Practical Preparation of a 1,3,5-Trisubstituted Pyridazin-4(1 H)-one Using Selective C1 Unit Insertion and Cyclization

Article abstract of DOI:10.1021/acs.oprd.8b00394

A novel and practical preparation of the selective phosphodiesterase 10A (PDE10A) inhibitor 1 having the core moiety of a 1,3,5-trisubstituted pyridazin-4(1H)-one has been achieved. The facile preparation of 1 in 42% overall yield involves the following key features: (1) the finding that filling the headspace of the reaction vessel with Ar gas and controlling the flow rate of the gas were found to be important to complete the substitution of an aryl iodide with pyrazole; (2) synthesis of a 3-acetyl-5-methoxy-substituted pyridazin-4(1H)-one via regioselective dimethylaminomethylenation of a diazo compound and simultaneous cyclization; and (3) regioselective ring formation of a 1,5-disubstituted pyrazole through reaction of a dimethylaminomethylene group with phenylhydrazine. In addition, an alternative synthesis of 1 via selective alkylation of 1-phenylpyrazole has been discovered.

Full text of DOI:10.1021/acs.oprd.8b00394

Article
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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Practical Preparation of a 1,3,5-Trisubstituted Pyridazin-4(1H)‑one
Using Selective C1 Unit Insertion and Cyclization
Akihiro Suzuki,*,† Naohiro Fukuda, Takeshi Kajiwara,† and Tomomi Ikemoto*,†
Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi 2-chome,
Yodogawa-ku, Osaka 532-8686, Japan
S
* Supporting Information
ABSTRACT: A novel and practical preparation of the selective phosphodiesterase 10A (PDE10A) inhibitor 1 having the core
moiety of a 1,3,5-trisubstituted pyridazin-4(1H)-one has been achieved. The facile preparation of 1 in 42% overall yield involves
the following key features: (1) the finding that filling the headspace of the reaction vessel with Ar gas and controlling the flow
rate of the gas were found to be important to complete the substitution of an aryl iodide with pyrazole; (2) synthesis of a 3-
acetyl-5-methoxy-substituted pyridazin-4(1H)-one via regioselective dimethylaminomethylenation of a diazo compound and
simultaneous cyclization; and (3) regioselective ring formation of a 1,5-disubstituted pyrazole through reaction of a
dimethylaminomethylene group with phenylhydrazine. In addition, an alternative synthesis of 1 via selective alkylation of 1-
phenylpyrazole has been discovered.
KEYWORDS: 1,3,5-trisubstituted pyridazin-4(1H)-one, regioselective C1 insertion, regioselective ring formation, PDE10A inhibitor
was expected to require the discovery of two regioselective
formations for the pyridazine and pyrazole rings.
INTRODUCTION
■
Phosphodiesterase 10A (PDE10A) is one of a superfamily of
enzymes that is predominantly expressed in dopaminorecep-
tive medium spiny neurons of the striatum, and PDE10A
inhibitors are expected to be therapeutic agents for neuro-
logical disorders. Compound 1 (TAK-063), showing selective
inhibition of PDE10A, was identified by Takeda Pharmaceut-
ical Company Limited (Scheme 1).1,2
The medicinal chemistry synthesis of 1 is shown in Scheme
1.2a Diazonium formation of aniline 2 with NaNO2 followed by
the reaction with β-keto ester 3 provided diazo compound 4.
Pyridazin-4(1H)-one ester 5 was obtained by C1 insertion of 4
with N,N-dimethylformamide dimethyl acetal (DMFDMA)
(used as a solvent) and simultaneous cyclization.3 The ester
group of 5 was converted into the acetyl group in two steps to
give pyridazin-4(1H)-one ketone 6. After dimethylaminome-
thylenation of 6, pyridazin-4(1H)-one pyrazole 8 was derived
by cyclization with phenylhydrazine. Finally, the coupling
reaction of 8 with pyrazole in the presence of Cu2O and
salicylaldoxime afforded 1. In order to support the clinical and
toxicological studies, a practical preparation of 1 on a scale of
tens of kilograms was required.
Preparation of 1 from 9 (Route B). First, the
transformation to 1 using 9 as the starting material (route
B) was conducted as shown in Scheme 3. Reaction of the
lithiated compound derived from 9 using 1.5 equiv of n-BuLi at
−70 °C was carried out with epoxide 10 at 25 °C to synthesize
regioselectively 11 as an oily compound in 57% yield, whereas
the reaction did not proceed at −70 °C (Table 1, run 1).4
Increasing the amount of n-BuLi to 4.0 equiv increased the
yield to 77%, but 9 was incompletely consumed (run 2). When
the lithiation was conducted at 0 or −30 °C, the yield
decreased (runs 3 and 4). It was thought from these results
that the lithiated compound was more stable at −70 °C than at
−30 or 0 °C. Thus, both the lithiation and the alkylation were
performed at −70 °C in the presence of an additive. When
BF3·OEt2 (1.5 equiv) was added for the alkylation, it was
necessary to raise the reaction temperature to −20 °C for the
reaction to proceed (run 5). On the other hand, the addition of
hexamethylphosphoramide (HMPA) (2% v/w) or t-BuOK
(1.5 equiv) allowed the reaction to proceed at −70 °C (runs 6
and 7). Interestingly, increasing the amounts of n-BuLi and t-
BuOK improved the conversion of 9, affording 11 in 90%
isolated yield (run 8).5 A variety of oxidation conditions were
screened for 11. In the case of SO3·pyridine as the oxidant, 11
was completely consumed, but ketone 12 was not detected.6
Also, the system of Me-AZADO/NaOCl7 and the combination
of N-tert-butylphenylsulfenamide/N-chlorosuccinimide/1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) did not produce 12,
and 11 mainly remained.8 On the other hand, Swern oxidation
RESULTS AND DISCUSSION
■
Our synthetic strategy to obtain 1 is described in Scheme 2. In
medicinal synthesis, five steps were required to establish the 3-
(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one moiety D
from A in low yield (route A). To reduce the number of
reaction steps needed to produce 1, we envisioned two
alternative routes. One was that 1-phenylpyrazole (9) would
be converted to 1 through selective alkylation of the 5-lithiated
pyrazole moiety (route B).4 The other was that the cyclization
of 3-(2-substituted hydrazinylidene)-1-methoxypentane-2,4-
dione B with DMFDMA could be transformed to C in only
one step, which would then lead to D (route C). This route
Special Issue: Japanese Society for Process Chemistry
Received: November 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00394
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Scheme 1. Medicinal Chemistry Synthesis of 1
Scheme 2. Our Synthetic Strategy for 1
Scheme 3. Synthesis of 1 from 1-Phenylpyrazole (9)
Table 1. Regioselective Alkylation of 9 with 10
c
ratio of products (%)
a
b
run
equiv of n-BuLi
temp 1 (°C)
additive
temp 2 (°C)
9
11
isolated yield of 11 (%)
1
2
3
4
5
6
7
8
1.5
4.0
1.5
1.5
1.5
1.5
1.5
2.0
−70
−70
0
−30
−70
−70
−70
−70
−
−
−
−
25
25
25
55.0
31.4
76.9
65.2
58.2
66.6
51.1
6.9
39.7
62.0
18.7
29.6
12.9
28.6
40.5
82.5
57
77
−
−
−
−
−
90
25
BF3·OEt (1.5 equiv)
HMPA (2% v/w)
t-BuOK (1.5 equiv)
−20
−70
−70
−70
t-BuOK (2.0 equiv)
a
b
c
Temperature at lithiation. Temperature at alkyation. Liquid chromatography area percent (LCAP) of the reaction mixture.
