Continuous-Flow Process for the Synthesis of 2-Ethylphenylhydrazine Hydrochloride

Article abstract of DOI:10.1021/acs.oprd.5b00115

An expeditious process for the synthesis of 2-ethylphenylhydrazine hydrochloride via a continuous-flow reactor from 2-ethylaniline in 94% yield was described. The main steps in this synthesis involved not only the generation of diazonium salt intermediate in situ but also the temperature-programmed reduction by sodium sulfite in the tandem loop reactor. Total residence time was reduced to less than 31 min by increasing the reaction temperature and thereby taking advantage of improved mass and heat transfer of a continuous-flow system. The purification process was simplified by extraction of impurities in situ.

Full text of DOI:10.1021/acs.oprd.5b00115

Subscriber access provided by NEW YORK UNIV
Technical Note
A Continuous Flow Process for The Synthesis
of 2-Ethylphenylhydrazine Hydrochloride
Zhiqun Yu, Gang Tong, Xiaoxuan Xie, Pengcheng Zhou, Yanwen Lv, and Weike Su
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00115 • Publication Date (Web): 12 Jun 2015
Downloaded from http://pubs.acs.org on June 24, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
A Continuous Flow Process for The Synthesis of
2ꢀEthylphenylhydrazine Hydrochloride
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†
†
†
†
‡
,†
Zhiqun Yu, Gang Tong, Xiaoxuan Xie, Pengcheng Zhou, Yanwen Lv, and Weike Su*
†
National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative
Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, P.R. China.
‡
Quzhou University, Quzhou 324000, P.R. China.
*
Corresponding author: Tel: (+86)57188320899. Eꢀmail: pharmlab@zjut.edu.cn.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table of Contents Graphic:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment

Page 3 of 16
Organic Process Research & Development
1
Abstract: An expeditious process for synthesis of 2ꢀethylphenylhydrazine hydrochloride via a continuous flow
reactor from 2ꢀethylaniline in 94% yield was described. The main steps in this synthesis involved not only the
generation of diazonium salt intermediate in situ, but also the temperatureꢀprogrammed reduction by sodium sulfite in
the tandem loop reactor. Total residence time was reduced to less than 31 min by increasing reaction temperature and
thereby taking advantage of improved mass and heat transfer of a continuous flow system. Purification process was
simplified by extraction of impurities in situ.
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Keywords: continuous flow; diazotization; temperatureꢀprogrammed reduction; 2ꢀethylphenylhydrazine
hydrochloride
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Introduction
Aryl hydrazine moiety has been shown as a key pharmacophore in many pharmaceutically active
1
agents . Target product 2ꢀethylphenylhydrazine hydrochloride is an important starting material for
synthesis of Etodolac, which is a nonsteroidal antiꢀinflammatory drug (NSAID) licensed for the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
treatment of inflammation and pain caused by osteoarthritis and rheumatoid arthritis .
Figure 1. Etodolac.
Preparation of 2ꢀethylphenylhydrazine hydrochloride can be fulfilled by diazotization of
2
ꢀethylaniline to form the diazonium salt, which is subsequently reduced in different approaches to form
the final product. One approach is Japp–Klingemann reaction with βꢀketoꢀacid and hydrazinolysis of
3
hydrazone . Versatility of this method is limited by long reaction route and low yield. Another approach
4
is reduction of diazonium salt by reductants (e.g. SnCl , Na SO , NaHSO , etc), which is the
2
2
3
3
benchmark method for preparation of aryl hydrazines. However, some disadvantages that amount of
wastes, byproducts, low efficiency, yield stability and yield reliability are still need to be improved
especially in scaleꢀup of batch process.
ACS Paragon Plus Environment

