Development of a practical and scalable synthesis of a potent CRTH2 antagonist

Article abstract of DOI:10.1021/op3001492

This contribution describes the process research and development of a practical and scalable synthetic method towards compound 1, which has a potent CRTH2 antagonistic activity. The medicinal chemistry synthetic route and second generation synthetic route

Full text of DOI:10.1021/op3001492

Article
pubs.acs.org/OPRD
Development of a Practical and Scalable Synthesis of a Potent CRTH2
Antagonist
Shinya Yoshida,*,† Toshitaka Yoshino,‡ Akio Miyafuji,† Hironobu Yasuda,§ Takenori Kimura,∥
Takumi Takahashi,⊥ and Takashi Mukuta†
†Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi-shi, Ibaraki 318-0001, Japan
‡Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan
§Astellas Research Technologies Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan
∥Astellas Research Technologies Co., Ltd., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
⊥Supply Chain Management, Astellas Pharma Inc., 2-3-11, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan
ABSTRACT: This contribution describes the process research and development of a practical and scalable synthetic method
towards compound 1, which has a potent CRTH2 antagonistic activity. The medicinal chemistry synthetic route and second
generation synthetic route had several issues in scale-up synthesis. In contrast, the synthetic method described here does not
require purification by column chromatography for all steps, and the formation of impurities is suppressed well. This highly
efficient and scalable process was successfully demonstrated in the large-scale synthesis of 1.
- Many steps (step c, f, g, h, and j) required SiO2 column
chromatography.
INTRODUCTION
4-{3-[3-(3-Benzhydryl-6-oxo-1,6-dihydropyridazin-1-yl)-
propyl]phenoxy}butanoic acid (1, Figure 1) has potent
■
- Yield of compound 102 was low (typically 33%).
- Preparation of iodide 7 via mesylate 6 was undesirable
from the point of view of efficiency; rather, direct
alkylation using mesylate 6 with pyridazinone 11 would
be a more efficient strategy.
Second-Generation Synthetic Method (400-g-Scale
Synthesis). We were urgently required to prepare 400 g of
final product 1 for preclinical study. To address these issues
with the medicinal chemistry synthetic method, we focused on
the preparation of 10 and 12 (Scheme 2). First, we attempted
to synthesize 10 using the aldol reaction with a base. The
combination of LDA and ethyl glyoxylate (9) worked well, and
the desired 10 was obtained. After treatment with hydrazine
hydrate, pyridazinone 11 was prepared in a typically 65% yield.
For the N-alkylation step, the exchange of mesylate 6 to iodide
7 was avoided; rather, direct alkylation was accomplished using
LiH as a base, and the desired product 12 was prepared. Finally,
we were able to prepare 435 g of 1 for preclinical study.
However, a number of issues were identified during the
preparation of this sample that required improvement for
delivery of a 30-kg campaign, as listed below.
Figure 1. Structure of compound 1.
CRTH2 antagonistic activity. CRTH2 is expressed on
inflammatory cells, such as Th2 cells, eosinophils, and
basophils, and induces the chemotaxis of these cells. CRTH2
also plays important roles in cytokine release by Th2 cells and
in the degranulation of eosinophils. CRTH2 antagonists are
expected to be useful as anti-inflammatory agents in the
treatment of patients with allergic diseases.1 The medicinal
chemistry synthetic method for compound 1 had several
disadvantageous issues with regard to scale-up synthesis
(Scheme 1). Further, the second-generation synthetic method
constructed via aldol reaction with a base (Scheme 2) included
a poorly reproducible reaction that should be avoided in scale-
up synthesis. Under such circumstances, we were required to
synthesize 30 kg of 1. This article describes our efforts to
develop an efficient synthetic method for the first GMP delivery
of 1 which is capable of being operated on a scale-up synthesis
level.
- SiO2 column chromatography was necessary in step b.
- Low reproducibility of the aldol reaction might be a
significant issue for large-scale synthesis.
- Low yield at the pyridazinone ring formation step.
- Use of LiH in the N-alkylation step might be unfavorable
from the point of view of safety.
- In the final recrystallization step, loss of final product 1 to
the filtrate should be prevented (approximately 25%).
RESULTS AND DISCUSSION
■
The medicinal chemistry synthetic method is shown in Scheme
1. This method was associated with several drawbacks, as
summarized below.
