Optimization and sustainability assessment of a continuous flow Ru-catalyzed ester hydrogenation for an important precursor of a β2-adrenergic receptor agonist

Article abstract of DOI:10.1039/d0gc02225j

The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H₂) gas is reported. The reaction was utilized for the reduction of an important precursor in the synthesis of abediterol, a β₂-adrenoceptor agonist that has undergone phase IIa clinical trials for the treatment of asthma and chronic obstructive pulmonary disorder. The reaction was investigated within a batch autoclave by using a design of experiments (DoE) approach to identify important parameter effects. The optimized flow process was successfully operated over 6 h with inline benchtop¹⁹F NMR spectroscopy for reaction monitoring. The protocol is shown to be high yielding (98% yield, 3.7 g h^?1) with very low catalyst loading (0.065 mol%). The environmental impact of the Ru-catalyzed hydrogenation was assessed and compared to an existing stoichiometric lithium aluminum hydride (LAH) reduction and sodium borohydride (NaBH₄) reduction. The process mass intensity (PMI) for the Ru-catalyzed hydrogenation (14) compared favorably to a LAH reduction (52) and NaBH₄reduction (133).

Full text of DOI:10.1039/d0gc02225j

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DOI: 10.1039/D0GC02225J
Article
Optimization and sustainability assessment of a continuous flow
Ru-catalyzed ester hydrogenation for an important precursor of a
β2-adrenergic receptor agonist
Received 00th January 20xx,
Accepted 00th January 20xx
ab
b
c
c
Michael Prieschl, Jorge García-Lacuna, Rachel Munday, Kevin Leslie, Anne O’Kearney-
c
ab
ab
DOI: 10.1039/x0xx00000x
McMullan, Christopher A. Hone* and C. Oliver Kappe*
The development of a ruthenium-catalyzed continuous flow ester containing sensitive functional groups.4 Heterogeneously
hydrogenation using hydrogen (H
was utilized for the reduction of an important precursor in the by Adkins and co-workers. Adkins-type catalysts (CuO/CuCr
synthesis of abediterol, a β -adrenoceptor agonist that has typically utilize very harsh conditions (>200 °C and >200 bar).
2
2
) gas is reported. The reaction catalyzed ester hydrogenations were described as early as 1931
5
2
O
4
5
)
undergone phase IIa clinical trials for the treatment of asthma and Despite the requirement for elevated temperatures and
chronic obstructive pulmonary disorder. The reaction was pressures, these catalysts are still used in modern applications
6
investigated within a batch autoclave by using a design of for unselective reduction of fatty acids and their esters.
experiments (DoE) approach to identify important parameter Subsequently, milder methods were developed for the
effects. The optimized flow process was successfully operated over reduction of the esters which also conserve olefin functionality,
1
9
7
6
h with inline benchtop F NMR spectroscopy for reaction thus facilitating the production of unsaturated fatty alcohols.
monitoring. The protocol is shown to be high yielding (98% yield, More recent methods have further progressed to the use of less
.7 g/h) with very low catalyst loading (0.065 mol%). The harsh conditions, for instance a bimetallic Ag-Au catalyst was
3
environmental impact of the Ru-catalyzed hydrogenation was shown to reduce dimethyl oxalate at temperatures as low as
8
assessed and compared to an existing stoichiometric lithium 145 °C and 30 bar pressure. The heterogeneous hydrogenation
aluminum hydride (LAH) reduction and sodium borohydride of esters was recently achieved at room temperature using
(
NaBH
4
) reduction. The process mass intensity (PMI) for the Ru- ruthenium-based catalysts with phosphorus ligands covalently
9
catalyzed hydrogenation (14) compared favorably to a LAH attached to a polymeric support under 50 bar pressure.
reduction (52) and NaBH
4
reduction (133).
Homogeneous catalysts have been shown to perform with
high turnover numbers under relatively mild conditions and
The reduction of esters into their corresponding alcohols is
traditionally performed in batch reactors using stoichiometric
4,10-15
display high functional group tolerance
.
