Development of an Efficient Scale-Up Synthesis Method for a 3-Adrenergic Receptor Agonist, Ritobegron Ethyl Hydrochloride

Article abstract of DOI:10.1021/acs.oprd.0c00278

An efficient route for the multikilogram synthesis of a selective 3-adrenergic receptor agonist, ritobegron ethyl hydrochloride (1), was developed by changing the coupling method of 4-hydroxynorephedrine (2) with phenoxyacetate 3. This new method successf

Full text of DOI:10.1021/acs.oprd.0c00278

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Full Paper
Development of an Efficient Scale-up Synthesis Method for #3-
Adrenergic Receptor Agonist, Ritobegron Ethyl Hydrochloride
Junichi Sonehara, Hidetoshi Isawa, Kiyoshi Kasai, Norihiko Kikuchi, Takehiro
Ishikawa, Masahiro Kobayashi, Tetsuji Ozawa, Ritsu Suzuki, Makoto Kobayashi,
Takayuki Ainai, Masayuki Nishimura, Yohei Saito, and Kyoko Nakagawa-Goto
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00278 • Publication Date (Web): 31 Jul 2020
Downloaded from pubs.acs.org on July 31, 2020
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Development of an Efficient Scale-up Synthesis
Method for β3-Adrenergic Receptor Agonist,
Ritobegron Ethyl Hydrochloride
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Junichi Sonehara,*,†,‡ Hidetoshi Isawa,§ Kiyoshi Kasai,§ Norihiko Kikuchi,§ Takehiro Ishikawa,┴
Masahiro Kobayashi,§ Tetsuji Ozawa, § Ritsu Suzuki,‡ Makoto Kobayashi,‡ Takayuki Ainai,‡
Masayuki Nishimura,‡ Yohei Saito,† and Kyoko Nakagawa-Goto*,†,#
AUTHOR ADDRESS
† School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences,
Kanazawa University, Kanazawa, 920-1192, Japan
‡ Joetsu Chemical Laboratories, Kissei Pharmaceutical Co., Ltd.; 197-5 Kamiyoshi, Kubiki,
Joetsu, Niigata 942-0145, Japan
§ Head Office, Kissei Pharmaceutical Co., Ltd.; 19-48 Yoshino, Matsumoto, Nagano 399-8710,
Japan
┴ Central Research Laboratories, Kissei Pharmaceutical Co., Ltd.; 4365-1 Hotakakashiwabara,
Azumino, Nagano 399-8304, Japan
# UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-7568, United States
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ABSTRACT
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An efficient route for the multikilogram synthesis of a selective β3-adrenergic receptor agonist,
ritobegron ethyl hydrochloride (1), was developed by changing the coupling method of 4-
hydroxynorephedrine (2) with phenoxyacetate 3. This new method successfully overcame
several obstacles in the first-generation method via the use of aldehyde 3b derived from
hemiacetal 10 to couple with 2. The main advantages of the key intermediate, 10 were that it was
sufficiently stable to enable handling at large scales, it could be synthesized without an
exothermic reaction or excessive use of expensive reagents, and the ability to reduce impurities
by purification prior to coupling with 2. The resulting second-generation method improved the
overall yield from 27% to 43%, and the purity from up to 98.5% to 99.5%. Furthermore, it was
effective for 69 kg-scale synthesis, representing a major improvement over the hundred-gram
scale of the first-generation method.
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KEYWORDS: β3-adrenergic receptor agonist, multikilogram synthesis, ritobegron ethyl
hydrochloride, second-generation
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Introduction
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Adrenergic receptors (ARs) are a class of G protein-coupled receptors that are roughly
classified into two groups, α and β, which are further divided into α1, α2, β1, β2, and β3 subtypes.
Among β-ARs, the β3-subtype is the predominant receptor in the human bladder, where it
mediates the relaxation of the smooth muscles. Thus, β3-AR agonists have recently attracted
attention as potential therapeutic agents for overactive bladder, as they are associated with a
reduced risk of side effects, such as dry mouth and constipation, compared to anticholinergics.1–4
Ritobegron ethyl hydrochloride (1; Figure 1) is a prodrug of ritobegron, which is a promising
agonist with high selectivity for β3-ARs that was discovered by Kissei Pharmaceutical Co. Ltd.
(Nagano, Japan).5–6 In order to support the preclinical and clinical development of 1, a large-
scale synthetic method needs to be developed. The basic strategy of synthesis (Scheme 1)
includes the coupling of commercially available 4-hydroxynorephedrine (2)7–11 with
phenoxyacetate 3, which can be prepared from 2,5-xylenol (4), which is an inexpensive
compound.
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The first-generation method entailed the coupling of 2 with phenethyl bromide 3a. The
synthesis begins with the O-alkylation of 4 with ethyl chloroacetate to obtain phenoxyacetate 5,
followed by Friedel–Crafts acylation with bromoacetyl bromide to yield phenacyl bromide 6.12
Reduction of 6 with triethylsilane was conducted to obtain 3a12 in crystalline form (73% overall
yield) from 4. The coupling of 3a with 2, followed by treatment with hydrogen chloride in
ethanol and toluene produced crude salt 1, which was purified by recrystallizaion from tert-
butylmethylether–ethanol to obtain pure 1 (47% overall yield) from 2.
