Continuous Flow Process for the Synthesis of Betahistine via Aza-Michael-Type Reaction in Water

Article abstract of DOI:10.1021/acs.oprd.0c00543

A continuous flow process for the preparation of betahistine with a 90% isolated yield has been reported. 2-Vinylpyridine and saturated methylamine hydrochloride aqueous solution were used as starting materials to achieve excellent results in the silicon carbide flow reactor, which can tolerate the corrosion of chloride ions at high temperature (170 °C) and pressure (25 bar). In the continuous flow process, the product can be obtained in 2.4 min with excellent conversion (>99%) and product selectivity (94%). The throughput can reach 1.06 kg h-1, and the purity of the final product was greater than 99.9% by distillation, which were in accordance with the needs of production. This new process using environmentally friendly water as the solvent is energy-efficient, time- and cost-economic, and offers a 50% reduction in process mass intensity compared to the batch process.

Full text of DOI:10.1021/acs.oprd.0c00543

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Article
Continuous Flow Process for the Synthesis of Betahistine via Aza-
Michael-Type Reaction in Water
Maolin Sun, Jingxin Yang, Youtian Fu, Chaoming Liang, Hong Li, Guoming Yan, Chao Yin, Wei Yu,
Yueyue Ma,* Ruihua Cheng,* and Jinxing Ye*
Cite This: https://doi.org/10.1021/acs.oprd.0c00543
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ABSTRACT: A continuous flow process for the preparation of betahistine with a 90% isolated yield has been reported. 2-
Vinylpyridine and saturated methylamine hydrochloride aqueous solution were used as starting materials to achieve excellent results
in the silicon carbide flow reactor, which can tolerate the corrosion of chloride ions at high temperature (170 °C) and pressure (25
bar). In the continuous flow process, the product can be obtained in 2.4 min with excellent conversion (>99%) and product
−
1
selectivity (94%). The throughput can reach 1.06 kg h , and the purity of the final product was greater than 99.9% by distillation,
which were in accordance with the needs of production. This new process using environmentally friendly water as the solvent is
energy-efficient, time- and cost-economic, and offers a 50% reduction in process mass intensity compared to the batch process.
KEYWORDS: betahistine, continuous flow, process intensification, energy-efficient, environmentally friendly
INTRODUCTION
intensification), automation, high repeatability, flexibility of
production scale, on-line purification, smaller manufacturing
■
Betahistine (1), which acts as an orally active histamine H1
receptor agonist and partial H3 receptor antagonistic,
mainly used to treat various diseases such as cluster headaches,
vertigo syndrome, and Meniere’s syndrome.
special merits: excellent safety profile and unique pharmaco-
logical properties. Besides, the pharmacokinetic results of
radioisotope labelled drugs showed that betahistine could be
quickly absorbed by human body after oral administration. 2-
Pyridine ethylamine and 2-pyridine acetic acid were the main
metabolites of betahistine, and the latter was mainly excreted
in urine. At the same time, the metabolites can be completely
excreted within 24 h. The evidence suggested 2-pyridine
ethylamine may also be active and play a similar role to
19−23
1
−4
plant area, and so forth.
At present, the continuous flow
is
synthesis has successful been applied in several drug
24
25
5
−9
manufactures, such as ciprofloxacin, dolutegravir, and
It has two
2
6
prexasertib. Taking the advantages of continuous flow
synthesis, herein, we report a continuous flow synthesis
process of betahistine in water, which greatly shortened the
reaction time and improved the reaction yield (d, Scheme 1).
This protocol is expected to provide a more economical,
reliable, and environmentally friendly method for the industrial
production of betahistine.
RESULTS AND DISCUSSION
■
10
betahistine on ampullary receptors in vivo.
Ever since the first synthesis of betahistine by Loffler and
Optimization in Batch. Before the synthesis of betahistine
was performed in flow, a detailed optimization study was
carried out in batch. Considering the production cost and
safety, methylamine hydrochloride was chosen as the amine
source rather than methylamine aqueous solution. Given the
requirement of avoiding the generation of any precipitates in
the context of continuous flow synthesis, the solvents were
screened first. Typically, the mixture of 2-vinylpyridine (0.25
g) and methylamine hydrochloride (0.41 g, 3.0 equiv) in
different solvents, such as dimethylformamide (DMF),
11
Kirschner in 1904, various protocols have been devel-
1
2−18
oped.
As shown in Scheme 1, one of the most practical
methods is the nucleophilic addition between methylamine (3)
and 2-vinylpyridine (2) via aza-Michael reaction (a, Scheme
1
2,13,15,16,18
1
).
h) was required to improve conversion (b, Scheme 1).
Because of impurities generated from side reactions, high
In the previous reports, longer reaction time (>8
12
15
purity product (>99.9%) was difficult to acquire. Excessive
reagents and organic solvents (toluene and isopropanol) also
lead to high production cost and environmental pollution (c,
Scheme 1). Thus, the development of green, efficient, and cost-
effective method for the synthesis of betahistine is appealing
and challenging in organic synthesis.
dimethyl sulfoxide (DMSO), i-PrOH, EtOH, and H O, was
2
heated at 110 °C for 5 h in a high-pressure glass bottle. As
Received: December 18, 2020
Recently, continuous flow synthesis has become one of the
most attractive technologies that can significantly affect the
synthetic chemistry. This technology is characterized with
precise control of reaction variables, safe process, possibility of
reaction under high temperature and pressure (process
©
XXXX American Chemical Society
https://doi.org/10.1021/acs.oprd.0c00543
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
A

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Article
Scheme 1. Schematic for the Synthesis of Betahistine
Table 1. Screening of Solvents for the Synthesis of Betahistine
a
a
a
entry
solvent
mL
conv. (%)
select. (%)
observation
area % ratio (2:1: impurities)
1
2
3
4
5
6
7
8
9
i-PrOH/H O (1:1)
4
4
4
4
4
4
4
1
2
8
81
81
62
68
75
90
87
92
89
82
80
80
75
70
52
74
82
81
83
83
clear
clear
clear
clear
clear
clear
clear
clear
clear
clear
19:65:16
19:65:16
38:47:15
32:48:20
25:39:36
10:67:23
13:71:16
8:75:17
2
toluene/H O (1:1)
2
DMF/H O (1:1)
2
DMSO/H O (1:1)
2
THF/H O (1:1)
2
EtOH/H O (1:1)
2
H O
2
H O
2
H O
2
11:74:15
18:68:14
1
0
H O
2
a
Monitored by HPLC.
Figure 1. Continuous flow setup for the synthesis of betahistine.
B
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Table 2. Reaction Conditions for the Continuous Flow Synthesis of Betahistine
a
a
a
entry
residence time (min)
temperature (°C)
3 (equiv)
conv. (%)
select. (%)
area % ratio (2:1: impurities)
b
1
2
3
4
5
6
7
8
9
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
0.8
1.5
130
150
160
170
180
170
170
170
170
170
170
170
170
170
1.3
1.3
1.3
1.3
1.3
1.4
1.5
1.6
1.7
1.8
2.0
1.7
1.7
1.7
93
93
95
89
94
95
95
98
97
98
77
98
93
71
75
83
80
82
84
87
94
93
92
73
91
89
7:66:27
7:70:23
5:79:16
11:71:18
6:77:17
5:80:15
5:83:12
2:92:6
3:90:7
2:90:8
23:56:21
2:89:9
7:83:10
1
1
1
1
1
0
1
2
3
4
3.0
a
b
Monitored by HPLC. The reaction solution was two-phase, and no reaction occurred.