Received: June 8, 2012
Published: August 9, 2012
© 2012 American Chemical Society
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a
Scheme 1. Medicinal chemistry synthetic method (first-generation method)
a
Reagents and conditions: (a) H2SO4 (cat.), EtOH, reflux, 24 h, quantitative yield, (b) DIBAL (3.3 equiv), CH2Cl2, 5 °C, 1 h, 94% yield, (c) K2CO3
(2.6 equiv), ethyl 4-bromobutyrate (1.2 equiv), DMF, 60 °C, 10 h, SiO2 column chromatography, 81% yield, (d) MsCl (1.3 equiv), Et3N (1.8 equiv),
CH2Cl2, 5 °C, 1 h, quantitative yield, (e) NaI (4 equiv.), acetone, 25 °C, 12 h, 96% yield, (f) 9 (1 equiv), neat, 135 °C, 1 day, SiO2 column
chromatography, 33% yield, (g) hydrazine hydrate (1 equiv), MeOH, 130 °C, 1 day, SiO2 column chromatography, 77% yield, (h) LiH (3 equiv),
DMF, 25 °C, 4 h, SiO2 column chromatography, 91% yield, (i) aq NaOH, MeOH, 25 °C, 12 h, then aq HCl, 94% yield, (j) SiO2 column
chromatography, CH2Cl2−MeOH, 73% yield.
New Approach for 30-kg-Scale Synthesis (Third
Generation). Under such circumstances, there was strong
demand for the development of a suitable production process
for 1 with higher overall yield that does not require SiO2
column chromatography purification. Our efforts were focused
on designing a safe, scalable, efficient, and reproducible
synthesis of 1 that incorporates the following key points: (1)
aldol reaction, (2) pyridazinone ring formation, and (3)
recrystallization conditions. During this research, 3-(3-
hydroxypropyl)phenol (compound 4) could be purchased as
a commercially available compound. We investigated a new
strategic approach to the 30-kg synthesis campaign of 1, which
we describe and discuss below.
than one at a higher temperature. When the reaction was
conducted at less than −60 °C, the formation of impurity A was
suppressed until it represented an area of less than 5%. This
means that a higher temperature increased the equilibrium of
tertiary enolate B because of thermodynamic stability and also
gave impurity A (Scheme 3).
To optimize reaction conditions, the effect of an equivalent
of ethyl glyoxylate (9) was investigated. Results showed that the
best yield was obtained with the use of 2.0 equiv of 9. Further,
solvent screening was done using THF, CPME, and toluene
(Table 1, entries 3 and 4). THF was selected because it gave
the best reaction profile on HPLC. In the next stage, the
stability of 10 during the quenching and concentration
processes was investigated. During quenching with an aqueous
acid such as HCl, the ratio of product 10 was gradually
decreased, and the formation of impurity B was observed. In
spite of the maintenance of neutral conditions, the product was
progressively decomposed, and the formation of impurity C
was observed (Figure 3). Further, compound 10 was degraded
during storage at 5 °C. These factors may have been significant
in large-scale synthesis
Optimization for Aldol Reaction.3 Aldol reaction was
attempted under various conditions (Table 1).
As shown in Table 1, LDA gave the best results in
comparison with those with other bases such as TMP−n-
BuLi (entry 6), and LHMDS (entry 7). The use of sodium
hexamethyldisilazane (NaHMDS) did not give the desired
compound (entry 8). Further, no significant difference was
observed between −78 °C and −65 °C (entries 1 and 2). In the
second-generation synthesis, the aldol reaction was not
reproducible. To solve this issue for scale-up synthesis, we
focused on the reaction temperature for enolization (Figure 2).
As expected, a lower-temperature reaction gave better results
Pyridazinone Ring Formation.4 Owing to the instability of
compound 10, a one-pot reaction with hydrazine hydrate was
attempted as shown Figure 4. During the reaction, dihydropyr-
idazinone intermediate A was observed at around −10 °C on
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a
Scheme 2. Second generation synthetic method (400-Gram-Scale Synthesis)
a
Reagents and conditions: (a) Red-Al (5.5 equiv), toluene, THF, 70 °C, 2 h, (b) K2CO3 (3.0 equiv), ethyl 4-bromobutyrate (1.1 equiv), DMF, 80
°C, 3 h, SiO2 column chromatography, 78% yield in 2 steps, (c) MsCl (1.3 equiv), Et3N (1.8 equiv), toluene, 25 °C, 1 h, 95% yield, (d) LDA (1.5
equiv), THF, −60 °C then 9 (2.1 equiv, polymer in toluene), −60 °C, 1.5 h, (e) hydrazine hydrate (4.3 equiv), EtOH, toluene, 140 °C, 65% yield in
2 steps, (f) LiH (3 equiv.), DMF, 25 °C, (g) aq NaOH, MeOH, 50 °C, 2 h, then aq HCl, 85% yield in 2 steps, (h) recrystallization with EtOAc, 73%
yield, loss to the filtrate; 25%.
