Stereoselective Catalytic Synthesis of Active Pharmaceutical Ingredients in Homemade 3D-Printed Mesoreactors

Article abstract of DOI:10.1002/anie.201612192

3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.

Full text of DOI:10.1002/anie.201612192

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201612192
German Edition: DOI: 10.1002/ange.201612192
Continuous-Flow Chemistry
Stereoselective Catalytic Synthesis of Active Pharmaceutical
Ingredients in Homemade 3D-Printed Mesoreactors
Sergio Rossi, Riccardo Porta, Davide Brenna, Alessandra Puglisi,* and Maurizio Benaglia*
Abstract: 3D-printed flow reactors were designed, fabricated
from different materials (PLA, HIPS, nylon), and used for
a catalytic stereoselective Henry reaction. The use of readily
prepared and tunable 3D-printed reactors enabled the rapid
screening of devices with different sizes, shapes, and channel
dimensions, aimed at the identification of the best-performing
reactor setup. The optimized process afforded the products in
high yields, moderate diastereoselectivity, and up to 90% ee.
The method was applied to the continuous-flow synthesis of
biologically active chiral 1,2-amino alcohols (norephedrine,
metaraminol, and methoxamine) through a two-step sequence
combining the nitroaldol reaction with a hydrogenation. To
highlight potential industrial applications of this method,
a multistep continuous synthesis of norephedrine has been
realized. The product was isolated without any intermediate
purifications or solvent switches.
employed for water electrolysis[9] and for continuous-flow
organic reactions, such as imine synthesis and reduction.[10] In
these pioneering studies, Cronin and co-workers reported the
reductive amination of in situ generated benzaldimines in 3D-
printed polypropylene (PP) reactors.[11]
Despite the tremendous increase in interest in 3D-printed
devices over the last few years, the use of 3D-printed reactors
in organic synthesis is still limited to a small number of
reactions and, to the best of our knowledge, remains virtually
unexplored in catalytic enantioselective transformations. 3D-
printed flow reactors are easily tunable devices that are
designed and fabricated on demand on very short timescales
(Figure 1). Considering the interest of the chemical industries
T
he development of 3D-printing devices and technologies
has been associated with a new industrial revolution, where
“real-life objects” are built in a faster, cheaper, and, most
importantly, customized fashion. Instead of producing multi-
ple copies of a single type of object, a single machine creates
endless variations of an object with high accuracy.[1] Today, 3D
printers based on fused filament fabrication (FFF) technology
are accessible at low costs and are commonly available in
many stores.[1c] 3D printing has been used in many different
fields, from pneumatics to general medical applications. To
date, in the chemical sciences, 3D-printed devices have been
employed for creating 3D-printed crystallographic models
from CIF (crystallographic information framework) data[2]
and molecular models for chemical education purposes,[3] but
also to build research equipment.[4] 3D printers have found
application in the biomedical sciences[5] for the assembly of
biodegradable tissue, and for the realization of bone tissue.[6]
The potential of 3D printing technologies has had
a significant impact in the field of microfluidic devices.[7]
Recently, a commercial microstereolithography 3D printer
was used to fabricate conventional polydimethylsiloxane
(PDMS) glass lab-on-a-chip devices for glucose concentration
diagnostics.[8] 3D-printed flow plates have also been
Figure 1. Fabrication of 3D-printed reactors.
in innovative technologies, their use in sophisticated enantio-
selective reactions would represent a crucial step towards
a new, modern, efficient, and sustainable approach for process
chemistry.
We herein describe the development of stereoselective,
catalytic continuous-flow reactions in 3D-printed mesoreac-
tors.[12] A copper-catalyzed enantioselective Henry reaction
was successfully performed in homemade 3D-printed flow
reactors (Figure 1) built of different materials, such as
poly(lactic acid) (PLA), high-impact polystyrene (HIPS),
and nylon, with different sizes and shapes. This method was
applied to the continuous-flow synthesis of biologically active
chiral 1,2-amino alcohols (norephedrine, metaraminol, and
methoxamine) in a two-step sequence combining a nitroaldol
reaction with a hydrogenation (Scheme 1).
