A Continuous Flow Process for the Synthesis of Hymexazol

Article abstract of DOI:10.1021/acs.oprd.9b00047

Hymexazol is an efficient and low-toxicity soil fungicide. In this work, a fully continuous flow process for the synthesis of hymexazol has been developed. This process begins with combining ethyl acetoacetate and hydroxylamine hydrochloride to form a hydroxamic acid intermediate. The reaction solution is then quenched with concentrated hydrochloric acid to obtain the final product, hymexazol. Under the optimized process conditions, the total yield of the target product reached 86%. In addition, production was successfully scaled-up to a kilogram scale. The continuous flow method not only greatly decreases the reaction time but also significantly inhibits the side reactions.

Full text of DOI:10.1021/acs.oprd.9b00047

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Full Paper
A Continuous-Flow Process for the Synthesis of Hymexazol
Xinpeng Ma, Jinsha Chen, and Xiao-Hua Du
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00047 • Publication Date (Web): 15 May 2019
Downloaded from http://pubs.acs.org on May 15, 2019
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A Continuous-Flow Process for the Synthesis of
Hymexazol
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Xin-peng Ma, Jin-sha Chen, and Xiao-hua Du*
Catalytic Hydrogenation Research Center, Zhejiang University of Technology, Zhejiang Key
Laboratory of Green Pesticides and Cleaner Production Technology, Zhejiang Green Pesticide
Collaborative Innovation Center, Hangzhou 310014, PR China.
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Table of Contents Graphic
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ABSTRACT: Hymexazol is an efficient and low-toxic soil fungicide. In this paper, a fully
continuous flow process for synthesizing hymexazol has been developed. This process began
with combining ethyl acetoacetate and hydroxylamine hydrochloride to form the intermediate
product: hydroxamic acid. The reaction solution was then quenched with concentrated
hydrochloric acid to obtain the final product: hymexazol. Under optimized process conditions,
the total yield of the target product reached 86%. In addition, production was successfully
scaled-up to a kilogram scale. The continuous-flow method not only greatly decreases the
reaction time but also significantly inhibits the side reactions.
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KEYWORDS: continuous flow reaction, hymexazol, synthesis, optimization
INTRODUCTION
Hymexazol, 3-hydroxy-5-methyl-isoxazole (3), is an excellent broad-spectrum fungicide.1 It is
used for soil sterilization and seed disinfection, and it has significant regulatory effects on plant
diseases caused by various fungi such as Fusarium, Mortierella and Rhizoctonia solani.2 In
addition, this agent has little effect on bacteria and actinomycetes other than pathogenic bacteria
in the soil, so, it does not affect the ecology of microorganisms in the soil, and can be
decomposed into very low-toxicity compounds.3
Thus far, several synthetic routes to hymexazol have been reported.4 Among these pathways,
the synthetic route shown in Scheme 1 was considered to be the most economical and practical
for industrial production. This synthesis used ethyl acetoacetate (1) and hydroxylamine
hydrochloride as starting materials to obtain hydroxamic acid (2), followed by quenching with an
excess of concentrated hydrochloric acid. Although the synthetic route is simple and low-cost,
the yield is not sufficiently high.5 The highest yield of the target product reported in the literature
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is 70%.6 Therefore, a more efficient synthetic method for the industrial production of hymexazol
is needed.
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Scheme 1. Synthetic Routes of Hymexazol
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OH
O
O
O
O
NH2OH•HCl
NaOH
conc.HCl
N
NHOH
O
O
1
2
3
In recent years, the application of continuous flow technology to the field of chemical
synthesis has become an area of intense interest. There have been many reports addressing the
applications of flow reactors.7 The continuous flow reactor has unique features, that can enhance
the mixing effect and achieve precise temperature control, as well as greatly shorten the cycle of
process screening and process amplification.8 Compared with conventional batch vessels, flow
reactors can not only improve the reaction performance and reduce waste, but also improve
safety.9 From the literature we have learned that the process of synthesizing 2 from 1 has a strong
dependence on alkaline and low temperature environments, and the preparation of intermediate 2
plays a crucial role in the synthesis of 3.5a Therefore, we decided to introduce the reaction into a
flow reactor to investigate whether a continuous flow system is beneficial to increase the yield of
3. To our knowledge, the method of synthesizing 3 with a continuous flow reactor has never
been reported. In this paper, we describe an efficient, stable and practical method for the
preparation of compound 3.