Ruthenium based
catalyst systems have been demonstrated as highly efficient catalysts
1
metal hydride reagents, such as LiAlH
4
and NaBH
4
. The highly
4,12-15
for ester hydrogenations.
In 2006, the group of Milstein
2
reactive hydride species should be carefully handled. While
these reactions are often high yielding and selective, a
stoichiometric reagent is necessary which consequently results
in a large amount of waste that can be hazardous and expensive
introduced a new type of ruthenium catalyst utilizing pincer
12
ligands for the hydrogenation of esters. Subsequently, the
Takasago International Corporation reported Ru-MACHO (A) as
13
an efficient catalyst system. Ru-MACHO is uninhibited by
3
to destroy. Moreover, the workup is particularly challenging
alcohols, thus is catalytically active in alcoholic solvents and is
also not deactivated by the product. Gusev and co-workers
reported the development of Ru-SNS (B) as an alternative
owing to the highly exothermic hydrolysis step that forms
precipitates. Catalytic reductions of esters using hydrogen gas
have been demonstrated as an atom economic alternative to
14
catalyst system. The benefit of Ru-SNS is that it does not use
4
using stoichiometric reagents, with minimal waste generated.
phosphine ligands, which can be relatively expensive. The
switch from stoichiometric hydride reductions to Ru-catalyzed
hydrogenations is estimated to reduce the E-factor (kg waste/kg
Heterogeneous catalysts are generally limited to the use of
harsh conditions and are incompatible with substrates
1
5
product) by approximately 3 to 5- fold. Currently, Ru-MACHO
and Ru-SNS are the most industrially viable homogeneous
ruthenium catalysts for ester hydrogenation.
a. Centre for Continuous Synthesis and Processing (CCFLOW), Research Center
Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria
b.
The use of hydrogen gas within batch reactors generally
requires the use of high pressure to ensure sufficient dissolution
of gas within the liquid phase. Consequently, specialized and
expensive equipment is required and scale-up can be
challenging. Continuous flow reactors have been demonstrated
Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstraße 28, A-8010
Graz, Austria. E-mail: christopher.hone@rcpe.at; oliver.kappe@uni-graz.at
Chemical Development, Pharmaceutical Technology & Development, Operations,
c.
AstraZeneca, Macclesfield, United Kingdom
†Electronic Supplementary Information (ESI) available. See DOI: 10.1039/
x0xx00000x
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Article
Journal Name
as a safe and scalable technology for the scale-up of gas-liquid Ikariya and coworkers previously demonstrated the use of Ru-
View Article Online
reactions.1 In recent years, there has been a greater focus on MACHO for the hydrogenation of alpha-fluorinated esters to
6-18
DOI: 10.1039/D0GC02225J
2
8
developing green processes that avoid waste and hazardous their corresponding alcohols under batch conditions.
compounds.19 Sustainable chemical processes rely not only on
Reaction optimization experiments for the hydrogenation of
effective chemistry but also on the implementation of reactor ethyl 2,2-difluoro-2-phenylacetate (1) were performed on a 5
technologies that enhance reaction performance, reduce mmol scale within a batch autoclave. Commercially available
energy consumption and improve overall safety. The utilization Ru-MACHO (A) was used as catalyst and sodium methoxide
of continuous flow reactors can significantly contribute towards (NaOMe) as base (Scheme 2). A relatively short reaction time of
this endeavor.20 Energy efficient heating enables the 1 h was used for all batch reactions to facilitate easy transfer
sustainable utilization of intensified conditions for maximizing from batch to flow. Furthermore, we were also interested in
yield and throughput. Precise parameter control, such as identifying conditions that dissolved all reaction components.
mixing, temperature and pressure, can improve product yield The conversion of ester 1 (−103.9 ppm) to alcohol 2 (−106.7
1
9
and selectivity. The safe use of highly atom efficient routes that ppm) could be monitored offline by F NMR with a low field
would be inaccessible or too dangerous under traditional batch benchtop spectrometer (Spinsolve Ultra 43 MHz, Magritek).
