Convergent and streamlined synthesis of 6-etherified imidazo[1,2-b] pyridazine-2-amine derivatives possessing VEGFR-2 kinase inhibitory activity

Article abstract of DOI:10.1016/j.tet.2013.07.087

A convergent and streamlined synthesis of selective vascular endothelial growth factor receptor (VEGFR) 2 kinase inhibitors has been achieved using a synthetic strategy based on an S_NAr reaction of 6-chloroimidazo[1,2- b]pyridazine with phenols in the final step. For the synthesis of 6-chloroimidazo[1,2-b]pyridazine, a one-pot reaction using 3-amino-6- chloropyridazine, cyclopropanecarboxamide, and bromoacetyl bromide was developed. The phenols were easily prepared by chemoselective acylation of 3-aminophenols with pyrazole carboxylic acids, and an efficient and high-yielding synthesis of N-ethylpyrazole was also developed. The S _NAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in DMSO in the presence of cesium carbonate successfully proceeded at 100-110 C to give the target products in good yields. This new chromatography-free process will be not only useful for the further bulk supply of these compounds but also applicable to the synthesis of other compounds containing the 6-etherified imidazo[1,2-b]pyridazin-2-amine core.

Full text of DOI:10.1016/j.tet.2013.07.087

Tetrahedron 69 (2013) 8564e8571
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convergent and streamlined synthesis of 6-etherified imidazo[1,2-b]
pyridazine-2-amine derivatives possessing VEGFR-2 kinase
inhibitory activity
*
Kazuhisa Ishimoto , Yasuhiro Sawai, Naohiro Fukuda, Toshiaki Nagata,
Tomomi Ikemoto
Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku,
Osaka 532-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2013
Received in revised form 26 July 2013
Accepted 28 July 2013
Available online 1 August 2013
A convergent and streamlined synthesis of selective vascular endothelial growth factor receptor (VEGFR)
2 kinase inhibitors has been achieved using a synthetic strategy based on an SNAr reaction of 6-
chloroimidazo[1,2-b]pyridazine with phenols in the final step. For the synthesis of 6-chloroimidazo
[1,2-b]pyridazine, a one-pot reaction using 3-amino-6-chloropyridazine, cyclopropanecarboxamide,
and bromoacetyl bromide was developed. The phenols were easily prepared by chemoselective acylation
of 3-aminophenols with pyrazole carboxylic acids, and an efficient and high-yielding synthesis of N-
ethylpyrazole was also developed. The SNAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in
DMSO in the presence of cesium carbonate successfully proceeded at 100e110 ꢀC to give the target
products in good yields. This new chromatography-free process will be not only useful for the further
bulk supply of these compounds but also applicable to the synthesis of other compounds containing the
6-etherified imidazo[1,2-b]pyridazin-2-amine core.
Keywords:
VEGFR-2 kinase inhibitor
6-Etherified imidazo[1,2-b]pyridazine-2-
amine core
Convergent synthesis
One-pot reaction
Chromatography-free process
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Compounds 1 and 2 were identified as potent VEGFR-2 kinase
inhibitors in Takeda Pharmaceutical Company Limited (VEGFR-2
Vascular endothelial growth factor (VEGF) is known to be one of
the critical regulators of angiogenesis.1 The VEGF family consists of
five structurally related proteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D,
and PLGF: Placental growth factor). The binding of these factors to
their respective receptor tyrosine kinases (VEGFR-1, VEGFR-2, and
VEGFR-3) activates the signaling pathway that regulates pro-
liferation, vascular permeability, cell migration, and cell survival,
which are pivotal to angiogenesis. Preclinical models suggest that
angiogenesis is indispensable for tumor growth beyond a few cubic
millimeters and for metastasis.2 Without angiogenesis, tumors
display ‘dormant phenotype’ where the rate of cell proliferation
reaches equilibrium with the rate of cell death. Consequently, in-
hibition of angiogenesis has emerged as an important antitumor
strategy. Due to its central role in tumor angiogenesis, the VEGF/
VEGFR pathway has been a major focus of basic research and drug
development in the field of oncology.3
kinase inhibitory activities of compounds 1 and 2 are IC50¼1.1 nM
and IC50¼1.1 nM, respectively), and have been developed as potent
anticancer drugs.4 Structures of these compounds are characterized
by a 6-etherified imidazo[1,2-b]pyridazine-2-amine core. Among
the huge number of known heterocycles, derivatives of imidazo[1,2-
b]pyridazine have attracted much attention for their intriguing bi-
ological activities in a wide range of therapeutic areas.5e14 However,
only a few groups have so far reported the synthesis and biological
activities of compounds containing the 6-etherified imidazo[1,2-b]
pyridazine-2-amine core.15 Therefore, efficient synthesis of 1 and 2
would be of great interest not only to medicinal chemists but also to
synthetic chemists.
Medicinal chemistry synthesis of these compounds was based
on a linear route, using 3-amino-6-iodopyridazine 3 as a starting
material (Scheme 1).4b The synthesis started with the reaction of 3
with ethyl (2-chloroacetyl)carbamate 4 in the presence of Na2HPO4
to give 6-iodo-imidazo[1,2-b]pyridazine 5. Subsequent depro-
tection of 5 with aqueous barium hydroxide followed by acylation
with cyclopropanecarbonyl chloride afforded the intermediate 7,
which was converted to 9 by SNAr reaction with 3-amino-4-
fluorophenol 8 in a rather harsh condition. Compound 9 was
* Corresponding author. Tel.: þ81 6 6300 6797; fax: þ81 6 6300 6251; e-mail
address: kazuhisa.ishimoto@takeda.com (K. Ishimoto).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.087

K. Ishimoto et al. / Tetrahedron 69 (2013) 8564e8571
8565
Scheme 1. Medicinal chemistry synthesis of 1 and 2. Reagents and conditions: (a) ethyl (2-chloroacetyl)carbamate 4, Na2HPO4, DMAC, 81%; (b) Ba(OH)2, NMP/H2O, 76%; (c) cy-
clopropanecarbonyl chloride, DMAC, 80%; (d) 3-amino-4-fluorophenol 8, K2CO3, DMF, 150 ꢀC, 24 h, 73%; (e) 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid 10a, (COCl)2, cat DMF,
THF, then concentration and add 9 in DMAC for 1, 52%; (f) 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride, DMAC for 11, 66%; (g) fumaric acid, THF/EtOAc, 83%.
acylated with 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid 10a
and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride to give 1 and 11,
respectively. Hemifumarate 2 was obtained by treatment of 11 with
fumaric acid in THF/EtOAc.
development of the new streamlined synthesis of VEGFR-2 kinase
inhibitors 1 and 2.