The first-generation method successfully provided a hundred-gram scale of 1; however, several
serious problems regarding safety, economy, and quality hinder its synthesis on a multikilogram
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scale. First, an extreme and uncontrollable exotherm and foaming were observed on the scale-up
of the Friedel–Crafts acylation. Second, several derivatives are generated by side reactions in the
coupling with 2, such as by overalkylation of 3a and by β-elimination of 3a. These impurities
induce the generation of other undesired and irremovable compounds with each step. In total, the
final compound 1 with only up to 98.5% purity was obtained. Third, an excessive amount
(2.5 equiv) of the relatively expensive compound triethylsilane is required for the reduction of 6
to 3a. Furthermore, only a moderate yield (55%) of the desired crude product was obtained from
the coupling of 3a with expensive 2. The latter two issues are directly related to the economic
problems associated with the first-generation method.
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O
HO
O
OEt
•HCl
N
H
OH
Figure 1. Chemical structure of ritobegron ethyl hydrochloride (1)
Scheme 1. Basic Retrosynthetic Strategy for 1
O
HO
O
OH
OEt
1
+
R
NH2
OH
2
3a : R = CH2Br
3b : R = CHO
4
Scheme 2. The First-Generation Route to 1
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O
O
ClCH2COOEt
K2CO3, DMF
BrCOCH2Br
Et3SiH
O
O
AlCl3
BF3•OEt2
OEt
OEt
4
toluene
Br
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9
O
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Economic issue
Uses excessive amount (2.5 equiv)
of relatively expensive Et3SiH
Safety issue
Extreme exotherm and foaming
O
2
1) , iPr2NH
O
recrystalization
DMF
OEt
1
1
crude salt
2) HCl / EtOH
toluene
Br
tBuOMe - EtOH
4
2
Overall yield 27% from
47% from
3a
4
73% yield from
Economic issue
Moderate yield (55%)
Quality issue
1
Unacceptable purity of (up to 98.5%)
2
using expensive
To solve the above problems, an efficient scale-up synthesis of 1 was developed as a second-
generation method. We report herein on the improved new process, which uses crystalline
hemiacetal 10 to enable the multikilogram-scale production of 1 with higher purity and overall
yield than what was obtained using the previous method.
Results and Discussion
In the second-generation method, the hemiacetal form of aldehyde 3b was used in the coupling
process of 2 (Scheme 3), as the undesired issues in the first-generation method stem primarily
from the synthetic and treatment processes used for phenethyl bromide 3a. The hemiacetal form
of aldehyde 3b, compound 10, could be synthesized while avoiding the exothermic Friedel–
Crafts acylation using a Lewis acid and an excessive quantity of relatively expensive
triethylsilane. Furthermore, the condensation of the primary amine of 2 with the aldehyde 3b
derived from hemiacetal 10 under reductive conditions could be more reactive than the N-
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alkylation of 2 with phenethyl bromide 3a. Our expectation of the instability of aldehyde 3b led
us to prepare the related hemiacetal or acetal form as its equivalent. The synthesis began with the
aqueous base-promoted hydroxyalkylation of 4 with glyoxal dimethylacetal13 to result in 80%
yield of 7 with high regioselectivity (para:ortho = 97:3). O-alkylation of 7 with ethyl
chloroacetate successfully enabled the production of benzyl alcohol 8 with 96.8area% purity and
90% yield.
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Scheme 3. Second-Generation Route to 1
Key reaction steps and workup processes
OMe
O
MeO
CHO
ClCH2CO2Et
K2CO3, cat. NaI
OH
OH
O
NaOH aq., 50 oC
OMe
OMe
OEt
DMF, 60 oC
then HCl aq.
MeCN-H2O
MeO
MeO
OH
7
OH
90% yield
4
8
80% yield
O
(COOH)2
MeCN-H2O, 40 oC
cat. AcOH
EtOH-n-heptane
TMSCl, NaI
O
MeCN, -18 oC
OMe
MeO
OEt
3b
then
MeOH and Et3N
9
78% yield (2 steps)
O
2
1) , H2, cat. 10%P-C
O
OH
OEt
THF, 40 oC
Purity 99.5%
recrystalization
tBuOMe-EtOH
91% yield
1
4
2
Overall yield 43% from
76% from
EtO
2) HCl–EtOH
toluene
10
Purity 99.1%
83% yield
The reduction of benzyl alcohol 8 was the first difficulty to overcome, as various catalytic
hydrogenations with W-4 Raney Ni, Pt/C, Rh/alumina, Rh/C, Pd(OH)2, Pd/BaSO4, and Rh/Pt/C,
as well as reduction with triethylsilane, were unsuccessful. The only condition for producing a
satisfactory, laboratory-scale yield (ca. 80%) of dimethylacetal 9 was that which used three equiv
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of TMSCl–NaI–MeCN reagents14–16 at −10 °C. Further optimization was necessary to increase
the yield of the scale-up synthesis and to reduce impurities, such as aldehyde 3b and styryl ether
1317 (Scheme 4). Overreaction of 8 was predicted to generate the intermediate 11 under this
condition,14,18 which could easily be converted to the relatively unstable 3b or undesired 13 in
the presence of water or a base, respectively, during the workup process. The formation of these
impurities was effectively suppressed by the addition of methanol19 during the workup process,
due to the quick conversion of the intermediate 11 into dimethyl acetal 9 with the use of
methanol, resulting in a quantitative yield of 9 in the first plant operation. However, another
impurity, methyl ester 12,20 was generated due to transesterification with methanol under the