B
DOI: 10.1021/acs.oprd.8b00394
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Table 2. Optimization of the Coupling Reaction of 12 with the Diazonium Salt Derived from 13·HCl
a
ratio of products (%)
b
run
equiv of 13·HCl
base (equiv)
14
15
16
assay yield of 14 (%)
1
2
3
4
5
1.0
1.2
1.5
1.2
NaOAc (6.0)
NaOAc (7.2)
NaOAc (9.0)
NaOAc (3.0)
Na2CO3 (7.2)
59.2
71.9
58.5
62.5
34.1
11.9
6.2
4.5
6.8
9.9
9.7
10.3
13.0
19.2
26.7
51
68
64
61
25
1.2
a
b
LCAP of the reaction mixture. Determined by HPLC using an external standard.
Scheme 4. Alternative Route to 1 from Diketone 19
Table 3. Optimization of the Coupling Reaction of 17 with Pyrazole
a
ratio of products (%)
run
solvent
base (equiv)
equiv of Cu2O
time (h)
13
17
yield of 13·HCl (%)
1
2
3
4
5
6
DMF
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
K3PO4 (1.2)
K2CO3 (1.2)
DBU (1.2)
0.3
9
4
6
5
6
6
89.6
93.5
93.5
93.2
79.8
59.3
2.2
0.7
1.5
0.5
12.4
34.9
−
77
−
77
−
DMSO
DMAc
DMSO
DMSO
DMSO
0.12
0.12
0.12
0.12
0.12
−
a
LCAP of the reaction mixture.
of 11 using trifluoroacetic anhydride (TFAA)/dimethyl
sulfoxide (DMSO)/NEt3 in EtOAc was carried out to give
12 as an oily product in 75% yield after chromatographic
purification.9
The diazonium salt derived from 1.0 equiv of 13·HCl
(described below) using NaNO2 was reacted with 12 in the
presence of 6.0 equiv of NaOAc to give a complex mixture
including 14 in 51% assay yield along with 15 and 16 as
estimated by LC/MS (Table 2, run 1). While an increase in
the amount of 13·HCl to 1.2 equiv to consume 12 improved
the yield to 68%, the use of 1.5 equiv of 13·HCl did not
increase the yield (runs 2 and 3). Although the amount of
NaOAc was decreased to 3.0 equiv and Na2CO3 was used in
order to avoid conversion of the F group into OH, the yield of
14 was not improved (runs 4 and 5). Compound 14 was
purified by silica gel chromatography and reacted with 1.5
equiv of DMFDMA for 2 h at 80 °C. After completion of the
reaction, water was added to the resulting reaction mixture to
C
DOI: 10.1021/acs.oprd.8b00394
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Table 4. Effect of the Headspace Volume on the Reaction Rate
ratio of products
a
(%)
run
mass of 17 used (g)
approximate headspace volume (L)
gas
time (h)
13
17
yield of 13·HCl (%)
1
2
3
4
5
6
7
10
10
50
50
50
50
50
0.12
0.92
0.10
2.6
2.6
2.6
N2 flow
N2 flow
N2 flow
N2 flow
N2 balloon
N2 bubbling
Ar flow
5
7
4
7
5
4
5
93.8
88.5
92.8
92.8
83.2
94.0
92.9
0.3
6.4
0.6
1.1
11.0
0.5
−
−
78
−
−
76
76
2.6
0.9
a
LCAP.
Table 5. Optimization of the Flow Rate of Ar Per Headspace Volume
a
residual ratio of 17 (%)
run mass of 17 used (g) approximate headspace volume (L) flow rate of Ar per headspace volume (mL min−1 L−1
)
2 h
3 h
4 h
5 h
6 h
1
2
3
4
5
50
50
10
2.6
2.6
0.92
3.4
100
89
133
133
133
133
13.8
9.3
10.0
8.0
−
6.1
4.3
3.4
3.5
−
3.0
1.7
1.6
1.4
−
1.6
0.9
0.7
0.5
2.5
0.8
−
−
−
1.0
200
39500
a
LCAP.
crystallize 1 in 49% yield. Thus, a four-step synthesis of 1 was
discovered, but it was thought that route B would be difficult
to apply for a large-scale preparation because three chromato-
graphic purifications were required.
completed in 6 h under these conditions (Table 5, run 5).