Table 1. Base and solvent screening for aldol reaction
e
HPLC area %
entry
base (equiv)/solvent
10
8
impurity A
comments
a
c
1
LDA (1.1)/THF
70
70
69
45
57
65
64
−
13
14
12
40
13
22
13
−
4
3
−
−
−
−
−
−
−
b
c
2
LDA (1.1)/THF
a
c
3
LDA (1.5)/THF
7
a
c
4
LDA (1.5)/CPME
5
a
c
5
LDA (1.5)/toluene
15
5
a
d
6
TMP −n-BuLi (1.1)/THF
a
7
LHMDS (1.1)/THF
11
40
a
8
NaHMDS (1.1)/THF
messy
a
b
c
d
Reaction temperature −65 °C. Reaction temperature −78 °C. LDA was prepared in situ between n-BuLi and diisopropylamine in THF. 2,2,6,6-
Tetramethylpiperidine. Determined by HPLC method A (see Experimental Section).
e
LC−MS analysis. However, the following dehydration reaction
did not complete at this temperature but was accelerated by
warming of the reaction mixture to around 40 °C. The yield of
desired pyridazinone 11 was typically 60%, which was
unsatisfactory. During this stage of optimization for scale-up
synthesis, the hydrazone intermediate B was observed in the
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Figure 3. Structures of impurity B and C.
to 97% without loss to the filtrate. This highly efficient process
was successfully demonstrated in large-scale synthesis, and 32.7
kg of crude 1 was prepared.
Recrystallization Step. To improve loss to the filtrate and
increase the purity of crude 1 to meet our desired purity
(>99%), recrystallization conditions were studied. Most low
polar impurities that were detected back on HPLC analysis
(HPLC method A) in comparison with 1 were removed to the
filtrate during crystallization in the preceding step. We were
therefore required to remove the highly polar impurities which
were detected forward of 1 on HPLC analysis. We therefore
focused on the aqueous conditions as solvents. The conditions
of aqueous EtOH, aqueous i-PrOH, and aqueous acetone were
tested for the recrystallization step (Table 3). From these
results, aqueous i-PrOH was selected in consideration of
refining efficiency (entry 1). Further, to avoid amorphous
contamination, the crystallization process was accomplished as
shown in Figure 5. Important factors in this procedure were
timing of the addition of water and addition of seed crystals.
Using this newly developed synthetic method, 30.6 kg of 1 was
synthesized with a purity of 99.7% in 94.2% yield (Table 4).
Loss to the filtrate was only 1.8%. The procedure is described in
detail in the Experimental Section.
Figure 2. Effect of reaction temperature.
aqueous layer that was produced after quenching. It was
possible that the hydrazone intermediate B might be hydro-
lyzed to the desired pyridazinone 11 (Figure 4).5 As expected,
intermediate B was converted to the desired pyridazinone 11
during heating at 70 °C for 24 h. Finally, the pyridazinone 11
was obtained in 76% yield, which was an increase of 11% over
that with the second-generation synthetic method. This highly
reproducible process was demonstrated in a large scale, and
26.3 kg of 11 was prepared.
Synthesis of Crude 1. In the second-generation synthetic
method, the compound 5 was purified with SiO2 column
chromatography. Here, however, one-pot synthesis of ester
compound 12 was attempted via mesylate. In the N-alkylation
step, the first- and second-generation methods used LiH as a
base. To avoid the use of LiH, various bases were screened,
including K2CO3, t-BuOK, EtONa, KOH, and NaOH (Table
2).6 From the results, NaOH in EtOH was selected as a
reaction condition that gave the best reaction profile. In the
second-generation synthetic method, extraction with a large
amount of toluene was necessary to recover the desired 12
from the reaction mixture. In contrast, following the improve-
ment of N-alkylation conditions, we had the chance to conduct
a one-pot hydrolysis reaction. As expected, subsequent
hydrolysis was performed by the addition of aqueous NaOH
to the N-alkylation reaction mixture. After acid treatment and
phase separation, the desired crude 1 was isolated as crystals
with n-heptane−EtOAc in good yield (typically 54−57% in four
reactions) (see Scheme 4). This crystallization method was
optimum, providing an increase in purity on HPLC from 86%
CONCLUSION
■
A practical and scalable synthetic method of 1 was developed.