Page 5 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Scheme 1. Synthetic route and byproducts
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We adopted the second approach in synthesis of 2ꢀethylphenylhydrazine hydrochloride (Scheme 1).
The synthesis started by reducing 2ꢀethylaniline with sodium nitrite in the presence of hydrogen
chloride followed by reduction of the diazonium salt, the use of sodium sulfite as reductant can avoid
post processing problems caused by tin (II) chloride. Hydrazine hydrochloride 1 was precipitated from
aqueous phase, followed by recrystallization to obtain qualified product (purity ≥ 98%). Diazotization of
aromatic amines is usually exothermic and fast, and usually performed on the bulk scale in anhydrous
5
conditions at low temperature. Researches have confirmed that diazotization presented potential safety
hazards for scaleꢀup. Thus, we turned our attention to developing a continuous flow process to address
the safety concerns. Continuous flow technology offers many advantages over batch methods, including
precise control of stoichiometry, residence time, and temperature; high reproducibility; easy to scaleꢀup;
6
and often better reaction yields . The much higher surface area to volume ratio under flow conditions
renders highly efficient heat transfer. Furthermore, safety hazards in handling exothermic reactions
associated with explosive intermediates are minimized while involving in a much smaller volume in the
7
reaction train .
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Results and discussion
Adapting the Batch Process to Continuous Flow.
For a great many industrial processes covered, diazotization of aromatic amines in batch manner has
8
been well studied . A continuous diazotization of anilines under substantially adiabatic conditions was
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
reported by Kidler et al. from the dye industry . More recently, there have been several reports on
generating diazonium salts as reactive intermediates (followed by iododeamination, chlorodeamination,
1
0
azo dyes, and chlorosulfonylation) using flow technology . Compared to micrometer scale reactor,
millimeter scale reactor, due to its relatively high productivity, is easier to promote in industrial
11
production. Browne et al. reported the generation and reduction of diazonium salts using vitamin C for
12
synthesis of hydrazines in a microreactor. Li et al. developed a continuous nonꢀaqueous diazotization
process in tandem with batch type reduction for syntheses of aryl hydrazines, however, the use of SnCl2
went against the promotion of technology application. Our group has been committed to continuous
1
3
diazotization process , and herein wish to establish a continuous flow process for synthesis of
14
2
ꢀethylphenylhydrazine hydrochloride .
1
5
Mechanism for reduction of diazotization by sodium sulfite has been revealed as shown in Scheme
2. Diazenesulfonate 3 which has poor water solubility and poor thermal stability can be formed via fast
nucleophilic substitution from diazonium chloride 2 and sodium sulfite. Then nucleophilic addition
takes place between 3 and sodium bisulfite, followed by hydrolysis in hydrochloric acid to form final
product 1. The transformation from 3 to 4 is relatively slow compared to nucleophilic substitution step.
In the design of a continuous flow process for synthesis of 1, our objectives were to avoid the
accumulation and isolation of energetic intermediates 2 and 3, and to combine continuous diazotization
and reduction within one flow reactor.
ACS Paragon Plus Environment

Page 7 of 16
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Scheme 2. Mechanism for reduction of diazotization
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Initial Process Design.
The original process discussed in this document was the direct conversion of the commonly used
batch methodology to a continuous flow system. Scheme 3 shows the continuous flow reactor
experimental setup. The equipment consists of two peristaltic pumps (P , P , Baoding Longer, China)
1
2
loaded with tubing connected by a Tꢀmixer which was connected to residence loop I (Hastelloy, 3 mm
i.d., 5 mm o.d.). The reacting tube was immersed in a thermostat controlled water bath. Solution A of
2
ꢀethylaniline in hydrochloric acid together with solution B of aqueous sodium nitrite were pumped into
reacting tube respectively. After a residence time (τ ) in loop I, solution C of aqueous sodium sulfite was
1
introduced into the reactor. Reduction of diazonium salt was taken place in residence loop II (SS316, 3
mm i.d., 5 mm o.d.) with another residence time (τ ), followed by hydrolysis with hydrochloric acid in
2
collection vessel to form final product 1. To avoid air pollution, tail gas (SO ) was absorbed by sodium
2
hydroxide solution to reproduce sodium sulfite. Crude product was purified by recrystallization from
water.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 16
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 3. Schematic of initial process experimental setup
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Solution A is 2ꢀethylaniline in hydrochloric acid, solution B is aqueous sodium nitrite, solution C is
aqueous sodium sulfite. Residence loop I is Hastelloy tube with 3 mm i.d., 5 mm o.d., residence loop II
is SS316 tube with 3 mm i.d., 5 mm o.d..
Optimization of this process started with continuous diazotization in tandem with reduction of
diazonium salt in batch manner (Scheme 4). This procedure was greatly facilitated by continuous flow
conditions and a significant number of runs were rapidly conducted in a sequential manner. The
experimental parameters were systematically investigated by varying residence time (τ ) and
1
temperature (T ). Solution A was 1.5 M 2ꢀethylaniline in 3.0 equiv hydrogen chloride aqueous with a
1
flow rate of 7.8 mL/min, solution B was 6.0 M sodium nitrite aqueous with a flow rate of 2.0 mL/min,
o
16
reductive conditions was same with literature parameters (2.5 equiv Na SO , 70ꢀ75 C, 2ꢀ3 h) . The
2
3
o
results were shown in Figure 2. Maximum yield of 75% was obtained when τ = 15 s, T = 25 C. Both
1
1
long τ with high T and short τ with low T lead to yield decreases. Raising the temperature can
1
1
1
1
accelerate the reaction rate, however, higher temperature along with longer residence time lead to
decomposition of diazonium salt. On the contrary, aniline was conversed incompletely while lower
ACS Paragon Plus Environment