acidic conditions that arose from the excess of TMSCl. Undesired 12 persisted throughout all
steps of drug synthesis, and was difficult to remove because it possesses chemical properties that
are almost identical to those of the desired ethyl ester 9. The formation of 12 can be suppressed
by the rapid addition of triethylamine in toluene solution while controlling the heat of
neutralization (Table 1). The yield of 12 increased as the batch scale expanded from 700 g (Table
1, entry 1) to 85 kg (Table 1, entry 2). We further optimized the process to reduce the production
of 12 by controlling the addition time of the trimethylamine-toluene solution and the internal
temperature. We found that the yield of 12 increased in a temperature- (Table 1, entries 3–5 and
entries 6/7) and time-dependent (Table 1, entries 3/6 and 4/7) manner. Additional experiments
(Table 1, entries 8 and 9) also supported that the rapid addition of a base might be more effective
than maintaining low temperature. Moreover, the calculated adiabatic temperature rise of 13 K21
for this reaction indicated the feasibility to add all at once below 0 °C by pre-cooling of
trimethylamine-toluene. Finally, the amount of undesired 12 was suppressed below 0.10% at
57 kg-scale production by the addition of triethylamine-toluene which was pre-cooled to -15 °C
10
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for 25 min after the reaction (Table 1, entry 10). The successful condition resulted in only an
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8 degree internal temperature rise, from −17 to −9 °C.
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Scheme 4. Role and Influence of Methanol during the Workup Process
O
O
O
1) TMSCl, NaI,
MeCN
OMe
OMe
O
OMe
OEt
8
MeO
MeO
2) MeOH
+
H , MeOH
12
9
O
Me C N TMS I-
promoted by
O
MeOH
O
OEt
H
O
H2O
3b
O
O
OEt
O
O
O
OEt
TMS
11
base
MeO
13
Table 1. Optimization of the Workup Process by Control of Methyl Ester 12 Generation
Entry
Internal
Time for addition of
Yield of
Scale
Temperature (°C) Et3N/toluene (min.) Methyl ester 12
1
2
3
−16 to −13
−14 to −13
−15
120
255
180
0.21%
0.62%
0.58%
700 g
85 kg
10 g
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−10
−5
180
180
120
120
60
0.89%
1.09%
0.46%
0.63%
0.14%
0.21%
0.08%
10 g
10 g
10 g
10 g
50 g
10 g
57 kg
6
−15
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−10
8
−8
9
0
50
10
−17 to −9
25
After we had produced 9, the hydrolysis reaction was optimized by the use of various acids
and reaction conditions (Figure 2)22 to obtain the relevant aldehyde 3b, which was allowed to
crystallize in order to ensure high purity. Perchloric acid hydrolyzed the acetal 9 immediately
with high reaction conversion; however, the reaction produced undesired products, such as the
related carboxylic acid, resulting in a reduction in purity (Figure 2, run 1). Other conditions, such
as the use of 1.5 equiv of sulfuric acid, oxalic acid, or phosphoric acid and 0.5 equiv of sulfuric
acid at 20 °C or 40 °C, also gave rise to unsatisfactory results (Figure 2, runs 2–6). Hydrolysis
with 0.5 equiv of oxalic acid at 40 °C was the most appropriate condition, with the reaction
reaching the desired end point (over 99%) and the purity remaining over 94.5% for 2 h (Figure 2,
run 7).
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Figure 2. Optimization of Hydrolysis Conditions (Left: Reaction Conversion, Right: Purity of
3b)
Crystallization is a preferred purification method for obtaining the desired compound with high
purity in multikilogram synthesis. Unfortunately, it was not easy to get 3b as a crystal probably
due to the low melting point.23 In addition, the instability of 3b required low-temperature drying
and refrigerated storage. Several attempts to recrystallize 3b23 serendipitously led us to find an
ideal intermediate, i.e., treatment with ethanol containing n-heptane. The resulting hemiacetal 10
was in a relatively stable crystalline form, which provided the advantages of easy handling at
large scales, and the ability to control the purity by recrystallization. The hemiacetalization of 3b
was accelerated in the presence of a catalytic amount of acetic acid to obtain 10 with 99.1area%
purity and 78% yield from 8.
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The reductive amination of 10 with 1.0 equiv of 2 at 40 °C proceeded smoothly, as anticipated.
However, an unexpected side reaction led to the production of alcohol 1424 (Scheme 5) (in less
than 1% yield). It should be noted that the starting material 10 was very pure without
contamination by benzyl alcohol 8, which might be converted into 14. Further investigation
indicated that the yield of 14 was dependent on the stirring time before hydrogen introduction.
The resulting imine required to be consumed by the reduction as soon as possible to avoid the
formation of 14, although we have no clear reasons. Meanwhile, the formation of trioxane 1525
was observed during the stability assessment of 10 in the ethanol solution. 15 could be related to
the formation of 14, since the amount of 14 was increased by the addition of 15 into the reaction
of 10 with 2. Taking all of this together, a possible reaction mechanism for 14 is proposed as
shown in Scheme 5. The enolate of 3b derived from 10 was partially oxidized in the presence of
oxygen. The resulting peroxide was coupled with aldehyde 3b to obtain 15, which could be
transformed to both the desired ritobegron ethyl and undesired 14.