Table 3. Scaling-Up Experiments for the Continuous Flow Synthesis of Betahistine
2 (mL min−1)
3 (mL min−1
)
reactor (mL)
conv. (%)
a
select. (%)
a
area % ratio (2:1: impurities)
a
entry
1
2
3
1.0
1.5
2.0
1.8
2.7
3.6
6
9
12
98
97
98
94
94
95
2:92:6
3:91:7
2:93:5
a
Monitored by HPLC.
shown in Table 1, no precipitates were observed in the above
solvents. Surprisingly, the water was found to present the
highest conversion and selectivity according to the high-
performance liquid chromatography (HPLC) analysis (Table
was slightly lower. The maximum conversion of 95% with
excellent selectivity of 83% was obtained at 170 °C (Table 2,
entry 4), which was better than that under batch conditions.
On increasing the temperature to 180 °C under similar flow
conditions (Table 2, entry 5), the conversion and selectivity
decreased slightly.
1
, entry 7). In terms of green chemistry, water is a perfect
solvent to satisfy the goal of green chemistry as it is a highly
accessible, nontoxic, and nonflammable solvent. Notably, the
conversion (up to 92%) was positively correlated with an
increase in concentration of the starting materials (Table 1,
entries 7−10).
Then, the influence of the amount of methylamine
hydrochloride was investigated (Table 2, entries 6−11).
Considering the economic effect, the maximum amount of
methylamine hydrochloride should be less than 2.0 equiv, and
the transformation proceeded effectively at the equivalence in
the range of 1.4−2.0. The conversion and selectivity reached
Continuous Flow Synthesis of Betahistine. Next, we
turned our attention to the translation of the optimized batch
toward a continuous flow process. The continuous flow setup
is shown in Figure 1. Due to the high temperature and the
presence of chloride ions in the reaction system, the corrosion-
resistant Hastelloy reactor was chosen. 2-Vinylpyridine and a
98 and 94%, respectively, when 1.7 equiv of methylamine
hydrochloride was used (Table 2, entry 9). When the amount
of methylamine hydrochloride was further increased, it resulted
in the decrease in selectivity (Table 2, entries 10 and 11). In
terms of the residence time, the reactants converted completely
saturated solution of methylamine hydrochloride in H O (9.0
2
M) were pumped into a micromixer by an HPLC pump,
respectively. The resulting solution was heated in the reactor
and then cooled in a stainless steel reactor coil. The mixture
was processed with an adjustable back-pressure regulator
(
98%) within 1.5 or 2.1 min (Table 2, entries 9 and 13). Lower
yields were obtained at shorter residence times because of the
incomplete conversion (Table 2, entry 12), while longer
residence times also led to lower yields of betahistine (Table 2,
entry 13). Therefore, the reaction residence time was set as 2.1
min. As a result, on the 3.0 mL Hastelloy reactor, the best
conditions for the continuous flow synthesis of betahistine was
(
BPR).
Table 2 shows the effects of the reaction conditions on the
continuous flow synthesis of betahistine. At 130 °C, because
the collected reaction solution was separated into two-phase,
almost no conversion occurred within a residence time of 2.1
min (Table 2, entry 1). At 150 or 160 °C (Table 2, entries 2
and 3), the conversion of 2-vinylpyridine was comparable with
that under batch conditions, but the corresponding selectivity
−
1
as follows: pump A: 2-vinylpyridine (neat, 0.5 mL min ),
pump B: saturated methylamine hydrochloride solution (9.0
−
1
M, 0.9 mL min , 1.7 equiv), reaction temperature at 170 °C,
residence time at 2.1 min, and system pressure at 7 bar.
C
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Figure 2. Continuous flow setup for the synthesis of betahistine in a SiC reactor.
Table 4. Scaling-Up Experiments for the Continuous Flow Synthesis of Betahistine in the SiC Reactor
2 (mL min−1)
3 (mL min−1
)
residence time (min)
conv. (%)
a
select. (%)
a
area % ratio (2:1: impurities)
a
entry
1
2
3
4
20
15
10
15
36
27
18
30
2.0
2.6
3.9
2.4
95
86
90
91
94
5:82:13
0:90:10
0:91:9
0:94:6
>99
>99
>99
a
Monitored by HPLC.