2. Results and discussion
Along with the development of preclinical studies of 1 and 2, we
started the investigation into the synthesis of 1 and 2 in order to
prepare for the bulk supply of these compounds. Unfortunately, the
medicinal chemistry synthesis was not suitable for scale-up, as it
required five or six linear steps and provided the target compounds
in only moderate overall yields (approximately 20%). In addition,
the use of highly expensive 3 as a starting material, the necessity of
chromatographic purification, the need for quite a high reaction
temperature for SNAr reaction of 7 with 8 (150 ꢀC), and the prep-
aration of pyrazole 10a, which is unavailable in bulk quantity, all
remained as key issues to be overcome for the scale-up. This situ-
ation led us to explore a more convergent, high-yielding, and
scalable synthesis of these compounds, and here, we describe the
Retrosynthetic analysis of 1 and 11 is outlined in Scheme 2. To
achieve convergent synthesis, SNAr reaction of 6-chloro-imidazo
[1,2-b]pyridazine 12 with phenols 13a/13b in the last step was
envisioned. It was assumed that 12 could be synthesized directly
from 2-haloacetyl carboxamide 14a/14b and 3-amino-6-chloropyri
dazine 15 without using carbamate 4, which would require
deprotection and acylation with cyclopropanecarbonyl chloride in
the later step. If it is possible to use 12 for the final coupling instead
of 7, the cheaper and more readily available 3-amino-6-chloropyri
dazine 15 could be used as a starting material instead of 3. Phe-
nols 13a/13b were thought to be obtainable by acylation of 8
with 10a/10b, although there remained a concern about the
Scheme 2. Retrosynthetic analysis of 1 and 11.

8566
K. Ishimoto et al. / Tetrahedron 69 (2013) 8564e8571
chemoselectivity of the OH and NH2 groups of 8. With this strategy
in mind, each step was investigated intensively.
without base. After addition of 15 and K3PO4, the reaction mixture
was aged at 80 ꢀC for 3 h, followed by addition of H2O. Compound
12 was isolated by filtration, and its purity was determined by HPLC
analysis (Table 1). When 1.0 equiv of 18b was used, the yield and
purity of the product was quite low (entries 1 and 2, approximately
20% yield). The increase of the amount of 18b from 1.0 equiv to
1.5 equiv led to higher yield (entry 3), while the use of 2.0 equiv of
18b and 2.0 equiv of K3PO4 resulted in a decreased yield (entry 4).
The best yield (45%) was achieved when 2.0 equiv of 17, 1.5 equiv of
18b, and 1.5 equiv of K3PO4 were used for the reaction (entry 6). The
purity of 12 obtained in this one-pot reaction was slightly lower
(91 wt %, entry 6) than the purity of 12 obtained by the sequential
reactions in which isolated 14b was used for the condensation with
15, probably due to the contamination of inorganic salts in the
product. Fortunately, recrystallization of the crude 12 from DMSO/
H2O effectively increased the purity, affording 12 in 92% yield with
>99 wt % purity. The chromatography-free process was found to be
amenable to scale-up. For the scale-up synthesis (3.81 kg of 15 was
used), a modified robust work-up procedure was applied as fol-
lows: After the one-pot reaction was completed, insoluble matter
generated during the reaction was filtered off. Then 12 was
extracted with EtOAc/THF and washed with 5% aqueous NaHCO3.
After concentration of the solvent, 12 was crystallized from DMSO/
H2O to give crude 12 in 46% yield. Subsequent recrystallization of
crude 12 from DMSO/H2O gave pure 12 in 91% yield (2.88 kg) with
>99 wt % purity.
2.1. Preparation of 12
It was reported that condensation of 3-amino-6-chloropyrida
zine 15 with amide 16a did not proceed under a variety of condi-
tions and 15 was recovered unchanged.16 Meanwhile, the reactions
of carbamates, such as 4 with 3-aminopyridazine derivatives were
reported to give the corresponding imidazo[1,2-b]pyridazin-2-
amine derivatives in low to good yield.15a,16,17 These results imply
that protection of the NH2 group of amide 16 is prerequisite for the
condensationwith 15. Interestingly, to the best of our knowledge, the
protection of the NH2 group of amide 16 in this condensation has
been limited to carbamate so far, and the use of other protecting
groups has not been reported.18 Therefore, our initial attention was
focused on the preparation of imide 14a/14b and examining whether
or not 14a/14b could be condensed with 15 to give 12 (Scheme 3).
Acylation of 16a with cyclopropanecarbonyl chloride in THF in the
presence of triethylamine gave 14a in low yield (8%), while acylation
of 2-bromoacetamide 16b with cyclopropanecarbonyl chloride did
not give 14b. On the other hand, treatment of cyclopropanecarboxa
mide 17 with 2-chloroacetyl chloride 18a in n-BuOAc at 100 ꢀC gave
14a in 67% yield, and treatment of 17 with 2-bromoacetyl bromide
18b in n-BuOAc at 80 ꢀC gave 14b in 36% yield. Subsequent reaction of
14a with 15 in DMAC in the presence of Na2HPO4 at 100 ꢀC for 4 h
successfully afforded 12 in 48% yield. When 14b was reacted with 15
in the presence of Na2HPO4 in DMAC at 85 ꢀC for 3 h, the yield in-
creased to 77%. In this reaction, addition of H2O to the reaction
mixture gave rise to crystallization of 12, which enabled facile iso-
lation of pure 12 by filtration.
With this promising result in hand, our next effort was directed
toward the one-pot synthesis of 12 from 17, which would allow us
to avoid the isolation of the potentially irritating agents 14a/14b.
For a one-pot synthesis, 14b was selected as an intermediate, be-
cause the use of 14a gave 12 as a dark brown solid in the pre-
liminary experiment. At the beginning of the investigation, the
effect of added base (Na2HPO4, K3PO4, Na2CO3, NaOAc, and
NaHCO3) was examined, using DMAC as a solvent, and the study
revealed that the addition of base was not necessary for the re-
action of 17 with 18b. On the other hand, in the reaction of 14b with
15, addition of K3PO4 and Na2HPO4 gave a better result than in the
absence of base, while the use of NaOAc and Na2CO3 did not give 12.
Then, the ratio of 17, 18b and K3PO4 was optimized according to the
following procedure: 17 was first reacted with 18b at 60 ꢀC for 1 h
2.2. Preparation of 10a
Preparation of 10a, which is not commercially available in
bulk quantity, is a key issue for the synthesis of 1. Until now, only
one group has reported the synthesis of the methyl ester of 10a,
using methyl 2-{(dimethylamino)methylene}-3-oxobutanoate, the
methyl ester analogue of 19a and ethylhydrazine oxalate as starting
materials.19 However, their method suffered from low regiose-
lectivity, affording a 53:46 mixture of the methyl ester of 10a and
the methyl ester of the corresponding regioisomer. On the other
hand, it was reported that the reaction of ethyl 2-(ethoxy-
methylene)-4,4,4-trifluoro-3-oxobutanoate, the trifluoroacetyl an-
alogue of 19b, with ethylhydrazine in toluene/H2O in the presence
of sodium hydroxide afforded the N-ethylpyrazole with the same
substitution pattern as 10a and with as much as 89:11 selectivity.20
These results imply that regioselectivity in the N-ethylpyrazole
synthesis using ethylhydrazine largely depends on the structure of
the substrates and reaction conditions.
