Aminolysis of epoxides in a microreactor system: A continuous flow approach to β-Amino alcohols

Article abstract of DOI:10.1021/op9003136

The use of a continuous flow microreactor for β-amino alcohol formation by epoxide aminolysis is evaluated. Comparison to microwave batch reactions reveals that conditions obtainable in the microreactor can match or improve yields in many cases. By increasing the pressure of the system, maximum temperatures can also exceed those accessible using a microwave unit. The use of a microreactor for epoxide aminolysis reactions in the synthesis of two pharmaceutical relevant compounds is described.

Full text of DOI:10.1021/op9003136

Organic Process Research & Development 2010, 14, 432–440
Aminolysis of Epoxides in a Microreactor System: A Continuous Flow Approach to
ꢀ-Amino Alcohols
Matthew W. Bedore,† Nikolay Zaborenko,‡ Klavs F. Jensen,*,‡ and Timothy F. Jamison*,†
Departments of Chemistry and Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts AVenue,
Cambridge, Massachusetts 02139, U.S.A.
Abstract:
assisted aminolysis of epoxides in an efficient and straightfor-
ward manner.3b,6
The use of a continuous flow microreactor for ꢀ-amino alcohol
formation by epoxide aminolysis is evaluated. Comparison to
microwave batch reactions reveals that conditions obtainable in
the microreactor can match or improve yields in many cases. By
increasing the pressure of the system, maximum temperatures can
also exceed those accessible using a microwave unit. The use of a
microreactor for epoxide aminolysis reactions in the synthesis of
two pharmaceutical relevant compounds is described.
The use of microreactor technology and continuous flow
approaches has become an increasingly popular endeavor in
both academia and the pharmaceutical industry.7 This technol-
ogy can serve as a means to streamline efficiency in the
production of biologically active materials.8 The commercial
availability of continuous flow devices as well as detailed
descriptions of “homemade” ones has enabled easier access to
this expanding field. Microreactors in particular have unique
advantages over conventional batch processes. Due to rapid heat
and mass transfer, reaction profiles are often improved, and high
temperatures and pressures not easily attainable in batch
chemistry can now safely be realized while allowing for rapid
reaction monitoring.7b Many of these same principles can be
achieved using microwave chemistry;9 however, limitations in
microwave penetration depth have hampered scale-up to the
industrial realm. The advent of continuous flow microwave
processes has quickly become one of the answers to the scale-
up issues.10 However, conditions attainable in microreactors can
often rival those obtained in traditional microwave processes.11
Continuous flow microreactors also eliminate the need to scale
up hazardous batch reactions, can easily be “scaled out” by
linking them in parallel, and have the further benefit of not
requiring microwave generators.12
Introduction
ꢀ-Amino alcohols are an important class of compounds to
the synthetic and pharmaceutical communities. Oxycontin,
Coreg, and Toprol-XL display this functional group pattern,
and other pharmaceutical drugs such as Zyvox and Skelaxin
feature oxazolidones that can be formed through ꢀ-amino
alcohol precursors. A variety of methods to construct ꢀ-amino
alcohols have been described in the literature, and one of the
more frequently used approaches involves ring-opening of
epoxides with amine nucleophiles.1 Significant advances have
been made in the promotion of epoxide aminolyses by addition
of lanthanide triflates,2 Lewis acids,3 solid acid supports,4 or
by using solvents such as water.5 While these methods are
effective for relatively simple substrates, the opening of epoxides
with amines at high temperatures remains one of the more
general means of amino alcohol formation. Microwave irradia-
tion is often used to rapidly achieve high reaction temperatures;
indeed, Lindsay and co-workers recently described microwave-
Our efforts have focused on adapting pharmaceutically
prevalent batch reactions, such as ꢀ-amino alcohol formation
through epoxide aminolysis, to a continuous flow microreactor
process. To the best of our knowledge, this constitutes the first
* Authors for correspondence. E: mail: kfjensen@mit.edu; tfj@mit.edu.
† Department of Chemistry.
(6) (a) Robin, A.; Brown, F.; Bahamontes-Rosa, N.; Wu, B.; Beitz, E.;
Kun, J. F. J.; Flitsch, S. L. J. Med. Chem. 2007, 50, 4243. (b) Lidstro¨m,
P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
(7) (a) Wiles, C.; Watts, P. Eur. J. Org. Chem. 2008, 1655. (b) Mason,
B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T.
Chem. ReV. 2007, 107, 2300. (c) Kirshning, A.; Jas, G. Chem.sEur.
J. 2003, 9, 5708. (d) Wiles, C.; Watts, P. Expert Opin. Drug DiscoVery
2007, 2, 1487.
‡ Department of Chemical Engineering.
(1) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(2) For examples see: (a) Chini, M.; Crotti, P.; Favero, L.; Macchia, F.;
Pineschi, M. Tetrahedron Lett. 1994, 35, 433. (b) Procopio, A.;
Gaspari, M.; Nardi, M.; Oliverio, M.; Rosati, O. Tetrahedron Lett.