2
1
conditions is possible with continuous flow reactors. The Methanol was used as solvent due to its relatively green
2
9
reduction of different functional groups within continuous flow credentials. Toluene (PhMe), tetrahydrofuran (THF), methyl
reactors was recently reviewed by Riley and co-worker in tetrahydrofuran (MeTHF) and tert-butyl alcohol/PhMe were
018.2
2,23
also screened, but provided inferior results (Table S1). These
2
Abediterol (AZD0548) (Figure 1) is a potent, long-acting poorer results were probably caused by the limited base
inhaled -adrenoceptor agonist that was first solubility in the solvent. For the batch optimization, a design of
β
2
2
4
pharmacologically characterized in 2012. It has undergone experiments (DoE) approach was selected. A four-parameter,
Phase IIa trials for the treatment of asthma and chronic two-level full factorial experimental design was implemented,
2
5
obstructive pulmonary disease (COPD). A route for the corresponding to 19 experiments including 3 center point
synthesis of the lipophilic amine tail portion of abediterol was repeats to measure reproducibility (Table 1). Pressure was
published in 2019.26 An annual demand in the order of varied between 10 and 30 bar, temperature between 40 and 60
kilograms would be expected due to the very high potency of °C, catalyst loading between 0.03 and 0.10 mol% and base
the drug candidate. The first step in the synthesis is a lithium between 0.1 and 0.3 equivalents. During the initial experiments,
aluminum hydride (LAH) reduction to afford 2,2-difluoro-2- an acid side product 3 (−101.3 ppm) and a hemiacetal
phenylethanol (2) (Scheme 1a). An alternative protocol which intermediate 4 (−108.7 and −111.0 ppm) could also be
uses stoichiometric NaBH
transformation.27
4
has also been reported for the identified. The methyl ester 5 derivative (−103.7 ppm) was
observed from transesterification, but this did not influence the
course of the hydrogenation reaction. The responses for the
conversion of 1, alcohol 2, acid side product 3, and hemiacetal
intermediate 4 were measured during experiments.
O
OH
F F
H
HN
HO
N
O
6
H
H
H
H
H
(
Abediterol, AZD0548)
Et
N
PPh2
CO
N
PPh2
CO
S
PPh3
SEt
Figure 1 Structure of abediterol (AZD0548), a β
2
-adrenoceptor agonist.
Ru
H
Ru
Ru
P
P
N
Ph
Ph
H
2
2
Cl
Cl
BH3
a) Existing work:
LiAlH (1.1 equiv.)
4
A
B
C
THF (0.8 M), reflux
F
F
F
F
Figure 2. Hydrogenation catalysts: Ru-MACHO (A), Ru-SNS (B) and Ru-MACHO-BH (C)
OEt
OH
Ph
Ph
NaBH (1 equiv.)
2
O
4
1
F
F
Ru-MACHO (A)
F
F
F F
MeOH (0.29 M), 0 C
F
F
OEt
H2
OH
OEt
+
+
Ph
b) This work:
Ph
OH Ph
Ru cat.
Ph
NaOMe
MeOH
O
O
OH
H2
F
F
F
F
1
2
3
4
OEt
Ph
OH
Scheme 2. Ru-catalyzed hydrogenation of ester 1 to alcohol 2. Acid 3 is generated
as a side product and hemiacetal 4 as an intermediate.
Ph
O
1
NaOMe
MeOH
2
Scheme 1 Synthesis of 2,2-difluoro-2-phenylethanol (2): a) a previously reported LAH
reduction (ref. 28); and NaBH
catalyzed hydrogenation (this work).
Gratifyingly, very high conversion and selectivity towards
reduction (ref 27); b) continuous flow homogeneous Ru- the desired alcohol 2 were achieved for a number of
4
experiments (Table 1). Under milder conditions, the conversion
of ester 1 and yield of alcohol 2 were lower, while intermediate
We were interested in developing
continuous flow protocol with hydrogen gas as a sustainable,
safe and scalable alternative for the synthesis of 2 (Scheme 1b).
a Ru-catalyzed
4
was observed at higher levels for these experiments. Side
product 3 was observed at similar levels for all the experiments.