Table 5. Comparison Between the Batch and Continuous Flow Process for the Synthesis of 1.0 kg of Betahistine
2
-vinylpyridine
(kg)
methylamine hydrochloride
(kg)
toluene
(kg)
yield
a
PMI
(kg/kg)
entry
H O (kg)
2
catalyst (mL)
operation time (h)
(%)
b
1
1.10
0.86
1.47
1.05
5.3
2.1
1.7
36 wt % HCl (420)
8.0
1.0
71
90
27.2
13.5
c
2
a
b
c
Isolated yield of betahistine. Batch process. Continuous flow process.
Scaling-Up Experiments. We further focused on estab-
(90−91%). Increasing the amount of methylamine hydro-
chloride to 1.9 equiv at the total flow rate of 45 mL min− led
to full conversion with the best selectivity (>99, 94%, entry 4,
Table 4). Therefore, the optimum conditions for the
continuous flow synthesis of betahistine in the SiC reactor
1
lishing more practical conditions to improve productivity. In
order to scale up the reaction, the flow rate was increased by
increasing the retention volume of the reactor via extending
the length of the Hastelloy reactor coil on the continuous flow
device. Accordingly, the system pressure of 10 bar was required
to achieve a stable flow. As shown in Table 3, excellent
conversion (97−98%) and selectivity (94−95%) of the
reaction were obtained, reflecting the good reaction scalability
of continuous flow.
−
1
was as follows: pump A: 2-vinylpyridine (neat, 15 mL min ),
pump B: saturated methylamine hydrochloride (9.0 M, 30 mL
−
1
min , 1.9 equiv), reaction temperature of 170 °C, retained
volume of SiC reactor 110 mL (22 mL × 5), and system
pressure of 25 bar.
Due to the strong corrosive effect of the chloride ion in the
reaction system under high-T/P conditions, the Hastelloy
reactor coil would be corroded inevitably in industrial
production during a long run. The heating operation might
become more difficult and dangerous at higher flow rate, and a
safer protection was required. In this regard, sintered silicon
carbide (SiC) could be applied in highly corrosive reagents
Long Run. With the optimized conditions in the SiC
reactor in hand, 2-vinylpyridine (flow rate: 15 mL min ) and
−
1
a solution of methylamine hydrochloride (9.0 M) in H O
2
−
1
(flow rate: 30 mL min ) were pumped into the SiC reactor
under the conditions of 170 °C and an estimated residence
time of 2.4 min. During the steady state (after about 2.0 min),
the reaction solution was analyzed by HPLC every 10 min per
hour (see Supporting Information for details). For the
analytical samples, the conversions were above 99% and the
selectivity was about 94%. Thus, the reaction performed
smoothly with an identical standard in the long run study, and
27,28
under harsh conditions.
SiC flow reactors have been used
in the pharmaceutical industry, such as handling fluorine gas in
a safe and scalable manner, as well as Wolff−Kishner
2
9−31
reduction.
Therefore, on the scale-up synthesis of
−
1
betahistine under continuous flow conditions, we used a
commercially available modular SiC reactor with static mixing
elements (Figure 2), which provided seamless capabilities for
the manufacturing process.
the productivity of betahistine could reach 1.06 kg h .
Comparison of the continuous flow process to the batch
process reveals dramatic improvements in economy and
environmental friendliness (Table 5). In the continuous flow
process, the amount of raw materials was remarkably reduced.
Then, the use of organic solvents and hydrochloric acid could
be avoided, and this also could simplify the post-treatment
operations and reduce the amount of alkali used in post-
treatment. In addition, the process operation time could be
significantly shortened from 8.0 to 1.0 h. Compared with the
batch process, this new continuous flow process represented a
50% reduction in process mass intensity (PMI, see the
Supporting Information for details).