Page 9 of 16
Organic Process Research & Development
1
temperature along with shorter residence time.
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Scheme 4. Schematic of continuous diazotization experimental setup
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Solution A is 2ꢀethylaniline in 3.0 equiv hydrochloric acid with a flow rate of 7.8 mL/min, solution B
is aqueous sodium nitrite with a flow rate of 2.0 mL/min. Residence loop I is Hastelloy tube with 3 mm
i.d., 5 mm o.d..
Figure 2. Effect of temperature and residence time on diazotization. Yields of 1 were calculated from
2ꢀethylaniline.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Amount of sodium nitrite was then optimized. Molar flow ratios of sodium nitrite to 2ꢀethylaniline
were varied by adjusting flow rate of solution B. Results were shown in table 1. Sodium nitrite can be
slightly excessive to 1.03 equiv, while too much overdose leads to decreased yields since excessive
nitrous acid may accelerate decomposition of diazonium salt.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 1. Effect of amount of sodium nitrite
a
b
Sodium nitrite / 2ꢀethylaniline
1.00
Yield (%)
72
75
75
73
69
1
1
1
1
.03
.05
.08
.10
a
b
Molar flow ratios of sodium nitrite to 2ꢀethylaniline.
Yields of 1 were calculated from 2ꢀethylaniline.
With diazotization parameters in hand, optimization of continuous reduction was then undertaken.
Experiments were carried out in accordance with procedure of Scheme 3. Solution A was 1.5 M
2ꢀethylaniline in 3.0 equiv hydrogen chloride aqueous with a flow rate of 7.8 mL/min, solution B was
6
.0 M sodium nitrite aqueous with a flow rate of 2.0 mL/min, Solution C was 1.8 M aqueous sodium
sulfite with a flow rate of 16.2 mL/min (molar flow ratio was 2.5 equiv to 2ꢀethylaniline). Residence
time (τ ) was prolonged by increasing the tube length while maintaining the same flow rates. Reductive
2
o
temperature (T ) was investigated varying from traditional batch process parameter (70 C) to maximum
2
temperature at atmospheric pressure. However, the result was not satisfied (maximum yield was 80%
o
when τ = 30 min, T = 100 C) due to the formation of a black tar. The main reason could be thermal
2
2
decomposition of diazonium chloride 2, during formation of 3. Amount of reductant was also optimized
(Table 2). Molar flow ratios of sodium sulfite to 2ꢀethylaniline were varied by adjusting flow rate of
ACS Paragon Plus Environment