Scheme 3. Synthesis of 14a and 14b, and their reaction with 15.

K. Ishimoto et al. / Tetrahedron 69 (2013) 8564e8571
8567
Table 1
One-pot synthesis of 12
Entry
17 (equiv)a
18b (equiv)a
K3PO4 (equiv)a
Yieldc (%)
Purityd (wt %)
1
2
3
4
1.5
1.5
1.5
1.5
2.0
2.0
2.0
1.0
1.0
1.5
2.0
1.5
1.5
1.5
1.0
1.5
1.5
2.0
1.0
1.5
2.0
20
18
44
21
38
45
42
48
77
95
32
92
91
92
5
6b
7
a
Based on the amount of 15.
Insoluble matter was filtered off before addition of H2O.
Isolated yield corrected by the purity (based on 15).
Purity (wt %)¼(weight of 12 in the obtained solid/gross weight of the obtained solid)ꢂ100. Weight of 12 in the obtained solid was determined by HPLC analysis using an
b
c
d
authentic sample.
Taking these reports into consideration, investigation of the
synthesis of 10a by the condensation of ethylhydrazine with 19a21
and 19b22 was initiated. Both 19a and 19b were synthesized
according to the literature, and used as an E/Z mixture without
purification by chromatography or distillation. With 19a and 19b in
hand, screening of solvents was carried out to obtain the desired
product regioselectively (Table 2). When 19a was used as a sub-
strate, only low to moderate regioselectivity was observed. In-
terestingly, the reaction of 19a with ethylhydrazine in EtOH gave
the undesired 20b with high regioselectivity (20a:20b¼10:90, en-
try 2), indicating that this condition could be applicable to the
regioselective synthesis of 20b. In contrast, when 19b was used as
a substrate, good regioselectivity (20a:20b>84:16) was observed
regardless of the solvent used. The best regioselectivity
(20a:20b¼91:9) was achieved when 1,2-dimethoxyethane (DME)
was used as solvent (entries 16 and 17).
By using the condition of entry 17, 10a was prepared from the
readily available 21 via 19b (Scheme 4). Compound 21 was treated
with 2.0 equiv of triethyl orthoformate in acetic acid anhydride at
100 ꢀC for 11 h, and after evaporation of the solvent, crude 19b was
dissolved into DME and treated with ethylhydrazine at ꢁ20 to
ꢁ10 ꢀC to afford a 91:9 mixture of 20a and 20b. Solvent was
switched to EtOH and then hydrolysis was performed with 8 M
NaOH. Adjustment of pH to 4.0e4.5 by addition of 6 M HCl led to
crystallization, affording 10a in 76% yield over 3 steps from 21
without detectable amount of the regioisomer.
Table 2
Regioselectivity in the reaction of ethylhydrazine with 19a/19ba
Entry
Substrate
Solvent
Ratiob 20a:20b
1
2
3
4
5
6
7
8
19a
19a
19a
19a
19a
19a
19a
19a
19b
19b
19b
19b
19b
19b
19b
19b
19b
THF
68:32
10:90
73:27
70:30
58:42
48:52
64:36
65:36
90:10
84:16
88:12
90:10
90:10
90:10
88:12
91:9
EtOH
Toluene
EtOAc
MeCN
DMAC
IPE
Scheme 4. Synthesis of 10a.
DME
THF
9
2.3. Preparation of 1 and 11
10
11
12
13
14
15
16
17c
EtOH
Toluene
EtOAc
MeCN
DMAC
IPE
Development of the efficient and robust synthesis of 3-amino-4-
fluorophenol 8 using readily available materials will be discussed
elsewhere.23 Compounds 13a/13b were prepared by acylation of
aminophenol 8 with the acid chloride of the pyrazole carboxylic
acid 10a/10b (Scheme 5). Compounds 10a/10b were treated with
1.1 equiv of thionyl chloride in DMAC at 0e10 ꢀC followed by por-
tionwise addition of 8 without base. Upon completion of the re-
action, aqueous NaOH was added to the reaction mixture for
neutralization, which gave rise to crystallization of the product.
DME
DME
91:9
a
The reaction was conducted using 1.0 equiv of E/Z mixture of 19a/19b and
1.5 equiv of ethylhydrazine at 0e10 ꢀC for 1 h.
b
Molar ratio was determined by HPLC analysis of the reaction mixture.
The reaction was conducted at ꢁ20 to ꢁ10 ꢀC.
c

8568
K. Ishimoto et al. / Tetrahedron 69 (2013) 8564e8571
Table 3
Preparation of hemifumarate 2
Entry Solvent (v/w)
Fumaric Obtained
Yield (%)
71
acid
product
(equiv)
1a
THF (28)/EtOAc (40)
1.05
2
Solvate of 2c 79 (THF 6.9%,
EtOAc 5.1%)d
2a
3a
4a
5a
6a
7a
8a
9a
10b
DMSO (2)/EtOAc (10)
DMSO (2)/acetone (14)
DMSO (2)/2-butanone (20)
DMSO (2)/EtOH (8)
DMSO (2)/2-propanol (8)
DMF (4)/EtOAc (20)
NMP (3)/EtOAc (15)
DMAC (4)/EtOAc (20)
10% aqueous 2-butanone (20) 1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
Free 11
Free 11
Free 11
Free 11
Free 11
Free 11
Free 11
Free 11
2
46
40
10
62
61
66
54
72
49
Solvate of 2c 60 (2-butanone
Scheme 5. Synthesis of 13a/13b.
4.8%)d
Free 11þ2
64
74
76
75
11b
12b
13b
10% aqueous 2-butanone (20) 2.0
10% aqueous 2-butanone (20) 3.0
15% aqueous 2-butanone (20) 3.0
2
2
2
Subsequent filtration afforded pure 13a and 13b in 57% and 94%
yield, respectively. Fortunately, in these reaction conditions, only
a trace amount of the O-esterified product of 8 was observed. The
moderate yield of 13a was partly due to the unoptimized crystal-
lization condition, which caused approximately a 20% loss of
product into the mother liquor. Further optimization of the prep-
aration of 13a is an issue for the future.