2008, 49, 2289. (c) Yadav, J. S.; Reddy, A. R.; Narsaiah, A. V.; Reddy,
B. V. S. J. Mol. Catal. A: Chem. 2007, 261, 207. (d) Cepanec, I.;
Litvic´, M.; Mikuldasˇ, H.; Bartolincˇec´, A.; Vinkovic´, V. Tetrahedron
2003, 59, 2435.
(8) Roberge, D. M.; Zimmermann, B.; Rainon, F.; Gottsponer, M.;
Eyholzer, M.; Kockmann, N. Org. Process Res. DeV. 2008, 12, 905.
(9) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
(3) For listings of metal-promoted epoxide aminolysis references see: (a)
Cossy, J.; Bellosta, V.; Hamoir, C.; Desmurs, J.-R. Tetrahedron Lett.
2002, 43, 7083. (b) Desai, H.; D’Souza, B. R.; Foether, D.; Johnson,
B. F.; Lindsay, H. A. Synthesis 2007, 902.
(10) (a) Bowman, M. D.; Holcomb, J. L.; Kormos, C. M.; Leadbeater, N. E.;
Williams, V. A. Org. Process Res. DeV. 2008, 12, 41. (b) Glasnov,
T. N.; Kappe, C. O. Macromol. Rapid Commun. 2007, 28, 395. (c)
Moseley, J. D.; Woodman, E. K. Org. Process Res. DeV. 2008, 12,
967. (d) Bowman, M. D.; Schmink, J. R.; McGowan, C. M.; Kormos,
C. D.; Leadbeater, N. E. Org. Process Res. DeV. 2008, 12, 1078.
(11) (a) Benito-Lopez, F.; Egberkin, R. J. M.; Renhoudt, D. N.; Verboom,
W. Tetrahedron 2008, 64, 10023. (b) Razzaq, T.; Glasnov, T. N.;
Kappe, C. O. Eur. J. Org. Chem. 2009, 9, 1321.
(4) For examples see: (a) Onaka, M.; Kawai, M.; Izumi, Y. Chem. Lett.
1985, 779. (b) Vijender, M.; Kishore, P.; Narender, P.; Satyanarayana,
B. J. Mol. Catal. A: Chem. 2007, 266, 290. (c) Maheswara, M.; Rao,
K. S. V. K.; Do, J. Y. Tetrahedron Lett. 2008, 49, 1795. (d) Kumar,
S. R.; Leelavathi, P. J. Mol. Catal. A: Chem. 2007, 266, 65.
(5) For recent examples see: (a) Bonollo, S.; Finguelli, F.; Pizzo, F.;
Vaccaro, L. Green Chem. 2006, 8, 960. (b) Azizi, N.; Saidi, M. R.
Org. Lett. 2005, 7, 3649.
(12) Murphy, E. R.; Martinelli, J. R.; Zaborenko, N.; Buchwald, S. L.;
Jensen, K. F. Angew. Chem., Int. Ed. 2007, 46, 1734.
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10.1021/op9003136  2010 American Chemical Society
Published on Web 01/26/2010

Scheme 1. Aminolysis reaction conducted in the synthesis of the COPD drug indacaterol (1)
synthesis of pharmaceutically relevant compounds indacaterol
and metoprolol are presented herein.
study of epoxide aminolysis completed in a microreactor.13
Further interest in this area was piqued by reports of the ꢀ-amino
alcohol indacaterol 1 (Scheme 1), a novel ꢀ-adrenoceptor
agonist developed by Novartis.14 This drug candidate, currently
in phase III clinical trials, is used in the treatment of chronic
obstruction pulmonary disease (COPD) and has shown promise
as a one-dose daily bronchodilator.15
The reported current synthesis of 1 centers on the aminolysis
of epoxide 2 with amine 3 to afford precursor 4 under a
protracted reaction time.16 In addition, the regioisomer 5 and a
product of double alkylation 6 are also formed in significant
quantities. Our initial efforts focused toward decreasing reaction
time in order to enable the use of a microscale flow system.
Attempts to catalyze the aminolysis with solid acid supports
such as PMA-alumina,4d Amberlyst-15,4b and ZnClO4-alumina4c
led to little or no product formation even after extended periods
of time. Catalysis with lanthanide triflates such as Er(OTf)32b
and Yb(OTf)32a ultimately led to shorter reaction times (ap-
proximately 5 h) but yielded large amounts of undesired
byproduct.
Results and Discussion
Microfluidic System. A 120 µL silicon microreactor system
was used, providing a chemically and physically robust
environment capable of rapid thermal equilibration (Figure 1).
The silicon channels were coated with silicon nitride to provide
chemical resistance, enabling the reactor to withstand slightly
basic conditions at high temperatures. Although the use of
silicon nitride is a slight departure from typical glass systems,
the significantly higher resistance of nitride to caustic corrosion,
as compared to that of oxide, is a major advantage, expanding
the utility of the microreactor to a wider range of chemical
systems. Additionally, as the microfabrication process of nitride
deposition is no more difficult than that of silicon oxide growth,
there is no inherent drawback to its usage over that of oxide.
Combined with Kalrez (a fluoroelastomer) O-rings, the
reactor system is capable of withstanding a wide range of
solvents and chemical conditions. The elasticity of the O-rings
and rigidity of silicon easily allows for the 500 psi pressure
applied in this study to access the desired temperatures; similar
reactor configurations have been applied to synthesis at super-
critical fluid conditions.17
Interfacial forces are dominant at the microfluidic scale.