Undesirable features of the medicinal chemistry and second-
generation synthesis methods were avoided by employing the
aldol reaction, pyridazinone ring formation, N-alkylation
reaction, and recrystallization conditions. From 8 was
manufactured 26.3 kg of pyridazinone 11 in 76% yield in a
practical operation, representing an increase of 11% in
comparison with that using the second-generation synthesis.
During manufacturing, impurities were well controlled at low
levels in all steps. As a consequence, 30.6 kg of the highly pure
Scheme 3. Formation of the impurity A
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Figure 4. One-pot procedure for the preparation of pyridazinone ring formation.
Table 2. Base screening for N-alkylation step
a
HPLC area %
entry
conditions
11
12
1
unknown impurity
comments
b
1
LiH (3 equiv) DMF, 25 °C, 48 h
K2CO3 (2.4 equiv) DMF, 70 °C, 48 h
t-BuOK (1.1 equiv) DMF, 25 °C, 48 h
EtONa (1 equiv) EtOH, 50 °C, 48 h
KOH (1 equiv) EtOH, 50 °C, 48 h
NaOH (1 equiv) EtOH, 50 °C, 48 h
2.7
7.4
2.5
3.4
5.1
2.0
80.1
78.9
73.3
70.8
76.0
82.0
<1
<1
<0.5
2.1
former method
b
2
−
−
−
−
b
3
2.9
<1
5.9
3.9
7.3
4
5
6
6.2
1.1
<0.5
the best condition; used in next step without isolation
a
b
Determined by HPLC method A (see Experimental Section). Large amount of toluene was required for the extraction of 12.
1
drug substance 1 was prepared for GMP delivery. Overall yield
was improved from 34.9% with the second-generation method
to 51.1% with the first scale-up synthesis.
purification. H and 13C NMR spectra were recorded in the
specified deuterated solvent. Chemical shifts of 1H NMR
spectra are reported in parts per million (ppm) on the δ scale
from an internal standard of residual solvent (CHCl3 7.26 ppm;
DMSO-d6 2.50 ppm) or TMS. Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, dd =
doublet doublet, t = triplet, q = quartet, m = multiplet, and br =
EXPERIMENTAL SECTION
■
General. Starting materials, reagents and solvents were
obtained from commercial suppliers and used without further
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Scheme 4. Synthesis of crude 1
a
6-Benzhydryl-2,3-dihydropyridazin-3-one (11). Prep-
aration of LDA solution was as follows. To a solution of
diisopropylamine (14.7 kg, 145.3 mol) in THF (135 kg) was
added n-BuLi (15% in n-hexane, 62.2 kg, 145.3 mol) at −30 to
−5 °C, and the mixture was aged for 1 h. The batch was cooled
to −78 °C. To a solution of LDA, a solution of 1,1-
diphenylacetone (8) (27.8 kg, 132.2 mol) in THF (70.1 kg)
was added below −70 °C (−78 to −73 °C), and the mixture
was aged for 1 h. To the mixture was added ethyl glyoxylate 9
(54.1 kg, 265.0 mol, polymer type, 50% solution in toluene)
below −70 °C (−78 to −76 °C), and the mixture was aged for
0.5 h, after which time HPLC analysis indicated that <1%
starting material 8 remained (HPLC method A). To the batch
was added hydrazine hydrate (33.1 kg, 661.2 mol) below −70
°C. The reaction mixture was poured into toluene (20.1 kg)
followed by washing with THF (13.1 kg) and toluene (12.0 kg)
at −10 °C. The batch was aged for 12 h, after which time
HPLC analysis indicated that <1% compound 10 remained
(HPLC method A). The batch was warmed to 40 °C and aged
for 3 h, after which time HPLC analysis indicated that <1%
intermediate A remained (HPLC method A). To the batch was
added water (139 kg) and toluene (40.0 kg). To the solution
was added 6 N HCl (32.7 kg), and pH was adjusted to 10.1.
The resulting organic layer was washed twice with a 20% (w/w)
aqueous solution of NaCl (28 L). These aqueous layers were
combined, heated to 70 °C, and aged for 24 h, after which time
Table 3. Solvent selection for recrystallization step
b
b
entry
solvent (15 w/v)
purity of 1 (%)
loss to the filtrate (%)
1
2
3
i-PrOH/water =1:1
EtOH/water =1:1
acetone/water =1:1
99.7
99.0
97.7
1.8
3.9
8.8
a
b
Purity of crude 1 = 97.0%, temperature = 0 °C. Determined by
HPLC method A (see Experimental Section).
broad), coupling constant (Hz), and integration. Chemical
shifts of proton-decoupled 13C NMR spectra are reported in
ppm from the central peak of CDCl3 (77.0 ppm), DMSO-d6
(39.5 ppm) on the δ scale. HPLC was performed using a
HITACHI D-2500 or D-7500 system. HPLC methods are
described below.