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Scheme 5. A Possible Mechanism of Impurity 14 generation
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O
O
-EtOH
OEt
OH
3b
10
7
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O2
O
O
2
O
O
OEt
OEt
OH
OH
O
O
O
O
O
3b
HO
O
OEt
N
H
O
OH
O
2
Ritobegron ethyl
OEt
O
OH
O
EtO
O
O
O
HO
O
O
OEt
N
H
15
OH
OH
Impurity 14
Several effective processes were discovered during our efforts aimed at suppressing the
generation of impurity 14; these included the following: (1) removal of O2 from the solution by
multiple nitrogen purge with vacuum manner and compressed manner (refer to Experimental
section) to mitigate oxidization; (2) decreasing the solubility of 10 by cooling below −13 °C
before starting the reaction to minimalize the imine formation; and (3) heating immediately after
the completion of all raw material charging at −13 °C to rapidly consume the resulting imine
(Figure 3). The obtained ritobegron ethyl was treated with hydrogen chloride solution to produce
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crude salt 1, which was recrystallized from tert-butyl methyl ether-ethanol. As a result, 69 kg of
1 was obtained from 2 with 99.5area% purity and 76% yield.
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9
Countermeasure
N2 gas purge
(vacuummanner)
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Removalof O2
THF
Charging
Charging
10
cooled below −13 oC
Countermeasure
N2 gas purge
(vacuummanner)
Decrease in Solubility
Charging
2
below −13 oC
N2 gas purge
(vacuummanner)
Charging
10% Pd–C
below −13 oC
N2 gas purge
(compressed
manner)
H2 gas purge
(compressed
manner)
0.1 MPa
below −13 oC
Countermeasure
Heating Up to 40 oC
Rapid Comsumeof
the Resulting Imine
Reaction
Figure 3. Production Flow for Suppressing Impurity 14
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Conclusion
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In summary, the efficient scale-up synthesis method for ritobegron ethyl hydrochloride (1) was
established. The new process overcomes the main issues encountered in the first-generation
process by changing the intermediate to crystalline hemiacetal 10 and optimizing the reaction
conditions. It also enables the multikilogram production of 1 with improved overall yield and
higher purity (Table 2). Finally, 69 kg of 1 for clinical study was obtained from 4 in six steps,
with 99.5area% purity and 76% overall yield.
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Table 2. Comparison between the First-Generation Process and the New Process
Item
First Generation
Second Generation
improved
Total Number of Steps
Overall yield from 4
Overall yield from 2
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6
27%
47%
43% (1.6 times)
76% (1.6 times)
Area% purity of 1
Up to 98.5%
99.5%(1 point increase)
by HPLC
Experimental Section
General. All air- and moisture-sensitive manipulations were performed under a nitrogen
atmosphere. All substrates, reagents, and solvents were purchased from commercial suppliers
and used without further purification. 1H NMR and 13C NMR spectra were recorded on a Burker
AVANCE 400M (400 MHz) or AVANCE DRX500 (500 MHz) spectrometer using
tetramethylsilane as the internal standard in the indicated solvents. High-resolution mass spectra
(HRMS) were measured on an Agilent Technologies Q-TOF 6520 mass spectrometer. Elemental
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analysis was conducted on an Elementar Analysensysteme GmbH vario EL III elemental
analyzer.
7
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Analytical HPLC method A for measuring the purity of 7: XbridgeC18 column (4.6 x 250 mm,
5 μm); mobile phase A: 20 mM KH2PO4; mobile phase B: acetonitrile; UV detection at 225 nm;
flow rate: 1.0 mL/min; column temperature: 55 °C; gradient initial conditions: A-70%:B-30%;
hold at A-70%:B-30% from 0−5 min; linear ramp to A-40%:B-60% from 5−20 min.
Analytical HPLC method B for measuring the purity of 8: XbridgeC18 column (4.6 x 250 mm,
5 μm); mobile phase A: 20 mM KH2PO4; mobile phase B: acetonitrile; UV detection at 225 nm;
flow rate: 1.0 mL/min; column temperature: 55 °C; gradient initial conditions: A-65%:B-35%;
hold at A-65%:B-35% from 0−10 min; linear ramp to A-35%:B-65% from 10−30 min; hold
from 30−60 min.
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Analytical HPLC method C for measuring the purity of 10: Intertsil ODS-P column (4.6 x
250 mm, 5 μm); mobile phase A: 20 mM H3PO4 (pH 2.3); mobile phase B: acetonitrile; UV
detection at 225 nm; flow rate: 1.0 mL/min; column temperature: 40 °C; gradient initial
conditions: A-55%:B-45%; hold at A-55%:B-45% from 0−15 min; linear ramp to A-30%:B-70%
from 15−25 min; hold from 25−45 min.
Analytical HPLC method D for measuring the purity of 1: Intertsil ODS-3 column (4.6 x
250 mm, 5 μm); mobile phase A: 20 mM H3PO4 (pH 3.0); mobile phase B: acetonitrile; UV
detection at 225 nm; flow rate: 1.0 mL/min; column temperature: 40 °C; gradient initial
conditions: A-74%:B-26%; hold at A-74%:B-26% from 0−20 min; linear ramp to A-30%:B-70%
from 20−50 min; hold from 50−60 min.