After the reaction, 13 was extracted with EtOAc followed by
washing with an aqueous citric acid solution. Subsequently, the
EtOAc extract was treated with zeolite to remove any tarlike
products and then washed with both an aqueous NH4OH
solution and aqueous NH4Cl solution. Then 4 M HCl/EtOAc
containing the same amount of HCl as the assayed amount of
13 in the organic solution was added to crystallize 13·HCl
(99.8% purity, LCAP) in 78% yield (Scheme 4).
Preparation of 13·HCl. The preparation of 1 according to
the planned route C was performed as shown in Scheme 4.
Compound 17 was reacted with pyrazole (1.5 equiv), Cu2O
(0.3 equiv), and Cs2CO3 (1.2 equiv) in DMF at 100 °C for 9 h
under a N2 atmosphere to give 13 (Table 3, run 1).10 When
DMF was changed to DMSO or N,N-dimethylacetamide
(DMAc), the reaction time was reduced to 4 or 6 h in the
presence 0.12 equiv of Cu2O (runs 2 and 3). While K3PO4 in
DMSO gave 13 in 77% yield after 5 h, K2CO3 or DBU
prolonged the reaction time (runs 4, 5, and 6). From these
results, it was found that K3PO4 as the base and DMSO as the
solvent were the best combination.
The coupling reaction of 17 with pyrazole under these
reaction conditions showed that the reaction time differed
depending on the reaction scale. As a result of investigation, it
was found that the reaction time was longer for larger volumes
of headspace, though the same amounts of 17, pyrazole, Cu2O,
K3PO4, and DMSO were used under the same rate of N2 flow
(Table 4, runs 1 vs 2 and 3 vs 4). On the other hand, the
reaction rate decreased remarkably when a N2 balloon was
used (run 5). Also, both bubbling of N2 and an Ar flow
improved the reaction rate to reduce the reaction time (runs 6
and 7). From these results, it was presumed that efficient
replacement of the gas in the reaction vessel with an inert gas
during the reaction accelerated the reaction rate. As a purpose-
built facility would be required to apply the bubbling of N2 in a
large-scale preparation, the conditions under a flow of Ar were
selected and optimized (Table 5). When the flow rate of Ar per
headspace volume was set up as 89 mL min−1 L−1, the reaction
time for amidation was 6 h (run 1). Increasing the rate to
133mL min−1 L−1 reduced the reaction time to 5 h in the case
of a different headspace volume and scale (runs 2−4). Thus,
these conditions were thought to be the best for large-scale
preparation. At the scale of 39.5 kg of 17, the reaction was
Preparation of 20. A solution of 18 (1.0 equiv) and
acetone (1.3 equiv) was added dropwise to a suspension of t-
BuONa (1.7 equiv) in tetrahydrofuran (THF) at room
temperature, and the reaction mixture was stirred for 18 h to
precipitate the sodium salt of 19, which was collected by
filtration in 57% yield. However, 19 was used as an aqueous
solution in the reaction with the diazonium salt formed from
13 because the sodium salt showed high hygroscopicity and
poor filterability. To enable efficient extraction into the
aqueous layer, the reaction solvent was changed to toluene.
After the reaction in toluene, aqueous HCl was added to the
reaction mixture to adjust it to pH 10, and 19 was obtained in
57% assay yield. Alternatively, the reaction mixture was added
to aqueous HCl followed by adjustment with aqueous NaOH
to pH 10, which gave an assay yield of 65%. It was thought that
19 decomposed to byproducts under the aqueous strongly
basic conditions. In addition, as a result of optimizing the
amounts of the reagents, the reaction using acetone (1.0 equiv)
and t-BuONa (1.2 equiv) provided 19 in 74% assay yield. The
optimal conditions were successfully scaled up to the kilogram
scale using 23.8 kg of 18 to afford a 10.5 % w/w aqueous
solution of 19 in 86% assay yield. This solution was used in the
next reaction without further purification. Separately, 27.0 kg
of 13·HCl was reacted with NaNO2 in 3 M HCl for 1 h to give
the diazonium salt, which was reacted with 1.44 equiv of 19 in
the presence of NaOAc in MeOH, followed by filtration to give
20 (98.8% purity, LCAP) in 93% yield.
Preparation of 21. The reaction of 20 with 3.0 equiv of
DMFDMA was carried out in DMAc as the solvent for 2 h at
D
DOI: 10.1021/acs.oprd.8b00394
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80 °C to provide the target product 21 regioselectively in 85%
LCAP purity, and the undesired product 22 (Figure 1) was
26 was removed in the mother liquor, most of 23 remained in
the crystals. Increasing the amount of phenylhydrazine to 2.0
equiv reduced the reaction time and improved the
regioselectivity, but 23 still remained after crystallization
from EtOH/TFA/water (run 2). Although the use of AcOH
as a solvent led to slightly increased amount of 26, pure 1 was
obtained because 26 and 23 were eliminated by crystallization
from AcOH/H2O (run 3). Thus, these conditions were
applied to the cyclization reaction using 30.0 kg of 21 to give
crude 1 in 93% yield, which was recrystallized from DMSO/
EtOH to afford 28.4 kg of pure 1 (more than 99.9% purity,
LCAP) in 91% yield. Also, the residual amount of phenyl-
hydrazine, which is strictly controlled as a mutagenic impurity,
was not more than 10 ppm.
Figure 1. Estimated impurities in the ring formation to obtain 21.
obtained in 5% LCAP purity. The 1H NMR spectrum of 20 in
DMSO-d6 indicated that 20 existed as a 1:1 mixture of E and Z
isomers. It was presumed that the reaction of 20 with
DMFDMA proceeded preferentially at the position α to the
carbonyl group possessing a methoxymethyl group because of
the inductive effect of the methoxy group and that the resulting
structure cyclized to form 3-acetyl-5-methoxypyridazin-4(1H)-
one, followed by a second dimethylaminomethylenation of the
acetyl group with DMFDMA, accompanying E/Z isomer-
ization. The addition of EtOAc to the reaction mixture led to
crystallization of 21, and subsequent filtration afforded 21
(99.0% purity, LCAP) in 74% yield, resulting in the complete
removal of 22 to the mother liquor, although 23, 24, and 25
(estimated by LC/MS) remained in the crystals of 21. The
reaction temperature was changed to 60 °C to suppress the
production of byproducts while maintaining the conversion of
21. On the basis of these experimental results, the reaction of
74.7 kg of 20 with DMFDMA was conducted, followed by
addition of EtOAc, filtration of crystals, and washing with
EtOAc to give crude 21 in 77% yield. Recrystallization of 68.7
kg of crude 21 from DMSO/EtOAc afforded 61.2 kg of pure
21 (99.6% purity, LCAP) in 89% yield. The remaining
amounts of 23, 24, and 25 were all less than 0.05% (LCAP).