Combined with the smoothness of the channel walls, these
forces result in solvent superheating to above boiling temper-
atures, which has been confirmed experimentally. Using the
Antoine equation, the boiling points for ethanol and acetonitrile
were calculated at 250 psi to be at 174 and 208 °C, respectively,
and at 500 psi, 206 and 259 °C, respectively. However, within
the microreactor, pure ethanol was not observed to boil at 250
psi until 217 °C was attained, with freshly incoming material
ceasing to boil when the reactor was cooled to 206 °C. At 500
In contrast, we found that simple heating of the reaction in
ethanol at 150 °C under microwave irradiation or in an oil bath
resulted in complete conversion within 35 min with moderate
(∼60%) product formation. Given the demonstrated effective-
ness of microreactors in achieving high temperatures and
pressures in a continuous flow manner, we pursued a study of
epoxide aminolysis reactions using this technology. These
results as well as the application of this technique toward the
(13) We are aware of one report of epoxide aminolysis in a continuous
flow manner: Tachibana, S.; Yoshiyama, R., Oishi, T.; Sakurai, M.;
Ishida, K.; Tsujiuchi, T.; Hidehisa, M.; Araki, R.; Saito K. WO/2007/
JP65354, 2007;Chem. Abstr. 2007, 149, 56033.
(14) Cuenoud, B.; Bruce, I.; Fairhurst, R.; Beattie, D. WO/2000/75114,
2000; Chem. Abstr. 2000, 1434, 42074.
(15) Sturton, R. G.; Trifilieff, A.; Nicholson, A. G.; Barnes, P. J.
J. Pharmacol. Exp. Ther. 2008, 324, 270.
(16) Lohse, O.; Vogel, C. WO/2004/076422, 2004; Chem. Abstr. 2004,
141, 260556.
(17) Marre, S.; Park, J.; Rempel, J.; Guan, J.; Bawendi, M. G.; Jensen,
K. F. AdV. Mater. 2008, 20, 4830.
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the temperature at any point within the silicon reaction zone
was expected to be within 2 °C of that measured by the
thermocouple, inserted into the heating chuck 0.5 mm below
the chuck surface. Additionally, the spiral channel layout
ensured that any inhomogeneity in temperature would have little
effect on the reaction. The etched-out area of the reactor
establishes thermal separation between the inlet/outlet area
(including the mixing zone) and the reaction area of the reactor.
This allows the area in contact with polymer O-rings and fittings
to remain at room temperature when the compression chuck is
water-cooled, while the reaction zone is at temperatures of up
to 300 °C. In addition to enabling simple fluidic packaging,
the small volumes within the microreactor ensure that the
reaction mixture is rapidly brought to room temperature upon
leaving the reaction zone, providing highly efficient quenching
and accurate residence time evaluation.
General Aminolysis of Epoxides. In order to test the
limitations and effectiveness of microreactors in the aminolysis
of epoxides, a variety of substrates were investigated. Of
particular interest was the direct comparison of results obtained
under standard batch microwave protocols and those obtained
using the microreactor under similar conditions. We selected
this comparison for many reasons. For one, microwave reactors
allow for superheating of organic solvents in a medium-to-high
throughput fashion (using an autosampler). More importantly,
the heating profile in microfluidic reactors appears to be more
akin to that in microwave reactors than that observed in typical
batch heating, particularly the time to reach desired reaction
temperature. However, it should be noted that the cooling profile
in microfluidic reactors is far superior to that generally observed
in batch microwave reactors, and moreover, it is important to
consider that the microreactor setup is capable of operating at
higher temperatures than those ultimately obtained in the
microwave due to higher pressure tolerances. Ethanol was
chosen as the initial solvent due to its good solvating properties,
high dielectric constant, and low toxicity. The results of these
reactions are summarized in Table 1.
The ring-opening of phenyl glycidyl ether 7 with 2-ami-
noindan 8 was first investigated. Under microwave irradiation
in a sealed vial, complete conversion was obtained in 30 min
at 150 °C (Table 1, entry 1). The pressures attained in a 5 mL
vial with 1 mL of solution ranged anywhere from 100 to 130
psi during the course of the reaction. The major product obtained
resulted from nucleophilic attack at the R-terminal end of the
epoxide, and only minor isolated amounts (∼1-2%, not
quantified by HPLC analysis) of the regioisomer were observed.
Formation of the bis-alkylated product, derived from the
subsequent reaction of the product with an additional equivalent
of the epoxide, was also prevalent in this example and overall
mass balances were excellent. Using a 250 psi backpressure
regulator and a flow rate of 4 µL/min (30 min residence time)
at 150 °C, complete conversion was obtained in the microre-
actor, and product distributions mirrored those of the microwave
experiment (Table 1, entry 2). With an epoxide concentration
of 1 M and 250 psi of backpressure, ethanol was easily
superheated to 195 °C without boiling being observed in the
microreactor, and near complete conversion was realized at this
temperature in 2 min (Table 1, entry 2).