The addition of nitroalkanes to aldehydes, the so-called
Henry reaction, is a powerful and efficient method for the
construction of carbon–carbon bonds and results in the
formation of b-nitro alcohols, which can be easily converted
into 1,2-amino alcohols.[13] Owing to the great importance of
these compounds, the catalytic stereoselective procedure to
afford enantiomerically enriched products very soon gained
particular attention and led to the development of various
[*] Dr. S. Rossi, R. Porta, D. Brenna, Dr. A. Puglisi, Prof. Dr. M. Benaglia
Dipartimento di Chimica
Universitꢀ degli Studi di Milano
Via C. Golgi, 19, 20133 Milano (Italy)
E-mail: alessandra.puglisi@unimi.it
maurizio.benaglia@unimi.it
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612192.
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Running the reaction at 258C,
a residence time of 5 min resulted in
the formation of 1 in 61% yield as
a 60:40 mixture of diastereomers in
favor of the anti isomer and in 70%
ee (Table 1, entry 1). When the reac-
tion temperature was lowered to 08C,
the stereoselectivity of the process
improved (entries 3 and 4). At À208C
and for a residence time of 10 min,
the anti-configured nitro alcohol was
obtained in 75:25 d.r. and 81% ee
(entry 5)., The best results were
obtained at À208C and with a resi-
Scheme 1. Enantioselective catalytic synthesis of pharmaceutically active chiral 1,2-amino alcohols
in 3D-printed flow reactors.
chiral metal-[14] and non-metal-based[15] catalysts.
Compared with the well-developed reaction of
aldehydes with nitromethane, Henry reactions
with other nitroalkanes are more challenging as
they often suffer from low reactivity and poor
stereoselectivity. The simultaneous control of the
diastereo- and enantioselectivity of the transforma-
tion has been a formidable challenge, and only
a limited number of suitable asymmetric catalysts
have been identified.[16] Moreover, anti selectivity is
Scheme 2. Enantioselective copper-catalyzed Henry reaction in 3D-printed flow
reactors.
even more difficult to achieve, and only recently,
a few efficient catalysts have been developed for
this purpose.[16g–n] In this framework, among the
metal-based methods, those using copper com-
plexes as catalysts hold a prominent position, in particular
owing to their relatively low cost.[17] Therefore, based also on
our previous experience,[18] we focused our attention on
a readily available and inexpensive chiral copper(II) complex
that was generated in situ by mixing copper diacetate and
a camphor-derived aminopyridine.[19]
At first, the batch reaction between 3-(benzyloxy)benzal-
dehyde and nitroethane was studied.[20] Upon screening
different reaction conditions, it was found that at À458C in
ethanol and in the presence of 20 mol% of ligand A and
Cu(OAc)2, the reaction afforded the nitroaldol product 1 in
91% yield, 70:30 anti/syn selectivity, and 92% ee for the
major anti isomer. We next moved to continuous-flow experi-
ments.[21] A 1 mL 3D-printed reactor made of HIPS (square
channel: 1.41 ꢀ 1.41 mm2) was first selected as the continuous-
flow reactor. On the basis of preliminary experiments in flow,
ethanol was identified as the solvent of choice (Scheme 2).
Syringe I was charged with a preformed mixture of
Table 1: Screening of reaction conditions.
t[a]
[min]
Yield[b]
[%]
d.r.[b]
(anti/syn)
eeanti
[%]
[c]
Entry
T
[8C]
Flow rate
[mLminÀ1
]
1
2
3
4
25
25
0
0.2
0.1
0.1
0.05
0.1
5
10
10
20
10
30
30
61
87
73
91
20
72
75
60:40
50:50
65:35
63:37
75:25
73:27
71:29
70
49
85
78
81
87
86[e]
0
5
À20
À20
À20
6
0.033
0.033
7[d]
[a] Residence time. [b] Determined by 1H NMR analysis of the crude
product. [c] Determined by HPLC analysis on a chiral stationary phase,
value for the 1S,2R enantiomer. [d] The ligand with the opposite
configuration was used. [e] For the 1R,2S enantiomer.
dence time of 30 min (72% yield, 73:27 d.r., and 87% ee for
the major anti isomer with 1S,2R configuration; entry 6).