HPLC Methods. Method A. Waters, XBridge C18, 3.5 μm,
4.6 mm ×150 mm column, elution 0.05 M KH2PO4 aq/
CH3CN = 4:6, over 30 min, 1.0 mL/min, at 40 °C, with UV
detection at 235 nm.
8: 4.6 min, intermediate A: 2.2 min, intermediate B: 1.4 min,
10: 3.2 min, 11: 2.5 min, 6: 4.2 min, 12: 15.4 min, 1: 4.4 min.
Method B. Waters XTerra MS C8, 3.5 μm, 4.6 mm ×150
mm column, elution 0.05 M K2HPO4 (adjust pH 8.0 by aq
H3PO4)/CH3CN = 6/4,over 45 min, 1.0 mL/min, at 25 °C,
with UV detection at 235 nm.
4: 2.1 min, 5: 6.0 min, 6: 12.9 min.
Figure 5. Procedure for recrystallization step.
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Table 4. Quality of crude 1 and 1
a
HPLC area %
entry
1.6
2.0
2.3
2.4
4.0
4.4 (1)
5.5
6.9
13.3
1
2
crude 1
1
0.7
0.2
0.2
0.8
0.3
97.0
99.7
0.2
0.2
0.3
N.D.
N.D.
N.D.
0.05
0.11
0.14
N.D.
N.D.
a
Retention time on HPLC is described (min), as determined by HPLC method A (see Experimental Section).
HPLC analysis indicated that <1% intermediate B remained
(HPLC method A). To the mixture was added THF (25.0 kg),
toluene (96.0 kg) and a 20% (w/w) aqueous solution of NaCl
(28 L). The resulting organic layer was combined with the
former organic layer and concentrated in vacuo to 82 L. To the
resulting residue was added n-heptane (57.0 kg) for 1 h, and
the mixture was aged for 2 h. The resulting slurry was filtered
and washed with a solution of toluene (29.0 kg) and n-heptane
(34.0 kg). The wet cake was dried in vacuo at 40 °C to afford
the desired 11 with 97% purity via HPLC method A (26.3 kg,
75.8% yield from 8).
Ethyl 4-{3-[3-(mesyloxy)propyl]phenoxy}butanoate
(6). To a solution of 5 in toluene were added Et3N (22.7 kg,
224.3 mol) and toluene (4.0 kg). The batch was cooled to 5 °C,
and methanesulfonyl chloride (18.6 kg, 162.4 mol) was added,
followed by washing with toluene (3.0 kg). The reaction
mixture was aged for 3 h at 10 °C, after which time HPLC
analysis indicated that <1% compound 5 remained (HPLC
method B). To the batch was added water (95.0 kg), and the
resulting organic layer was washed with a 20% (w/w) aqueous
solution of NaCl (38.0 L). The resulting organic layer was
concentrated in vacuo to 57 L. To the residue was added EtOH
(22.0 kg), and the resulting solution was used in the next step
without purification. An analytical sample of 6 was purified by
SiO2 column chromatography (n-heptane/EtOAc = 2:1).
ESI-MS: m/z 345 (M + H)+.
An analytical sample of 10 was purified by SiO2 column
chromatography (n-heptane/EtOAc = 1:1).
Compound 10. ESI-MS: m/z 335 (M + Na)+.
1H NMR (400 MHz, DMSO-d6): δ 7.15−7.40 (10H, m),
5.62 (1H, d, J = 6.0 Hz), 5.40 (1H, s), 4.35−4.45 (1H, m), 4.05
(2H, q, J = 7.1 Hz), 2.75−2.95 (2H, m), 1.14 (3H, t, J = 7.1
Hz).
1H NMR (400 MHz, DMSO-d6): δ 7.15 (1H, t, J = 8.0 Hz),
6.65−6.77 (3H, m), 4.15 (2H, t, J = 6.2 Hz), 4.02 (2H, dd, J =
14.4, 7.2 Hz), 3.92 (2H, t, J = 15.4 Hz), 3.13 (3H, s), 2.52−2.62
(2H, m), 2.40 (2H, t, J = 7.4 Hz), 1.85−1.98 (4H, m), 1.14
(3H, t, J = 7.2 Hz).