Page 11 of 16
Organic Process Research & Development
1
solution C, but only slight increase in yield was gained. The yield of 1 was 81% when 2.8 equiv of
sodium sulfite was used, more amount can’t get further raise due to decomposition of diazonium salt.
Table 2. Effect of amount of sodium sulfite
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
b
Sodium sulfite / 2ꢀethylaniline
Yield (%)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
2
.0
.3
.5
.8
69
76
80
81
81
3.0
a
b
Molar flow ratios of sodium sulfite to 2ꢀethylaniline.
Yields of 1 were calculated from 2ꢀethylaniline.
Advanced Process Design.
According to the thermal decomposition problems of initial method, an improved process was
developed by temperatureꢀprogrammed reduction. Diazenesulfonate 3 was generated at a slightly lower
temperature and then intermediate 4 was formed at a higher temperature. The primary challenge of this
continuous process was poor solubility of diazenesulfonate 3 and the problem of clogging tube. A dilute
concentration of regents will increase the burden of subsequent processes, and seems not an economic
method. Therefore, increasing diameter of reacting tube was chosen for the improved process.
An advanced optimized process was then designed (Scheme 5), and optimal conditions were achieved
by flowing solution A (1.5 M 2ꢀethylaniline in hydrochloric acid aqueous) together with solution B (6.0
o
M sodium nitrite aqueous) for a residence time of 15 s at 25 C, followed by introduction of solution C
o
(
1.8 M aqueous sodium sulfite) into the reactor for a residence time of about 30 s at 25 C and then 30
o
17
min at 100 C . Residence loop III was heated by oil bath and the temperature was regulated by a
thermostat. The flow rates of three solutions were 7.8, 2.0, 18.2 mL/min respectively, and molar flow
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ratio of 2ꢀethylaniline to NaNO to Na SO was 1.0 : 1.03 : 2.8. Inner diameters of residence loop II and
2
2
3
III were both 6 mm. With these adjustments, yield of 1 was significantly improved to 92~93% with a
pressure drop of less than 1 bar.
Though a significantly improvement of yield was gained, qualified product of more than 98% purity
was only obtained after recrystallization. Some modifications of this process were required to facilitate
purification process. Toluene was added in the hydrolysis reactor, impurities were extracted into organic
layer while hydrolysis by hydrochloric acid. Bright white crystals of target product were precipitated
while cooling the mixture, after filtration and drying, a purity of more than 99% was got directly. A
slight increase of yield of approximately 1% was also achieved.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Scheme 5. Schematic of advanced process experimental setup
a
Solution A is 1.5 M 2ꢀethylaniline in 3.0 equiv hydrochloric acid, solution B is 6.0 M aqueous sodium
nitrite, solution C is 1.8 M aqueous sodium sulfite. Residence loop I is Hastelloy tube with 3 mm i.d., 5
mm o.d., residence loop II and III are SS316 tube with 6 mm i.d., 8 mm o.d., the volume of three
residence loops are 2.45 mL, 14 mL, 840 mL respectively.
ACS Paragon Plus Environment