Using the non-natural camphor-derived chiral ligand with the
opposite configuration under the same reaction conditions,
the product 1 was also formed with opposite absolute
configuration as an immediate precursor of metaraminol,
and was isolated in comparable efficiency (75% yield, 71:29
d.r., 86% ee for the anti isomer, 1R,2S configuration; entry 7).
Having identified the best reaction conditions in terms of
the temperature (À208C) and residence time (30 min), we
explored the use of different types of flow reactors. As HIPS
may suffer from some incompatibility problems with organic
solvents, the use of 3D-printed reactors made from PLA,
which is more robust and less sensitive to decomposition by
organic solvents, was investigated. Using a 1 mL 3D-printed
3-(benzyloxy)benzaldehyde
(0.25 mmol),
ligand
A
(0.0625 mmol), and Cu(OAc)2 (0.05 mmol) in EtOH (1 mL,
0.250m). Syringe II was charged with nitroethane (2.5 mmol),
DIPEA (0.25 mmol), and EtOH (750 mL). The two syringes
were connected to a syringe pump, and the reagents were
injected into the flow reactor at the indicated flow rate and
temperature. The output of the reactor was collected in
a cooled bath (À788C), where the crude product was treated
with HCl (10%) at the end of the process. After extraction
with EtOAc, the product was isolated by column chromatog-
raphy on silica gel. The results of the continuous-flow
experiments are reported in Table 1.
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reactor made of PLA (square channel: 1.41 ꢀ 1.41 mm2), nitro
alcohol 1 was obtained in very good yield (87%), 65:35 d.r.,
and 80% ee for the anti isomer.
Table 2: Screening of different 3D-printed flow reactors.
Entry Flow reactor
Conv.[a] d.r.[a]
[b]
eeanti
(anti/syn) [%]
[%]
Next, we focused our attention on the preparation of
intermediate 2, a precursor of norephedrine (Scheme 3).
1
2
3
4
5
6
1 mL PTFE coiled tube
92
65:35
67:33
68:32
67:33
67:33
74:26
80
80
81
84
85
90
(circular channel, id=1.69 mm)
1 mL 3D-printed PLA
96
97
98
98
96
(square channel, 1.41ꢁ1.41 mm2)
1 mL 3D-printed nylon
(square channel, 1.41ꢁ1.41 mm2)
1 mL 3D-printed PLA
(circular channel, id=1.59 mm)
1 mL 3D-printed PLA
(square channel, 1.0ꢁ1.0 mm2)
10 mL 3D-printed PLA
(square channel, 2.65ꢁ2.65 mm2) (80)[c]
[a] Determined by 1H NMR analysis of the crude product. [b] Determined
by HPLC analysis on a chiral stationary phase. [c] Yield of isolated
product given in parentheses. id=inner diameter.
Scheme 3. Stereoselective catalytic reactions in 3D-printed flow reac-
tors.
Employing the previously described experimental setup and
optimized reaction conditions (À208C in ethanol, 30 min
residence time), the use of flow reactors made of different
materials was studied (Table 2). The use of 1 mL 3D-printed
reactors made of PLA (square channel: 1.41 ꢀ 1.41 mm2) or
nylon (square channel: 1.41 ꢀ 1.41 mm2) for the copper-
catalyzed stereoselective Henry reaction gave similar results
(entries 2 and 3). Changing the size or the shape of the 3D-
printed PLA reactors did not have a significant effect on the
outcome of the reaction; intermediate 2 was obtained in very
good conversions, reasonable d.r., and good ee (entries 4 and
5).[22] Finally, the reaction was scaled up by using a 10 mL 3D-
printed reactor (square channel: 2.65 ꢀ 2.65 mm2) made from
PLA; pleasingly, nitroaldol 2 was obtained in very good yield,
74:26 d.r., and 90% ee. For the sake of comparison, a 1 mL
coiled tube made of PTFE (circular channel; inner diameter:
1.69 mm) was also employed as a continuous-flow reactor; the
product was then isolated in slightly lower yield and
enantioselectivity (entry 1).
cases, the 3D-printed devices afforded better results than
traditional PTFE tubings of similar dimensions).