Preparation of 1. The formation of the pyrazole ring by
reaction of 21 with phenylhydrazine was conducted to give 1
(Table 6).11 When 1.06 equiv of phenylhydrazine was used,
the reaction was completed in 18 h at room temperature in
19:1 EtOH/TFA to achieve the regioselective cyclization with
an 89:1 ratio of 1 to the isomer 26. Addition of water to the
reaction mixture gave crystals of 1 in 85% yield (run 1). While
CONCLUSION
■
A practical synthesis of 1 by a novel route was developed. The
diketone 19 obtained from acetone and methyl 2-methox-
yacetate (18) provided an E/Z mixture of diazo compound 20
upon reaction with the diazonium salt derived from 13.
Dimethylaminomethylenation of 20 with DMFDMA pro-
ceeded preferentially at the methylene position followed by
cyclization and subsequent C1 insertion to afford 21.
Treatment of 21 with phenylhydrazine prompted a regiose-
lective cyclization to form the 1,5-disubstituted pyrazole ring,
affording 1. These regioselective transformations led to the
minimization of byproducts in each process and enabled facile
isolation of the pure product in good yield without the need
for cumbersome purification procedures such as column
chromatography, and they were successfully scaled up to a
multikilogram scale. In addition, we have discovered an
alternative synthesis of 1 using a selective alkylation at the 5-
position of 1-phenylpyrazole as the key reaction.
EXPERIMENTAL SECTION
■
General. All chemicals were purchased from commercial
suppliers and used without further purification. Melting points
were measured on a Stanford Research Systems OptiMelt
MPA 100 instrument. NMR spectra were taken on a Bruker
AVANCE 600 (600 MHz) NMR spectrometer with
tetramethylsilane as the internal standard. High-resolution
mass spectrometry (HRMS) data were obtained on a
Shimadzu Prominence UFLC system with a Thermo Fisher
Table 6. Optimization of the Pyrazole Ring Formation by Reaction of 21 with Phenylhydrazine
a
ratio of products (%)
run
equiv of PhNHNH2
solvent (v/w)
conditions
1
26
23
yield of 1 (%)
1
2
3
1.06
2.0
1.05
EtOH/TFA (19:1)
EtOH/TFA (19:1)
AcOH (7.5)
rt, 18 h
rt, 3.5 h
rt, 3 h
89 (96.6)
92 (96.6)
94 (99.1)
1 (0.2)
1 (0.1)
3 (0.2)
3 (2.2)
1 (0.7)
1 (n.d.)
85
94
91
a
LCAP of the reaction mixture. Values in parentheses are LCAPs of crystal 1.
E
DOI: 10.1021/acs.oprd.8b00394
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LTQ Orbitrap Discovery system. IR spectra were recorded on
a Thermo Electron FT-IR Nicolet 4700 (ATR) spectrometer.
Mass spectral analyses were carried out at Takeda Analytical
Research Laboratories, Ltd. LC/MS analyses were conducted
using a Thermo Finnigan TSQ 7000 system.
5-yl)propan-2-one (14). To a mixture of 13·HCl (139 mg,
0.651 mmol) in 3 M HCl (1.12 mL) at 0 °C was added a
solution of NaNO2 (67.4 mg, 0.977 mmol) in water (0.2 mL).
The reaction mixture was stirred for 2 h. The resulting mixture
was added to a mixture of 12 (150 mg, 0.651 mmol) and
NaOAc (320 mg, 3.91 mmol) in MeOH (1.4 mL). The
reaction mixture was stirred for 1 h at 0 °C. After the resultant
mixture was diluted with EtOAc, the organic layer was washed
with water. The organic layer was concentrated in vacuo. The
resulting residue was purified by silica gel to afford 14 (110
The following HPLC conditions were used: (A) Inertsil
ODS-3 column, 5 μm, 150 mm × 4.6 mm i.d.; UV detector at
254 nm; isocratic elution with CH3CN/50 mM aqueous
KH2PO4 (50:50) at a flow rate of 1.0 mL/min; column
temperature of 30 °C. (B) Inertsil ODS-3 column, 5 μm, 150
mm × 4.6 mm i.d.; UV detector at 254 nm; isocratic elution
with CH3CN/50 mM aqueous KH2PO4 (pH 7.0 by 8 N
NaOH) (70:30) at a flow rate of 1.0 mL/min; column
temperature of 30 °C. (C) Inertsil ODS-3 column, 5 μm, 150
mm × 4.6 mm i.d.; UV detector at 254 nm; isocratic elution
with CH3CN/50 mM aqueous AcONH4 (pH 4.6 by AcOH)
(70:30) at a flow rate of 1.0 mL/min; column temperature of
30 °C. (D) Inertsil ODS-3 column, 5 μm, 150 mm × 4.6 mm
i.d.; UV detector at 254 nm; isocratic elution with CH3CN/50
mM aqueous AcONH4 (65:35) at a flow rate of 0.9 mL/min;
column temperatureof 25 °C. Purities were determined by
HPLC and presented as the area percentage of the compound
peak relative to the total area of all the peaks integrated.
1-Methoxy-3-(1-phenyl-1H-pyrazol-5-yl)propan-2-ol
(11). To a solution of 1-phenylpyazole (9) (500 mg, 3.47
mmol) in THF (15 mL) at −70 °C were added t-BuOK (777
mg, 6.94 mmol) and n-BuLi (1.6 M in hexane, 4.34 mL, 6.94
mmol). The resulting mixture was stirred at −70 °C for 1 h.