RESULTS AND DISCUSSION
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Scheme 2. Main Byproduct
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O
O
O
O
NOH O
+NH2OH
H2O
OH
OH
ring closure
OH
+
7
4
5
C2H5O
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O
O
O
O
ring closure
H2O
+NH2OH
C2H5OH
HO
O
O
ONH2
O
N
N
H
1
10
8
main byproduct
ring closure
+NH2OH
O
NOH O
HOHN OH
H2O
O
O
9
6
As shown in Scheme 2, the synthetic route in this study (Scheme 1), provides several possible
attack modes of hydroxylamine on 1; in addition to generating our target product 3, it also leads
to the formation of an undesired byproduct, 3-methyl-2-isoxazolin-5-one (10).10 The amount of
this byproduct is usually large, resulting in a low yield of the desired product (3). In the batch
reaction, we achieved a product yield of only 68%, and a by-product 10 content of 22% was
detected. The key factors affecting the reaction pathway are pH and reaction temperature.4a, 5a At
a pH of 10, hydroxamic acid 2 is the primary intermediate produced and can be acidified to 3.
Lowering or raising the pH will result in the formation of different intermediates that are not
capable of forming the desired product 3. In the batch preparation of target product 3, the
hydroxylamine hydrochloride solution was added to the sodium hydroxide solution at a low
temperature to obtain a solution with a pH 9-10, and then 1 was added dropwise into the mixed
solution at -5~5 °C; after 2 hours of reaction, acidification was carried out with hydrochloric acid
to obtain 3. In theory, the efficient heat transfer and mass transfer capacity of the continuous
flow reactor can effectively avoid inhomogeneous pH and temperature profiles during material
mixing, thereby reducing the occurrence of side reactions and the decomposition of
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hydroxylamine. Therefore, our goal was to develop a continuous-flow process that reduced side
reactions and increased the total yield.
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1. Switch from Batch to Continuous-Flow process.
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Figure 1. Semicontinuous flow process for the synthesis of hymexazol.
The process equipment we designed includes the feeding system (three plunger metering pumps),
two T-shaped mixers (M1 and M2, Hastelloy C276, 1.77 mm internal diameter), and a tubular
reactor (R1, Hastelloy C276, 1.77 mm internal diameter). In addition, the tubular reactor and the
T-shaped mixers were both submerged in a thermostatic bath to control the temperature. The pH
of the reaction solution at the outlet of the reactor was measured using a pH meter. As shown in
Figure 1, there were three streams in total. The thermostatic bath temperature was set to -5 °C.
Then, two plunger pumps were used to separately introduce sodium hydroxide solution (3 mol/L)
and hydroxylamine hydrochloride solution (3 mol/L) into M1 for mixing and precooling. The
solution flow rates were 24.5 ml/min and 12.25 ml/min, respectively. The combined solution was
mixed with 1 (4.44 ml/min, 7.89 mol/L) in M2, and the resulting solution was passed through R1.
After running for six minutes (at this time, residence time τ = 40 s), the system reached a steady
state. The output of the reactor was collected in a flask, continuously collected for 5 minutes, and
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then the collected mixture was poured into 10 equivalents (based on compound 1) of ice-cooled
concentrated hydrochloric acid, where it was allowed to react at 25 °C for 12 hours. The pH of
the reaction mixture was adjusted to 3-4 with a 30 wt% sodium hydroxide solution, followed by
three extractions with dichloromethane. The organic phases were combined, and the solvent was
evaporated in vacuo to generate crude product 3. The crude product was recrystallized from
cyclohexane to gain pure product 3. To our satisfaction, excellent results were obtained using
this continuous process.
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Figure 2. Effect of temperature (T1) and residence time (τ1) on the yield of product 3. Yield was
determined by external standard method (HPLC).
To find appropriate reaction conditions, the effects of residence time τ1 and reaction
temperature T1 on the first reaction step were systematically investigated (Figure 2). As the
residence time τ1 was prolonged, the yield was increased to a constant value. Higher
temperatures caused an increase in side reactions, resulting in lower yields. We found a
significant increase in yield when the temperature was lowered to -5 °C, which also indicated
that the lower temperature favored the main reaction. Lower temperatures caused lower
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conversion rates (-10 °C), so we extended the residence time τ1 in an attempt to increase the
yield, but the results did not meet our expectations, with a yield of only 72%. Therefore, the
reaction conditions of T1 = -5 °C and τ1 = 40 s were selected.