Figure 1. Microreactor layout diagram and setup for epoxide
aminolysis.
psi, ethanol did not boil until 250 °C, with flashing ceasing
when cooled to 246 °C. A similar effect was observed with
acetonitrile, which, at 250 psi, only boiled at 246 °C, ceasing
at 239 °C. At 500 psi, boiling was not achieved even when
heated to 300 °C. Thus, the dominance of interfacial forces on
the microscale further extends the range of operating temper-
atures beyond even those afforded by the pressurization.
Boiling was easily observed visually, as the top side of the
microreactor consists of transparent borosilicate glass, allowing
an unfettered view into the reaction channel and further
demonstrating the utility of the applied reactor design. When it
occurred, boiling was observed at the transition between the
cooled mixing zone and the heated reaction zone, where the
reaction stream flashed, or was rapidly transformed primarily
into gas phase with only small volumes of liquid phase
remaining. When temperature was sufficiently decreased, flash-
ing was seen to cease, with the reaction stream remaining
homogeneous (liquid-phase) throughout the reaction zone.
The high thermal conductivity of silicon (148 W/m/K
compared to stainless steel ∼40 W/m/K) greatly aids in
spreading heat and significantly reduces the occurrence of hot
spots. The use of aluminum for the heating chuck and of
graphite as the liner between the chuck and the reactor further
helped distribute the heat while providing high heat transfer.
Based on heat transfer calculations and finite element modeling,
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Table 1. General aminolysis reactions performed in a continuous-flow microreactor
a All reactions were run in ethanol at 1 M concentration in epoxide. b Combined flow rate of both reagents. c All yields are calculated by HPLC analysis with an internal
standard with the exception of Trials 10-14 which were analyzed by GC. d Bis-alkylation arises from product reaction with starting material to give the tertiary amine. e 1 mL
f
volume in a 5 mL vial. ∼1-2% of regioisomer was isolated but not quantified. g 2 mL volume in a 5 mL vial.
The role of volatile amines in epoxide aminolysis was critical
to understanding the benefits of microreactors over typical batch
conditions. tert-Butylamine 9 was utilized for this study due to
its relatively low boiling point (46 °C) and because it enabled
the examination of a rather hindered substrate. Opening of
phenyl glycidyl ether at the terminal position of the epoxide
was complete after microwave irradiation for 30 min. However,
the product distributions were found to be dictated by the
reaction volumes (Table 1, entries 5 and 6). Notable increases
in the amount of bis-alkylation product were observed when 1
mL of solution was heated in a 5 mL sealed vial, whereas 2
mL of the reaction mixture gave improved results. This variance
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is likely due to the reduction in available headspace and
concomitant decrease in the amount of amine in the vapor phase.
Since the amine is more volatile than the solvent, its vaporization
decreases its concentration in solution, reducing the reaction
efficiency. In contrast, the absence of headspace in the continu-
ous-flow microreactor led to consistent product distributions,
independent of reaction volumes (Table 1, entry 7). When this
volatile amine was used, reaction temperatures could also be
maintained at 195 °C to afford almost complete conversion with
residence times of 3 min (Table 1, entries 8 and 9). Product
distribution as a function of vial headspace was also observed
in the opening of styrene oxide 10 with tert-butylamine (Table
1, entries 10-12).
Internal and trisubstituted epoxides were also examined
under microreactor conditions. Using the hindered secondary
amine, indoline 12, and 1,4-dihydronaphthalene oxide 13,
aminolysis was conducted both in the microwave and microre-
actor at 150 °C (Table 1, entries 18 and 19). Unfortunately,
only moderate substrate conversion was obtained in each case.
The higher conversions observed in the microwave process
compared to the microreactor can be attributed to two factors.
First, the overall concentration in a microwave vial is somewhat
higher due to the headspace available to volatilize the solvent.
Second, microwave reaction times are slightly extended due to
periods of warming and cooling during the pre- and post-
reaction phases. Since microreactors take advantage of large
surface-to-volume ratios, high reaction temperatures are achieved
rapidly and passage through the “cooling zone” allows for a
similar prompt lowering of the overall temperature after the
reaction. Replacement of the 250 psi backpressure regulator in
the initial microreactor setup with a 500 psi regulator allowed
for superheating of ethanol to 245 °C before boiling was
observed. At this reaction temperature, nearly complete conver-
sion was observed in 30 min; however, the appearance of a
new unidentified byproduct was observed by HPLC analysis.
It is probable that degradation of the product occurs at such
high temperatures. It is notable that temperatures approaching
245 °C for ethanol in a microwave vial were ultimately not
attainable in batch reactions due to the pressure limitations of
the microwave system.18
Ring-opening of trisubstituted epoxides has also been a
challenge in microwave-assisted aminolysis of epoxides.3b As
expected, the microreactor gave similar results and poor
conversions, even when a large excess of propylamine 14 was
used to open 1-phenylcyclohexene oxide 15 (Table 1, entries
22 and 23). Gratifyingly, the use of the 500 psi backpressure
regulator enabled a reaction temperature of 240 °C to be
reached, affording moderate conversions after 30 min residence
times (Table 1, entry 24). The use of 5 equiv of amine represents
flowing almost a neat amine solution in one syringe; however,
high reaction temperatures could still be maintained in the
microreactor without flashing.