The experimental repeats displayed very good reproducibility
2
| J. Name., 2012, 00, 1-3
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(
entries 17-19). Furthermore, it was shown that by lowering mol% A) it is possible to shift the selectivity ofVtiehweArrtieclaecOtniloinne
temperature, pressure or catalyst loading (10 bar, 40 °C, 0.03 towards the hemiacetal intermediate 4. DOI: 10.1039/D0GC02225J
Table 1. Input parameter levels and results from the design of experiments performed within a batch autoclave.a
Entry
p (bar)
10
30
10
30
10
30
10
30
10
30
10
30
10
30
10
30
20
20
20
T (°C)
40
40
60
60
40
40
60
60
40
40
60
60
40
40
60
60
50
50
50
Catalyst loading (mol%)
Base (eq)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.2
0.2
0.2
Conversion 1 (%)
33.0
72.9
64.7
>99
Alcohol 2 (%)
23.3
66.8
56.9
94.9
38.1
96.3
93.0
95.2
7.7
Side product 3 (%)
Hemiacetal 4 (%)
1
2
3
4
5
6
7
8
9
0.03
0.03
0.03
0.03
0.1
7.3
5.0
7.3
5.1
6.6
3.7
5.9
4.8
8.0
7.6
8.9
5.8
6.0
5.3
5.9
5.7
6.2
5.3
4.8
2.3
1.1
<1
<1
47.0
>99
2.4
<1
0.1
0.1
99.1
>99
<1
0.1
<1
0.03
0.03
0.03
0.03
0.1
27.7
71.1
86.6
>99
12.1
5.6
<1
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
57.8
76.9
94.2
64.3
94.7
94.1
94.3
93.8
94.7
95.2
<1
75.1
>99
4.7
<1
0.1
0.1
>99
<1
0.1
>99
<1
0.065
0.065
0.065
>99
<1
>99
<1
>99
<1
a
Standard reaction conditions: 1 (5 mmol scale) in MeOH (2.5 mL) with stirring at 600 rpm for 1 h. Conversion and product distribution were determined by integration
1
9
of F NMR. Conversion of 1 was calculated based on the combined integration of the ethyl ester 1 and methyl ester 5.
Figure 3. Model-predicted contour plots showing the influence of different parameters on: a) alcohol 2 yield; and b) side product 3 yield. Constant conditions: 1 (5 mmol scale) in
MeOH (2.5 mL) with stirring at 600 rpm for 1 h.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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COMMUNICATION
Journal Name
View Article Online
DOI: 10.1039/D0GC02225J
F
F
OEt
Ph
O
In-line NMR
1
Ru-MACHO
MeOH
Pump 1
Pump 2
SS coil
60 mL
H2
F
F
BPR
OH
NaOMe in MeOH
Ph
2
Pump 3
long run
MFC
2
Figure 4. Continuous flow setup for the Ru-catalyzed hydrogenation of ester 1 to alcohol 2. MFC = mass flow controller for the introduction of H and BPR = back pressure regulator.
The dashed blue box indicates the part of the setup utilized for the inline analysis with NMR which was implemented during the long run.
We were interested in comparing the results for the Ru-MACHO-BH rapidly decomposes, with the hydrolysis of the
hydrogenation of ethyl 2,2-difluoro-2-phenylacetate (1) with borane group, in the presence of air (Figure S8). Thus, we
less reactive methyl trifluoroacetate as substrate (Table S2). selected Ru-MACHO (A) as the catalyst of choice for the flow
Under similar conditions, lower conversion and higher amounts experiments.