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Table 1. Total yield of hymexazol under different reaction conditionsa
b
Entry
1
N1: Nh: Ns
1:1:1.3
PH
8.5
9.0
9.5
9.8
10.3
10.8
11.4
12.0
10.3
10.4
10.1
10.2
10 (HPLC area %) Yieldc of 3 (%)
57.3
38.6
28.8
19.1
8.5
19.6
28.6
30.1
8.2
30.1
51.6
65.2
72.1
81.8
70.1
62.3
58.6
82.5
80.8
79.2
77.1
2
3
4
5
6
7
8
9
1:1:1.5
1:1:1.7
1:1:1.9
1:1:2.0
1:1:2.1
1:1:2.3
1:1:2.5
1:1.05:2.1
1:1.10:2.2
1:1.15:2.3
1:1.20:2.4
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12
8.9
10.0
13.8
aAll cyclization procedures were carried out with 10 equivalents (based on compound 1) of
concentrated hydrochloric acid, reacted at 25 °C for 12 hours. Molar feed ratio of 1:
hydroxylamine hydrochloride: sodium hydroxide = N1: Nh: Ns. The reaction yield was
b
c
determined by external standard method (HPLC).
The effect of the molar flow ratio of 1, hydroxylamine hydrochloride and sodium hydroxide (N1:
Nh: Ns) was then investigated, in an attempt to increase the yield (Table 1). The amount of
sodium hydroxide was varied to investigate the effects of alkaline conditions on yield (entries
1−8). It can be seen that the alkaline conditions have a strong influence on the reaction. Too
much or too little sodium hydroxide was not conducive to the formation of target product 3
because hydroxylamine attacked 1 in a weaker alkaline environment resulting in the formation of
compound (6), and the hydroxylamine was deprotonated (NH2O-) under overbased conditions,
producing some intermediates that were incapable of forming 3. In addition, the study shows that
1.05 equivalents of hydroxylamine hydrochloride was a good compromise because excessive
hydroxylamine hydrochloride led to an increase in side reactions (entries 9−12). The results
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show that N1: Nh: Ns = 1:1.05:2.1 was the most suitable molar ratio. Therefore, we determined
the optimum conditions for the continuous flow process to be τ1 = 40 s, T1 = -5 °C, and N1: Nh:
Ns = 1:1.05:2.1 (pH = 10.3). Under these conditions, an isolated yield of 82% was successfully
obtained with a purity of 99%.
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Scheme 3. Hydrolysis of hydroxamic acid
O
O
O
O
O
NOH O
ring closure
NH2OH
H2O
H
O
OH
NHOH
H2O
OH
N
by-product 10
2
7
4
In step 2 (the cyclization process), excessive strong acid is crucial for obtaining a large amount
of target product 3.5a It is known from the literature that hydroxamic acid can be hydrolyzed.11
As shown in Scheme 3, insufficient acidic conditions can cause hydroxamic acid (2) to be
hydrolyzed to produce acetoacetic acid (4), which is then reacted with hydroxylamine to give
compound 7 that is followed by cyclization to form byproduct 10. Therefore, the cyclization
process (step 2) also has the potential to generate impurities. To reduce the formation of
byproducts, we have explored the cyclization process. The results are shown in Figure 3.When
the amount of concentrated hydrochloric acid was insufficient, a large amount of byproducts was
formed due to hydrolysis of 2, resulting in low yield. As the amount of concentrated
hydrochloric acid increased, the yield increased to a constant value. The results showed that the
yield reached a maximum of 82% with approximately 9 equivalents (based on compound 1) of
concentrated hydrochloric acid. The effect of cyclization temperature (T2) on the yield of product
was then investigated. The highest yield was obtained at a temperature of 30 °C. Low conversion
rates caused by low-temperature conditions or side reactions caused by high-temperature
conditions can result in a decrease in yield. We thus achieved a maximum yield of 84.6% at T2 =
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30 °C using 9 equivalents of concentrated hydrochloric acid. Byproduct 10 was reduced to 7%.
This result indicated that the continuous flow process could be successfully utilized, and the
yield of product 3 was greatly improved compared with that of the conventional batch reaction.