Figure 2. Altering regioselectivity in the aminolysis of styrene
oxide with aniline.
the benzylic position (giving 16) over the terminal position
(leading to 17) (Figure 2). Switching to bulkier solvents, such
as ethanol and isopropanol, eventually led to attack favoring
the terminal end of the epoxide. Interestingly, increasing the
temperature in the microreactor from 150 to 245 °C also gave
a reversal in selectivity, with attack favored at the terminal end
of the epoxide.
Application to Metoprolol. Following our initial success
with epoxide aminolysis reactions using a continuous flow
microreactor, we intended to highlight this approach through
the formation of pharmaceutically relevant ꢀ-amino alcohols.
We first chose metoprolol 19, a selective ꢀ1-adrenoreceptor
blocking agent, due to its rather simple structure, (Table 2) to
illustrate the efficiency of epoxide aminolysis using the newly
developed method.
Metoprolol is used in the treatment of hypertension20 and is
licensed under a variety of different names.21 Currently, a
shortage of metoprolol exists and a new efficient means of
production could prove useful. The synthesis centers around
the aminolysis of the readily available epoxide 20 with isopropyl
amine. The epoxide aminolysis is typically performed using
multiple equivalents of isopropyl amine at reflux in a polar
protic solvent, with reaction times ranging from 2 to 5 h.22 In
examining batch microwave conditions, we again noted that
the amount of 19 and bis-alkylation side product 21 were
dependent on reactor headspace due to the low boiling point
of isopropyl amine (Table 2, entries 1 and 2). Under microre-
(19) For examples of poor selectivity in the aminolysis of styrene oxide
see ref 5.
The opening of styrene oxide with aniline represents a unique
aminolysis example as selectivity for the terminal over the
benzylic position can be poor.19 Indeed, a batch microwave
reaction in methanol led to aminolysis favoring the attack on
(20) Waagstein, F.; Bristow, M. R.; Swedberg, K.; Camerini, F.; Fowler,
M. B.; Silver, M. A.; Gilbert, E. M.; Johnson, M. R.; Gross, F. G.;
Hjalmarson, A. Lancet 1993, 342, 8885.
(21) Metoprolol is isolated as the succinate or tartrate salt and is sold under
a variety of names including: Lopressor (Novartis), Toprol-XL
(AstraZeneca, Novartis), Metrol (Arrow Pharmaceuticals), Betaloc
(AstraZeneca), Neobloc (Trima Pharmaceuticals), and Corvitol (Berlin-
Chemie AG) among others.
(18) The Biotage Initiator used for the batch reactions has a pressure
limitation of 20 bar.
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Table 2. Results of metoprolol formation under microreactor-enabled conditions
,
entry
conditions (psi)
amine (equiv) temp (°C) flow ratea (µL/min)
time
yield 19b c (%) yield 21 (%) conversion (%)
1
2
3
4
5
6
7
8
batch µwd (∼100)
batch µwe (∼100)
µreactor (500)f
µreactor (500)f
µreactor (500)f
µreactor (500)f
µreactor (500)f
µreactor (500)f
1.2
1.2
1.2
1.2
1.2
2.0
2.0
4.0
150
150
240
240
240
240
240
240
-
30 min
30 min
15 s
65
69
61
69
72
80
86
91
31
28
14
21
24
8
100
100
76
-
480
240
120
480
240
480
30 s
92
1 min
15 s
30 s
15 s
99
89
12
6
99
98
c
a Combined flow rate of both reagents. b All yields and conversions are calculated on the basis of HPLC analysis with an internal standard. ∼1% of the regioisomer can
be isolated but was not quantified. d 1 mL in a 5 mL vial. e 2 mL in a 5 mL vial. f Backpressure regulator.
Scheme 2. Microwave aminolysis of styrene oxide with
2-aminoindan for 30 min at 150 °C
actor conditions, loss of the volatile amine at high temperatures
was not a concern; accordingly we focused on maximizing
conversion and throughput. At 500 psi, temperatures up to 240
°C were achieved before flashing of ethanol was observed in
the microreactor. Increasing the amount of isopropyl amine at
this temperature led to decreases in both bis-alkylation and the
reaction time, with complete reaction occurring in as short as
15 s (Table 2, entry 8). Under these conditions, a single 120
µL microreactor working under continuous flow operation is
capable of delivering 7.0 g/h (61 kg/year) of metoprolol.
Operating 17 microreactors in parallel could ultimately produce
over 1 t of this important drug per year.
