J = 7.2 Hz, 1H), 7.32−7.45
(m, 3H), 7.50−7.57 (m, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.86 (d, J = 7.5
Hz, 1H), 7.96 (s, 1H), 8.02 (s, 1H), 8.55 (d, J = 5.0 Hz, 1H), 12.10−
12.25 (br s, 1H).
1
mmol, 13%) as a white solid. H NMR (400 MHz, DMSO-d6) δ 3.80
(s, 3H), 7.12 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.30 (dd, J =
4.8, 7.2 Hz, 1H), 7.44 (dd, J = 1.6, 8.0 Hz, 1H), 7.51 (ddd, J = 1.6, 7.2,
8.0 Hz, 1H), 7.59 (td, J = 1.2, 7.6 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H),
7.78 (dd, J = 1.2, 7.6 Hz, 1H), 7.83 (td, J = 1.6, 8.0 Hz, 1H), 7.92 (d, J
= 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.47
(d, J = 2.8 Hz, 1H), 8.57 (br d, J = 4.0 Hz, 1H). 13C NMR (CDCl3,
150 MHz) δ 56.0, 112.3, 112.5, 117.9, 118.6, 118.8, 120.9, 121.9,
128.1, 128.5, 128.7, 129.7, 130.6, 131.2, 132.2, 133.2, 137.1, 138.9,
140.0, 140.4, 149.7, 153.3, 154.4, 160.3. HRMS calculated for
(C24H17N3O2) [M + H]+ 380.1394; found 380.1382.
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(4-methoxyphenyl)-1,2-
dihydropyridin-2-one (38c). Compound 27c was prepared
according to the procedure described for the synthesis of 22 using
26 (500 mg, 2.0 mmol) and 4-methoxyphenylboronic acid to give 27c
(137 mg, 0.4 mmol, 20%).
Compound 38c was prepared according to the procedure described
for the synthesis of 38f using 27c (100 mg, 0.28 mmol) and 2-(1,3,2-
dioxaborinan-2-yl)benzonitrile to give 38c (33 mg, 0.087 mmol, 31%)
as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 7.02 (d,
J = 8.8 Hz, 2H), 7.21 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.42−7.80 (m,
8H), 8.29 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 8.58−8.60 (m,
1H). 13C NMR (150 MHz, CDCl3) δ 55.6, 112.5, 114.6 2*C, 118.2,
118.6, 118.8, 122.0, 127.8 2*C, 128.2, 128.8, 131.1, 132.3, 133.2,
133.8, 137.1, 138.3, 138.8, 140.4, 149.7, 153.1, 159.7, 160.7. HRMS
calculated for (C24H17N3O2) [M + H]+ 380.1394; found 380.1406.
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(2-fluoropyridin-5-yl)-1,2-
dihydropyridin-2-one (38d). Compound 27d was prepared
according to the procedure described for the synthesis of 27f using
26 (108 mg, 0.430 mmol) and 4-fluoro-3-pyridylboronic acid to give
27d (69 mg, 0.200 mmol, 46%). Compound 38d was prepared
3-(2-Methoxyphenyl)-5-(2-pyridyl)-2(1H)-pyridone (37b).
Pd(PPh3)4 (0.3 g) was added to a mixed solution of 5-(2-pyridyl)-3-
bromo-2-methoxypyridine (35) (1.19 g, 4.49 mmol), 2-methoxyphe-
nylboronic acid (1.0 g, 6.58 mmol), Et3N (1.5 g), and DMF (15 mL),
and the mixture was stirred at 140 °C in a nitrogen atmosphere
overnight. After the mixture was cooled to room temperature, EtOAc
was added and the mixture was washed with water and a saturated
saline solution and dried over MgSO4. The solvent was concentrated
in vacuo and the residue was purified by silica gel column
chromatography (EtOAc/n-hexane = 1:3) to give 3-(2-chlorophen-
yl)-5-(2-pyridyl)-2-methoxypyridine 36b (1.06 g, 3.63 mmol, 81%). A
mixture of 36b (1.0 g, 0.70 mmol) and 48% HBr (8 mL) was stirred at
70 °C for 2 h. After the mixture was cooled to room temperature,
potassium carbonate was added to neutralize it, followed by extraction
with EtOAc. The EtOAc layer was washed with water and a saturated
saline solution and dried over MgSO4. The solvent was concentrated
in vacuo and the residue was purified by silica gel column
chromatography (EtOAc/n-hexane = 1:1) to give 37a (105 mg, 0.40
mmol, 58%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ
3.73 (s, 3H), 6.96−7.03 (td, J = 1.2, 7.2 Hz, 1H), 7.06−7.09 (dd, J =
0.8, 8.0 Hz, 1H), 7.22−7.26 (ddd, J = 1.2, 4.8, 7.2 Hz, 1H), 7.27−7.30
(dd, J = 1.6, 8.0 Hz, 1H), 7.32−7.37 (ddd, J =1.6, 7.2, 8.0 Hz, 1H),
7.76−7.81 (ddd, J = 1.6, 7.2, 8.0 Hz, 1H), 7.82−7.84 (dt, J = 1.2, 8.0
Hz, 1H), 8.13 (s, 2H), 8.53−8.56 (ddd, J = 0.8, 1.6, 4.8 Hz, 1H), 11.96
(br s, 1H).