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Figure 3. Effect of HCl and temperature (T2) on the yield of product 3.Yield was determined by
external standard method (HPLC).
2. Fully Continuous Flow Process
Figure 4. Fully Continuous Flow Process
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Next, we attempted to establish a fully continuous flow process for the preparation of product 3.
As shown in Figure 4, unlike the semicontinuous process previously described, a fourth pump
was introduced for the delivery of concentrated hydrochloric acid, and a tubular reactor (R2,
Hastelloy C276, 1.77 mm internal diameter) and a T-shaped mixer (M3, Hastelloy C276, 1.77
mm internal diameter) replaced the original cyclized flask. There were four streams in total. The
thermostatic bath temperature T1 was set to -5 °C. Then, two plunger pumps were used to
separately introduce sodium hydroxide solution (24.5 ml/min, 3 mol/L) and hydroxylamine
hydrochloride solution (12.25 ml/min, 3 mol/L) into M1 for mixing and precooling. The
combined solution was mixed with 1 (4.44 ml/min, 7.89 mol/L) in M2, and the resulting solution
was passed through R1. Then, the obtained mixture was mixed with the stream of concentrated
hydrochloric acid (29.2 ml/min, 12 mol/L) via M3 and pumped into R2 for the cyclization
reaction. M3 and R2 were immersed in a separate constant temperature bath to control the
temperature T2. After a steady state was reached, the product solution was collected. The pH of
the reaction mixture was adjusted to 3-4 with a 30 wt% sodium hydroxide solution, which was
followed by three extractions with dichloromethane. The organic phases were combined and the
solvent was evaporated in vacuo to afford crude product 3. The crude product was recrystallized
from cyclohexane to obtain pure product 3.
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Figure 5. Effect of different reaction conditions on the yield of product 3. Yield was determined
by external standard method (HPLC).
The cyclization process parameters were systematically investigated, including testing the
concentrated hydrochloric acid amount, reaction temperature T2, and residence time τ2, as shown
in Figure 5. For the case in which the amount of concentrated hydrochloric acid was small, the
yield of the product was lower due to the hydrolysis of 2. As the amount of concentrated
hydrochloric acid increased, the yield increased to a constant value. We found that only 7
equivalents (based on compound 1) of concentrated hydrochloric acid were required for the yield
to reach a maximum. Next, the effect of cyclization temperature (T2) on the yield of product was
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investigated. The highest yield was obtained at a temperature of 50 °C. Low conversion rates
caused by low-temperature conditions or side reactions caused by high-temperature conditions
can lead to a decrease in yield. Insufficient residence time led to incomplete conversion; the yield
increased with the extension of the residence time τ2 and remained essentially unchanged after 45
s. This result indicated that τ2 = 45 s was a suitable residence time. Therefore, the optimum
conditions for the continuous flow cyclization process were determined to be T2 = 50 °C, τ2 = 45
s, and 7 equivalents of concentrated hydrochloric acid. After the cyclization process was
introduced into the continuous flow reactor from the reaction flask, we found that when the
cyclization temperature was raised to 50 °C, a yield of 87% was obtained with a residence time
of 45 s (τ2), and the content of byproduct 10 was only 4%. In addition, the amount of
concentrated hydrochloric acid used was reduced to 7 equivalents. The product from the fully
continuous flow process was purified to give an isolated yield of 86.2%. The advantages of the
continuous process were significant compared to the batch process.
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To evaluate the advantages of the continuous flow process in the synthesis of 3, we compared
the optimal results of several modes of operation. As shown in Figure 6, in the two-step
continuous flow process, the major byproduct 10 was significantly inhibited. Side reactions
caused by inhomogeneous pH and temperature profiles during the mixing process can thus be
effectively avoided in the continuous flow processes.
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Figure 6. The content of byproduct 10 in different operation modes
As shown in Table 2, different results were obtained with the same synthetic route and
different modes of operation. In the continuous flow reactor, the reaction time was greatly
shortened compared with the batch reactor, and the yield of the final product 3 was also
remarkably improved.