13C NMR (100 MHz, DMSO-d6): δ 207.1, 173.1, 138.0 (2
carbons), 129.1 (4 carbons), 128.2 (4 carbons), 127.5 (2
carbons), 66.1, 63.8, 62.5, 47.4, 14.5.
13C NMR (100 MHz, DMSO-d6): δ 173.1, 159.1, 142.9,
129.9, 121.1, 115.0, 112.5, 70.2, 66.8, 60.4, 37.1, 31.5, 30.7,
30.6, 24.8, 14.6.
Compound 11. ESI-MS: m/z 263 (M+H)+.
1H NMR (400 MHz, CDCl3): δ 11.93 (1H, s), 7.10−7.40
(11H, m), 6.88 (1H, d, J = 9.7 Hz), 5.44 (1H, s).
13C NMR (100 MHz, CDCl3): δ 161.5, 150.0, 140.7, 134.5,
130.2 (2 carbons), 129.1 (4 carbons), 128.8 (4 carbons), 127.3
(2 carbons), 55.9.
Ethyl 4-{3-[3-(3-benzhydryl-6-oxo-1,6-dihydropyrida-
zin-1-yl)propyl]phenoxy}butanoate (12). To a solution of
6 in EtOH was added compound 11 (24.0 kg, 91.5 mol). To
the batch was added a solution of NaOH in EtOH (NaOH: 6.0
kg, 150.0 mol in EtOH: 150.0 kg) followed by washing with
EtOH (8.0 kg). The batch was warmed to 50−65 °C and aged
for 48 h, after which time HPLC analysis indicated that <2%
compound 6 remained (HPLC method A). This reaction
mixture, which contained 12, was used in the following
hydrolysis.
Ethyl 4-[3-(3-hydroxypropyl)phenoxy]butanoate (5).
To a solution of 3-(3-hydroxypropyl)phenol (4) (19.0 kg,
124.8 mol) in DMF (90.0 kg) at 25 °C were added ethyl 4-
bromobutanoate (30.2 kg, 154.8 mol) and potassium carbonate
(25.9 kg, 187.4 mol). The batch was warmed to 85−90 °C, and
the mixture was aged until compound 4 < 1% in the reaction
mixture (HPLC check, this usually takes 60 h, HPLC method
B). The batch was cooled to 25 °C, and toluene (115.2 kg) and
water (190.0 kg) were added. To the batch was added a 17.5%
aqueous solution of HCl (35% aqueous HCl 8.4 kg/water 7
kg), and pH was adjusted to 8.3. The resulting organic layer
was washed with a 20% (w/w) aqueous solution of NaCl (38.0
L) and concentrated in vacuo to afford the desired compound 5.
This was mixed with toluene (95.0 kg), and this solution was
used in the next step without purification. An analytical sample
of 5 was purified by SiO2 column chromatography (n-heptane/
EtOAc = 2:1).
An analytical sample of 12 was purified by SiO2 column
chromatography (n-heptane/EtOAc = 4:3).
ESI-MS: m/z 511 (M+H)+.
1H NMR (400 MHz, DMSO-d6): δ 7.25−7.31 (6H, m),
7.15−7.23 (6H, m), 6.84−6.87 (1H, m), 6.60−6.70 (3H, m),
5.51 (1H, s), 4.01−4.05 (2H, m), 3.88−3.98 (4H, m), 2.38−
2.43 (4H, m), 1.85−2.00 (4H, m), 1.12 (3H, t, J = 7.0 Hz).
13C NMR (100 MHz, DMSO-d6): δ173.1, 159.4, 159.2,
148.9, 143.5, 141.9 (2 carbons), 133.9, 130.2 (2 carbons), 130.1
(2 carbons), 129.7 (2 carbons), 129.4 (2 carbons), 129.0 (2
carbons), 127.3, 121.1, 115.0, 112.5, 66.8, 60.4, 55.2, 50.5, 32.7,
31.8, 30.7, 29.9, 25.0, 14.9.
ESI-MS: m/z 267 (M + H)+.