3-(2-Cyanophenyl)-5-(2-pyridyl)-2-(1H)-pyridone (37c).
Chlorotrimethylsilane (0.1 mL, 7.88 mmol) was added to a suspension
of 3-(2-cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine 36c (200 mg,
O
dx.doi.org/10.1021/jm301268u | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
according to the procedure described for the synthesis of 38f using
27d (11 mg, 0.032 mmol) and 2-(1,3,2-dioxaborinan-2-yl)benzonitrile
to give 38d (5 mg, 0.014 mmol, 42%) as a brown solid. 1H NMR (400
MHz, CDCl3) δ 7.11 (dd, J = 3.2, 8.8 Hz, 1H), 7.25 (m, 1H), 7.42−
7.84 (m, 6H), 8.08 (ddd, J = 2.7, 6.8, 8.7 Hz, 1H), 8.30 (t, J = 2.8 Hz,
2H), 8.41 (m, 1H), 8.61 (ddd, J = 1.0, 1.6, 5.0 Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 110.1 (d, J(c,f) = 39.6 Hz), 112.6, 118.4, 118.8,
119.1, 122.5, 128.6, 129.4, 130.9, 132.5, 133.3, 135.4 (d, J(c,f) = 4.6
Hz), 137.0, 137.3, 139.4, 139.8, 140.1 (d, J(c,f) = 8.9 Hz), 145.1 (d,
J(c,f) = 16.1 Hz), 149.9, 152.5, 160.3, 162.7 (d, J(c,f) = 242.8 Hz).
HRMS calculated for (C22H13FN4O) [M + H]+ 369.1146; found
369.1137.
intracellular free Ca2+ concentration ([Ca2+]i) were measured using
the fluorescent Ca2+ indicator dye fura-2 acetoxymethyl (AM), as
previously described.27 Cells were incubated with fura-2 AM (10 μM)
in a 5% CO2/95% air incubator at 37 °C for 2 h and washed with Ca2+
assay buffer (140 mM NaCl, 5 mM KCl, 2 mM MgCl2, 3 mM CaCl2,
24 mM D-(+)-glucose, 10 mM HEPES, 1 μM MK801; pH 7.4 adjusted
with NaOH). Changes in [Ca2+]i were determined by fluorimetry
(fluorescence drug screening system, Hamamatsu Photonics, Shizuoka,
Japan) by measuring changes in the fluorescence emission ratio of
fura-2 after consecutive excitations at 340 and 380 nm wavelengths.
The inhibitory effects of compounds on the [Ca2+]i response induced
by 1 μM AMPA were assessed. IC50 values of test compounds were
calculated from the concentration−response curves. Data are
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(2-cyanophenyl)-1,2-di-
hydropyridin-2-one (38e). Compound 38e was prepared according
to the procedure described for the synthesis of 38f using 27e (110 mg,
0.312 mmol) and 2-(1,3,2-dioxaborinan-2-yl)benzonitrile to give 38e
presented as the mean
three experiments.
standard deviation and are the result of
Mouse AMPA-Induced Seizure Model. Male 5-week-old ddY
mice were used. Test compounds were suspended in 0.5% MC and
were orally administered 1 h before each test. Clonic seizures were
elicited by intracerebral-ventricle infusion of AMPA at a constant
speed of 2 nmol/5 μL/min. The latency to occurrence of a clonic
seizure was measured, and the lowest dose providing statistically
significant prolongation of latency was defined as the MED.
DMPK. In Vitro Metabolism Study in Liver Microsomes.
Hepatic intrinsic clearance (CLint) was calculated from the substrate
disappearance rate in liver microsomes. Each compound (0.1 μmol/L)
was incubated with a reaction mixture (150 μL) consisting of mouse,
rat, or human liver microsomal protein (0.2 mg/mL) in 100 mM
potassium phosphate buffer (pH 7.4) and 0.1 mM EDTA. After
preincubation for 5 min at 37 °C, the enzyme reaction was initiated by
adding an NADPH-generating system (0.33 mmol/L β-NADP+, 8
mmol/L glucose 6-phosphate, 6 mmol/L MgCl2, and 0.1 unit/mL
glucose 6-phosphate dehydrogenase). After incubation of the micro-
somal matrix for 15 min at 37 °C, 150 μL of internal standard (1
μmol/L propanolol in methanol/acetonitrile [3/7, v/v]) was added to
the reaction mixture and mixed vigorously. After centrifugation, the
supernatant was subjected to LC/MS/MS analyses in positive ion
mode with multiple reaction monitoring.