Table 2. Comparison of Batch and Continuous Flow
Operation manner
batch
Total reaction time
2 h + 12 hours
40 s + 12 hours
40 s + 45 s
Isolated Yield of 3 (%)
68.0
84.0
86.2
semicontinuous flow
fully continuous flow
3. Scale-Up of the Continuous Process
Finally, scaled-up production was carried out. The process equipment was changed to a larger
geometry tube as shown in Figure 7. The inner diameters of all tubular reactors and T-shaped
mixers were increased to 3 mm. To increase productivity, the flow rate of the feed was also
increased. After running continuously for 3.5 hours, 1.78 kg of 3 was produced at an isolated
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yield of 85%. The obtained product had a purity of 99%. The results showed the stability and
utility of the continuous flow process and demonstrated its potential for industrial production.
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Figure 7. Scale-Up of the Continuous Process
EXPERIMENTAL SECTION
General Information.
All reagents were purchased from Shanghai Aladdin Bio-Chem Technology Co., Ltd. All pumps
were purchased from Jiangsu Hanbon Science And Technology Co., Ltd. (Jiangsu, China). 13C
NMR and 1H NMR spectra were recorded on an AVANCE III spectrometer (Bruker, Hangzhou,
China) at 125 and 500 MHz NMR, respectively. MS data were recorded on a Thermo DSQ II
GC-MS spectrometer equipped with an EI source and controlled by MassHunter software.
Melting points were carried out on a B-545 melting point apparatus (Buchi, Hangzhou, China)
and were uncorrected.
HPLC Method: The HPLC method for analyzing the yield and purity of hymexazol employed
a Shim-Pack VP-ODS 250 mm × 4.6 mm (S-5μm, 12nm) column. The mobile phase consisted of
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MeOH and pure water at a ratio of 60:40 and was pumped into the VP-ODS column at a total
flow rate of 1.0 mL/min. Detection temperature was 25 °C, and the injection volume was 2.0 μL.
Detection was carried out at 226 nm. The relative retention time of hymexazol at the time of
elution was 3.48 min.
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Batch Experiment
Sodium hydroxide (25 g, 0.6 mol) was dissolved in 200 ml of water, and a solution of
hydroxylamine hydrochloride (3mol/l, 100ml, 0.3 mol) was added with stirring at 0 °C to
achieve a solution of pH = 10; then, 1 (39.4 g, 0.3 mol) was added dropwise into the mixed
solution at -5°C during 45 min, and after 2 hours of reaction, the mixture was poured into 250
mL of ice-cold concentrated hydrochloric acid , then it was allowed to stand at room temperature
for 12 hours. Finally, the pH of the reaction mixture was adjusted to 3-4 with a 30 wt% sodium
hydroxide solution, and then extracted with dichloromethane (3×250 g). The organic phases were
combined and the solvent was evaporated in vacuo to afford crude product 3. It was
recrystallized from cyclohexane to obtain 19.5 g of white crystalline solid product 3 in 65% yield
with a purity of 99%. CAS number 10004-44-1. mp 83-84 °C (lit.5b mp 84-85 °C); GC-MS (EI)
m/z 99 ([M]+, 99); 1H NMR (500 MHz, Chloroform-d) δ/ppm: 2.34 (s, 3H), 5.69 (s, 1H), 10.58
(s, 1H); 13C NMR (125 MHz, Chloroform-d) δ/ppm: 12.90, 93.93, 170.38, 171.34.
General procedure for semicontinuous flow synthesis of hymexazol
As shown in Figure 1, aqueous sodium hydroxide (3 mol/L, 300 ml), hydroxylamine
hydrochloride solution (3 mol/L, 150 ml), and ethyl acetoacetate (98%, 49.8 g, 0.38 mol) were
prepared. The thermostatic bath temperature was set to -5 °C. Then, two plunger pumps were
used to separately introduce sodium hydroxide solution (24.5 ml/min) and hydroxylamine
hydrochloride solution (12.25 ml/min) into M1 for mixing and precooling. The combined
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solution was mixed with 1 (4.44 ml/min, 7.89 mol/L) in M2, and the resulting solution was
passed through R1. After running for six minutes, the system reached a steady state. The output
of the reactor was collected in a flask, continuously collected for 10 minutes, and then the
collected mixture was poured into 292 ml (3.5 mol) ice-cooled concentrated hydrochloric acid
and allowed to react at 25 °C for 12 hours. The pH of the reaction mixture was adjusted to 3-4
with a 30 wt% sodium hydroxide solution, followed by extraction with dichloromethane three
times. The organic phases were combined, and the solvent was evaporated in vacuo to afford
crude product 3. It was recrystallized from cyclohexane to obtain 28.9 g of white crystalline solid
product 3 with 82.5% yield and a purity of 99%.