Page 13 of 16
Organic Process Research & Development
1
To underline the advantages of the proposed flow synthesis, a comparison with the reaction
performed in batch manner was summarized in table 3. Molar ratio of reagents in batch reaction was
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
same with continuous flow, the sequence of operations was diazotization of 2ꢀethylaniline at 0 C
4b
followed by the temperatureꢀprogrammed reduction of diazonium salt .
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. Comparison of batch process with continuous process
Operate manner
Yield (%)
Batch
87
Continuous flow
94
Purity (%)
99 (after recrystallization)
stirred for hours after completing the
addition of reagents
99
Diazotization: 15 s
Reduction: 30.5 min
Reaction time
Conclusion
In summary, an expeditious and highꢀyielding process for synthesis of 2ꢀethylphenylhydrazine
hydrochloride from 2ꢀethylaniline via a continuous flow reactor has been set up. Thermal decomposition
of diazonium salt was avoided by temperatureꢀprogrammed reduction, and product isolation and
purification method was polished by extraction in situ. The process is readily adapted for preparation of
analogous compounds and can easily be scaledꢀup by increasing reactor size or operating several
reactors with high throughput in parallel. The apparatus used to deliver the results for the large scale
experiment is still being used for further batches.
Experimental Section
All chemicals were purchased from commercial sources and were used without further purification.
1
Melting points were determined on Buchi 540 melting point apparatus and were uncorrected. H NMR
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
spectra was recorded on Varian 400 MHz spectrometer using tetramethylsilane (TMS) as internal
standard. HPLC analysis for 1 was carried out on an Agilent 1200 system equipped with a RPꢀ18 250
mm × 4.0 mm column and detected at 275 nm, eluted with 50:25:25 0.03 M NaH PO
2
4
aqueous/CH CN/CH OH at 1.0 mL/min.
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Continuous flow experimental procedure of advanced process. As shown in Scheme 5, solution A
of 2ꢀethylaniline (303 g, 2.5 mol), 30% aqueous hydrochloric acid (911 g, 7.5 mol) in 432 g of water,
and solution B of sodium nitrite (178 g, 2.6 mol) in 357 g of water were pumped into the flow reactor
via a Tꢀjoint by P and P at flow rates of 7.8 mL/min and 2.0 mL/min respectively, after a residence
1
2
o
time of 15 s at 25 C in residence loop I (Hastelloy, 3 mm i.d., 5 mm o.d.), solution C of sodium sulfite
(
882 g, 7 mol) in 3528 g of water was introduced into the reactor by P at a flow rate of 18.2 mL/min,
3
o
after another residence time of 30 s at 25 C in residence loop II (SS316, 6 mm i.d., 8 mm o.d.) and 30
o
min at 100 C in residence loop III (SS316, 6 mm i.d., 8 mm o.d.), mixture flowed through the outlet
and accumulated in the collection vessel (filled with 100 g of toluene and 1458 g of hydrochloric acid in
o
advance, and preheated to 100 C). Continuous stirring was done vigorously. Large amount of gas was
released, and SO was absorbed by sodium hydroxide solution. After flow reaction was complete,
2
reaction mixture was stirred for another 30 min. Then hot solution was separated in a separator funnel
o
and toluene was recovered by distillation. The aqueous phase was cooled to 0 C, and solid was
precipitated. The precipitate was filtered and dried in vacumm to give bright white crystals (406 g) in 94%
o
1
yield with 99% HPLC purity. M.p. 180ꢀ181 C, H NMR (400 MHz, d ꢀDMSO) δ/ppm: 10.20 (s, 3H),
6
7
.17ꢀ7.11 (m, 2H), 6.97 (d, 1H, J = 8.0 Hz), 6.91 (t, 1H, J = 7.6 Hz), 2.58 (q, 2H, J = 7.6 Hz), 1.15 (t,
3H, J = 7.6 Hz).
ACS Paragon Plus Environment