4-(1-Hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (7) A 60% aqueous solution of
glyoxal dimethylacetal (235 kg, 1350 mol, 1.5 equiv) was steadily added to a mixture of sodium
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hydroxide (36.0 kg, 900 mol, 1.0 equiv), water (875 L), and 2,5-xylenol (4) (110 kg, 900 mol) at
50 °C; the reaction mixture was stirred at this temperature for 8 h. The conversion was monitored
by HPLC analysis. After acetonitrile (96.8 kg) was added at 0 °C, 7.5% hydrochloric acid
(139 kg) was steadily added over a duration of 1 h, and compound 7 (80 g) were added as a seed
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crystal. The mixture was stirred for 1 h between −5 and 10 °C to precipitate the product.
Additional 7.5% hydrochloric acid (278 kg) was steadily added over a duration of 2 h between
−5 and 10 °C and the suspension was stirred for 2 h, and then filtered. The resulting cake was
washed with a mixed solvent of acetonitrile (8.8 kg) and water (275 L), and dried at 60 °C under
reduced pressure to obtain 7 (163 kg, 97.2area% purity). 1H NMR (DMSO-d6, 400 MHz, δ): 2.06
(s, 3H), 2.16 (s, 3H), 3.08 (s, 3H), 3.35 (s, 3H), 4.24 (d, 1H, J = 6.8 Hz), 4.55 (dd, 1H, J = 4.3,
6.8 Hz), 4.93 (d, 1H, J = 4.3 Hz), 6.49 (s, 1H), 7.04 (s, 1H), 8.94 (br s, 1H). 13C NMR (DMSO-
d6, 100 MHz, δ): 14.2, 17.3, 52.2, 53.6, 67.4, 106.5, 114.2, 118.8, 127.9, 128.8, 132.1, 152.3.
HRMS (m/z): [M+Na]+ calcd for C12H18O4Na, 249.1097; found, 249.1091. Retention time
(analytical HPLC method A): 4.8 min.
Ethyl 2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (8) A mixture of
7 (40.8 kg, 180 mol), potassium carbonate (32.4 kg, 234 mol, 1.3 equiv), sodium iodide (0.81 kg,
5 mol, 0.03 equiv) and DMF (99.2 kg) was charged. A solution of ethyl chloroacetate (25.4 kg,
207 mol, 1.15 equiv) in DMF (17.6 kg) was added at 60 °C; the reaction mixture was stirred at
this temperature for 3 h. The reaction completion was confirmed by HPLC analysis. After
toluene (326 kg) and water (163 L) were added, the upper layer was collected. The organic layer
was successively washed with 15% sodium chloride aqueous solution (122 kg) and water
(163 L), and concentrated under reduced pressure. The residue was dissolved at 60 °C by adding
n-heptane (326 kg) and toluene (39.9 kg) and then stirring the mixture for 1 h each at 30 °C and
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0 °C, followed by filtration. The resulting cake was washed twice with n-heptane (94 kg) and
dried under reduced pressure for 12 h at 30 °C, 15.5 h at 50 °C to obtain 8 as white powder
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9
1
(50.7 kg, 96.8area% purity). H NMR (CDCl3, 400 MHz, δ): 1.29 (t, 3H, J = 7.1 Hz), 2.26 (s,
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3H), 2.31 (s, 3H), 2.60 (br s, 1H), 3.21 (s, 3H), 3.49 (s, 3H), 4.26 (q, 2H, J = 7.1 Hz), 4.32 (d,
13
1H, J = 6.6 Hz), 4.60 (s, 2H), 4.79 (d, 1H, J = 6.6 Hz), 6.48 (s, 1H), 7.24 (s, 1H). C NMR
(CDCl3, 100 MHz, δ): 14.2, 15.9, 19.5, 55.1, 56.4, 61.2, 65.8, 70.1, 108.5, 113.3, 124.7, 129.3,
130.5, 135.0, 155.4, 169.2. HRMS (m/z): [M+NH4]+ calcd for C16H28O6N, 330.1911; found,
330.1911; [M+Na]+ calcd for C16H24O6Na, 335.1465; found, 335.1465. Retention time
(analytical HPLC method B): 12.8 min.
Ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (9) A solution of 8 (56.8 kg,
182 mol) in acetonitrile (80 L) was steadily added at −19 to −18 °C for 53 min to the suspension
of sodium iodide (84.5 kg, 564 mol, 3.1 equiv), trimethylsilyl chloride (61.2 kg, 564 mol,
3.1 equiv), and acetonitrile (364 L). After stirring for 30 min, methanol (5.83 kg, 182 mol,
1.0 equiv) was added, and a mixed solution of triethylamine (27.6 kg, 273 mol, 1.5 equiv) and
toluene (227 L), which was pre-cooled to -15 °C, were charged for 25 min at −17 to −9 °C. A
solution of sodium erythorbate (51.1 kg) and potassium carbonate (19.9 kg) in water (460 L) was
steadily added for 10 min at −9 to 7 °C, and the mixture was stirred for 1 h at 15 °C to obtain the
organic layer. The obtained layer was successively washed with water (114 L) and 20% sodium
chloride aqueous solution (102 L) twice, and concentrated under reduced pressure. Acetonitrile
(364 L) was added to the residue, and the mixture was concentrated under reduced pressure
again. Acetonitrile (292 L) was added to obtain the acetonitrile solution of 9 [53.9 kg (theoretical
amount)]. The sample for analysis of 9 was obtained by the concentration of the acetonitrile
solution. 1H NMR (CDCl3, 400 MHz, δ): 1.29 (t, 3H, J = 7.1 Hz), 2.23 (s, 3H), 2.27 (s, 3H), 2.82
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(d, 2H, J = 5.6 Hz), 3.32 (s, 6H), 4.26 (q, 2H, J = 7.1 Hz), 4.47 (t, 1H, J = 5.6 Hz), 4.59 (s, 2H),
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64.2, 103.6, 111.6, 122.6, 126.4, 131.0, 133.1, 152.8, 167.5. HRMS (m/z): [M+NH4]+ calcd for
C16H28O5N, 314.1962; found, 314.1961, [M+Na]+ calcd for C16H24O5Na, 319.1516; found,
319.1516.
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Ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (10) Oxalic acid
(8.2 kg, 91 mol, 0.5 equiv) and water (216 L) were added to a acetonitrile solution of 9 (53.9 kg
[theoretical amount], 182 mol). The reaction mixture was stirred for 3 h at 42 °C and reaction
completion was confirmed by HPLC analysis. 7% potassium carbonate aqueous solution
(180 kg), toluene (59 L), and t-butylmethylether (271 kg) were added to the mixture at
26 to 30 °C. The organic layer was separated, washed with 7% potassium carbonate aqueous
solution (180 kg), 5% sodium bicarbonate aqueous solution (164 kg), and 10% sodium chloride
aqueous solution (162 kg) twice, and dried over anhydrous sodium sulfate (38 kg). After the
removal of sodium sulfate, the filtrate was concentrated below 50 °C under reduced pressure.
After the residual oil was solved in ethanol (70 L) and n-heptane (108 kg), acetic acid (0.54 kg,
9 mol, 0.05 equiv) and compound 10 (5.4 g) was successively added as a seed crystal. The
mixture was stirred for 2 h at 20 °C to achieve a suspension of 10. n-Heptane (443 kg) was
steadily added over a duration of 1.5 h at the same temperature; the suspension was stirred for
1 h at 20 °C and for 2 h at −2 to 8 °C, and then filtered. The resulting cake was washed with n-
heptane (108 kg) twice and dried at 0 to 10 °C under reduced pressure to obtain 10 (42.2 kg,
1
99.1area% purity). H NMR (DMSO-d6, 400 MHz, δ): 1.06 (t, 3H, J = 7.1 Hz), 1.21 (t, 3H, J =
7.1 Hz), 2.12 (s, 3H), 2.20 (s, 3H), 2.62 (dd, 1H, J = 6.0, 13.9 Hz), 2.71 (dd, 1H, J = 5.0, 13.9
Hz), 3.28 (dq, 1H, J = 7.1, 9.6 Hz), 3.66 (dq, 1H, J = 7.1, 9.6 Hz), 4.16 (q, 2H, J = 7.1 Hz), 4.57–
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4.66 (m, 1H), 4.71 (s, 2H), 5.91 (d, 1H, J = 7.6 Hz), 6.59 (s, 1H), 6.93 (s, 1H). 13C NMR
(DMSO-d6, 100 MHz, δ): 14.5, 15.7, 16.0, 19.2, 40.2, 61.0, 61.5, 65.5, 97.3, 113.5, 123.1, 129.1,
133.1, 135.1, 154.4, 169.5. HRMS (m/z): [M+H]+ calcd for C14H18O4, 251.1278; found,
251.1276 detected as aldehyde 3b. Retention time (analytical HPLC method C): 13.8 min
(detected as aldehyde 3b).
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Ritobegron
ethyl
hydrochloride
(1)
(Ethyl
[4-(2-{[(1R,2S)-1-hydroxy-1-(4-
hydroxyphenyl)propan-2-yl]amino}ethyl)-2,5-dimethylphenoxy]acetate
monohydrochloride) After charging THF (320 L) to a sub reactor under reduced pressure, the
pressure was released with nitrogen gas followed by cooling THF below −13 °C. Separately, 10
(63.5 kg, 212 mol, 1.0 equiv, 99.1% purity) was added to a main reactor that was purged by
decompression and release with nitrogen gas to reduce oxygen below 0.5% (vacuum manner),
and then cooled THF was added to a main reactor. After the above-mentioned nitrogen gas
purge, (1R,2S)-2-amino-1-(4-hydroxyphenyl)-1-propanol (2) (35.5 kg, 212 mol) and THF (39 L)
were successively added to a main reactor below −13 °C. After the same nitrogen gas purge
again, the suspension of 10% Pd-C (ca. 50% water content) (11.9 kg) in THF (39 L) without gas
purge were added below −13 °C. The reactor was purged by repeating compression up to 0.5
MPa with nitrogen gas and release three times to reduce oxygen below 0.5% (compressed
manner) followed by the hydrogen gas purge in the same manner. The reaction mixture was
stirred at 40 °C with 0.1 MPa of hydrogen gas for 3 h, and its conversion was monitored by
HPLC analysis. After the removal of palladium by filtration using celite, the filtrate was
concentrated below 50 °C under reduced pressure; THF (39 L) and toluene (288 L) were added
to the residue. Water (284 L) to the residue, the organic layer was separated and successively
washed with 1% sodium bicarbonate aqueous solution (180 kg) and 18% sodium chloride
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aqueous solution (217 kg), and then dried over anhydrous sodium sulfate (36 kg). After removal
of sodium sulfate, the filtrate was concentrated below 50 °C under reduced pressure, and toluene
(206 L) was added to the residue. The solution was concentrated below 50 °C under reduced
pressure, and then toluene (132 L) and ethanol (34.5 kg) were added to the residue. A 20%
hydrogen chloride solution in ethanol (35.0 kg, 212 mol, 1.0 equiv) was steadily added at
0 to 9 °C, and the mixture was stirred for 1 h at 3 to 8 °C. Toluene (213 L) was added, the
suspension was stirred for 1 h at the same temperature range, and then filtered. The resulting
cake was washed with the mixed solvent of ethanol (13 kg) and toluene (146 L) twice, and dried
below 50 °C under reduced pressure to give crude compound of 1 (76.9 kg).
