An automated-flow microreactor system for quick optimization and production: application of 10- and 100-gram order productions of a matrix metalloproteinase inhibitor using a Sonogashira coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2009.08.089

Sonogashira coupling reaction leading to a matrix metalloproteinase inhibitor was investigated using an automated microreactor system, which is a sequential temperature- and flow rate-programed reaction evaluation system. By repeating the use of this comp

Full text of DOI:10.1016/j.tetlet.2009.08.089

Tetrahedron Letters 50 (2009) 6364–6367
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An automated-flow microreactor system for quick optimization
and production: application of 10- and 100-gram order productions
of a matrix metalloproteinase inhibitor using a Sonogashira coupling reaction
b
b
Atsushi Sugimoto a, Takahide Fukuyama b, , Md. Taifur Rahman , Ilhyong Ryu
*
a Synthetic Chemistry, CMC Development Laboratories, Shionogi & Co., Ltd, Amagasaki, Hyogo 660-0813, Japan
b Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Sonogashira coupling reaction leading to a matrix metalloproteinase inhibitor was investigated using an
automated microreactor system, which is a sequential temperature- and flow rate-programed reaction
evaluation system. By repeating the use of this computer-controlled system four times, we were able
to determine the optimal conditions and quickly apply them to a 10 g scale synthesis using the same mic-
roreactor system. The optimal conditions were also applied to a 100 g scale production by using another
Received 11 July 2009
Revised 26 August 2009
Accepted 27 August 2009
Available online 31 August 2009
microflow system composed of a T-shaped micromixer (200
lm id) and a stainless tube reactor (2000 lm
id and 20 m length). Total time spent for both optimization and production was as short as 50 h.
Ó 2009 Elsevier Ltd. All rights reserved.
Microreaction systems have recently attracted attention in the
field of organic synthesis.1–3 In order to generalize microreaction
technology and make it more chemist friendly, the development
of a microreactor system that will allow speedy optimization of
reaction conditions, such as flow rates and temperatures, is highly
desirable because tedious and repetitious setup is generally re-
quired for each experiment of different microflow conditions. We
have developed an automated PC-controlled microreactor system,
which can accommodate the easy execution of multiple reaction
conditions, such as flow rates and temperatures, with essentially
a single setup.4 Herein, we report that a Sonogashira reaction5
leading to a matrix metalloproteinase inhibitor6 can be quickly
optimized using this automated microreactor system.3a,7 We also
report that the optimal conditions were immediately applied to a
100-g scale synthesis. Remarkably, the total time, including opti-
mization and production, can be as little as 50 h.
gramming temperatures and flow rates, and, therefore, the temper-
ature and residence time can be quickly optimized (first stage,
Scheme 1). The optimal conditions thus obtained can be applied
to large-scale production using a robust microflow system (second
stage).
The Sonogashira coupling reaction represents the cross-cou-
pling of terminal alkynes and aryl halides leading to internal al-
kynes by the palladium catalyst, a copper co-catalyst, and a
base.5 The coupling reaction of bromothiophene derivative 1 and
p-tolylacetylene (2) to obtain 3, a matrix metalloproteinase inhivi-
tor,6 was settled upon as the model reaction for this work (Eq. 1).
H
H
SO2
N
Pd,Cu cat.
base
Br
S
+
CO2H
N
H
1
2
ð1Þ
Our group collaborated with Dainippon Screen Mfg. Co., Ltd, to
develop an automated microreactor system that could be used to
quickly identify optimal reaction conditions (Fig. 1). This microre-
H
N
S
SO2
CO2H
actor system consists of a micromixer (1000
lm), a residence time
N
H
3
unit (RTU, 1000 m id and 10 m length), two pumps, and a fraction
l
collector. Individual flow rates for solutions A and B, and tempera-
tures of the micromixer and the RTU can be attired sequentially
and automatically, based on the initial input from the software.
The reaction mixture for each condition exiting the system is auto-
matically sampled by a fraction collector. This system allows
screening of up to 120 reaction conditions in one operation by pro-
For the initial screening of the Sonogashira reaction, seven con-
ditions with different temperatures (70–110 °C) and residence
times (20–60 min) were tested (Fig. 2). It was found that the opti-
mal conditions (reaction temperature: 110 °C and residence time:
60 min) gave the desired coupling product in an 88% HPLC ratio
(condition 7).8 Although tolylacetylene (2) was totally consumed,
a small amount of 1 remained due to the undesirable homocou-
pling of 2.
* Corresponding author. Tel./fax: +81 72 254 9695.
E-mail address: fukuyama@c.s.osakafu-u.ac.jp (T. Fukuyama).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.089

A. Sugimoto et al. / Tetrahedron Letters 50 (2009) 6364–6367
6365
1 (0.45 M)
2 (1.08 equiv)
PdCl2(PPh3)2 (1 mol%)
fraction collector
CuBr (2 mol%)
DMF
micromixer
3
RTU
pumps
iPr2NEt (2.5 equiv)
heat
micromixer and
residence time unit
RTU
1000 µm i.d.
10 m lentgth
micromixer
500 µm depth
1000 µm width
Figure 2. First screening, solution A: 1 (0.45 M in DMF), 2 (1.08 equiv), PdCl2(PPh3)2
(1 mol %), CuBr (2 mol %), solution B: diisopropylethylamine (2.5 equiv).
Figure 1. Pictures of the employed microreactor system (DSASS).
Figure 3. Second screening, solution A:
1 (0.45 M in DMF), tolylacetylene
(1.3 equiv), PdCl2(PPh3)2 (1 mol %), and CuBr (2 mol %), solution B: diisopropyleth-
ylamine (2.5 equiv).
Scheme 1. Concept of the present model work.
To investigate the optimal amount of p-tolylacetylene (2), reac-
tions were carried out at 120 °C by adjusting the flow rates of solu-
tions A and B. The results are shown in Figure 4. When 1.25 equiv
of p-tolylacetylene was used, both 1 and 2 were almost consumed,
whereas a small amount of 1 remained (condition 6). Similarly, we
investigated the optimal amount of amine (Fig. 5), and found that
when using 3 equiv of amine with a 20 min residence time, both 1
and 2 were almost consumed. Therefore, we adopted a condition 4
for gram-scale production. Continuous operation of the same sys-
tem with no fraction collector was performed and 3 was obtained
(8 h, 84% yield, 14 g of 3) with no problems.
Thus, a second set of experiments was carried out to improve
the conversion of 1 using increased amounts of 2 (1.3 equiv)
(Fig. 3). We examined another six conditions at 110 and 120 °C
at varied residence times. The reaction at 110 °C with a 40 min res-
idence time gave the desired product in good yield (condition 3).
When the reaction was carried out at 120 °C under the same resi-
dence time, the pressure inside the microreactor rose gradually be-
cause of clogging, and the system was shut down for safety. The
speculation was that the insoluble substances gradually accumu-
lated inside the RTU and eventually clogged it. Gratifyingly, reac-
tion with shorter residence time (20 min) could be carried out
without any clogging. Therefore, we judged the reaction having
the shorter residence time (condition 5) to be the best reaction
condition for this screening. Although almost complete consump-
tion of bromothiophene 1 was attained, the remaining tolylacety-
lene (2) posed a problem.
Although numbering up of microflow system allows large scale
production, it is also important to increase the through put for one
system. Encouraged by the above results, we next executed a 100-g
scale production of 3 using a different robust microreactor system
(Scheme 2), which was composed of pumps, a micromixer (MiChS
type
a lm id) and a RTU (2 mm id and 20 m
micromixer,9 200
length). Temperature and residence time were set at 120 °C and
20 min. To realize high productivity, we used a RTU with a larger

6366
A. Sugimoto et al. / Tetrahedron Letters 50 (2009) 6364–6367
1 (149.4 g, 0.45 M)
2 (1.25 equiv)
PdCl2 (PPh3)2 (1 mol%)
CuBr (2 mol%)
DMF
1 (0.45 M)
120 °C
PdCl2(PPh3)2 (1 mol%)
CuBr (2 mol%)
iPr2NEt (2.5 equiv)
DMF
20 min residence time
2.62 mL/min
RTU
micromixer
200 µm
micromixer
3
RTU
2 mm x 20 m
iPr2NEt (3 equiv)
0.52 mL/min
2
120 °C
H
N
S
SO2
CO2H
3 (113 g after 6 h)
Scheme 2. 100-g scale production of 3.
N
H
by its ability to eliminate the time lag between optimization and
production as well as to shorten total processing time.
Acknowledgments
We thank MCPT and NEDO for financial support of this work.
I.R. acknowledges JSPS and MEXT Japan for funding. The microreac-
tor system was offered by Dainippon Screen Mfg. Co., Ltd.
Figure 4. Third screening, solution A: 1 (0.45 M in DMF), PdCl2(PPh3)2 (1 mol %),
CuBr (2 mol %), diisopropylethylamine (2.5 equiv), solution B: 2, reaction temper-
ature: 120 °C.
References and notes
1. For selected reviews, see: (a) Ehrfeld, W.; Hessel, V.; Lowe, H. Microreactors:
New Technology for Modern Chemistry; Wiley-VCH: Weinheim, 2000; (b)
Wirth, T. Microreactors in Organic Synthesis and Catalysis; Wiley-VCH:
Weinheim, 2008; (c) Yoshida, J.. Flash Chemistry. Fast Organic Synthesis in
Mirosystem; Wiley: Chichester, 2008; (d) Hessel, V.; Renken, A.; Schouten, J. C.;
Yoshida, J. Micro Process Engineering; Wiley-VCH: Weinheim, 2009; (e)
Jahnisch, K.; Hessel, V.; Lowe, H.; Baerns, M. Angew. Chem., Int. Ed. 2004, 43,
406; (f) Geyer, K.; Codée, J. D. C.; Seeberger, P. H. Chem. Eur. J. 2006, 12, 8434;
(g) Kobayashi, J.; Mori, Y.; Kobayashi, S. Chem. Asian J. 2006, 1, 22; (h) Ahmed-
Omer, B.; Brandt, J. C.; Wirth, T. Org. Biomol. Chem. 2007, 5, 733; (i) Yoshida, J.;
Nagaki, A.; Yamada, T. Chem. Eur. J. 2008, 14, 7450.
internal volume that would allow for higher flow rates (total flow
rate: 3.14 mL/min). When the system was continuously operated
for 6 h, 113 g of 3 was obtained after recrystallization (70% yield).10
In conclusion, a Sonogashira coupling reaction leading to a ma-
trix metalloproteinase inhibitor was investigated as a model reac-
tion using the originally developed automated microflow system.
Quick optimization of reaction conditions was accomplished and
the application to a 10 g order synthesis with this system was
achieved. Using the optimal conditions and a different robust mic-
roreactor system, we successfully carried out a 100-g scale produc-
tion. The real and practical advantage of this system is manifested
2. For an account of our work using microreactors, see: Fukuyama, T.; Rahman, M.
T.; Sato, M.; Ryu, I. Synlett 2008, 151.
3. For our recent work using microreactors, see: Sonogashira reaction: (a)
Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org. Lett. 2002, 4,
1691; Mizoroki-Heck reaction: (b) Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Org.
Process Res. Dev. 2004, 8, 477; Carbonylative Sonogashira reaction: (c) Rahman,
M. T.; Fukuyama, T.; Kamata, N.; Sato, M.; Ryu, I. Chem. Commun. 2006, 2236;
Photo-induced [2+2] cycloaddition: (d) Fukuyama, T.; Hino, Y.; Kamata, N.;
Ryu, I. Chem. Lett. 2004, 33, 1430; Photo-induced Barton reaction: (e) Sugimoto,
A.; Sumino, Y.; Takagi, M.; Fukuyama, T.; Ryu, I. Tetrahedron Lett. 2006, 47,
6197; (f) Sugimoto, A.; Fukuyama, T.; Sumino, Y.; Takagi, M.; Ryu, I. Tetrahedron
2009, 65, 1593; Tin hydride mediated radical reaction: (g) Fukuyama, T.;
Kobayashi, M.; Rahman, M. T.; Ryu, I. Org. Lett. 2008, 10, 533; Radical
Carboaminoxylation: (h) Wienhöfer, I. C.; Studer, A.; Rahman, M. T.;
Fukuyama, T.; Ryu, I. Org. Lett. 2009, 11, 2457; Radical carbonylation: (i)
Fukuyama, T.; Rahman, M. T.; Kamata, N.; Ryu, I. Beilstein. J. Org. Chem. 2009, 5,
34.
1 (0.45 M)
2 (1.25 equiv)
PdCl2(PPh3)2 (1 mol%)
CuBr (2 mol%)
DMF
micromixer
3
RTU
iPr2NEt
120 °C
4. For a catalyst-screening system using a microreactor, see: de Bellefin, C.;
Tanchoux, N.; Caravieilhes, S.; Grenouillet, P.; Hessel, V. Angew. Chem., Int. Ed.
2000, 39, 3442.
5. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467; For
reviews, see: (b) Sonogashira, K.. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, pp 521–549; (c)
Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998; pp 203–229; (d) Chinchilla, R.; Nájera,
C. Chem. Rev. 2007, 107, 874.
6. Tamura, Y.; Watanabe, F.; Nakatani, T.; Yasui, K.; Fuji, M.; Komurasaki, T.;
Tsuzuki, H.; Maekawa, R.; Yoshioka, T.; Kawada, K.; Sugita, K.; Ohtani, M. J. Med.
Chem. 1998, 41, 640.
7. Sonogashira reaction in a microflow system Kawanami, H.; Matsushima, K.;
Sato, M.; Ikushima, Y. Angew. Chem., Int. Ed. 2007, 46, 5129.
8. Product ratio was determined by HPLC analysis by comparing the peak area
with that of the standard solution containing an authentic sample. HPLC
analysis was performed under the following conditions: column, Cosmosil
5C18-AR (4.6 ꢀ 150 mm); solvent, MeCN/H2O/AcOH (50/50/0.1); flow rate,
1 mL/min; detection, 254 nm. It takes ca. 20 min to analyze one sample.
9. Stainless steel made micormixer having T-shaped microchannel (200
see: http://www.michs.jp/.
lm id).
10. Solution A (1 (149.4 g, 0.45 M), 2 (50.5 g, 1.25 equiv), PdCl2(PPh3)2 (2.44 g,
1 mol %) and CuBr (1.00 g, 2 mol %) in DMF (740 mL)) and solution
(diisopropylethylamine (134.9 g, 3.0 equiv)) were mixed in the micromixer
(200 m, flow rate; solution A: 2.62 mL/min, solution B: 0.52 mL/min), and
B
Figure 5. Fourth screening, solution A: 1 (0.45 M in DMF), PdCl2(PPh3)2 (1 mol %),
CuBr (2 mol %), and 2 (1.25 equiv), solution B: diisopropylethylamine, reaction
temperature: 120 °C.
l

A. Sugimoto et al. / Tetrahedron Letters 50 (2009) 6364–6367
6367
then the mixture was fed into the residence time unit (2 mm id, 20 m length,
temperature: 120 °C, residence time: 20 min). After 6 h, ethyl acetate (500 mL)
and 0.1 M hydrochloric acid (600 mL) were added to the reaction mixture.
After phases were separated, methanol (150 mL) was added to the organic
layer, and 10 wt % NaOH (260 mL) was dropped into the mixture to give a
crystal. After the filtration, the crystal that was obtained was dissolved in water
(480 mL) and ethyl acetate (1300 mL) was added. To this mixture was added
concd HCl (60 g). The ethyl acetate layer was separated and the solvent was
removed under reduced pressure. The crystal was dissolved in acetone
(800 mL). Then, water (1200 mL) was dropped into the solution to give the
crystal. The crystal was filtered and dried (113 g, 70% yield, mp = 180 °C, lit.6
mp = 180–182 °C).