Preclinical Pharmacokinetic Studies. For pharmacokinetic
experiments, compound 6 was administered intravenously or orally
to fasted male Sprague−Dawley rats at a dose of 1 mg/kg. Blood
samples were collected at designated time points. Plasma was obtained
by centrifugation and deproteinized using methanol/60% perchloric
solution (500:1 v/v). Plasma concentrations were determined by
HPLC with fluorescence. Pharmacokinetic parameters were calculated
by model-independent analysis. For assessment of brain penetration of
6, brain samples were obtained from male ddY mice and male
Sprague−Dawley rats after oral administration. Cerebrospinal fluid
(CSF) samples were collected from mice by cisternal puncture after
intraperitoneal administration. Brain was homogenized in two volumes
of water, and the brain homogenates and CSF samples were processed
and analyzed in a manner similar to that for plasma samples.
1
(85 mg, 0.227 mmol, 73%) as a white solid. H NMR (400 MHz,
CDCl3) δ 7.26−7.35 (m, 2H), 7.52−7.58 (m, 2H), 7.64−7.71 (m,
2H), 7.72−7.84 (m, 5H), 8.51 (d, J = 2.0 Hz, 1H), 8.68−8.72 (m,
1H), 8.77 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 107.1,
112.8, 115.8, 118.3, 120.3, 122.2, 122.8, 123.4, 125.5, 128.7, 131.4,
131.6, 133.0, 133.1, 133.4, 134.3, 137.1, 139.3, 139.7, 146.0, 150.1,
153.6, 155.4, 159.6. HRMS calculated for (C24H14N4O) [M + H]+
375.1240; found 375.1232.
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(4-cyanophenyl)-1,2-di-
hydropyridin-2-one (38f). Pyridine (568 mg, 7.20 mmol) was
added to a solution of 26 (600 mg, 2.40 mmol), 4-cyanophenylboronic
acid (423 mg, 2.88 mmol), and Cu(OAc)2 (1.31 g, 7.20 mmol) in
anhydrous DMSO (8 mL). The resulting mixture was stirred under an
oxygen balloon at 40−50 °C for 4 days. The reaction mixture was
quenched with water and extracted with EtOAc. The combined
organic layer was filtered through a pad of Celite. The filtrate was
washed with water, brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by silica gel column (n-
hexane/EtOAc = 1:1) to give 27f (600 mg, 1.71 mmol, 72%) as an off-
white solid.
DMF (10 mL) was added under a nitrogen atmosphere to a mixture
of 27f (350 mg, 1.00 mmol), Cs2CO3 (386 mg, 2.00 mmol), 2-(1,3,2-
dioxaborinan-2-yl)benzonitrile (275 mg, 1.47 mmol), and Pd(PPh3)4
(55 mg, 0.050 mmol, 5 mol %). The resulting mixture was degassed
and purged with nitrogen three times and stirred at 110−120 °C for
24 h. The reaction mixture was quenched with water (20 mL) and
extracted with EtOAc. The combined organic layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated. The residue
was purified by silica gel column chromatography (n-hexane/EtOAc =
1:1) to give 38f (60 mg, 0.160 mmol, 16%) as a white solid. 1H NMR
(400 MHz, CDCl3) δ 7.23−7.26 (m, 1H), 7.49 (dt, J = 1.2, 7.6 Hz,
1H), 7.61−7.86 (m, 9H), 7.28−7.30 (m, 2H), 8.60−8.62 (m, 1H). 13C
NMR (100 MHz, DMSO-d6) δ 111.8, 112.4, 118.1, 118.7, 118.7,
119.7, 122.8, 128.7 2*C, 129.2, 129.2, 131.4, 133.4, 133.5, 133.8 2*C,
137.8, 138.2, 139.5, 140.6, 144.9, 149.9, 152.6, 159.7. HRMS calculated
for (C24H14N4O) [M + H]+ 375.1240; found 375.1231.
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(2-methoxypyridyn-5-yl)-
1,2-dihydropyridin-2-one (38g). Compound 27g was prepared
according to the procedure described for the synthesis of 27f using 26
(563 mg, 2.24 mmol) and 4-methoxy-3-pyridylboronic acid to give
27g (417 mg, 52%).