Application to Indacaterol. The adaptation of the inda-
caterol aminolysis to a microreactor system presented several
unique challenges. First, the reported reaction time in diglyme
at elevated temperatures was approximately 15 h (Scheme 1).16
Such lengthy residence times are not possible in a microreactor
system due to difficulties in delivering the fluid in a stable
(nonpulsating) manner at such low flow rates. As described
above, attempts to catalyze this reaction with a variety of known
aminolysis promoters ultimately did not lead to reaction times
that were amenable to microreactors. Fortuitously, heating at
elevated temperatures in polar protic solvents such as ethanol
resulted in reaction times that could be considered in microre-
actors (approximately 30 min). In order to better understand
the effect of solvent on the aminolysis of a complicated example
such as indacaterol, we decided to take a deeper look into a
similar model system. We reasoned that the aminolysis of
styrene oxide with 2-aminoindan 8 should provide a similar
electronic and steric environment as the reaction between 2 and
3. Heating of this reaction mixture in the microwave at 150 °C
for 30 min led to complete conversion, giving 59% of the
desired product 22, as well as significant amounts of the
regioisomer 23 and bis-alkylation 24 side products (Scheme
2). While this represented a significant decrease in reaction time,
the overall selectivity for terminal over benzylic attack of the
epoxide was decreased relative to the indacaterol reaction in
diglyme.
As mentioned previously, regioselectivity was an issue in
ethanol. However, it has been reported that polar aprotic solvents
can improve selectivity in aminolysis reactions at the expense
of overall reaction rate.3b,23 With this in mind, we were able to
take advantage of two unique aspects of microreactor technol-
ogy. First, by altering temperature and flow rate, reaction
conditions can be scanned quickly to find optimum conversion
and product yield. Second, due to the absence of headspace,
mixtures of polar protic and polar aprotic solvents can easily
be employed without concern for the relative boiling point of
each component. In this manner, we could consider a polar
protic solvent as a potential promoter for the reaction. Using
ethanol as a baseline, the microreactor aminolysis was nearly
complete in 5 min at 195 °C to afford 59% of 22 along with
14% of the regioisomer 23. Switching to acetonitrile as the
solvent and operating with a 250 psi backpressure regulator,
temperatures up to 240 °C were easily obtained before flashing
of the solution was observed in the microreactor. Even at this
increased temperature, product yields were markedly lower
(22) (a) Palmer, S.; Sidenqvist, M. WO/1998/22426; Chem. Abstr. 1998,
129, 27813. (b) Carmen, A. A.; Jordi, B. I. L. WO/2007/141593; Chem.
Abstr. 2007, 148, 54739. (c) Mehra, J. K.; Choube, A.,; Srivastava,
B. K.; Porwal, R. K.; Gautam, P. U.S. Patent 2005/0107635, 2005;
Chem. Abstr. 2005, 142, 463445. (d) Roa, A. V. R.; Gurjar, M. K.;
Joshi, S. V. IN 177748, 1997. Chem. Abstr. 1997, 139, 23046.
(23) Anderson, S. R.; Ayers, J. T.; DeVries, K. M.; Ito, F.; Mendenhall,
D.; Vanderplas, B. C. Tetrahedron: Asymmetry 1999, 10, 2655.
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order to establish reaction parameters. Excellent conversion
(97%) was obtained at 185 °C in only 15 min with 68% of the
desired indacaterol precursor 4 produced (Table 3, entry 4).
Yields and selectivities observed under microreactor conditions
mirrored those obtained by heating in diglyme for a period 60
times longer.16 Small amounts of 2 were found to have
crystallized out in the syringe after 12 h but did not lead to
crystallization and clogging in the microreactor.24 At a slightly
decreased concentration of the starting solution (0.38 M), 2 was
completely soluble, and performing the aminolysis reaction in
quadruplicate under the same conditions led to only minor
variation in the yield of 4 (minimum of 68, maximum of 70%)
(Table 3, entries 5 and 6). Decreasing the temperature to 165
°C reduced the degree of thermal decomposition of 4 and
slightly increased yields were obtained at the expense of longer
reaction times (Table 3, Trial 7). Similarly, increasing the
temperature to 200 °C led to better conversion at shorter times
at the expense of overall product yield (Table 3, entry 8). Under
the best observed conditions (Table 3, entry 5), 1.5 g/d (0.5
kg/year) of the indacaterol precursor 4 could be obtained from
a single 120 µL microreactor.
Figure 3. Study of polar protic cosolvents as promoters in the
formation of 22.
when compared to those in ethanol at similar residence times
(Figure 3). However, a 30 min residence time resulted in com-
pletion of the aminolysis and up to 69% of 22 was obtained, as
quantified by HPLC analysis. The increase in overall product
yield was derived mainly from the improved regioselectivity
of the reaction, as attack at the terminal position of the epoxide
over the benzylic position is favored. Incorporation of a 9:1
mixture of acetonitrile to ethanol in the microreactor efficiently
accelerated the reaction to where conversions of 99% were
achieved in only 15 min. Yields of 22 were maintained at a
high level (68%). Changing the solvent system to either 75:25
acetonitrile/ethanol or 9:1 acetonitrile/methanol also gave
improved conversions at comparable residence times. Finally,
using a ratio of 9:1 acetonitrile/water, conversions at similar
time intervals surpassed those obtained in pure ethanol at 195
°C and nearly complete aminolysis was observed at a 10 min
residence time with 66% yield of 22.
The second obstacle to performing the indacaterol aminolysis
in the microreactor was low solubility of the starting epoxide 2
in commonly used solvents. The quinolinone structure provided
a highly crystalline material that had a limited solubility (<0.1
M) in most organic solvents, including ethanol and acetonitrile.
Formation of solids in the microreactor ultimately would clog
the inlets and prevent flow. To solve this problem, a solvent
screen was conducted. N-Methylpyrrolidone (NMP) emerged
as a likely reaction solvent, as 2 exhibited moderate solubility
(∼0.5 M), and the dielectric constant of NMP is similar to that
of acetonitrile. Operationally, we would also be able to keep
the concentration of the reaction high by premixing the amine
and epoxide in order to flow the mixture from one syringe. This
technique avoids further dilution of the reaction when the two
components are introduced separately, and thus enables higher
overall conversion.
Conclusion
In summary, the aminolysis of epoxides using a continuous
flow microreactor proved to be a highly efficient process.
Excellent yields and conversions with simple terminal epoxides
can be obtained at residence times under 5 min in ethanol under
high temperature and pressure. The aminolysis of more sterically
hindered epoxides also proved successful, although longer
reaction times were necessary. The continuous flow microre-
actor is capable of reaching temperatures that are not attainable
in microwave batch processes, and due to the elimination of
headspace, volatile amines can be used in the reaction without
affecting overall product distributions. The use of a small
amount of a polar protic solvent to accelerate the aminolysis
reaction can also be applied without concern for the volatility
of the solvent components. Application of epoxide aminolysis
in a continuous flow microreactor towards the production of
metoprolol led to product outputs of 7.0 g/h. In a more
challenging example, the penultimate intermediate in the
synthesis of indacaterol was also produced by this method at a
residence time that was 1/60th of that reported in the literature
with similar yield.
Experimental Section
Materials and Methods. The indacaterol substrates 214,16,25
and 326 were prepared according to literature procedures. The
epoxide 20 for metoprolol was synthesized from the corre-
sponding phenol and epichlorohydrin according to published
reports.22a
The last issue to address in the formation of 4 was the
thermal stability of the product as a free base; it has been
reported that 4 is unstable in organic solvents.16 In our own
studies we observed significant decomposition when the inda-
caterol precursor was heated to temperatures above 200 °C.
Considering these issues, a solution of 2 and 3 was prepared in
NMP, and 10% water was added as a promoter for the
aminolysis reaction. Initially, a 0.4 M solution was pumped
through the microreactor at 185 °C and varying flow rates in
All aminolysis reactions were initially performed as 1
M solutions in ethanol using a Biotage Initiator single
(24) Approximately 3% conversion to 4 was obtained in the syringe after
12 h at rt.
(25) (a) Beeley, J. L.; Dean, D. K. WO 1995/25104, 1995. Chem. Abstr.
1995, 124, 117293. (b) Lohse, O.; Vogel, C.; Abel, S. WO 2005/
123684, 2005. Chem. Abstr. 2005, 144, 88180. (c) Mammen, M.;
Trevor, M. WO/2006/023457, 2006. Chem. Abstr. 2006, 144, 274145.
(26) Prashad, M.; Hu, B.; Har, D.; Repicˇ, O.; Blacklock, T. J. Org. Process
Res. DeV. 2006, 10, 135.
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Table 3. Results of indacaterol precursor formation under microreactor-enabled conditions
temp flow rate
yield 4c yield 5 yield 6 conv.
entry conditions (psi)a
solvent
concnb (M) 2 (equiv) (°C) (µL/min)
time
(%)
(%)
(%)
(%)
1
2
3
4
5
6
7
8
Novartis (batch) diglyme
1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
110
110
185
185
185
185
165
200
-
-
8
15 h
68.7
68.4
68.1
67.8
70
68.3
72.1
60.7
7.8
6.4
6.3
8.6
8
8.2
8.6
6.8
12.4
10.4
7.7
9
7.1
7.5
7.9
6.4
-
oil bath (batch)
batch (µW)
diglyme
1
15 h
95.4
95.4
97
9:1 NMP/H2O
9:1 NMP/H2O
9:1 NMP/H2O
9:1 NMP/H2O
9:1 NMP/H2O
11:1 NMP/H2O
0.5
0.4
0.38
0.38
0.38
0.37
15 min
15 min
15 min
15 min
30 min
10 min
µreactor (250)
µreactor (250)
µreactor (250)
µreactor (250)
µreactor (250)
8
8
92.8
95.1
92.4
92.3
8
4
12
a Pressure of backpressure regulator. b Concentration of epoxide in reaction vessel or in one syringe premixed with the amine. c All yields and conversions are based on
HPLC analysis with an internal standard.
cavity microwave reactor under normal absorption and in
0.5-2 mL sealed vials (5 mL total volume). The products
were then separated either with preparative TLC on
precoated silica gel 60 F254 glass sheets or by chroma-
tography on Silicycle silica gel (230-400 mesh), eluting
with hexane/ethyl acetate or dichloromethane/methanol.
All components were analyzed by 1H and 13C NMR
spectroscopy using a Bruker-Avance 400 MHz spectrom-
eter and compared to known literature compounds when
available (see Supporting Information). HPLC quantitative
analysis was performed on an Agilent 1200 Series LC/
MS using either an Eclipse XDB-C18 or a Zorbax Eclipse
Plus C18 reverse phase column, a methanol/water mobile
phase, and a 254 or 210 nm wavelength detector. Yields
were calculated on the basis of normalization of response
factors using naphthalene as an internal standard. GC
quantitative analysis was performed on an Agilent 7890A
GC system. Yields were calculated on the basis of
normalization of response factors using dodecane as an
internal standard.