For the final coupling of 12 with 13a/b, a screening of bases and
solvents was initially conducted. Among the screened bases (15
bases) and solvents (10 solvents), the combination of Cs2CO3 and
DMSO was found to be the most effective for the fast conversion of
12 to 1/11. When 12 was treated with 1.2 equiv of 13a in DMSO in
the presence of 2.0 equiv of Cs2CO3 at 100e110 ꢀC, the reaction was
almost completed in 4 h (Scheme 6). Fortunately, addition of MeOH
and H2O to the reaction mixture led to crystallization of 1, and the
crude product was collected by filtration and reprocessed by
reslurrying in MeOH/H2O (2:1) to give pure 1 in 85% yield. The
reaction of 12 with 13b required longer reaction time. For complete
conversion, 12 was reacted with 1.2 equiv of 13b in DMSO in the
presence of 2.0 equiv of Cs2CO3 at 100e110 ꢀC for 9 h. Addition of
MeOH and H2O to the reaction mixture also led to crystallization,
affording 11 in 94% yield.
a
After 11 and fumaric acid were dissolved into the solvent, anti-solvent was
added at the room temperature.
b
After 11 and fumaric acid were dissolved into the solvent with heating, the
solution was gradually cooled to room temperature and aged at the same
temperature.
c
Aged at 0 ꢀC.
d
The numbers in parentheses refer to the residual solvent in the product. Re-
sidual solvent was determined by 1H NMR.
yield (entries 2e6). The use of other aprotic polar solvents also
provided free 11 (entries 7e9).
In the course of these investigations, addition of a small amount
of H2O was found to increase the solubility of 11 in THF and 2-
butanone. In the case of 10% aqueous 2-butanone, 20 v/w of sol-
vent was enough to dissolve 11 completely at 70 ꢀC. Following this
observation, salt formation in aqueous 2-butanone was examined.
When 1.05 equiv of fumaric acid was used, the result was not re-
producible (entry 10), sometimes giving 2 and other times a mix-
ture of 2 and free 11. When aging temperature was decreased to
0e10 ꢀC, the solvate of 2 was obtained in many cases. After much
trial and error, it was found that increasing the amount of fumaric
Scheme 6. Synthesis of 1 and 11.
2.4. Preparation of hemifumarate 2
acid was a key factor for reliable salt formation. When the amount
of fumaric acid was increased to 2.0e3.0 equiv, hemifumarate 2 was
consistently obtained in good yield (entries 11e13). The condition
of entry 13 proved to be amenable to scale-up. When 350 g of 11
was treated with 3.0 equiv of fumaric acid in 15% aqueous 2-
butanone, 2 was successfully obtained in 75% yield.
Preparation of hemifumarate 2 by salt formation of 11 with
fumaric acid required detailed investigation, since the conditions
used for the medicinal chemistry synthesis (fumaric acid:
1.05 equiv, solvent: THF/EtOAc) gave poor reproducibility, affording
2 and/or a solvate of 2 irregularly (Table 3, entry 1). Due to the low
solubility of 11 and fumaric acid in common organic solvents,
preparation of 2 in DMSO was first investigated. To our disap-
pointment, addition of various kinds of anti-solvents to a DMSO
solution of 11 and fumaric acid all gave free 11 with low recovered
3. Conclusions
In conclusion, we have developed a highly convergent and facile
synthesis of VEGFR-2 kinase inhibitors. One-pot reaction using 15,

K. Ishimoto et al. / Tetrahedron 69 (2013) 8564e8571
8569
17, and 18b and subsequent recrystallization gave pure 12 in
moderate yield without chromatographic purification. This is the
first example of the use of an imide for the preparation of imidazo
[1,2-b]pyridazine-2-amine derivatives by the condensation of the
imide with 3-aminopyridazine derivatives. As a result of the
screening of substrates and solvents, regioselectivity in the N-eth-
ylpyrazole formation was successfully increased up to 91:9, which
led to an effective synthesis of 10a from readily available starting
materials. SNAr reaction of 12 with 13a/b in the last step proceeded
smoothly when using DMSO as a solvent and Cs2CO3 as a base at
100e110 ꢀC. Addition of MeOH and H2O to the reaction mixture
gave rise to crystallization, and subsequent filtration afforded 1 and
11 in quite a high yield. In addition, a robust method for the
preparation of hemifumarate 2 was developed. The scalability of
this synthesis was demonstrated by the successful production of 2
on a kg-scale in our company. The facile chromatography-free
synthesis of 1 and 2 will support further bulk supply of these
compounds. At the same time, this new synthesis will be useful for
the preparation of other biologically active compounds containing
the 6-substituted imidazo[1,2-b]pyridazine-2-amine core.
d6)
d
0.83e0.86 (m, 2H), 0.88e0.92 (m, 2H), 1.98e2.03 (m, 1H), 4.50
9.1 (2C), 14.1,
(s, 2H), 11.30 (s, 1H); 13C NMR (125 MHz, DMSO-d6)
d
45.3, 167.4, 173.9; IR (ATR) 3255, 3174, 3023, 2983, 2944, 1744, 1698,
1515, 1448, 1408, 1394, 1314, 1210, 1173, 1158, 1105, 1060, 1027, 973,
940, 925, 889, 852, 825, 801, 776, 708, 604, 559 cmꢁ1; Anal. Calcd
for C6H8NO2Cl; C, 44.60; H, 4.99; N, 8.67; Cl, 21.94. Found: C, 44.49;
H, 4.99; N, 8.76; Cl, 22.15.
4.3. N-(2-Bromoacetyl)cyclopropanecarboxamide (14b)
To a suspension of 17 (2.00 g, 23.5 mmol) in n-BuOAc (20 mL) at
40e50 ꢀC was added 2-bromoacetyl bromide 18b (5.23 g,
25.9 mmol) dropwise, and the mixture was heated to 80 ꢀC and
stirred for 5 min. After cooling to room temperature, the mixture
was stirred for 0.5 h, and then filtered. Wet solids were washed
with n-BuOAc (5 mL) and dried in vacuo at 60 ꢀC to give the title
compound 14b (1.73 g, 36%) as a white solid; mp 153e154 ꢀC; 1H
NMR (500 MHz, DMSO-d6)
2.02e2.07 (m, 1H), 4.33 (s, 2H), 11.27 (s, 1H); 13C NMR (125 MHz,
DMSO-d6) 9.2 (2C), 14.2, 31.7, 167.0, 173.9; IR (ATR) 3255, 3174,
d 0.84e0.88 (m, 2H), 0.89e0.93 (m, 2H),
d
3018, 2947, 1741, 1697, 1513, 1450, 1392, 1283, 1175, 1144, 1103, 1059,
1025, 972, 937, 886, 848, 824, 797, 701, 581, 551, 419 cmꢁ1; Anal.