To the solution was added 10 (1.22 g, 13.88 mmol), and the
resulting mixture was stirred at −70 °C for 1 h. The reaction
was quenched by the addition of 1 M HCl (7 mL). The
mixture was extracted with EtOAc (30 mL). The separated
organic layer was concentrated in vacuo. The resulting residue
was purified by silica gel to afford 11 (724 mg, 90%) as a
1
mg, 40%) as a yellow solid. Mp 122−125 °C; H NMR (600
MHz, DMSO-d6) δ 3.12 (s, 3H), 4.65 (br s, 2H), 6.56 (s, 1H),
6.71−6.77 (m, 1H), 7.32−7.51 (m, 5H), 7.69−7.82 (m, 4H),
7.90 (d, J = 1.5 Hz, 1H), 8.51 (d, J = 2.6 Hz, 1H), 10.33 (s,
1H); 13C NMR (151 MHz, DMSO-d6) δ 58.2, 72.9, 106.6 (d, J
= 24.2 Hz), 108.0, 109.4, 114.7 (d, J = 3.0 Hz), 118.23, 118.24,
122.9, 127.5, 127.8, 129.1, 130.3, 133.3, 135.4 (d, J = 9.1 Hz),
139.9, 140.4, 141.1, 151.1 (d, J = 244.6 Hz), 192.3; IR (ATR)
434, 478, 654, 694, 752, 768, 812, 928, 995, 1045, 1103, 1234,
1501, 1508, 1528, 1558, 1686, 3138, 3316 cm−1; HRMS (ESI)
[M + H]+ calcd for C22H20FN6O2 419.1632, found 419.1624.
1-(2-Fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-
(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (1). To a
mixture of 14 (100 mg, 0.239 mmol) in DMAc (1 mL) was
added N,N-dimethylformamide dimethylacetal (DMFDMA)
(42.7 mg, 0.359 mmol) at rt. The mixture was stirred for 2 h at
75−85 °C. Water (1.5 mL) was added dropwise to the
solution, and the resulting mixture was stirred at 25 °C. The
resulting precipitates were collected by filtration, washed with
water, and dried at 40 °C in vacuo to give 1 (50 mg, 49%).
2-Fluoro-4-(1H-pyrazol-1-yl)aniline Hydrochloride
(13·HCl). DMSO (304.2 kg), 17 (39.5 kg, 166.7 mol),
pyrazole (17.0 kg, 249.7 mol), and K3PO4 (46.2 kg, 92%, 200.0
mol) were charged to a reaction vessel at 20−50 °C under an
argon atmosphere. The reaction vessel was evacuated and
backfilled with argon, and this procedure was repeated. After
Cu2O (2.86 kg, 20.0 mol) and DMSO (43.5 kg) were added to
the reaction vessel at 20−30 °C, the reaction vessel was again
evacuated and backfilled with argon, and this procedure was
repeated. The reaction mixture was stirred for 8 h at 95−105
°C under an argon flow (13.3 L/min). After the mixture was
cooled to 20−30 °C and moved to a 2000 L vessel, water (390
kg) was added at 25−45 °C, and the mixture was stirred for 0.5
h at 35−45 °C. EtOAc (426.6 kg) and 10% w/w aqueous citric
acid solution (409.9 kg) were added at 35−45 °C, and the
mixture was stirred for 0.5 h at the same temperature. After the
mixture was cooled to 20−30 °C, the two layers were
separated. Zeolite (2.0 kg) was added to the organic solution.
Insoluble matter was removed by filtration and rinsed with
EtOAc (35.6 kg). The combined filtrate was washed with a
mixture of 12% w/w aqueous NH4OH solution (186.8 kg) and
20% w/w aqueous NH4Cl solution (208.7 kg), a mixture of 6%
w/w aqueous NH4OH solution (191.5 kg) and 20% w/w
aqueous NH4Cl solution (208.7 kg), 10% w/w aqueous
NH4Cl solution (406.3 kg), and water (395.0 kg). The assay
yield of 13 was 91.6% (152.7 mol). HCl/EtOAc (4 M, 34.0 kg,
156.7 mol) was added to the organic solution, and the mixture
was stirred for 2.5 h at 20−30 °C. The resultant precipitate was
collected by filtration, washed with EtOAc (142.2 kg), and
dried in vacuo at 50 °C to give 13·HCl (gross 27.9 kg, content
99.8%, net 27.9 kg, 99.8 area % (HPLC conditions A), 78%
yield) as a bluish solid. Mp 215−218 °C; 1H NMR (600 MHz,
DMSO-d6) δ 6.57 (t, J = 2.1 Hz, 1H), 7.51 (t, J = 8.7 Hz, 1H),
1
yellow oil. H NMR (600 MHz, DMSO-d6) δ 2.67 (dd, J =
15.5, 8.3 Hz, 1H), 2.83 (dd, J = 15.5, 4.5 Hz, 1H), 3.15−3.24
(m, 5H), 3.79−3.85 (m, 1H), 4.97 (d, J = 5.3 Hz, 1H), 6.37
(d, J = 1.5 Hz, 1H), 7.42−7.47 (m, 1H), 7.47−7.54 (m, 4H),
7.58 (d, J = 1.5 Hz, 1H); 13C NMR (151 MHz, DMSO-d6) δ
30.4, 58.3, 68.3, 76.1, 106.4, 125.3, 127.7, 129.0, 139.5, 139.7,
140.7; IR (ATR) 419, 698, 770, 928, 1015, 1072, 1124, 1200,
1396, 1456, 1501, 1599, 2891, 3337 cm−1; HRMS (ESI) [M +
H]+ calcd for C13H17N2O2 233.1290, found 233.1281.