Microreactor Fabrication and Set Up. The microreactor
was fabricated using standard silicon micromachining tech-
niques.27 Channel layout was defined by photolithography and
realized by deep reactive ion etching (DRIE) of a silicon wafer
(15 cm diameter; 0.65 mm thickness) to a depth of 0.40 mm.
A silicon nitride layer (500 nm) was grown on the silicon
surface, and the entire device was capped and sealed by
anodically bonding a Pyrex wafer (1.0 mm thickness).
The inlet and outlet sections of the reactor were compressed
in a custom microfluidic chuck machined out of aluminum.
Kalrez O-rings (Z1028 FFKM, size 005, Marco Rubber) were
used to seal the fluidic connections. The chuck was machined
with 10-32 ports, and polyetheretherketone (PEEK) fittings
were used (Upchurch Nanotight headless fittings, F-333N),
connecting to 1/16” OD, 0.020” ID PEEK tubing. The third
inlet, which remained unused, was capped with a PEEK plug
(Upchurch P-550). Inlet tubing was connected to 8-mL high-
pressure stainless steel syringes (702267, Harvard Apparatus),
which were independently driven by two syringe pumps (PHD
2200, Harvard Apparatus). The outlet tubing was connected to
a backpressure regulator, either 250 psi (U-608, Upchurch) or
500 psi (U-609, Upchurch).
chuck. The reaction zone of the reactor was compressed
between a 3/8” thick piece of borosilicate glass and a 1/16”
thick piece of graphite, which was in direct contact with a
custom-machined aluminum heating chuck. The heating chuck
was drilled with two holes for insertion of 1/8”-diameter
cartridge heaters (35 W, 120 V, CSS-01235/120 V, Omega)
and a 1-mm-diameter hole for a wire thermocouple (K-type,
SC-GG-K-30-36, Omega), placed 0.5 mm beneath the chuck
surface. The thermocouple provided data to a PID controller
(CN742, Omega), which controlled the cartridge heaters via a
solid-state relay (SSRL240DC10, Omega).
General Batch Microwave Protocol. The desired epoxide
(1.0 mmol), amine (1.2 mmol), and internal standard
(10-20 mol %) were combined in a 0.5-2 mL (5 mL
total volume) microwave vial and diluted to 1 mL with
ethanol. The vial was then sealed, placed in the microwave
cavity, and irradiated at normal absorption for 30 min at
150 °C. Samples for quantitative analysis were then taken
before the reaction mixture was concentrated, and the
crude products were purified by chromatography on silica
gel or preparative TLC. The desired products were
1
analyzed by H and 13C NMR spectroscopy as well as
HRMS and were compared to known literature compounds
when available (see Supporting Information).
Microreactor Protocols for General and Metoprolol
Epoxide Aminolysis. A solution of the desired epoxides
(10 mmol) and napthlalene (internal standard, 10-20 mol
%) was diluted to 5 mL with ethanol and placed in an 8
mL high-pressure stainless steel syringe. A solution of
the amine (12 mmol for 1.2 equiv) was diluted to 5 mL
with ethanol and placed in a separate 8 mL syringe before
being connected to the microreactor. The reagent streams
were pumped through the microreactor (250 or 500 psi
backpressure regulators were used) at identical flow rates,
and reaction times and temperatures were varied. In
general, five microreactor volumes (5 × 120 µL) were
allowed to pass through the outlet after each change in
conditions in order to achieve steady state before samples
were taken for quantitative analysis.
Microreactor Protocol for Formation of Indacaterol
Precursor 4. The epoxide 2 (234.2 mg, 0.79 mmol) and
naphthalene (internal standard, 15.7 mg, 0.120 mmol) were
dissolved in NMP (1.8 mL), and the suspension was heated
gently to affect dissolution of the solid. After cooling,
H2O (200 µL) and amine 3 (181.7 mg, 0.96 mmol) were
The fluidic compression chuck was cooled by house cooling
water via two channels 3/16” in diameter drilled through the
(27) Jensen, K. F. Mater. Res. Soc. Bull. 2006, 31, 101.
Vol. 14, No. 2, 2010 / Organic Process Research & Development
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439

added to the mixture and stirred before being placed in
an 8 mL high-pressure stainless steel syringe and con-
nected to the microreactor. The reaction mixture was
pumped through the microreactor (250 psi backpressure
regulator) at desired flow rates and temperatures. In
general, five microreactor volumes (5 × 120 µL) were
allowed to pass through the outlet before 5 µL samples
were taken for quantitative analysis.
for stimulating discussions, in particular Gerhard Penn, Berthold
Schenkel, Thierry Schlama, Mike Girgis, Oljan Repic, Lukas
Padeste, and Felix Kollmer.
Supporting Information Available
Quantitative analysis procedures and spectral data for ami-
nolysis reactions. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment
This work was supported by the Novartis-MIT Center for
Continuous Manufacturing. We thank the members of this team
Received for review December 3, 2009.
OP9003136
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