Analogous results were obtained in the synthesis of nitro
alcohol 3, a precursor of methoxamine. Using a 1 mL 3D-
printed PLA reactor, the product was isolated in 90% yield,
73:27 d.r., and 87% ee for the anti isomer, which compares
well with the results of the batch reaction (72% yield, 70:30
d.r., 91% ee). Similarly, the stereoselective Henry reaction
between 3,4-bis(benzyloxy)benzaldehyde and nitroethane in
a mixture of EtOH/THF as the solvent at À208C afforded the
corresponding product 4 in 67% yield, 65:35 d.r., and 80% ee.
To obtain the desired chiral amino alcohols, the nitroaldol
products 1–3 were subjected to a continuous-flow hydro-
genation in a ThalesNano H-Cube Mini device equipped with
a cartridge of Pd/C (10 wt%) as the catalyst (Scheme 4). A
rapid screening of reaction conditions was performed using
nitro alcohol 2 (see the Supporting Information, Table S3).
When the reaction was performed in MeOH at 308C and
15 bar H2 pressure, complete conversion of the starting
material into amino alcohol 6 was observed. Considering
a possible multistep process, we also investigated the use of
ethanol as the reaction medium. When 2 was used as a 0.1m
solution in EtOH, it was reduced with a conversion of 80%
after 2.5 hours under the same reaction conditions. To
increase the reaction conversion from 80% to 98%, it was
However, it should be noted that 3D-printed reactors are
extremely cheap and can be designed and modified ad hoc by
the operator (see the Supporting Information for a series of
3D-printed reactors of different geometries and shapes
prepared by our group). To further demonstrate the versa-
tility and advantages that easily customizable 3D-printed
reactors may offer over other flow
reactors, the performance of PLA
Table 3: Reactions in 3D-printed flow reactors of different geometries and designs.[a]
reactors with different geometries,
sizes, and shapes was investigated,
including new devices with zigzag
flow channels. Nitroaldol reactions
with benzaldehyde and 3-(benzy-
loxy)benzaldehyde were then run in
these microreactors at À208C with
short residence times (3 and 5 min;
see Table 3 for selected results).
The reactor design indeed influ-
enced the conversion and, to
a smaller extent, also the stereose-
Entry
ArCHO
Flow reactor
Conv.[b]
[%]
d.r.[b]
(anti/syn)
1
2
3
4
5
PhCHO
1 mL PTFE coiled tube
8
15
10
21
18
74:26
80:20
61:39
71:29
60:40
(circ. channel, id=1.69 mm)
1 mL 3D-printed PLA
PhCHO
(rect. zigzag channel, 1.1ꢁ1.7 mm2)
1 mL 3D-printed PLA
3-(BnO)C6H4CHO
3-(BnO)C6H4CHO
3-(BnO)C6H4CHO
(circ. channel, id=1.59 mm)
1 mL 3D-printed PLA
(rect. zigzag channel, 1.1ꢁ1.7 mm2)
1 mL 3D-printed PLA
(circ. zigzag channel, id=1.59 mm)
lectivity of the reaction (in some [a] Residence times of 5 min. [b] Determined by 1H NMR analysis of the crude product.
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easily recycled by simple treatment of the silica gel with
ethanolic HCl solution.
In the experimental setup, the two syringes were con-
nected to a syringe pump, and the reagents were injected into
the 3D-printed flow reactor at À208C for a residence time of
30 min. The output of the reactor (dark blue solution, 3 mL)
was filtered over a short pad of silica (h = 1 cm, d = 2 cm) by
elution with EtOH (6 mL). To the resulting mixture (light
yellow), 30 equiv of AcOH were added, and the resulting
mixture was subjected to continuous-flow hydrogenation with
H-Cube (T= 308C, p = 1 bar, flow rate = 1 mLminÀ1, t =
2.5 h). The solvent was then evaporated, and the resulting
mixture was treated with 33% aqueous NH4OH and
extracted five times with EtOAc. Amino alcohol 6 was
obtained in 90% yield (over 2 steps), 70:30 d.r., and 81% ee
as a pure white solid. Taking advantage of the powerful
possibility offered by 3D printing to easily and quickly modify
the reactor design, it was also possible to fabricate a custom-
ized reactor containing the flow channels and the short
column of silica in a single device (Scheme 5). The nitroaldol
intermediate was then obtained in 96% yield, 65:35 d.r., and
83% ee (see the Supporting Information for details).