Page 15 of 16
Organic Process Research & Development
Acknowledgment
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
We are grateful for the National Natural Science Foundation of China (No. 21406203) and Zhejiang
Technology and Service Platform of New Drug Innovation (PNDI) (No. 2011E61003) for financial
support.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
References
(1) (a) Yoshioka, T.; Fujita, T.; Kanai, T.; Aizawa, Y.; Kurumada, T.; Hasegawa, K.; Hiroyoshi, H. J.
Med. Chem. 1989, 32, 421–428. (b) Pete, B. L.; Bitter, I. N.; Harsányi, K. L. N.; Tõke, L. S.
Heterocycles 2000, 53, 665–673.
(2) (a) Hughes, P.; DeVirgilio, J.; Humber, L. G.; Chau, T.; Weichman, B.; Neuman, G. J. Med. Chem.
1989, 32, 2134–2137. (b) Soll, R. M.; Guinosso, C.; Asselin, A. J. Org. Chem. 1988, 53, 2844–2847.
(c) Humber, L. G.; Christopher, A.; Demerson, C. A.; Swaminathan, P.; Birdt, P. H. J. Med. Chem.
1986, 29, 871–874.
(3) González, A. Synthetic Commun. 1991, 21, 669–674.
(
4) (a) Demerson, C. A.; Humber, L. G. US 4585877, 1986. (b) Dai, L. Y.; Wang, X. Z.; Chen, Y. Q. J.
Chem. Ind. Eng. (China) 2005, 56, 1536–1540.
(5) Petrillo, G.; Novi, M.; Garbarino, G.; Dell’Erba, C. Tetrahedron 1986, 42, 4007–4016.
(6) (a) Hessel, V. Chem. Eng. Technol. 2009, 32, 1655–1681. (b) Wahab, B.; Ellames, G.; Passey, S.;
Watts, P. Tetrahedron 2010, 66, 3861–3865. (c) Riva, E.; Gagliardi, S.; Mazzoni, C.; Passarella, D.;
Rencurosi, A.; Vigo, D.; Rencurosi, A. Tetrahedron 2010, 66, 3242–3247. (d) Wegner, J.; Ceylan, S.;
Kirschning, A. Adv. Synth. Catal. 2012, 354, 17–57. (e) Wiles, C.; Watts, P. Green Chem. 2012, 14,
38–54. (f) Wiles, C.; Watts, P. Green Chem. 2014, 16, 55–62.
(7) (a) Kulkarni, A. A.; Kalyani, V. S.; Joshi, R. A.; Josh, R. R. Org. Process Res. Dev. 2009, 13, 999–
1002. (b) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem., Int. Ed. 2009,
48, 4017–4021. (c) Yu, Z. Q.; Lv, Y. W.; Yu, C. M.; Su, W. K. Org. Process Res. Dev. 2013, 17, 438–
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 16
4
42.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
8) Zollinger, H. Diazo Chemistry I: Aromatic and Heteroaromatic Compounds; VCH
Verlagsgesellschaft mbH: Dꢀ69451 Weinheim, 1994.
(
9) Kindler, H.; Schuler, D. US 3423391, 1964.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(10)(a) MaletꢀSanz, L.; Madrzak, J.; Holvey, R. S.; Underwood, T. Tetrahedron Lett. 2009, 50,
7
263−7267. (b) Fortt, R.; Wootton, R. C. R.; de Mello, A. J. Org. Process Res. Dev. 2003, 7,
62−768. (c) Wootton, R. C. R.; Fortt, R.; de Mello, A. J. Lab Chip 2002, 2, 5−7. (d) MaletꢀSanz, B.;
7
Madrzak, J.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324−5332. For more reviews
on diazonium and diazo compounds in flow, see: (e) Mueller, S. T. R.; Wirth, T. ChemSusChem
2
015, 8, 245−250. (f) Deadman, B. J.; Collins. S. G.; Maguire, A. R. Chem. Eur. J. 2015, 21, 2298–
2308.
(
11)Browne, D. L.; Baxendale, I. R.; Ley, S. V. Tetrahedron 2011, 67, 10296−10303.
12)Li, B.; Widlicka, D.; Boucher, S.; Hayward, C.; Lucas, J.; Murray, J. C.; O’Neil, B. T.; Pfisterer, D.;
Samp, L.; VanAlsten, J.; Xiang, Y.; Young, J. Org. Process Res. Dev. 2012, 16, 2031−2035.
13) (a) Yu, Z. Q.; Lv, Y. W.; Yu, C. M. Org. Process Res. Dev. 2012, 16, 1669−1672. (b) Yu, Z. Q.; Lv,
Y. W.; Yu, C. M.; Su, W. K. Tendrahedron Lett. 2013, 54, 1261−1263.
(
(
(
14)As an extension of previous work: Lv, Y. W.; Yu, Z. Q.; Su, W. K. Org. Process Res. Dev. 2011, 15,
4
71−475.
(15)(a) Pan, F. Y.; Yang, J. G. Chin. J. Pharm. 1998, 29, 89. (b) Chen, Y. J.; Xu, D. J.; Hao, J.; Wang, Y.
J. Shenyang Inst. of Chem. Technol. 1999, 13, 243−247.
(
16)Patel, V. R.; Desai, H. T. J. At. Mol. 2013, 3, 520–523.
(17)With large amount of solute in this aqueous reaction system and pressure drop, the boiling point
o
was elevated, thus, no evident out gassing under the reaction temperature of 100 C.
ACS Paragon Plus Environment