1-Methoxy-3-(1-phenyl-1H-pyrazol-5-yl)propan-2-
one (12). To a solution of DMSO (1.68 g, 21.6 mmol) and 11
(1.0 g, 4.31 mmol) in THF (20 mL) was added TFAA (1.80
mL, 12.9 mmol) at 0 °C. The resulting mixture was stirred at 0
°C for 30 min. To the mixture was added NEt3 (2.18 g, 21.6
mmol), and the resulting mixture was stirred at rt for 1 h. The
reaction was quenched by the addition of 10% aqueous
Na2CO3. The mixture was extracted with EtOAc. The
separated organic layer was concentrated in vacuo. The
resulting residue was purified by silica gel to afford 12
(738.9 mg, 75%) as a yellow oil. 1H NMR (600 MHz, DMSO-
d6) δ 3.18 (s, 3H), 3.97 (s, 2H), 4.04 (s, 2H), 6.37 (d, J = 1.9
Hz, 1H), 7.37−7.46 (m, 3H), 7.48−7.55 (m, 2H), 7.62 (d, J =
1.9 Hz, 1H); 13C NMR (151 MHz, DMSO-d6) δ 35.8, 58.3,
76.3, 108.0, 124.7, 127.8, 129.1, 135.6, 139.4, 139.5, 203.6; IR
(ATR) 698, 770, 926, 1105, 1396, 1501, 1597, 1719, 1732,
2824, 2988 cm−1; HRMS (ESI) [M + H]+ calcd for
C13H15N2O2 231.1134, found 231.1127.
1-(2-(2-Fluoro-4-(1H-pyrazol-1-yl)phenyl)-
hydrazineylidene)-3-methoxy-1-(1-phenyl-1H-pyrazol-
F
DOI: 10.1021/acs.oprd.8b00394
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Organic Process Research & Development
Article
7.71 (dd, J = 8.5, 2.1 Hz, 1H), 7.76 (d, J = 1.5 Hz, 1H), 7.85
(dd, J = 11.9, 2.5 Hz, 1H), 8.53 (d, J = 2.6 Hz, 1H), 9.35 (br s,
3H); 13C NMR (151 MHz, DMSO-d6) δ 106.5 (d, J = 24.2
Hz), 107.8, 114.7 (d, J = 3.0 Hz), 121.6, 125.2, 127.8, 135.2,
140.9, 153.1 (d, J = 243.1 Hz); IR (ATR) 461, 507, 600, 650,
762, 804, 878, 889, 914, 955, 1030, 1047, 1109, 1142, 1211,
1277, 1393, 1510, 1524, 1626, 2577, 2758, 2797, 2974 cm−1;
HRMS (ESI) [M + H]+ calcd for C9H9FN3 178.0781, found
178.0775.
1-Methoxypentane-2,4-dione (19). Toluene (165.7 kg),
and t-BuONa (26.4 kg, 274.3 mol) were charged to a reaction
vessel at 20−30 °C under a nitrogen atmosphere. The
suspension was stirred for 10 min at 20−30 °C and cooled
to 0−10 °C. A mixture of 18 (23.8 kg, 228.6 mol) and acetone
(13.3 kg, 228.6 mol) was added dropwise to the suspension at
0−10 °C, and the reaction mixture was stirred for 18 h at 20−
30 °C and then cooled to 0−10 °C. HCl (2 M, 98.5 kg) was
added, followed by adjustment with 2 M NaOH (70.0 kg) to
pH 10.25−10.75. The two layers were separated, and 90% w/w
AcOH (21.4 kg, 320.0 mol) was added to the aqueous solution
to give a solution of 19 (gross 243.1 kg, content 10.5% w/w,
net 25.5 kg, HPLC purity 93.7 area % (HPLC conditions B),
86% yield). This solution was used in the next reaction without
further purification.
1522, 1641, 1668, 3115 cm−1; HRMS (ESI) [M + H]+ calcd
for C15H16FN4O3 319.1206, found 319.1197.
3-(3-(Dimethylamino)acryloyl)-1-(2-fluoro-4-(1H-pyr-
azol-1-yl)phenyl)-5-methoxypyridazin-4(1H)-one (21).
Me2NCH(OMe)2 (83.9 kg, 704.1 mol), 20 (74.7 kg, 234.7
mol), and DMAc (189.6 kg) were charged to a reaction vessel
at 20−30 °C under a nitrogen atmosphere. The mixture was
stirred for 3 h at 57−67 °C and cooled to 45−55 °C. EtOAc
(1008.5 kg) was added dropwise at 45−55 °C, and the mixture
(1500 L) was stirred for 2 h at 20−30 °C. The mixture was
separated into two volumes, 850 and 650 L. The resultant
precipitate from the 850 L portion was collected by filtration
and washed with EtOAc (114.3 kg) to give wet crude 14 (43.4
kg), and the resultant precipitate from the 650 L portion was
collected by filtration and washed with EtOAc (87.4 kg) to
give wet crude 21 (32.9 kg). The combined wet crude 21 was
dried in vacuo at 50 °C to give crude 21 (68.8 kg, 77% yield)
as a light-brownish solid. A suspension of crude 21 (68.7 kg)
and DMSO (377.9 kg) was dissolved at 80−90 °C, and the
solution was cooled to 45−55 °C and stirred for 0.5 h at the
same temperature. EtOAc (618.3 kg) was added dropwise over
3 h at 45−55 °C, and the mixture was stirred for 0.5 h at the
same temperature. After cooling to 20−30 °C, the mixture
(1050 L) was stirred for 1.5 h at the same temperature. The
mixture was separated into two volumes, 520 and 530 L. The
resultant precipitate from the 520 L portion was collected by
filtration and washed with EtOAc (91.9 kg) to give wet 21
(31.3 kg), and the resultant precipitate from the 530 L portion
was collected by filtration and washed with EtOAc (93.6 kg) to
give wet 21 (32.9 kg). The combined wet 21 was dried in
vacuo at 50 °C to give 21 (61.2 kg, 99.6 area % (HPLC
conditions C), 89% yield) as a light-yellowish solid. Mp 225−
227 °C; 1H NMR (600 MHz, DMSO-d6) δ 2.82 (s, 3H), 3.09
(s, 3H), 3.79 (s, 3H), 5.22 (br s, 1H), 6.64 (s, 1H), 7.38 (br s,
1H), 7.81−7.88 (m, 2H), 7.92 (dd, J = 8.7, 2.3 Hz, 1H), 8.05
(dd, J = 12.1, 2.3 Hz, 1H), 8.49 (s, 1H), 8.67 (d, J = 2.6 Hz,
1H); 13C NMR (151 MHz, DMSO-d6) δ 36.8, 44.3, 56.1,
106.6 (d, J = 25.7 Hz), 108.8, 114.2 (d, J = 3.0 Hz), 126.3,
128.2, 128.5, 129.0 (d, J = 10.6 Hz), 140.6 (d, J = 10.6 Hz),
142.0, 154.4, 155.1 (d, J = 250.7 Hz), 161.7; IR (ATR) 436,
457, 513, 606, 629, 652, 685, 758, 814, 854, 864, 910, 966,
1028, 1042, 1063, 1117, 1202, 1321, 1364, 1439, 1514, 1568,
1597, 3123 cm−1; HRMS (ESI) [M + H]+ calcd for
C19H19FN5O3 384.1472, found 384.1460.
