Organic Process Research & Development
Article
setup, 708 g of pure edaravone was obtained after 1 h of
continuous operation, with a yield of 88.4% and a purity of
4.2. Traditional Method in Batch. Phenylhydrazine (50
g, 0.46 mol) was added to ethyl acetoacetate (60.2 g, 0.46 mol)
in ethanol (600 mL) at room temperature. The reaction
mixture was heated at reflux for 5 h and then cooled, filtered,
and recrystallized from ethanol−water to afford target
compounds edaravone 59.7 g, yield 74.2%. The purity was
96.04%.
4.3. New Method in Batch. Phenylhydrazine (50 g, 0.46
mol) was added to ethyl acetoacetate (60.2 g, 0.46 mol) in
ethanol (240 mL) at room temperature, and the mixture was
stirred for 1 h. Then, NaOH (60 mL, 15.36 mol/L) was added
slowly. The reaction mixture was heated at 60 °C for 2 h and
then cooled down to 0 °C. Then, the pH was adjusted to 7
with HCl (6 M), filtered, and recrystallized from ethanol−
water to afford the target compound edaravone 68.5 g, yield
85.0%. The purity was 98.92%.
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9.95% after undergoing recrystallization once. The current
flow method has been proved to be a convenient and rapid
method, and because of its stability compared to the batch
process, it can better produce edaravone on a large scale.
To compare the differences among three methods for
synthesis of edaravone (traditional method in batch, new
method in batch, and new method in continuous flow), three
corresponding experiments were carried out with the same
amount of raw materials (phenylhydrazine 50 g, 0.46 mol;
ethyl acetoacetate 60.2 g, 0.46 mol), which greatly showed the
advantages of continuous flow (Table 5). The results showed
that the yields of the new method (85.0 and 88.4%) were
higher than that of the traditional method (74.2%), which
indicated the significance of the base. Although the yields of
the two new methods were similar in batch or flow, the purity
is quite different even if the same recrystallization processes
were carried out. The purity of this batch was 98.92%, and the
content of four impurities exceeded 0.1%, which does not meet
the requirements of pharmacopeia. The purity of continuous
flow was 99.95%, and the content of one impurity was only
4.4. New Method in a Continuous Flow Process in 1
h. As shown in Figure 5, two plunger pumps were separately
used to introduce phenylhydrazine (7.68 mol/L in ethanol)
and ethyl acetoacetate (7.68 mol/L in ethanol) into the
microreactor R1 (25 °C, 0.5 min, 1 bar); the flow rates were
both 10 mL/min. Then, the solution flowed into the
microreactor R2 after passing through the prewarm device,
which was used to keep the solution at 60 °C. At the same
time, NaOH (15.36 mol/L in water) was introduced by a
plunger pump (10 mL/min) into the microreactor R2 (60 °C,
1 min, 1 bar). The resulting mixture was collected in a
container for 1 h and cooled down to 0 °C after passing
through a back pressure regulator (1 bar). Solids precipitated
when the pH was adjusted to 7 with 6 M HCl and filtered (736
g of crude product was obtained; crude yield 92.0%). Then,
pure edaravone was obtained after recrystallizing from
ethanol−water as white solid (708 g, total yield 88.4%). The
0
.05%. Therefore, when the same new methods were used, the
continuous flow process had higher purity and shorter
operation time compared to the batch process, which was
more advantageous in the industry. To further demonstrate the
high efficiency and time-saving characteristic of continuous
flow, productivity and space−time yield (STY) were estimated.
Thanks to these continuous flow process improvements, the
productivity and STY of the whole process were greatly
improved in the manufacturing scale.
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. CONCLUSIONS
1
purity was 99.95%. H NMR (400 MHz, Chloroform-d): δ
A new production process for the edaravone using continuous
flow has been developed, which can reduce the impurities and
increase the yield. The synthesis was carried out in two steps
continuously. In the second step, it was easier to promote the
reaction with sodium hydroxide. The pH was set to make the
product directly precipitate out to obtain white solid after the
outflow. Compared with batch experiments, this process was
more effective and faster and was more suitable for industrial
production. In addition, the flow process was demonstrated
stably with a productivity of 11.328 kg/day.
7
3
.98−7.78 (m, 2H), 7.47−7.33 (m, 2H), 7.22−7.15 (m, 1H),
+
.42 (s, 2H), 2.19 (s, 3H). MS m/z: 175.09 [M + H] .
ASSOCIATED CONTENT
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sı Supporting Information
Mass spectrum of intermediate 7; HPLC spectrum of
1
intermediate 7; mass spectrum of edaravone; H NMR
spectrum (400 MHz, CDCl ) of edaravone; HPLC
3
spectrum of the reaction solution at 100 °C in ethanol
4
. EXPERIMENTAL SECTION
.1. General Information. All chemicals and solvents
(Table 1, entry 6); HPLC spectrum of edaravone from
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the new method in a continual flow process before
crystallization; HPLC spectrum of edaravone from the
new method in a continual flow process after
crystallization; HPLC spectrum of edaravone from the
new method in a continual flow process after
recrystallization; HPLC spectrum of edaravone from
the traditional method in batch; HPLC spectrum of
edaravone from the new method in batch; and
calculations of productivity, space−time yield (STY)
and process mass intensity (PMI) (PDF)
were purchased from commercial suppliers, and they were used
without further purification. Mass spectra were obtained on an
Agilent 1100 series LC/MSD Tarp (SL). The H NMR
spectrum was recorded on a Bruker AV-400 spectrometer, and
TMS was used as the internal standard. Product purities were
determined by HPLC conducted on an Agilent 1100 system
using a reverse-phase C18 column (4.6 mm in inside diameter
1
and 25 cm in length), and MeOH-H O was used as the mobile
2
phase; the wavelength was 240 nm. The samples were
dissolved in methanol to prepare a solution of 1 mg/mL and
injected with 20 μL for determination. Continuous flow
instruments include a microreactor (with an inner diameter of
Corresponding Authors
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0
.76 mm, channel length of 10−70 m, pipe material of
Hastelloy C276), plunger pumps (Hastelloy C276), and a high
and low temperature circulation device (Oushisheng (Beijing)
Technology Co., Ltd.).
Chengjun Wu − Key Laboratory of Structure-Based Drug
Design and Discovery, Shenyang Pharmaceutical University,
Ministry of Education, Shenyang 110016, P. R. China;
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX