100 gram scale synthesis of a key intermediate of matrix metalloproteinase inhibitor in a continuous-flow system based on a copper-free sonogashira reaction using an ionic liquid as a catalyst support

Article abstract of DOI:10.1055/s-0031-1290456

The key intermediate of matrix metalloproteinase (MMP) inhibitor was synthesized using a flow microreactor for a copper-free Sonogashira coupling reaction in an ionic liquid. The ionic liquid [emim]NTfwas used as a solvent and a catalyst support. A 100 g scale synthesis was achieved in combination with a flow-extraction/catalyst-recycling system, in which the ionic liquid containing the palladium catalyst was continuously recycled. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0031-1290456

LETTER
▌2279
letter
100 Gram Scale Synthesis of a Key Intermediate of Matrix Metalloproteinase
Inhibitor in a Continuous-Flow System Based on a Copper-Free Sonogashira
Reaction Using an Ionic Liquid as a Catalyst Support
Continuous-Flow Synthesis of a Key Intermediate of MMP Inhibitor
Takahide Fukuyama,*a Md. Taifur Rahman,a Yukihito Sumino,b Ilhyong Ryu*a
a
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
b
Quality, Safety and Regulatory Affairs Management Division, SHIONOGI & Co., LTD., Osaka, Osaka 541-0045, Japan
Fax +81(72)2549695; E-mail: fukuyama@c.s.osakafu-u.ac.jp
Received: 30.05.2012; Accepted after revision: 28.06.2012
tinuous microflow system for carrying out a copper-free
Abstract: The key intermediate of matrix metalloproteinase
Sonogashira coupling reaction,6 the Mizoroki–Heck reac-
(MMP) inhibitor was synthesized using a flow microreactor for a
tion,7 and a carbonylative Sonogashira reaction8 using low
viscosity IL such as [bmim]NTf2 as a reaction medium
copper-free Sonogashira coupling reaction in an ionic liquid. The
ionic liquid [emim]NTf2 was used as a solvent and a catalyst sup-
port. A 100 g scale synthesis was achieved in combination with a and a palladium N-heterocyclic carbene complex (Pd–
flow-extraction/catalyst-recycling system, in which the ionic liquid
containing the palladium catalyst was continuously recycled.
NHC) as a catalyst, in which IL can serve as a catalyst
support.9,10 We also developed a continuous catalyst-
Key words: microreactor, flow reaction, ionic liquids, palladium,
Sonogashira coupling, matrix metalloproteinase inhibitor
recycling system by connecting with a microextraction
system, which allowed the 100 g scale synthesis of butyl
cinnamate via the Mizoroki–Heck reaction.7 Then, we
embarked on the construction of a bench-top production
In the last decade, rapidly evolving microreaction technol- facility to synthesize 100 grams of 1 using such a
ogy based on tiny microchannels, typically tens to hun- catalyst-/medium-recycling protocol (Scheme 2).
dreds of μm wide and/or deep, has attracted broad
attention in organic synthesis, because of its great poten-
tial as a reaction apparatus for chemical reactions, since it
CO2H
O
O
allows efficient mixing, efficient heat and mass transfer,
precise residence time control, and high operational
safety.1,2 Microreaction systems when coupled with a con-
tinuous-flow system have good potentials as a tool for
chemical production.3 We recently reported the synthesis
of matrix metalloproteinase (MMP) inhibitor 14 (Figure 1)
via a Pd/Cu-catalyzed Sonogashira coupling reaction
in DMF using an automated microreactor system
(Scheme 1).5 Time-saving optimization of flow-reaction
conditions was accomplished using our home-made auto-
mated microreactor system, and the optimal conditions
could be immediately applied to a 100 gram scale produc-
tion. In this system, however, the recovery and the reuse
of the Pd/Cu catalysts has yet to be realized, since the used
solvent DMF, created a homogeneous solution.
S
Br
S
N
N
H
H
2
Tol
3
PdCl2(PPh3), CuBr
DMF
i-Pr2NEt
CO2H
Tol
O
O
S
S
N
N
H
H
1
CO2H
Scheme 1 Microflow synthesis of MMP inhibitor 15
O
O
S
S
N
N
H
H
separation
mixing
reaction
1
substrates
product
residence time unit
Figure 1 Matrix metalloproteinase (MMP) inhibitor 1
continuous recycling
Pd cat.
ionic liquid
Ionic liquids (IL) can act as excellent supports for transi-
tion-metal NHC complexes, and we have reported a con-
Scheme 2 Concept of a continuous catalyst-recycling system using
an IL as a reaction medium
SYNLETT 2012, 23, 2279–2283
Advanced online publication: 14.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290456; Art ID: ST-2012-U0463-L
© Georg Thieme Verlag Stuttgart · New York

2280
T. Fukuyama et al.
LETTER
To investigate the viability of a microflow version of the
above-mentioned step using IL as a solvent, we initially
checked a batch reaction (Scheme 3). Methyl ester 2′ was
used as the Sonogashira precursor, which was prepared by
the reaction of 5-bromo-2-thiophenesulfonyl chloride and
methyl ester of tryptophan. The batch reaction was carried
out using [emim]NTf2 as a reaction medium and Pd–NHC
complex A as a catalyst. Although the reaction was com-
pleted within 30 minutes to give the desired product 1′,
this reaction was unsuitable as a flow system for the fol-
lowing reasons: (i) the solubility of 2′ in a [emim]NTf2
solution containing (p-tolyl)acetylene (3) and diisopro-
pylamine was quite low, and (ii) the product could not be
extracted efficiently from a polar IL layer by a nonpolar
solvent such as cyclohexane.
O O
S
S
Br
OR
Tol
O
O
4
Pd
IL
S
S
+
OR
Tol
H
5
CO2Me
N
H
NH2
6
CO2Me
Tol
O
O
S
S
N
H
N
H
CO2Me
1'
Pd cat. A (5 mol%)
i-Pr2NH (2.4 equiv)
O
O
S
Tol
Scheme 4 Modified protocol for synthesis of MMP inhibitor’s pre-
cursor 1′
Br
S
N
H
+
N
[emim]NTf2
80 °C, 30 min
H
3 (1.2 equiv)
2'
obtained coupling product 5 reacted with compound 6 in
the presence of bases at 90 °C for 18 hours to give a 78%
yield of 1′ (Scheme 6).
CO2Me
Tol
O
O
S
S
N
N
H
Other sulfonyl esters, such as ethyl ester 4b and neopentyl
ester 4c, were found unsuitable for this protocol (Figure 2).
The Sonogashira coupling reaction of 4b with 3 gave a
complex mixture. In the case of 4c, while the coupling
product was obtained in good yield, the reaction with 6
was very sluggish.
H
1'
N
N
+N
NEt
Me
n-Bu
Me
(CF3SO2)2N–
Ph3P Pd Cl
Cl
Pd-carbene complex A
[emim]NTf2
O
O
O O
S
S
S
S
Br
Br
OEt
O
Scheme 3
4b
4c
To circumvent such limitations, we had to reconsider
another strategy suitable for the microflow system using
an IL. We planned to use sulfonyl ester derivatives 4
(Scheme 4), since the sulfonyl ester 4 should meet the fol-
lowing requirements: (i) sulfonyl ester derivatives 4
would be soluble with 3 and amine to give a homogeneous
solution; (ii) the copper-free Sonogashira reaction would
be successful in IL; (iii) the coupling product 5 would be
separated from the IL layer by an extraction using nonpo-
lar or less polar solvent; and, (iv) the coupling product 5
would react readily with a methyl ester of tryptophan 6 to
give the desired precursor 1′.
Figure 2
We then investigated the reaction of 4a with 3 in a micro-
flow system using a T-shaped mixer (1000 μm i.d.) and a
stainless steel tube (1000 μm i.d. × 50 cm) under varied
conditions. These results are summarized in Scheme 7.
The reaction at 80 °C with two minutes residence time
gave a 17:83 mixture of 4a and 5. A higher reaction tem-
perature (95 °C) resulted in complete conversion. A simi-
lar result was obtained with a shorter residence time
(1.75 min), while a 1.5 minutes residence time resulted in
a remaining portion of the starting substrate 4a. In all cas-
es, the reaction mixture obtained had a higher viscosity
because of the formation of an ammonium salt byproduct.
Since a high viscous IL solution might not flow smoothly
and could overburden the pumps, we tested the reaction in
a mixed-flow system, in which 1.5 M potassium carbonate
aqueous solution was mixed with the reaction mixture to
remove the ammonium salt quickly from the IL layer. For-
tunately, prior addition of an aqueous solution to the reac-
tion mixture did not interfere with the formation of 5.
Several sulfonyl esters were tested, and we found penta-
fluorophenyl ester 4a to have the most potential as a sub-
strate. Thus, we examined the reaction of 4a with 3 in
[emim]NTf2 in the presence of i-Pr2NEt as a base. When
these compounds were mixed at room temperature, a
homogeneous solution resulted. During and after the reac-
tion (80 °C to r.t.), the mixture remained homogeneous.
The coupling product 5 could be extracted by 30% diethyl
ether in cyclohexane. After silica gel chromatography,
compound 5 was obtained in 70% yield (Scheme 5). The
Synlett 2012, 23, 2279–2283
© Georg Thieme Verlag Stuttgart · New York

LETTER
Continuous-Flow Synthesis of a Key Intermediate of MMP Inhibitor
2281
Tol
O
O O
O
Pd cat. A (5 mol%)
S
S
S
S
Br
Tol
H
+
OC6F5
OC6F5
i-Pr2NEt (2 equiv)
80 °C, 30 min
[emim]NTf2
3 (1.2 equiv)
4a
5 70%
homogeneous
SiO2
Et2O–cyclohexane
5
4a, 3
i-Pr2NEt
Pd cat. A
IL
4a + 3
5
heat
cool
i-Pr2NEt•HBr
Pd cat. A
IL
i-Pr2NEt•HBr
Pd cat. A
IL
5
Scheme 5 Batch synthesis of 5
With these promising results in hand, we then constructed was removed from the residence time unit after 1.75 min-
a continuous production system (Scheme 8). For the pro- utes and mixed with 30% diethyl ether in cyclohexane us-
duction, a 2000 μm i.d. tube was used as a residence time ing another T-shaped mixer (400 μm i.d.). The entire
unit to increase productivity. Thus, a homogeneous mix- mixture was then passed through another tube (2000 μm
ture of 4a, 3, and i-Pr2NEt was mixed with the IL contain- i.d. × 25 cm, 40 °C) to ensure extraction. The exiting re-
ing the Pd–NHC complex using a T-shaped mixer action mixture was collected by a Y-shaped container
(600 μm i.d.), followed by mixing with 1.5 M potassium where it was partitioned in three distinct phases: an IL lay-
carbonate aqueous solution. The resulting mixture was in- er (bottom), an aqueous layer (middle), and an organic
troduced into a 2000 μm i.d. tube that was heated at 95 °C layer containing the product (top). The IL layer was con-
for 1.75 minutes (residence time). The reaction mixture tinuously fed into the reaction system using another
pump. The process was run for 5.5 hours, and consumed
269 mmol of the starting material 4a. After workup, 103
g of the desired compound 5 was obtained (86% yield).
CO2Me
Tol
O
O
+
S
S
N
H
In summary, the key intermediate of matrix metallo-
proteinase (MMP) inhibitor was successfully synthesized
OC6F5
H2N
via
a flow copper-free Sonogashira reaction in
5
6 (2.5 equiv)
[emim]NTf2 as a solvent. Sulfonyl ester 4a was found to
be a suitable substrate for the present continuous-micro-
flow synthesis. A 100 gram scale synthesis of 5, the pre-
cursor for matrix metalloproteinase (MMP) inhibitor 1,
was achieved using the continuous catalyst-recycling sys-
tem.