Calcd for C6H8NO2Br; C, 34.98; H, 3.91; N, 6.80; Br, 38.78. Found: C,
34.83; H, 3.78; N, 6.80; Br, 38.95.
4. Experimental section
4.1. General
All materials were purchased from commercial suppliers and
4.4. N-(6-Chloroimidazo[1,2-b]pyridazin-2-yl)cyclopropane
used without any additional purification. Melting points were de-
carboxamide (12)
€
termined on a Buchi Melting Point B-540 and are uncorrected un-
less otherwise noted. DSC was recorded on a SII DSC6200. 1H NMR
and 13C NMR spectra were recorded on a BRUKER AVANCE 500
spectrometer. HPLC analysis of the compounds and reaction mon-
itoring was carried out on a Shimadzu SPD-10A/LC-10AT and SPD-
7A/LC-7. High-resolution mass spectrometry (HRMS) data was ob-
tained on a Shimadzu Prominence UFLC system with a Thermo-
fisher LTQ Orbitrap Discovery. IR spectra were recorded on
a Thermo Electron FT-IR Nicolet 4700 (ATR) and Shimadzu IR
Prestige-21 (Nujol). Elemental analyses were recorded on an Ele-
mentar vario MICRO cube for CHN analysis and Mitsubishi Chem-
ical Analytech XS-2100H/Dionex ICS-1600 for halogen analysis or
carried out by Takeda Analytical Research Laboratories, Ltd.
To a 100 L-glass lined vessel at 20e30 ꢀC were added 17 (5.01 kg,
58.9 mol) and DMAC (19.0 L), and the mixture was cooled to
0e10 ꢀC. To this solution at 0e10 ꢀC was added 18b (8.94 kg,
44.3 mol) dropwise over 1 h, followed by addition of DMAC (3.8 L).
The mixture was heated to 60 ꢀC and stirred for 1 h, and then cooled
to 0e10 ꢀC. To this mixture at 0e10 ꢀC were added K3PO4 (9.37 kg,
44.2 mol) and 3-amino-6-chloropyridazine 15 (3.81 kg, 29.4 mol),
followed by addition of DMAC (7.6 L). The mixture was heated to
80 ꢀC and stirred for 1 h, and then cooled to 25 ꢀC. To this mixture
was added THF (15.2 L), and the mixture was stirred at 25 ꢀC for 1 h,
and then filtered to remove insoluble matter. After addition of THF
(22.9 L), EtOAc (76.9 L) and 5% aqueous NaHCO3 (114.3 L) were
added to the combined filtrate, and then layers were separated. The
organic layer was washed with H2O (38.1 L), and concentrated
under reduced pressure. To the resulting residue was added DMSO
(7.6 L), and the mixture was heated to 70 ꢀC and stirred until the
mixture became a homogeneous solution. The solution was cooled
to 65 ꢀC, and at this point 12 (3.81 g) was added as seed. The
mixture was gradually cooled to 25 ꢀC over 1 h, and H2O (0.76 L)
was slowly added at this temperature. The resulting slurry was
cooled to 0 ꢀC and stirred for 2 h, and then filtered. Wet solids were
washed with DMSO/H2O (1:4, 3.8 L) and H2O (22.9 L), and dried in
vacuo at 60 ꢀC to give crude 12 (3.17 kg) as a brown solid. To a 20 L-
glass flask were added crude 12 and DMSO (8.5 L), and the mixture
was heated to 70 ꢀC and stirred until the mixture became a ho-
mogeneous solution. The solution was cooled to 65 ꢀC, and at this
point 12 (2.87 g) was added as seed. The mixture was gradually
cooled to 25 ꢀC over 1 h, and H2O (0.85 L) was slowly added at this
temperature. The slurry was cooled to 0 ꢀC and stirred for 2 h, and
then filtered. Wet solids were washed with DMSO/H2O (1:4, 2.8 L)
and H2O (17.1 L), and dried in vacuo at 60 ꢀC to give the title com-
pound 12 (2.88 kg, 41%) as a pale yellow solid; mp 190e191 ꢀC; 1H
HPLC conditions. (A) Inertsil ODS-3 column,
5
mm,
150 mmꢂ4.6 mm i.d.; UV detector at 254 nm; isocratic elution with
CH3CN/50 mM aqueous KH2PO4 (pH 7.0) (40:60) at 1.0 mL/min flow
rate; column temperature: 25 ꢀC. Retention times: 2 (7.9 min), 11
(7.9 min), 12 (5.2 min), 15 (2.0 min).
(B) Inertsil ODS-3 column, 5
m
m, 150 mmꢂ4.6 mm i.d.; UV de-
tector at 254 nm; isocratic elution with CH3CN/50 mM aqueous
KH2PO4 (30:70) at 1.0 mL/min flow rate; column temperature:
25 ꢀC. Retention times: 1 (23.7 min), 8 (3.5 min), 10a (2.3 min), 12
(10.0 min), 13a (5.6 min), 19a (3.1 min), 19b (7.1 min, 8.2 min), 20a
(10.9 min), 20b (11.9 min).
(C) Inertsil ODS-3 column, 5
m
m, 150 mmꢂ4.6 mm i.d.; UV de-
tector at 254 nm; isocratic elution with CH3CN/50 mM aqueous
KH2PO4 (40:60) at 1.0 mL/min flow rate; column temperature:
25 ꢀC. Retention times: 8 (2.8 min), 10b (1.6 min), 13b (3.8 min).
4.2. N-(2-Chloroacetyl)cyclopropanecarboxamide (14a)
To
a suspension of cyclopropanecarboxamide 17 (2.00 g,
23.5 mmol) in n-butyl acetate (n-BuOAc, 20 mL) at room temper-
ature was added 2-chloroacetyl chloride 18a (2.92 g, 25.9 mmol)
dropwise, and the mixture was heated to 100 ꢀC and stirred for 3 h.
After cooling to room temperature, the mixture was stirred for 1 h,
and then filtered. Wet solids were washed with n-BuOAc (10 mL)
and dried in vacuo at 50 ꢀC to give the title compound 14a (2.55 g,
67%) as a white solid; mp 156e157 ꢀC; 1H NMR (500 MHz, DMSO-
NMR (500 MHz, DMSO-d6)
7.33 (d, J¼9.0 Hz, 1H), 8.06 (dd, J¼9.5, 0.5 Hz, 1H), 8.25 (s, 1H), 11.25
(s, 1H); 13C NMR (125 MHz, DMSO-d6)
7.6 (2C), 13.6, 105.3, 118.3,
d 0.82e0.88 (m, 4H), 1.95e1.99 (m, 1H),
d
125.4, 133.9, 142.9, 144.9, 171.4; IR (ATR) 3337, 3118, 1667, 1618,
1536, 1514, 1441, 1402, 1329, 1279, 1233, 1205, 1190, 1163, 1130,
1096, 1064, 1044, 1010, 964, 939, 883, 844, 818, 793, 779, 711, 668,

8570
K. Ishimoto et al. / Tetrahedron 69 (2013) 8564e8571
636, 611, 590, 516 cmꢁ1; Anal. Calcd for C10H9N4OCl: C, 50.75; H,
3.83; N, 23.67; Cl, 14.98. Found: C, 50.62; H, 3.83; N, 23.51; Cl, 15.08.