As shown in Table 4, the conversion and selectivity in the
SiC reactor were lower than those in the Hastelloy reactor coil
at the residence time of 2.0 min with the total flow rate of 56
−
1
mL min (Table 4, entry 1), and no change was observed in
the reaction yield by increasing the mixing effect using the
mixer. Hence, the flow rate was reduced via increasing the
residence time to improve the reaction effect (Table 4, entries
−
1
2
and 3). At the total flow rate of 42 or 28 mL min ,
maximum conversion (>99%) was obtained in good selectivity
D
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Purification Process and Impurity Analysis. High-
purity betahistine was generally obtained by distillation after
post-treatment. It was important to select the distillation
column for distillation. In Figure 3, with the Vigreux column
Table 6. Decomposition Temperature Test of Impurity 4
entry
temperature (°C)
time (h)
HPLC area % ratio (4:2:1)
1
2
3
4
60
80
90
5
5
5
5
100:0:0
98.90:0.05:0.06
95.50:0.25:0.20
83.60:8.32:8.08
100
CONCLUSIONS
■
A continuous flow synthesis process of betahistine was
developed and reported. The switch from a traditional batch
process to a flow process allowed for the process intensification
and safety security. The process was optimized in high
conversion (>99%) and high product selectivity (94%) at 170
°C for 2.4 min with the total flow rate of 45 mL min− in the
SiC reactor. The flow process was demonstrated steadily in an
hour with a productivity of 1.06 kg h . The high purity
product (>99.9%) was obtained by optimizing the purification
process of distillation. This new process using environmentally
friendly water as the solvent is energy-efficient, time- and cost-
economic, and offers 50% reduction in PMI compared to the
batch process.
1
Figure 3. Distillation device in the purification process.
−
1
(C1), the highest purity of betahistine was only 95% at 150
°C/50 mmHg. Then, the glass spring fillers were loaded as
fillers into the distillation column (C2) to enhance the
separation efficiency. The separation purity increased to 99.1%
when the number of theoretical plates reached 5.0.
Although higher purity betahistine (>99%) could be
obtained by replacing the distillation column, the purity of
the product still did not meet the production requirement due
to the existence of a small amount of 2-vinylpyridine raw
material. Furthermore, it seemed that the reaction of 2-
vinylpyridine with betahistine caused the major side product,
which reversibly resulted in 2-vinylpyridine at a high
distillation temperature (Scheme 2). We tested 2-vinylpyridine
and betahistine performed under batch conditions for 4.5 h at
EXPERIMENTAL SECTION
■
General Remarks. All reagents were commercially
available and used without any further purification. If not
stated otherwise, reagents were weighed and handled in air at
room temperature. The HPLC pumps and the Hastelloy
microtube reactors were purchased from Bejing Xingda
Science & Technology Development Co. Ltd. The SiC flow
reactor was purchased from Jinde New Material. Thermal
regulation of the heating zone was carried out using a Viar
thermostat VMC-H480L (30−300 °C). The BPR was
1
15 °C, and impurity 4 was obtained in 82% yield (see the
Supporting Information). The source of side products
suggested a certain limitation in the reaction temperature
and time in the previous optimization process of continuous
flow synthesis.
1
purchased from Beijing Xiongchuan Technology Co., Ltd. H
NMR spectra were recorded on a Bruker 400 MHz instrument.
C NMR spectra were recorded on the same instrument at
1
3
The excessive side product in the reaction caused troubles in
the subsequent distillation purification. High distillation
temperature led to the contained 2-vinylpyridine partial from
the decomposition of side product in the product fraction;
while the product fraction was difficult to separate at low
distillation temperature. Therefore, the stability of impurities at
different temperatures was investigated (Table 6). In Table 6,
the impurity obviously decomposed when the temperature was
higher than 90 °C (entries 3 and 4). In this regard, the product
with >99.9% purity was afforded without loss of betahistine by
strictly controlling the bottom temperature of the kettle at 85
100 MHz. Analytical HPLC (Shimadzu LC20) analysis was
carried out on a C18 reversed-phase (RP) analytical column
(
150 mm × 4.6 mm, particle size 5 μm) at 30 °C using mobile
phases 80% (224 mg of ammonium acetate, 325 mL of pure
water, 1.44 g of sodium dodecyl sulfate, and 175 mL of
acetonitrile) and 20% (acetonitrile) at a flow rate of 0.5 mL
−
1
min .