ASSOCIATED CONTENT
■
S
* Supporting Information
HPLC purity data and data from radioligand binding assays.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Compound 38g was prepared according to the procedure described
for the synthesis of 38f using 27g (185 mg, 0.516 mmol) and 2-(1,3,2-
dioxaborinan-2-yl)benzonitrile to give 38g (148 mg, 0.389 mmol,
1
75%) as a white solid. H NMR (400 MHz, CDCl3) δ 4.00 (s, 3H),
AUTHOR INFORMATION
■
6.88 (d, J = 9.0 Hz, 1H), 7.23 (ddd, J = 0.8, 4.8, 7.4 Hz, 1H), 7.47 (td,
J = 1.2, 7.8 Hz, 1H), 7.59−7.62 (m, 1H), 7.65 (td, J = 1.2, 7.8 Hz, 1H),
7.73−7.82 (m, 4H), 8.28−8.31 (m, 3H), 8.60 (ddd, J = 0.8, 1.6, 4.8
Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 54.0, 111.2, 112.5, 118.5,
118.6, 118.8, 122.2, 128.4, 129.0, 131.0, 131.7, 132.4, 133.3, 137.2,
137.4, 137.8, 139.2, 140.1, 144.1, 149.8, 152.8, 160.6, 163.8. HRMS
calculated for (C23H16N4O2) [M + H]+ 381.1346; found 381.1337.
Biology. AMPA-Induced Ca2+ Influx Assays. E18 rat cerebral
cortical neurons were used for experiments on DIV 9. Changes in
Corresponding Author
*Address: Shigeki Hibi Product Creation Headquarters, Eisai
Product Creation Systems, Eisai Co., Ltd., Koishikawa 4-6-10,
Bunkyo-ku, Tokyo 112-8088, Japan. Phone: +81-3-3817-3656.
Fax: +81-3-3815-6702. E-mail: s-hibi@hhc.eisai.co.jp.
Notes
The authors declare no competing financial interest.
P
dx.doi.org/10.1021/jm301268u | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
(15) Justoni, R. New method of synthesis of pyrazole derivatives. II.
The behavior of malonic derivatives in experiments on the pyrazole
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ACKNOWLEDGMENTS
■
Editorial support was provided by Rick Flemming, Ph.D., and
Sian-Marie Lucas, Ph.D., of Complete Medical Communica-
tions and was funded by Eisai Inc. We thank Mami Gomibuchi,
Masaharu Gotoda, Satoko Naito, Yumi Yokoyama, and Eri Ena
for HRMS, HPLC, and NMR analyses. The work described in
this article was funded by Eisai Co., Ltd.
(16) Hoppenbrouwers, W. J. 1,3,4-Oxadiazines. Recl. Trav. Chim.
Pays-Bas Belg. 1934, 53, 325−354.
(17) Van Alphen, J. 1,3,4-Oxadiazines. II. Recl. Trav. Chim. Pays-Bas
Belg. 1928, 47, 909−919.
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Derivatives of 6-phenyl-3(2H)-pyridazinones. Chem. Pharm. Bull.
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ABBREVIATIONS USED
(19) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
New N- and O-arylations with phenylboronic acids and cupric acetate.
Tetrahedron Lett. 1998, 39, 2933−2936.
■
AMPA, (S)-2-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic
acid; kainate, (2S,3S,4S)-3-carboxymethyl-4-isopropenylpyrroli-
dine-2-carboxylic acid; NMDA, N-methyl-D-aspartic acid; NIS,
N-iodosuccinimide; CL, plasma clearance; CLint, intrinsic
clearance in liver microsomes; IVIVE, in vitro−in vivo
extrapolation
(20) Evans, D. A.; Katz, J. L.; West, T. R. Synthesis of diaryl ethers
through the copper-promoted arylation of phenols with arylboronic
acids. An expedient synthesis of thyroxine. Tetrahedron Lett. 1998, 39,
2937−2940.
(21) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M.
P.; Chan, D. M. T.; Combs, A. New aryl/heteroaryl C−N bond cross-
coupling reactions via arylboronic acid/cupric acetate arylation.
Tetrahedron Lett. 1998, 39, 2941−2944.
(22) Hanada, T.; Hashizume, Y.; Tokuhara, N.; Takenaka, O.;
Kohmura, N.; Ogasawara, A.; Hatakeyama, S.; Ohgoh, M.; Ueno, M.;
Nishizawa, Y. Perampanel: a novel, orally active, non-competitive
AMPA-receptor antagonist that reduces seizure activity in rodent
models of epilepsy. Epilepsia 2011, 52, 1331−1340.
(23) Tokuhara, N.; Hatakeyama, S.; Amino, H.; Hanada, T.;
Nishizawa, Y. Pharmacological Profile of Perampanel: A Novel,
Non-Competitive Selective AMPA Receptor Antagonist. Presented at
the 60th Annual Meeting of the American Academy of Neurology,
Chicago, IL, U.S., April 12−19, 2008; Abstract P02.112.
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dx.doi.org/10.1021/jm301268u | J. Med. Chem. XXXX, XXX, XXX−XXX