(0.25 L), the mixture was stirred at 0e15 ꢀC for 0.5 h. To this mixture
was added 8 (500.0 g, 3.93 mol) portionwise, maintaining the
temperature below 40 ꢀC. After addition of DMAC (0.75 L), the
mixture was stirred at 15e40 ꢀC for 1 h. Then, H2O (1.0 L), NaOH
(346.1 g, 8.65 mol) in H2O (4.5 L), and H2O (3.5 L) were successively
added dropwise at 15e40 ꢀC. The resulting slurry was stirred for
2 h, and then filtered. Wet solids were washed with H2O (1.5 L) and
dried in vacuo at 50 ꢀC to give the title compound 13b (923 g, 94%) as
a pale brown solid; mp 188e189 ꢀC; 1H NMR (500 MHz, DMSO-d6)
4.5. 1-Ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (10a)
To a solution of ethyl acetoacetate 21 (2.00 g, 15.4 mmol) in
acetic anhydride (7.86 g, 77.0 mmol) was added triethyl ortho-
formate (4.55 g, 30.7 mmol), and the mixture was refluxed for 11 h.
After cooling to room temperature, the mixture was concentrated
under reduced pressure to give crude 19b. To a solution of crude
19b in 1,2-dimethoxyethane (20 mL) at ꢁ20 to ꢁ10 ꢀC was added
ethylhydrazine (1.39 g, 23.1 mmol) dropwise, and the mixture was
stirred at 0e10 ꢀC for 1 h, and then at room temperature overnight.
The mixture was concentrated under reduced pressure to give
a mixture of 20a and 20b (molar ratio 91:9) as an oil. To this oil
were added EtOH (2.6 mL) and 8 M NaOH (2.6 mL), and the mixture
was heated to 60e65 ꢀC and stirred for 2 h. After cooling to room
temperature, the solution was concentrated under reduced pres-
sure until the weight of the solution became 6.3 g. To this solution
was added 6 M HCl and the pH was adjusted to 4.0e4.5. The
resulting slurry was stirred at room temperature for 1 h, and then
filtered. Wet solids were washed with H2O (6 mL) and dried in
vacuo at 50 ꢀC to give the title compound 10a (1.79 g, 76% for 3 steps
from 21) as a white solid; mp 156e157 ꢀC; 1H NMR (500 MHz,
d
2.19 (s, 3H), 3.98 (s, 3H), 6.62 (ddd, 4JHF¼3.3 Hz, J¼8.5, 3.3 Hz, 1H),
4
6.83 (s, 1H), 7.02 (dd, JHF¼6.5 Hz, J¼3.0 Hz, 1H), 7.07 (dd,
3JHF¼10.0 Hz, J¼9.0 Hz, 1H), 9.48 (br s, 1H), 9.85 (s, 1H); 13C NMR
(125 MHz, DMSO-d6)
d 13.0, 38.5, 107.5, 112.9, 112.9, 115.8
(2JCF¼21.3 Hz), 125.0 (2JCF¼12.5 Hz), 135.2, 145.4, 149.0
(1JCF¼235.0 Hz), 153.3 (3JCF¼1.3 Hz), 158.0; IR (ATR) 3229, 1651,
1625,1547,1531,1504,1452,1377,1303,1274,1260,1226,1178,1109,
1056, 1024, 973, 893, 850, 817, 804, 788, 771, 746, 678, 638, 624,
595, 527, 510, 461, 451, 432, 422, 412 cmꢁ1; Anal. Calcd for
C12H12N3O2F: C, 57.83; H, 4.85; N, 16.86. Found: C, 57.62; H, 4.69; N,
16.88.
4.8. N-(5-{[2-(Cyclopropanecarboxamido)imidazo[1,2-b]pyr-
idazin-6-yl]oxy}-2-fluorophenyl)-1-ethyl-3-methyl-1H-pyr-
azole-4-carboxamide (1)
DMSO-d6)
d
1.35 (t, J¼7.3 Hz, 3H), 2.31 (s, 3H), 4.06 (q, J¼7.3 Hz, 2H),
8.13 (s, 1H), 12.07 (s, 1H); 13C NMR (125 MHz, DMSO-d6)
d
13.1, 15.1,
To a solution of 12 (1.50 g, 6.33 mmol) in DMSO (7.5 mL) were
added 13a (2.00 g, 7.60 mmol) and cesium carbonate (4.12 g,
12.7 mmol), and the mixture was heated to 100e110 ꢀC and stirred
for 4 h. To this mixture at 45e55 ꢀC were added MeOH (15 mL) and
H2O (30 mL) dropwise in this sequence. The resulting slurry was
stirred at room temperature for 2 h, and then filtered. Wet solids
were suspended in MeOH/H2O (2:1, 45 mL) and stirred at 50 ꢀC for
1 h. After cooling to room temperature, the resulting slurry was
filtered. Wet solids were washed with H2O (50 mL) and dried in
vacuo at 50 ꢀC to give the title compound 1 (2.49 g, 85%) as a pale
brown solid; mp 192e193 ꢀC; 1H NMR (500 MHz, DMSO-d6)
46.1,111.4,133.8,149.4,164.5; IR (ATR) 3126, 2765, 2703, 2557, 2494,
2167, 2026, 1990, 1921, 1682, 1541, 1486, 1472, 1407, 1379, 1355,
1334,1254,1233,1166,1118,1086,1032, 954, 904, 783, 776, 711, 673,
636, 621, 556, 457 cmꢁ1; Anal. Calcd for C7H10N2O2; C, 54.54; H,
6.54; N, 18.17. Found: C, 54.42; H, 6.41; N, 18.19.
4.6. 1-Ethyl-N-(2-fluoro-5-hydroxyphenyl)-3-methyl-1H-pyr-
azole-4-carboxamide (13a)
To a solution of 10a (4.60 g, 29.8 mmol) in DMAC (15.8 mL) at
0
ꢀC was added thionyl chloride (3.72 g, 31.2 mmol) dropwise,
d
0.78e0.82 (m, 4H),1.39 (t, J¼7.3 Hz, 3H), 1.91e1.94 (m,1H), 2.34 (s,
maintaining the temperature below 20 ꢀC. After addition of DMAC
(1.8 mL), the mixture was stirred at 15e25 ꢀC for 1 h. To this mix-
ture was added 3-amino-4-fluorophenol 8 (3.50 g, 28.4 mmol)
portionwise, and the mixture was stirred at 15e25 ꢀC for 1 h. Then,
H2O (7 mL), 4 M NaOH (15.6 mL) and H2O (19.3 mL) were succes-
sively added. At this point, to this mixture was added a small
amount of 13a as seed, followed by slow addition of H2O (21 mL).