In conclusion, a two-step continuous-flow process for the
stereoselective catalytic synthesis of chiral 1,2-amino alcohols,
aimed at the preparation of biologically active targets
(norephedrine, metaraminol, and methoxamine), has been
developed. For the first time, homemade 3D-printed reactors
have been used in catalytic enantioselective reactions, and
reactor channels of different materials, geometries, sizes, and
shapes have been studied. The use of a 10 mL 3D-printed
reactor for a scaled-up version of the process has also been
demonstrated. Furthermore, a multistep continuous-flow
process for the synthesis of norephedrine through a Henry
reaction and nitro group reduction has been developed.
Under the optimized reaction conditions, the final product
was isolated without any intermediate purifications or solvent
switching, thus opening the way to a fully automated
continuous-flow process for the synthesis of enantiopure
1,2-amino alcohols. The unprecedented demonstration of the
possibility to use highly tunable, customizable 3D-printed
reactors in stereoselective catalytic reactions represents a key
step towards the widespread use of 3D-printed devices in
organic synthesis, even for the assembly of highly function-
alized chiral molecules. Customized 3D printing of reactors is
already a reality; the use of other 3D-printed devices in
combination with reactors, including homemade printed
syringe pumps,[23] and the possibility
Scheme 4. Continuous-flow hydrogenation of chiral nitro alcohols 1–3.
necessary to dilute the reaction mixture from 0.1 to 0.03m.
Amino alcohol 6 was obtained in its neutral form after
a simple treatment with NH4OH with no need for further
purification. In all cases, no erosion of the stereochemical
integrity of the process was observed (the ee was determined
after derivatization of norephedrine into its O,N-bisacety-
lated form). Analogously, the continuous-flow hydrogenation
of 3 proceeded with complete conversion into amino alcohol
7.
To obtain metaraminol, nitro alcohol 1 was subjected to
both nitro group reduction and O-debenzylation. After 2.5 h
of recirculation at 508C and under 50 bar of H2, amino alcohol
5 (as its acetate salt) was obtained with complete conversion
and without any erosion of its stereochemical purity.
Having confirmed the feasibility of a two-step sequence
for the synthesis of chiral 1,2-amino alcohols, we explored the
possibility of simulating a continuous-flow multistep process
without the need for isolation and purification of the nitro
alcohol intermediate or solvent switching (Scheme 5). This
procedure would be appealing for the synthesis of chiral 1,2-
amino alcohols on a preparative scale.
After the initial stereoselective Henry reaction in a 3D-
printed flow reactor, the key step was the removal of the
copper catalyst and the chiral ligand to avoid possible
interference with the continuous-flow palladium-catalyzed
hydrogenation. The reaction between benzaldehyde and
nitroethane was selected to develop a multistep flow process
for the synthesis of 1,2-amino alcohol 6. Filtration through
a short pad of silica followed by elution with EtOH was
identified to be a valid approach to remove the copper ligand
complex for the Henry reaction from the crude reaction
mixture. According to this strategy, no solvent switching is
necessary; additionally, the precious chiral ligand can be
to optimize the final design to fur-
ther reduce costs and printing times
are other feasible working plans for
the future.
Acknowledgements
M.B. thanks the Universitꢁ degli
Studi di Milano for financial support
(H2020 Transition Grant). D.B. and
Scheme 5. Multistep in-flow synthesis of pharmaceutically valuable chiral 1,2-amino alcohols.
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
R.P. thank the Universitꢁ degli Studi
4
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Conflict of interest
The authors declare no conflict of interest.
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Manuscript received: December 15, 2016
Revised: February 20, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Continuous-Flow Chemistry
S. Rossi, R. Porta, D. Brenna, A. Puglisi,*
M. Benaglia*
&&&& — &&&&
Stereoselective Catalytic Synthesis of
Active Pharmaceutical Ingredients in
Homemade 3D-Printed Mesoreactors
Homemade reactors: Stereoselective
catalytic reactions were conducted in
tunable homemade 3D-printed meso-
reactors. This method was applied to the
continuous-flow synthesis of biologically
active chiral 1,2-amino alcohols in a two-
step sequencing combining a nitroaldol
reaction and hydrogenation.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!