Crude 4-{3-[3-(3-Benzhydryl-6-oxo-1,6-dihydropyri-
dazin-1-yl)propyl]phenoxy}butanoic acid (Crude 1). To
the reaction mixture that contained compound 12 was added
water (114.0 kg) and a 25% (w/w) aqueous solution of NaOH
(14.0 kg, 87.5 mol) at 30 °C. The batch was aged for 4 h at 40
°C, after which time HPLC analysis indicated that <0.5%
compound 12 remained (HPLC method A). This reaction
mixture was cooled to 5−10 °C, and a 17.5% (w/w) aqueous
solution of HCl was added, and pH was adjusted to 1.4. To the
batch was added toluene (248.0 kg). The resulting organic layer
1H NMR (400 MHz, DMSO-d6): δ 7.11 (1H, t, J = 7.8 Hz),
6.60−6.72 (3H, m), 4.40 (1H, t, J = 5.0 Hz), 4.02 (2H, dd, J =
14.0, 6.8 Hz), 3.91 (2H, t, J = 6.4 Hz), 3.35 (2H, dd, J = 11.2,
6.4 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.40 (2H, t, J = 7.4 Hz),
1.85−1.97 (2H, m), 1.55−1.72 (2H, m), 1.13 (3H, t, J = 6.8
Hz).
13C NMR (100 MHz, DMSO-d6): δ 173.1, 156.0, 144.3,
129.7, 121.1, 115.0, 112.1, 66.8, 60.6, 60.4, 34.7, 32.2, 30.7,
24.8, 14.6.
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Organic Process Research & Development
Article
(d) Hirai, H.; Tanaka, K.; Yoshie, O.; Ogawa, K.; Kenmotsu, K.;
Takamori, Y.; Ichimasa, M.; Sugamura, K.; Nakamura, M.; Takano, S.;
Nagata, K. J. Exp. Med. 2001, 193, 255. (e) Xue, L.; Gyles, S. L.;
Wettey, F. R.; Gazi, L.; Townsend, E.; Hunter, M. G.; Pettipher, R. J.
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R.; Hansel, T. T.; Armer, R. Nat. Rev. Drug Discovery 2007, 6, 313.
(2) Wermuth, C. G.; Bourguignon, J. J.; Schlewer, G.; Gies, J. P.;
Schoenfelder, A.; Melikian, A.; Bouchet, M. J.; Chantreux, D.;
Molimard, J. C.; Heaulme, M.; Chambon, J. P.; Bizierez, K. J. Med.
Chem. 1987, 30, 239.
was concentrated in vacuo to 57 L. To the residue was added
EtOAc (86.0 kg), and the mixture was concentrated in vacuo to
57 L. To the resulting residue was added EtOAc (34.0 kg), n-
heptane (24.0 kg) and seed crystals of 1 (40.0 g). The mixture
was concentrated in vacuo to 57 L, and to the residue was added
EtOAc (17.0 kg) and n-heptane (22.5 kg). The resulting slurry
was aged for 2 h at 10 °C and filtered, followed by washing with
a solution of EtOAc (27.0 kg)/n-heptane (21.0 kg). The wet
cake was dried in vacuo at 40 °C to afford the desired crude 1
with 97% purity via HPLC method A (32.7 kg, 54.3% yield
from 4).
(3) (a) Martin, V. A.; Murray, D. H.; Pratt, N. E.; Zhao, Y.; Albizati,
K. F. J. Am. Chem. Soc. 1990, 112, 6965. (b) Pousse, G.; Cavelier, F.;
Humphreys, L.; Rouden, J.; Blanchet., J. Org. Lett. 2010, 12, 3582.
(c) Heathcock, C. H.; Hug, K. T.; Flippin, L. A. Tetrahedron Lett.
1984, 25, 5973. (d) Mukaiyama, T.; Kobayashi, S.; Murakami, M.
Chem. Lett. 1985, 14, 447. (e) Nakamura, E.; Shimizu, M.; Kuwajima,
I.; Sakata, J.; Yokoyama, K.; Noyori, R. J. Org. Chem. 1983, 48, 932.
(4) (a) Bornmann, W.; Peng, Z.; Stellrecht, C.; Gandhi, V.; Han, D.;
Ying, Y.; Maxwell, D. WO/2008/30744, 2008. (b) Melikian, A.;
Schlewer, G.; Chambon, J. P.; Wermuth., C. G. J. Med. Chem. 1992, 35,
4092. (c) Baraldi, P. G.; Bigoni, A.; Cacciari, B.; Caldari, C.;
Manfredini, S.; Spalluto, G. Synthesis 1994, 1158. (d) Tsubaki, K.;
Taniguchi, K.; Tabuchi, S.; Okitsu, O.; Hattori, K.; Seki, J.; Sakane, K.;
Tanaka, H. Bioorg. Med. Chem. Lett. 2000, 10, 2787.