The resulting slurry was stirred at room temperature for 1 h and
then filtered. Wet solids were washed with H2O (10.5 mL) and dried
in vacuo at 50 ꢀC to give the title compound 13a (4.29 g, 57%) as
3H), 4.10 (q, J¼7.3 Hz, 2H), 7.07 (d, J¼9.5 Hz, 1H), 7.11 (ddd,
4JHF¼3.5 Hz, J¼9.0, 3.5 Hz, 1H), 7.37 (dd, 3JHF¼9.5 Hz, J¼9.5 Hz, 1H),
7.68 (dd, 4JHF¼6.3 Hz, J¼2.8 Hz, 1H), 7.95 (s, 1H), 8.04 (d, J¼9.5 Hz,
1H), 8.40 (s, 1H), 9.54 (s, 1H), 11.08 (s, 1H); 13C NMR (125 MHz,
DMSO-d6) d; 7.4 (2C), 13.2, 13.6, 15.1, 46.3, 105.2, 110.6, 113.5, 116.3
(2JCF¼22.5 Hz), 117.5, 117.5, 126.7, 127.1 (2JCF¼13.8 Hz), 131.4, 133.4,
141.9, 148.8, 149.0, 151.7 (1JCF¼241.3 Hz), 159.0, 161.6, 171.1; IR (ATR)
3450, 3249, 3077, 1673, 1665, 1656, 1626, 1529, 1477, 1451, 1434,
1377, 1334, 1320, 1290, 1242, 1228, 1179, 1148, 1106, 1083, 1039,
1010, 984, 961, 880, 859, 804, 791, 756, 734, 708, 671, 628, 603, 536,
490, 447, 424, 416, 401 cmꢁ1; HRMS-ESI (m/z): [MþH]þ calcd for
C23H23N7O3F, 464.1841; found, 464.1840.
a white solid; mp 157e158 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 1.39
(t, J¼7.3 Hz, 3H), 2.35 (s, 3H), 4.09 (q, J¼7.3 Hz, 2H), 6.53 (ddd,
4JHF¼3.5 Hz, J¼9.0, 3.5 Hz, 1H), 7.03 (dd, 3JHF¼10.5 Hz, J¼9.0 Hz, 1H),
7.18 (dd, 4JHF¼6.5 Hz, J¼3.0 Hz, 1H), 8.36 (s, 1H), 9.27 (s, 1H), 9.36 (s,
4.9. N-(5-{[2-(Cyclopropanecarboxamido)imidazo[1,2-b]pyr-
idazin-6-yl]oxy}-2-fluorophenyl)-1,3-dimethyl-1H-pyrazole-
5-carboxamide (11)
1H); 13C NMR (125 MHz, DMSO-d6)
d 13.3, 15.1, 46.3, 111.4
(3JCF¼7.5 Hz), 111.9, 113.8, 115.5 (2JCF¼21.3 Hz), 126.2 (2JCF¼13.8 Hz),
131.2, 148.2 (1JCF¼233.8 Hz),148.9,153.2, 161.5; IR (ATR) 3459, 3129,
2988, 1644, 1634, 1608, 1555, 1480, 1460, 1444, 1402, 1378, 1366,
1357,1334,1299,1287,1258,1236,1195,1163,1120,1103,1081,1038,
1018,1004, 974, 954, 888, 872, 852, 815, 795, 753, 731, 637, 615, 600,
554, 531, 462, 451, 440 cmꢁ1; Anal. Calcd for C13H14N3O2F: C, 59.31;
H, 5.36; N, 15.96; F, 7.22. Found: C, 59.16; H, 5.29; N, 15.90; F, 7.06.
To a 5 L-flask equipped with a mechanical stirrer, a reflux con-
denser with argon gas inlet, and a thermometer was added DMSO
(775 mL), 12 (155.0 g, 0.66 mol), 13b (196.0 g, 0.79 mol) and cesium
carbonate (427.0 g, 1.31 mol) with consecutive evacuation and
backfilling with argon gas. The mixture was heated to 100e110 ꢀC
and stirred for 9 h under argon atmosphere. After cooling to
45e55 ꢀC, the mixture was transferred to a 10 L flask, followed by
rinsing with MeOH (465 mL). To this mixture were added MeOH
(1085 mL) and H2O (3.1 L) dropwise in this sequence. The mixture
was stirred at 20e30 ꢀC for 1 h and stored at 15e25 ꢀC overnight.
After stirring for an additional 1 h, the slurry was filtered. Wet
solids were washed with H2O (3ꢂ1.55 L) and dried in vacuo at 60 ꢀC
4.7. N-(2-Fluoro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-
5-carboxamide (13b)
To a solution of 10b (578.8 g, 4.13 mol) in DMAC (2.0 L) at 0 ꢀC
was added thionyl chloride (514.7 g, 4.33 mol) dropwise, main-
taining the temperature below 15 ꢀC. After addition of DMAC

K. Ishimoto et al. / Tetrahedron 69 (2013) 8564e8571
8571
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4. (a) Sakai, N.; Imamura, S.; Miyamoto, N.; Hirayama, T. U.S. Pat. Appl. US 2009/
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to give the title compound 11 (276.4 g, 94%) as a pale brown solid;
mp 237e238 ꢀC; 1H NMR (500 MHz, DMSO-d6)
0.78e0.84 (m, 4H),
d
1.91e1.96 (m, 1H), 2.20 (s, 3H), 3.99 (s, 3H), 6.86 (s, 1H), 7.07 (d,
4
J¼9.5 Hz, 1H), 7.22 (ddd, JHF¼3.5 Hz, J¼9.0, 3.5 Hz, 1H), 7.40 (dd,
3JHF¼9.8 Hz, J¼9.3 Hz, 1H), 7.55 (dd, 4JHF¼6.5 Hz, J¼3.0 Hz, 1H), 7.95
(s, 1H), 8.04 (d, J¼9.5 Hz, 1H), 10.10 (s, 1H), 11.08 (s, 1H); 13C NMR
(125 MHz, DMSO-d6)
d 7.4 (2C), 13.0, 13.6, 38.5, 105.2, 107.7, 110.6,
116.7 (2JCF¼21.3 Hz), 118.9, 119.1 (3JCF¼8.8 Hz), 125.8 (2JCF¼13.8 Hz),
126.8, 133.4, 134.9, 141.9, 145.5, 148.9, 152.6 (1JCF¼242.5 Hz), 158.1,
159.0, 171.1; IR (Nujol) 3443, 3254, 3177, 3084, 1697, 1657, 1628,
1541, 1466, 1439, 1377, 1333, 1294, 1225, 1180, 1150, 1109, 1009, 959,
887, 810, 746, 727, 677 cmꢁ1; Anal. Calcd for C22H20N7O3F: C, 58.79;
H, 4.49; N, 21.82. Found: C, 58.80; H, 4.53; N, 21.67.