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The obtained crude 1 (76.9 kg) was dissolved in ethanol (538 L) at 78 °C, the insoluble
materials was removed by filtration and washed with ethanol (77 L). The seed compound 1
(3.8 g) were added to the ethanol solution at 55 °C, t-butylmethylether (300 kg) was added at
46 to 48 °C, and the suspension was then stirred for 1 h at 46 °C. t-Butylmethylether (300 kg)
was added at 25 °C and the mixture was stirred for 1 h, settled for 5 h, and stirred for 3 h at
0 to 6 °C. After filtration, the obtained cake was successively washed with the solvent mixture
consisting of t-butylmethylether (192 kg) and ethanol (48 L), followed by t-butylmethylether
(231 kg), and then dried below 70 °C under reduced pressure to obtain 1 (68.6 kg, 99.5% purity).
1H NMR (DMSO-d6, 500 MHz, δ): 0.98 (d, 3H, J = 6.7 Hz), 1.22 (t, 3H, J = 7.1 Hz), 2.15 (s,
3H), 2,27 (s, 3H), 2.92–3.12 (m, 4H), 3.26–3.38 (m, 2H), 4.17 (q, 2H, J = 7.1 Hz), 4.75 (s, 2H),
5.13 (m, 1H), 5.95 (d, 1H, J = 3.9 Hz), 6.68 (s, 1H), 6.78 (d, 2H, J = 8.6 Hz), 6.97 (s, 1H), 7.18
(d, 2H, J = 8.6 Hz), 9.09 (br s, 2H), 9.45 (s, 1H). 13C NMR (DMSO-d6, 125 MHz, δ): 9.8, 14.5,
16.0, 19.4, 29.0, 45.5, 59.1, 61.0, 65.5, 69.7, 114.0, 115.4, 123.9, 127.4, 128.4, 131.2, 131.7,
134.9, 154.9, 157.1, 169.4. Elemental Analysis: Calcd for C45H28N4O7Cl: C, 63.08; H, 7.36; N,
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3.20; Cl, 8.10. Found: C, 62.98; H, 7.29; N, 3.15; Cl, 8.01. Retention time (analytical HPLC
method D): 19.6 min.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge at https://
Copies of NMR spectra of compounds 1, 7–10, 12, 14, and 15, synthetic scheme for hydrochrolic
acid of one isomer among impurity 14, and HRMS of 15. (PDF)
AUTHOR INFORMATION
Corresponding Authors
Junichi Sonehara – School of Pharmaceutical Sciences, College of Medical, Pharmaceutical
and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
Joetsu Chemical Laboratories, Kissei Pharmaceutical Co., Ltd.; 197-5, Kamiyoshi, Kubiki,
Joetsu, Niigata 942-0145, Japan
Email: junichi_sonehara@pharm.kissei.co.jp
Kyoko Nakagawa-Goto – School of Pharmaceutical Sciences, College of Medical,
Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-7568, United States
Email: kngoto@p.kanazawa-u.ac.jp
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ORCID: 0000-0002-1642-6538
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Authors
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Hidetoshi Isawa – Head Office, Kissei Pharmaceutical Co., Ltd.; 19-48 Yoshino, Matsumoto,
Nagano 399-8710, Japan
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Kiyoshi Kasai – Head Office, Kissei Pharmaceutical Co., Ltd.; 19-48 Yoshino, Matsumoto,
Nagano 399-8710, Japan
Norihiko Kikuchi – Head Office, Kissei Pharmaceutical Co., Ltd.; 19-48 Yoshino, Matsumoto,
Nagano 399-8710, Japan
Takehiro Ishikawa – Central Research Laboratories, Kissei Pharmaceutical Co., Ltd.; 4365-1,
Hotakakashiwabara, Azumino, Nagano 399-8304, Japan
Masahiro Kobayashi – Head Office, Kissei Pharmaceutical Co., Ltd.; 19-48 Yoshino,
Matsumoto, Nagano 399-8710, Japan
Tetsuji Ozawa – Head Office, Kissei Pharmaceutical Co., Ltd.; 19-48 Yoshino, Matsumoto,
Nagano 399-8710, Japan
Ritsu Suzuki – Joetsu Chemical Laboratories, Kissei Pharmaceutical Co., Ltd.; 197-5,
Kamiyoshi, Kubiki, Joetsu, Niigata 942-0145, Japan
Makoto Kobayashi – Joetsu Chemical Laboratories, Kissei Pharmaceutical Co., Ltd.; 197-5,
Kamiyoshi, Kubiki, Joetsu, Niigata 942-0145, Japan
Takayuki Ainai – Joetsu Chemical Laboratories, Kissei Pharmaceutical Co., Ltd.; 197-5,
Kamiyoshi, Kubiki, Joetsu, Niigata 942-0145, Japan
Masayuki Nishimura – Joetsu Chemical Laboratories, Kissei Pharmaceutical Co., Ltd.; 197-5,
Kamiyoshi, Kubiki, Joetsu, Niigata 942-0145, Japan
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Yohei Saito – School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and
Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
ORCID: 0000-0003-2313-8339
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Author Contributions
The manuscript was written with the contributions of all authors. All authors have given
approval to the final version of the manuscript.