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General procedure for synthesizing hymexazol in a fully continuous flow process
As shown in Figure 3, aqueous sodium hydroxide (3 mol/L, 250 ml), hydroxylamine
hydrochloride solution (3 mol/L, 125 ml), concentrated hydrochloric acid (12 mol/L, 300 ml),
and ethyl acetoacetate (98%, 46 g, 0.35 mol) were prepared. There were four streams in total.
The thermostatic bath temperature T1 was set to -5 °C, T2 was set to 50 °C. Then, two plunger
pumps were used to separately introduce sodium hydroxide solution (24.5 ml/min, 3 mol/L) and
hydroxylamine hydrochloride solution (12.25 ml/min, 3 mol/L) into M1 for mixing and
precooling. The combined solution was mixed with 1 (4.44 ml/min, 7.89 mol/L) in M2, and the
resulting solution was passed through R1. Then the obtained mixture was mixed with the fourth
stream of concentrated hydrochloric acid (29.2 ml/min, 12 mol/L) via M3 and pumped into R2 for
the cyclization reaction. A back pressure regulator was used to adjust the pressure to within 150
psi. After a steady state was reached, the output of the reactor was collected for 10 minutes. The
pH of the reaction mixture was adjusted to 3-4 with a 30 wt% sodium hydroxide solution,
followed by extraction with dichloromethane (3×300 ml). The organic phases were combined,
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and the solvent was evaporated in vacuo to afford crude product 3. It was recrystallized from
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cyclohexane to obtain 30.4 g of white crystalline solid product 3 with 86% yield and a purity of
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98%.
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Scale-Up of the Continuous Process
As shown in Figure 7, four plunger metering pumps (PEEK, 100 ml) were used to pump four
reagents. Three T-shaped mixers (M1, M2 and M3, Hastelloy C276, 3.0 mm internal diameter),
and two tubular reactors (R1 and R2, Hastelloy C276, 3.0 mm internal diameter) were used.
Aqueous sodium hydroxide (3 mol/L, 14 L), hydroxylamine hydrochloride solution (3 mol/L, 7
L), concentrated hydrochloric acid (12 mol/L, 17.5 L), and ethyl acetoacetate (98%, 2675 g, 21
mol) were prepared. The thermostatic bath temperature T1 was set to -5 °C, T2 was set to 50 °C,
and then sodium hydroxide solution (70.3 ml/min) and hydroxylamine hydrochloride solution
(35.2 ml/min) were separately introduced to M1 by two plunger pumps for mixing and
precooling. The combined solution was mixed with 1 (12.7 ml/min, 7.89 mol/L) in M2, and the
resulting solution was passed through R1. Then, the obtained mixture was mixed with the fourth
stream of concentrated hydrochloric acid (75 ml/min, 12 mol/L) via M3 and pumped into R2 for
the cyclization reaction. A back-pressure regulator was used to adjust the pressure to within 150
psi. After a steady state was reached, the product of the reactor was collected for 3.5 hours.
Procedure for Isolating 3: The pH of the reaction mixture was adjusted to 3-4 with a 30 wt%
sodium hydroxide solution, and then extracted with dichloromethane (3×25.5 kg). The organic
phases were combined and the solvent was evaporated in vacuo to give crude product 3. The
crude product was recrystallized from cyclohexane to gain pure product 3 as a white solid with
85% yield (1.78 kg) and 99% purity. Dichloromethane and cyclohexane can be recycled
repeatedly.
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CONCLUSION
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In summary, a stable and efficient continuous flow process for the synthesis of hymexazol has
been developed. Significant process intensification and suppression of side reactions have been
achieved compared to batch operations. After the initial scale-up of the continuous process, a
productivity of 508.5 g/h was obtained, and the isolated yield was stable at approximately 85%
with 99% purity. Furthermore, the utilization of continuous flow strategies provides a good
alternative for the synthesis of hymexazol and offers possibilities for industrial production.
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ASSOCIATED CONTENT
Supporting Information.
The following files are available free of charge on the ACS Publications website.
Copies of 1H/13C NMR, HPLC and GC-MS spectra for compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*Phone: +86-571-88320430. Fax: +86-571-88320066. E-mail: duxiaohua@zjut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are so grateful to the National Key Research and Development Plan (Grant
2018YFD0200106).
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