CO2Me
Tol
O
O
pyridine (2.5 equiv)
S
S
N
H
N
NMP
90 °C, 18 h
H
1' 78%
Scheme 6
O
O
S
S
Br
OC6F5
H
4a
Tol
(1.2 equiv)
5
1000 μm
RTU
i-Pr2NEt (2 equiv)
1000 μm x 50 cm
microflow
Pd-cat. A (5 mol%)
[emim]NTf2
temp
residence time
4/5a
80 °C
95 °C
95 °C
95 °C
2 min
2 min
17:83
0:100
0:100
5:95
1.75 min
1.5 min
a determined by 1H NMR analysis
Scheme 7 Microflow synthesis of 5
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2279–2283

2282
T. Fukuyama et al.
LETTER
Scheme 8 Synthesis of 5 on a 100 gram scale using a continuous-flow and catalyst-/solvent-recycling system
Aid for Scientific Research on Innovative Areas (No. 2105) from
the Ministry of Education, Culture, Sports, and Technology
(MEXT) of Japan.
Procedure for the 100 Gram Scale Synthesis of 5
A mixture of 4a (332.9 mmol, 136.2 g), (p-tolyl)acetylene (3,
400 mmol, 46.5 g), and i-Pr2NEt (674 mmol, 87.1 g) was loaded
into a container. The Pd catalyst A (5.1 mmol, 3.0 g) in [emim]NTf2
(75 mL) was loaded into another container. The flow rates were ad-
justed to 0.6 mL/min for both the substrates and the Pd-catalyst so-
lution, and the two solutions were mixed in a T-shaped micromixer
(MiChS α-600, 600 μm i.d.). The mixture was mixed with 5 M
K2CO3 aq solution in a T-shaped mixer with a 2000 μm i.d., and the
mixture was then fed into the residence time unit (2000 μm i.d. ×
1 m, residence time: 1.75 min), which was heated at 95 °C. The re-
action mixture was mixed with 30% Et2O in cyclohexane in another
T-shaped mixer (MiChS α-400, 400 μm i.d.), and the entire mixture
was passed through another tube (2000 μm i.d. × 25 cm, 40 °C) for
extraction. The exiting reaction mixture was collected in a Y-
shaped flask, where it was partitioned in three distinct phases. The
IL layer containing the Pd catalyst was pumped to the catalyst solu-
tion. This system was operated for 5.5 h and consumed 269 mmol
of the sulfonyl ester 4a. The organic phase was separated from the
aqueous phase and dried over MgSO4. After evaporation, a light
brown solid was obtained. The solid was washed with 10% Et2O–
hexane to remove any remaining 3 to give 90 g of 5 (mp 116–118 °C,
1H NMR analysis indicates a purity of >95%.). The washing (Et2O
+ hexane) was evaporated, and the resulting residue was purified by
SiO2 column chromatography (Et2O) providing another 13 g of pure
5 (mp 119–119.5 °C) (combined weight of 5 = 103 g, 86% yield).
1H NMR (500 MHz, CDCl3): δ = 7.20 (d, J = 7.8 Hz, 2 H), 7.25 (d,
J = 4.1 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 2 H), 7.68 (d, J = 4.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.7, 79.8, 99.2, 118.3, 129.5,
131.4, 131.8, 132.3, 135.2, 136.2, 136.9 (m), 139.0 (m), 140.3,
141.4 (m), 143.4 (m). IR (neat): 2253.4, 1520 cm–1. MS (EI): m/z =
408 [M+]. HRMS: m/z calcd for C10H2BrF5O3S2 [M+]: 407.8549;
found: 407.8540.
References
(1) (a) Wirth, T. Microreactors in Organic Synthesis and
Catalysis; Wiley-VCH: Weinheim, 2008. (b) Hessel, V.;
Renken, A.; Schouten, J. C.; Yoshida, J.-I. Micro Process
Engineering; Wiley-VCH: Weinheim, 2009. (c) Mason, B.