Funding Sources
This study was partially supported by a Grant-in-Aid from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT KAKENHI, Japan) awarded to K.N.G. (Grant Number
18H02583).
ACKNOWLEDGMENT
We thank the entire project team for their support in this work, in particular Dr. Hiromu
Harada, Dr. Tetsuro Tamai, Dr. Nobuyuki Tanaka, Dr. Harunobu Mukaiyama, and Mr. Yukihiko
Hotei for chemistry support, and Mr. Kazuma Hirata, Mr. Koji Kamata, and Dr. Hideyuki
Muranaka for analytical support.
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(15) Sakai, T.; Miyata, K.; Utaka, M.; Takeda, A. Me3SiCl–NaI–CH3CN as an Efficient and
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Practical Reducing Agent for Benzylic Alcohols. Tetrahedron Lett. 1987, 28, 3817–3818.
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(16) The mechanism for the reductive removal of benzylic hydroxyl groups was proposed in
the reference; Sakai, T.; Miyata, K.; Tsuboi, S.; Takeda, A.; Utaka, M.; Torii, S. A Convenient
Reductive Removal of Benzylic Hydroxyl and Trimethylsilyoxyl Groups with Me3SiCl–NaI–
CH3CN Reagent. Bull. Chem. Soc. Jpn. 1989, 62, 3537–3541.
(17) It was estimated as an E/Z mixture of styryl ether 13 according to specific peaks of E-
isomer (6,77 ppm, 5.84 ppm [J= 12.8 Hz]) and Z-isomer (6.10 ppm, 5.22 ppm [J= 7.2 Hz])
(18) Jung, M. E; Andrus, W. A.; Ornstein, P. L. Non-aqueous Conversion of Ketals to Ketones
via Treatment with Trimethylsiliyl Iodide. Tetrahedron Lett. 1977, 48, 4175–4178.
(19) Ethanol did not effectively suppress the production of impurities.
(20) The structure was confirmed by HPLC with alternatively synthesized 12 from dimethyl
acetal 9 by treatment with sodium methoxide in methanol. The analytical data refers to
supporting data. The retention time of 12 was 17.2 min and that of 9 was 24.4 min with
analytical HPLC method C (refer to Experimental section).
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(21) Reaction calorimetry was measured with Mettler Toledo MultiMax RB04-50 Reaction
Calorimeters. The adiabatic temperature was calculated based on 2.00 J/(g K) as the specific heat
of the reaction mixture and 1.71 J/(g K) as the specific heat of the triethylamine/toluene solution
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(22) The reaction with other strong acids, such as hydrochloric acid, gave a similar result to
that with sulfuric acid. The use of weak acids, such as acetic acid, did not promote hydrolysis.
(23) The following solvent systems were attempted: t-butylmethylether, t-butylmethylether–n-
hexane, diisopropyether, diisopropyether–n-hexane, toluene–n-hexane, n-hexane, ethyl acetate–
n-hexane, ethanol–n-hexane, n-heptane, and ethyl acetate–cyclohexane. Solid was obtained from
ethanol–n-hexane and diisopropylether; however, the latter easily melted around 20 °C.
(24) Impurity 14 is a mixture of diastereomers and each isomer has a respective retention time
of 12.7 and 13.1 min based analytical HPLC method D (refer to Experimental section). One
isomer, which is minimally removed and has a retention time of 13.1 min, was isolated from
ritobegron ethyl hydrochloride by preparative liquid chromatography and was synthesized as
1
hydrochloride salt. The structure was ascertained with H NMR and MS measurement (refer to
supporting data); however, the absolute configuration of the hydroxyl group has not been
determined.
(25) Impurity 15 has a retention time of 27.3 min under analytical HPLC method C (refer to
Experimental section). It was isolated by filtration of insoluble materials in the mixture. The
mixture was prepared by adding ethanol and water into the residue after the concentration of the
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aqueous acetonitrile solution of hemiacetal 10 with catalytic acetic acid, which was stirred for
two weeks at ambient temperature and for 1 day at 50 °C. The structure was determined with 1H
NMR, 13C NMR, HMQC, HSQC, and HRMS (refer to supporting data).
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