1-(2-Fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-
(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (1).
AcOH (225 L) and 21 (30.0 kg, 78.2 mol) were charged to
a reaction vessel at 20−30 °C under a nitrogen atmosphere,
and the mixture was dissolved at the same temperature.
Phenylhydrazine (8.88 kg, 82.1 mol) was added at 20−30 °C,
and the mixture was stirred for 4.6 h at 20−30 °C. HCl (1 M,
750 mL) was added to the reaction mixture kept at 20−30 °C,
and the mixture was allowed to stand overnight and then
stirred for 1 h at 20−30 °C. The resultant precipitate was
collected by filtration, washed with a solution of AcOH (21 L)
and water (39 L) and then with EtOH (150 L), and dried in
vacuo at 50 °C to give crude 1 (31.2 kg, 93% yield) as a light-
yellowish solid. DMSO (280 L) and crude 1 (31.2 kg) were
charged to a reaction vessel at 20−30 °C under a nitrogen
atmosphere, and the mixture was dissolved at 67−68 °C. The
solution was filtered with a microfiltration membrane filter and
rinsed with DMSO (31 L). To the combined filtrate was added
EtOH (315 L) dropwise at 60−70 °C. After cooling to 20−30
3-(2-(2-Fluoro-4-(1H-pyrazol-1-yl)phenyl)-
hydrazineylidene)-1-methoxypentane-2,4-dione (20).
HCl (3 M, 226.2 kg, 644.6 mol) and 13·HCl (gross 27.1 kg;
content 99.8% w/w, net 27.0 kg, 126.4 mol) were charged to a
reaction vessel (vessel A) at 20−30 °C under a nitrogen
atmosphere. A solution of NaNO2 (11.3 kg, 164.3 mol) and
water (27 kg) was added dropwise at 0−10 °C, and the
solution was stirred for 1 h at the same temperature (solution
A). A solution of 19 (gross 225.6 kg, content 10.5% w/w, net
23.7 kg, 182.1 mol), NaOAc (51.8 kg, 632.0 mol), and MeOH
(405.3 kg) were charged to a reaction vessel at 20−30 °C
under a nitrogen atmosphere, and the solution was stirred for
10 min at 20−30 °C and then cooled to 0−10 °C (vessel B).
Solution A was added dropwise to vessel B at 0−10 °C. After
MeOH (21.3 kg) was added, the mixture (1000 L) was stirred
for 2 h at 20−30 °C. The mixture was separated into two
volumes, 510 and 490 L. The resultant precipitate from the
510 L portion was collected by filtration, washed with water
(91.8 kg) three times, and 50% v/v aqueous MeOH (24.6 kg)
to give wet 20 (33.3 kg), and the resultant precipitate from the
490 L portion was collected by filtration, washed with water
(88.2 kg) three times, and 50% v/v aqueous MeOH (23.7 kg)
to give wet 20 (31.8 kg). The combined wet 20 was dried in
vacuo at 50 °C to give 20 (37.5 kg, 98.8 area % (HPLC
conditions A), 93% yield) as a yellowish solid comprising a 1:1
1
mixture of E and Z isomers. Mp 154−156 °C; H NMR (600
MHz, DMSO-d6) δ 2.42 (s, 1.5H), 2.52 (s, 1.5H), 3.33 (s,
1.5H), 3.34 (s, 1.5H), 4.56 (s, 1H), 4.69 (s, 1H), 6.59 (s, 1H),
7.79 (s, 1H), 7.81−7.86 (m, 1H), 7.87−7.97 (m, 2H), 8.57 (d,
J = 2.3 Hz, 1H), 14.51 (s, 1H); 13C NMR (151 MHz, DMSO-
d6) δ 26.1, 30.7, 58.41, 58.44, 73.3, 76.8, 106.2 (d, J = 24.2
Hz), 106.3 (d, J = 24.2 Hz), 108.3, 115.17 (d, J = 3.0 Hz),
115.22 (d, J = 3.0 Hz), 117.4, 117.6, 127.1 (d, J = 10.6 Hz),
127.2 (d, J = 9.1 Hz), 128.0, 133.0, 133.5, 137.22 (d, J = 9.1
Hz), 137.23 (d, J = 9.1 Hz), 141.5, 151.4 (d, J = 244.6 Hz),
151.5 (d, J = 244.6 Hz), 193.8, 196.3, 196.5, 197.0; IR (ATR)
449, 525, 600, 611, 654, 756, 789, 829, 876, 937, 949, 978,
1047, 1090, 1204, 1231, 1265, 1302, 1352, 1375, 1396, 1506,
G
DOI: 10.1021/acs.oprd.8b00394
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Organic Process Research & Development
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Selective, and Orally Active Phosphodiesterase 10A (PDE10A)
Inhibitor. J. Med. Chem. 2014, 57, 9627. (b) Suzuki, K.; Kimura, H.
TAK-063, a novel PDE10A inhibitor with balanced activation of
direct and indirect pathways, provides a unique opportunity for the
treatment of schizophrenia. CNS Neurosci. Ther. 2018, 24, 604.