Synthesis of Betahistine in Batch. 2-Vinylpyridine (0.25
g, 2.38 mmol) was slowly added to methylamine hydrochloride
0.41 g, 7.14 mmol) in a corresponding solvent. After the
(
reaction solution was kept at 100 °C for 5 h, it was acidified to
pH >11 with NaOH aqueous solution and extracted with
dichloromethane (3 × 5 mL). The combined organic layers
were dried over sodium sulfate and filtered, the solvent was
°C and the top temperature of the tower at 60 °C under a
vacuum degree of 2 mmHg.
Scheme 2. Formation Process of Impurity 4
E
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Article
collect fractions, and 2-vinylpyridine was removed; finally, the
vacuum was controlled to 2 mmHg, the temperature at the
bottom of the kettle was controlled at 85 °C, and the
temperature at the top of the tower was 60 °C. The fraction
was collected and the product (about 570 g, 90% yield) was
obtained as a colorless oil. The purity was 99.9% by HPLC.
Distillation column: Ø 30 × 300 mm packed column, Ø 5 × 8
1
mm glass spring fillers, 300 mm filling height. H NMR (400
MHz, CDCl ): δ 8.47 (dd, J = 4.8, 0.8 Hz, 1H), 7.53 (td, J =
3
7.7, 1.8 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.07−7.04 (m, 1H),
1
3
2.92 (s, 4H), 2.39 (s, 3H), 1.91 (s, 1H). C NMR (100 MHz,
CDCl ): δ 160.2, 149.3, 136.3, 123.2, 121.2, 51.3, 38.1, 36.2.
3
+
HRMS (ESI) m/z: calcd for C
H N [M + H] , 136.1000;
12 2
8
found, 136.1021.
General Flow Procedure for the Synthesis of
Betahistine in a Microtube Reactor. A microreactor
system consisting of two HPLC pumps, a micromixer (T-
shaped tee, 1/16″ OD, 0.02″ thru hole), and a Hastelloy
reactor coil was used. The temperature was controlled using an
oil bath. The reaction mixture was heat to 170 °C in the
Hastelloy reactor coil and rapid cooled to 30 °C in a short
stainless steel coil. An adjustable BPR was positioned at the
outlet of the flow reactor to allow a range of pressures (0−60
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00543.
■
*
sı
Continuous flow setup, additional experimental infor-
1
mation, PMI calculation, HPLC analysis, and H and
1
3
C NMR spectra (PDF)
−
1
bar) to be evaluated. 2-Vinylpyridine (flow rate: 0.5 mL min )
and a solution of methylamine hydrochloride (9.0 M) in H O
AUTHOR INFORMATION
Corresponding Authors
2
■
−
1
(
flow rate: 0.9 mL min ) were introduced into the
micromixer by an HPLC pump (PA, PB). The resulting
solution passed through the Hastelloy reactor coil (1/16″ OD,
V = 3.0 mL, 170 °C, t = 2.1 min) and rapidly cooled to 30 °C
in a short stainless steel coil (1/16″ OD, V = 0.7 mL, 30 °C).
After the pressure was adjusted to 100 psi through the BPR,
fractions were collected from the reactor output, and an aliquot
was taken for HPLC analysis.