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4.10. N-(5-[{2-(Cyclopropanecarboxamido)imidazo[1,2-b]pyr-
idazin-6-yl}oxy]-2-fluorophenyl)-1,3-dimethyl-1H-pyrazole-
5-carboxamide hemifumarate (2)
To a 10 L flask equipped with a mechanical stirrer, a reflux
condenser, and a thermometer were added 2-butanone (3.85 L),
H2O (1.05 L), and fumaric acid (271 g, 2.34 mol). To this solution was
added 11 (350.0 g, 0.78 mol), followed by addition of 2-butanone
(0.7 L). The mixture was heated to 70 ꢀC and stirred until 11 com-
pletely dissolved into the solution. The resulting solution was
suction filtered at 70 ꢀC through a glass filter to remove insoluble
matter, followed by washing with 2-butanone (1.4 L), and trans-
ferred to a 10 L flask. The solution was cooled to room temperature
and stirred for 3 h, and then filtered. Wet solids were washed with
2-butanone (1.05 L) and dried in vacuo at 60 ꢀC to give the title
compound 2 (295 g, 75%) as a white solid; mp 220 ꢀC (DSC); 1H NMR
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€
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Reville, T.; Jewell, C.; Hammond, C.; Chin, D. WO 2008/030579 A2, Mar 13,
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Gouveia, L.; Suto, M. J. U.S. Pat. Appl. US 2009/0062290 A1, Mar 5, 2009. (e)
Taniyama, D.; Kano, K.; Okamoto, K.; Fujioka, M.; Mitsuoka, Y. Eur. Pat. Appl. EP
2 277 881 A1, Jan 26, 2011. (f) Durand-Reville, T.; Jewell, C.; Hammond, C.; Chin,
D. U.S. Pat. Appl. US 2011/0021513 A1, Jan 27, 2011.
16. Mourad, A. E.; Wise, D. S.; Townsend, L. B. J. Heterocycl. Chem. 1993, 30,
1365e1372.
17. (a) Mourad, A. E.; Wise, D. S.; Townsend, L. B. J. Heterocycl. Chem. 1992, 29,
1583e1592; (b) Denyer, C. V.; Reddy, M. T.; Jenkins, D. C.; Rapson, E.; Watts, S.
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Pat. Appl. US 2010/0204235 A1, Aug 12, 2010.
18. Based on the results of our research, one patent describing the reaction of 14b
with 3-aminopyridazin derivatives has been reported from our company. In
this patent, one-pot reaction is not described. Bressi, J. C.; Chu, S.; Erickson, P.;
Komandla, M.; Kwok, L.; Lawson, J. D.; Stafford, J. A.; Wallace, M. B.; Zhang, Z.;
Das, S. WO 2010/019899 A1, Feb 18, 2010.
19. (a) Martin, S. W.; Bergstrom, C. P.; Gentles, R. G.; Yeung, K-S. WO 2009/029384
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WO 2010/093359 A1, Aug 19, 2010.
(500 MHz, DMSO-d6)
d 0.78e0.84 (m, 4H), 1.91e1.96 (m, 1H), 2.20
(s, 3H), 3.98 (s, 3H), 6.65 (s, 1H), 6.86 (s, 1H), 7.08 (d, J¼9.5 Hz, 1H),
4
3
7.22 (ddd, JHF¼3.5 Hz, J¼9.0, 3.5 Hz, 1H), 7.41 (dd, JHF¼9.5 Hz,
J¼9.5 Hz, 1H), 7.55 (dd, 4JHF¼6.5 Hz, J¼3.0 Hz, 1H), 7.95 (s, 1H), 8.05
(d, J¼9.5 Hz, 1H), 10.10 (s, 1H), 11.08 (s, 1H), 13.13 (br s, 1H); 13C NMR
(125 MHz, DMSO-d6)
d 7.4 (2C), 13.0, 13.6, 38.5, 105.2, 107.7, 110.6,
116.7 (2JCF¼22.5 Hz), 118.9, 119.1 (3JCF¼8.8 Hz), 125.8 (2JCF¼15.0 Hz),
126.8, 133.4, 133.9 (C]C fumaric acid), 134.9, 141.9, 145.5, 148.9,
152.6 (1JCF¼243.8 Hz), 158.1, 159.0, 165.9 (C]O fumaric acid), 171.1;
IR (Nujol) 3429, 3275, 3213,1688, 1626,1558,1537,1523,1464,1431,
1377, 1346, 1296, 1244, 1221, 1188, 1155, 1123, 1103, 1038, 1013, 982,
959, 928, 822, 743 cmꢁ1; Anal. Calcd for C48H44N14O10F2: C, 56.80;
H, 4.37; N, 19.32. Found: C, 56.87; H, 4.39, N, 19.28.
Acknowledgements
We thank Mr. Kenichi Oka for LC/MS analysis, Ms. Itsuko Nakase
for elemental analysis, Mr. Tetsuhiro Yamamoto for his helpful
advice on this work, and Dr. David Cork for his advice on the
manuscript.
20. Aihara, H.; Yokota, W.; Yamakawa, T.; Hirai, K. Eur. Pat. Appl. EP 1 854 788 A1,
Nov 14, 2007.
21. (a) Crombie, L.; Games, D. E.; James, A. W. G. J. Chem. Soc., Perkin Trans. 1
1979, 464e471; (b) Coates, R. M.; Hobbs, S. J. J. Org. Chem. 1984, 49,
140e152; (c) Doleschall, G.; Seres, P. J. Chem. Soc., Perkin Trans. 1 1988,
1875e1879.
22. (a) Menozzi, G.; Mosti, L.; Schenone, P. J. Heterocycl. Chem. 1987, 24, 1669e1675;
(b) Beck, J. R.; Lynch, M. P. J. Heterocycl. Chem. 1987, 24, 693e695; (c) McCombie,
S. W.; Metz, W. A.; Nazareno, D.; Shankar, B. B.; Tagat, J. J. Org. Chem. 1991, 56,
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23. Ishimoto, K.; Fukuda, N.; Nagata, T.; Sawai, Y.; Ikemoto, T. submitted for
publication.
References and notes
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