(c) Shiraishi, E.; Suzuki, K.; Harada, A.; Suzuki, N.; Kimura, H. The
Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves
Cognitive Functions Associated with Schizophrenia in Rodent
Models. J. Pharmacol. Exp. Ther. 2016, 356, 587. (d) Yoshikawa,
M.; Kamisaki, H.; Kunitomo, J.; Oki, H.; Kokubo, H.; Suzuki, A.;
Ikemoto, T.; Nakashima, K.; Kamiguchi, N.; Harada, A.; Kimura, H.;
Taniguchi, T. Design and synthesis of a novel 2-oxindole scaffold as a
highly potent and brain-penetrant phosphodiesterase 10A inhibitor.
Bioorg. Med. Chem. 2015, 23, 7138. (e) Yoshikawa, M.; Hitaka, T.;
Hasui, T.; Fushimi, M.; Kunitomo, J.; Kokubo, H.; Oki, H.;
Nakashima, K.; Taniguchi, T. Design and synthesis of potent and
selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting
with Tyr683 in the PDE10A selectivity pocket. Bioorg. Med. Chem.
2016, 24, 3447. (f) Suzuki, K.; Harada, A.; Suzuki, H.; Miyamoto, M.;
Kimura, H. TAK-063, a PDE10A Inhibitor with Balanced Activation
of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like
Effects in Multiple Paradigms. Neuropsychopharmacology 2016, 41,
2252. (g) Tohyama, K.; Sudo, M.; Morohashi, A.; Kato, S.; Takahashi,
J.; Tagawa, Y. Pre-clinical Characterization of Absorption, Distribu-
tion, Metabolism and Excretion Properties of TAK-063. Basic Clin.
Pharmacol. Toxicol. 2018, 122, 577. (h) Harada, A.; Suzuki, K.;
Kimura, H. TAK-063, a Novel Phosphodiesterase 10A Inhibitor,
Protects from Striatal Neurodegeneration and Ameliorates Behavioral
Deficits in the R6/2 Mouse Model of Huntington’s Disease. J.
Pharmacol. Exp. Ther. 2017, 360, 75. (i) Nakatani, A.; Nakamura, S.;
Kimura, H. The phosphodiesterase 10A selective inhibitor, TAK-063,
induces c-Fos expression in both direct and indirect pathway medium
spiny neurons and sub-regions of the medial prefrontal cortex in rats.
Neurosci. Res. 2017, 125, 29.
°C, the mixture was stirred for 1 h at the same temperature.
After cooling to 0−10 °C, the mixture was stirred for 1 h at the
same temperature. The resultant precipitate was collected by
filtration, washed with EtOH (156 L), and dried in vacuo at 50
°C to give 1 (28.4 kg, >99.9 area % (HPLC conditions D),
1
91% yield) as a light-yellowish solid. Mp 215−217 °C; H
NMR (600 MHz, DMSO-d6) δ 3.79 (s, 3H), 6.63 (s, 1H), 7.00
(d, J = 1.9 Hz, 1H), 7.18 (t, J = 8.5 Hz, 1H), 7.33−7.46 (m,
5H), 7.75 (dd, J = 8.7, 2.3 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H),
7.84 (d, J = 1.5 Hz, 1H), 7.99 (d, J = 12.3, 2.5 Hz, 1H), 8.53
(d, J = 1.5 Hz, 1H), 8.66 (d, J = 2.6 Hz, 1H); 13C NMR (151
MHz, DMSO-d6) δ 56.2, 106.5 (d, J = 24.2 Hz), 108.8, 110.5,
113.9 (d, J = 3.0 Hz), 124.4, 126.0 (d, J = 3.0 Hz), 127.3,
127.5, 128.5, 128.7 (d, J = 10.6 Hz), 128.9, 134.8, 139.6, 140.6
(d, J = 9.1 Hz), 140.8, 142.0, 144.9, 149.7, 154.6 (d, J = 250.7
Hz), 161.4; IR (ATR) 447, 525, 546, 602, 652, 694, 764, 802,
912, 928, 951, 989, 1055, 1229, 1391, 1452, 1497, 1508, 1518,
1522, 1597, 1624, 3055, 3115 cm−1; HRMS (ESI) [M + H]+
calcd for C23H18FN6O2 429.1475, found 429.1465.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00394.
■
S
1H and 13C NMR analyses (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail for A.S.: akihiro.suzuki@spera-pharma.co.jp.
*E-mail for T.I.: tomomi.ikemoto@spera-pharma.co.jp.
■
(3) Plescia, S.; Daidone, G.; Fabra, J.; Sprio, V. Studies on the
Synthesis of Heterocyclic Compounds. Part V. A Novel Synthesis of
Some Pyridazin-4-(1H)one Derivatives and their Reaction with
Hydrazine. J. Heterocycl. Chem. 1981, 18, 333.
(4) Micetich, R. G.; Baker, V.; Spevak, P.; Hall, T. W.; Bains, B. K.
The Sequential Lithiation of 1-Phenylpyrazoles. Heterocycles 1985, 23,
943.
(5) Schlosser, M.; Strunk, S. The “super-basic” butyllithium/
potassium tert-butoxide mixture and other lickor-reagents. Tetrahe-
dron Lett. 1984, 25, 741.
(6) (a) Parikh, J. R.; Doering, W. E. Sulfur Trioxide in the Oxidation
of Alcohols by Dimethyl Sulfoxide. J. Am. Chem. Soc. 1967, 89, 5505.
(b) Tidwell, T. T. Oxidation of Alcohols by Activated Dimethyl
Sulfoxide and Related Reactions: An Update. Synthesis 1990, 1990,
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ORCID
Akihiro Suzuki: 0000-0002-6653-9186
Present Address
†A.S., T.K., and T.I.: SPERA PHARMA, Inc., 17-85
Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-0024, Japan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Mr. Kenichi Oka and Mr. Keiichi Satou for LC/MS
analysis.
■
REFERENCES
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DOI: 10.1021/acs.oprd.8b00394
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