Yueyue Ma − Engineering Research Center of Pharmaceutical
Process Chemistry, Ministry of Education, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China; Email: mayueyue2012@sina.cn
Ruihua Cheng − School of Chemical Engineering, East China
University of Science and Technology, Shanghai 200237,
China; Email: rhcheng@ecust.edu.cn
Jinxing Ye − Engineering Research Center of Pharmaceutical
Process Chemistry, Ministry of Education, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China; School of Biomedical and
Pharmaceutical Sciences, Guangdong University of
Technology, Guangzhou 510006, China; orcid.org/0000-
General Flow Procedure for the Synthesis of
Betahistine in the SiC Reactor. The continuous flow
setup consisting of two HPLC pumps, an SiC reactor, and a
Hastelloy coil was used. The reaction was heat to 170 °C in the
SiC reactor and cooled to 30 °C in the Hastelloy coil. An
adjustable BPR was positioned at the outlet of the flow reactor
to allow a range of pressures (0−60 bar) to be evaluated. 2-
0003-3319-6807; Email: yejx@ecust.edu.cn, jinxingye@
−
1
Vinylpyridine (flow rate: 15 mL min ) and a solution of
gdut.edu.cn
methylamine hydrochloride (9.0 M) in H O (flow rate: 30 mL
2
−
1
min ) were introduced into the SiC reactor by an HPLC
pump (PA, PB). The resulting solution passed through the SiC
reactor (V = 110 mL, 170 °C) and rapid cooled to 30 °C in the
Hastelloy coil (1/8″ OD, V = 20 mL, 30 °C). After the
pressure was adjusted to 25 bar through the BPR, fractions
were collected from the reactor output, and an aliquot was
taken for HPLC analysis.
Authors
Maolin Sun − Engineering Research Center of Pharmaceutical
Process Chemistry, Ministry of Education, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China; School of Biomedical and
Pharmaceutical Sciences, Guangdong University of
Technology, Guangzhou 510006, China
Jingxin Yang − Engineering Research Center of Pharmaceutical
Process Chemistry, Ministry of Education, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Youtian Fu − Engineering Research Center of Pharmaceutical
Process Chemistry, Ministry of Education, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Chaoming Liang − Engineering Research Center of
Pharmaceutical Process Chemistry, Ministry of Education,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China; School of Biomedical
and Pharmaceutical Sciences, Guangdong University of
Technology, Guangzhou 510006, China
Purification of Betahistine. 1.5 L of product solution was
collected from the SiC reactor output, and pH was adjusted to
>
11 with NaOH aqueous solution. The resulting mixture was
extracted with dichloromethane (3 × 1.0 L). The combined
organic layers were dried over sodium sulfate and filtered, the
solvent was removed under reduced pressure, and the resulting
crude product was purified by distillation.
Distillation process: first, the vacuum was controlled at 50
mmHg, the temperature at the bottom of the kettle was
adjusted to 50 °C, the temperature at the top of the tower was
2
5 °C, the fraction was collected, and dichloromethane was
removed; then, the vacuum was controlled at 10 mmHg, the
temperature at the bottom of the kettle was adjusted to 50 °C,
and the temperature at the top of the tower was 40 °C to
F
https://doi.org/10.1021/acs.oprd.0c00543
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
Hong Li − Engineering Research Center of Pharmaceutical
Process Chemistry, Ministry of Education, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Guoming Yan − Shanghai Zhongxi Sunve Pharmaceutical
Co., Ltd., Shanghai 201419, China
Chao Yin − Shanghai Zhongxi Sunve Pharmaceutical Co.,
Ltd., Shanghai 201419, China
Wei Yu − Shanghai Zhongxi Sunve Pharmaceutical Co., Ltd.,
Shanghai 201419, China
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Selective Synthesis of Mono- and Di-Methylated Amines Using
Methanol and Sodium Azide as C1 and N1 Sources. Green Chem.
2018, 20, 3339−3345.
(18) Zhao, Y.; Ma, S.; Liu, G. Industrial method for preparing
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Complete contact information is available at:
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2
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19) Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.;
Battilocchio, C.; Ley, S. V.; Stevens, C. V. Taming Hazardous
cChemistry by Continuous Flow Technology. Chem. Soc. Rev. 2016,
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Notes
The authors declare no competing financial interest.
(
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ACKNOWLEDGMENTS
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21) Britton, J.; Raston, C. L. Multi-Step Continuous-Flow
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Center of Pharmaceutical Process Chemistry, Ministry of
Education and the Fundamental Research Funds for the
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https://doi.org/10.1021/acs.oprd.0c00543
Org. Process Res. Dev. XXXX, XXX, XXX−XXX