4-{3-[3-(3-Benzhydryl-6-oxo-1,6-dihydropyridazin-1-
yl)propyl]phenoxy}butanoic acid (1). The mixture of crude
1 (32.5 kg, 67.3 mol) in i-PrOH (163.3 kg) and water (52.0 kg)
was warmed to 40−50 °C. The resulting solution was filtered
through a 0.45 μm filter into another vessel, followed by
washing with a solution of i-PrOH (20.4 kg)−water (6.5 kg).
To the resulting filtrate was added water (141.6 kg) for 3 h at
30 °C. To the batch was added seed crystals of 1 (32.5 g), and
the mixture was aged for 2 h at 30 °C. In this stage, the
concentration of compound 1 in filtrate was 8.81 g/L, as
determined by HPLC. To the resulting slurry was added water
(33.9 kg) for 0.5 h at 30 °C, and the mixture was cooled to 0−
10 °C and aged for 13 h. The slurry was filtered and washed
with a solution of i-PrOH (51.0 kg)−water (65.0 kg) that was
prefiltered through a 0.45 μm filter. The wet cake was dried in
vacuo at 40 °C to afford the desired 1 with 99.7% purity as
determined by HPLC method A (30.6 kg, 94.2% yield).
ESI-MS: m/z 483 (M + H)+.
(5) Koever, P.; Hajos, G.; Riedl, Z.; Parkanyi, L.; Kollenz, G. Chem.
Commun. 2000, 18, 1785.
(6) (a) Suvorov, N. N.; Smushkevich, Y. I.; Velezheva, V. S.;
Rozhkov, V. S.; Simakov, V. S. Chem. Heterocycl. Cmpds. 1976, 12, 167.
(b) Reuschling, D.; Pietsch, H.; Linkies, A. Tetrahedron Lett. 1978, 7,
615. (c) Takahata, H.; Hashizume, T.; Yamazaki, T. Heterocycles 1979,
12, 1449. (d) Bonjoch, J.; Mestre, E.; Cortes, R.; Gpanados, R.; Bosch.,
J. Tetrahedron 1983, 39, 1723. (e) Somekawa, K.; Okuhira, H.;
Sendayama, M.; Suishu, T.; Shimo, T. J. Org. Chem. 1992, 57, 5708.
1H NMR (400 MHz, DMSO-d6): δ 12.11 (1H, br), 7.23−
7.52 (6H, m), 7.11−7.21 (6H, m), 6.83−6.87 (1H, m), 6.65−
6.70 (3H, m), 5.51 (1H, s), 3.97 (2H, t, J = 7.0 Hz), 3.90 (2H,
t, J = 6.4 Hz), 2.30−2.38 (4H, m), 1.85−1.95 (4H, m).
13C NMR (100 MHz, DMSO-d6): δ 174.7, 159.3, 159.1,
148.8, 143.3, 141.8 (2 carbons), 133.7, 130.0 (2 carbons), 129.8
(2 carbons), 129.5 (2 carbons), 129.3 (2 carbons), 129.0 (2
carbons), 127.3, 121.1, 114.9, 112.3, 66.9, 55.4, 55.2, 50.4, 32.5,
30.7, 29.9, 24.8.
Anal. Calcd for C30H30N2O4. Calcd: C (74.67%), H (6.27%),
N (5.81%). Found: C (74.57%), H (6.28%), N (5.77%).
AUTHOR INFORMATION
Corresponding Author
*shinya.yoshida@astellas.com. Telephone: +81-293-23-5478.
Fax: +81-293-24-2708.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Dr. T. Terasaka and Mr. S. Ito for their
helpful discussions about the medicinal chemistry synthetic
route. And we thank Mr. S. Sawa and Mr. S. Yamaguchi for
analytical study.
REFERENCES
■
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Nagata, H.; Imamura, Y.; Kobayashi, M.; Takeuchi, M.; Ohta, M.
Bioorg. Med. Chem. Lett. 2012, 22, 1194. (b) Terasaka, T.; Zenkoh T.;
Hayashida, H.; Matsuda, H.; Sato, J.; Imamura, Y.; Nagata, H.; Seki,
N.; Tenda, Y.; Tasaki, M.; Takeda, M.; Tabuchi, S.; Yasuda, M.;
Tsubaki, K. WO/2008/072784, 2008. (c) Nagata, K.; Tanaka, K.;
Ogawa, K.; Kemmotsu, K.; Imai, T.; Yoshie, O.; Abe, H.; Tada, K.;
Nakamura, M.; Sugamura, K.; Takano, S. J. Exp. Med. 1999, 162, 1278.
1551
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