P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade,
D. T. Chem. Rev. 2007, 107, 2300. (d) Yoshida, J.; Nagaki,
A.; Yamada, T. Chem.–Eur. J. 2008, 14, 7450. (e) Lin, W.-
Y.; Wang, Y.; Wang, S.; Tseng, H.-R. Nano Today 2009, 4,
470. (f) McMullen, J. P.; Jensen, K. F. Annu. Rev. Anal.
Chem. 2010, 3, 19. (g) Webb, D.; Jamison, T. F. Chem. Sci.
2010, 675. (h) Yoshida, J. Chem. Rec. 2010, 10, 332.
(i) Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun.
2011, 47, 4583.
(2) For a review of our work, see: Fukuyama, T.; Rahman, M.
T.; Sato, M.; Ryu, I. Synlett 2008, 151.
(3) For selected examples, see: (a) Hessel, V.; Hofmann, C.;
Löwe, H.; Meudt, A.; Scheres, S.; Schönfeld, F.; Werner, B.
Org. Process Res. Dev. 2004, 8, 511. (b) Wakami, H.;
Yoshida, J. Org. Process Res. Dev. 2005, 9, 787. (c) Iwasaki,
T.; Kawano, N.; Yoshida, J. Org. Process Res. Dev. 2006,
10, 1126. (d) Tanaka, K.; Motomatsu, S.; Koyama, K.;
Tanaka, S.; Fukase, K. Org. Lett. 2007, 9, 299.
(4) 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.
(5) Sugimoto, A.; Fukuyama, T.; Rahman, M. T.; Ryu, I.
Tetrahedron Lett. 2009, 50, 6364.
(6) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I.
Org. Lett. 2002, 4, 1691.
(7) Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Org. Process Res.
Dev. 2004, 8, 477.
Acknowledgment
T.F. thanks the Industrial Technology Research Grant Program
from the New Energy and Industrial Technology Development Or-
ganization (NEDO) (05A33715d). I.R. acknowledges a Grant-in-
Synlett 2012, 23, 2279–2283
© Georg Thieme Verlag Stuttgart · New York

LETTER
Continuous-Flow Synthesis of a Key Intermediate of MMP Inhibitor
2283
(8) Rahman, M. T.; Fukuyama, T.; Kamata, N.; Sato, M.; Ryu,
I. Chem. Commun. 2006, 2236.
40, 1347. (f) Petkovic, M.; Seddon, K. R.; Rebelo, L. P. N.;
Pereira, C. S. Chem. Soc. Rev. 2011, 40, 1383.
(10) For our reports on coupling reactions using ionic liquids,
see: (a) Liu, S. F.; Fukuyama, T.; Sato, M. Synlett 2004,
1814. (b) Fukuyama, T.; Yamaura, R.; Ryu, I. Can. J. Chem.
2005, 83, 711. (c) Rahman, M. T.; Fukuyama, T.; Ryu, I.;
Suzuki, K.; Yonemura, K.; Hughes, P. F.; Nokihara, K.
Tetrahedron Lett. 2006, 47, 2703. (d) Fukuyama, T.; Inouye,
T.; Ryu, I. J. Organomet. Chem. 2007, 692, 685.
(e) Fukuyama, T.; Rahman, M. T.; Maetani, S.; Ryu, I.
Chem. Lett. 2011, 40, 1027.
(9) For recent reviews, see: (a) Wasserscheid, P.; Welton, T.
Ionic Liquids in Synthesis; Wiley-VCH: Weinheim, 2008.
(b) Ranke, J.; Stolte, S.; Störmann, R.; Arning, J.; Jastorff,
B. Chem. Rev. 2007, 107, 21, 83. (c) Plechkova, N. V.;
Seddon, K. R. Chem. Soc. Rev. 2008, 37, 123. (d) Hallett, J.
P.; Welton, T. Chem. Rev. 2011, 111, 3508. (e) Isambert, N.;
del Mar Sanchez Duque, M.; Plaquevent, J.-C.; Génisson,
Y.; Rodriguez, J.; Constantieux, T. Chem. Soc. Rev. 2011,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2279–2283