of a hemiacetal intermediate were observed as the kinetic
Flow experiments were performed using a Uniqsis FlowSyn
product. The thermodynamic alcohol product could be favored system (Figure 4). The two liquid feeds were introduced with
under more aggressive conditions. These results suggest that a high performance liquid chromatography (HPLC) pumps and
less reactive fluorinated hemiacetal is stable enough to resist hydrogen gas was introduced through a mass flow controller
further conversion to the alcohol under carefully controlled (MFC, Bronkhorst EL-FLOW). The two liquid feeds were mixed
reaction conditions.
within an arrow-shaped mixer. Subsequently, the liquid and gas
The responses from the optimization experiments, shown in feed were combined using a Y-shaped mixer. A gas-liquid
Table 1, were fitted to polynomial models by using a statistical segmented (Taylor) flow regime was observed for all
experimental design software package (Modde v12). Models experiments. The reaction was performed within a heated
were successfully fitted for the alcohol 2 and side product 3 stainless steel reactor coil (60 mL, 1/8ꢀin. OD, 1/16ꢀin. ID).
1
9
from the F NMR data by using multiple linear regression (MLR) Pressure was applied by using an adjustable back pressure
Figures S6 and S7). Models were generated by including all regulator (BPR). For all flow experiments, fractions were
(
1
9
main and interaction terms and then non-significant terms were collected every 5 minutes and analyzed offline with F NMR. In
removed. A good fit was achieved for both models with R = 0.79 the initial flow configuration, the base and catalyst were
and R = 0.72 for the alcohol 2 and side product 3 respectively. introduced as one feed but this led to irreproducible results
2
2
The increase of pressure, temperature and catalyst loading (Table 2, entry 1). Interestingly, the catalyst has been previously
3
1
were shown to have a positive influence on the formation of reported to slowly decompose in the presence of base.
alcohol 2. The base loading did not show an influence on the Furthermore, as stated previously, the presence of a base
yield of 2. The increase in pressure and catalyst loading resulted results in the formation of side product 3. Thus, to avoid any
in a slight decrease in the yield of side product 3. Temperature undesired reactions occurring within the feed solutions, the
displayed no influence over side product 3 formation. Whereas catalyst and substrate in MeOH were introduced as one feed
increasing the base loading resulted in a higher yield of 3. The and the NaOMe in MeOH as the second feed.
models generated from the DoE were used to explore the
experimental design space and to identify promising initial concentration (1 M) than the batch experiments to ensure the
conditions for translation to flow (Figure 3). solubility of all the reaction components. A >90% product yield
We selected to commence our flow experiments at a lower
The formation of side product 3 was shown to increase with at 0.065 mol% catalyst loading, 20 bar pressure and 60 °C
the amount of NaOMe added. Furthermore, significant heat temperature was predicted from the model generated from the
was produced upon exposure of ester 1 to NaOMe, thus we batch studies. A reduction in base loading had also been
were interested in identifying a strategy to control this demonstrated in the DoE to reduce the yield of the acid side
exotherm. The reaction resulted in recovered starting material product 3 (Figure 3b), but not influence the yield of alcohol 2
1
in the absence of base, because base is necessary to form the (Figure 3a). The two liquid feeds were each pumped at 0.2
active catalyst. Ru-MACHO-BH (C) has been reported to work mL/min and the hydrogen gas at 30 mL /min, corresponding to
successfully without the addition of base for pre-activation of a residence time of approximately 50 min and 3.3 equiv of H . 2
the catalyst.30 We attempted Ru-MACHO-BH on our system; equiv of H
is necessary for the transformation, therefore only
however, Ru-MACHO-BH under base-free conditions resulted in a relatively small H excess (1.3 equiv) is used. A low base
n
2
2
2
only recovered starting material 1 (Table S4). On addition of loading of 0.1 equivalents unexpectedly resulted in a lower
base, the reaction then worked successfully affording alcohol 2 conversion than expected (entry 1) and provided inconsistent
in 98% yield. These results indicated that the catalyst could be results. This drop in conversion and the irreproducibility can be
decomposing during reaction preparation. We observed that explained by the nature of the side reaction. The base is
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Journal Name
Article
consumed in the presence of water by the reaction of esters 1 the flow setup after the BPR to enable inline analyVsiiesw(AFritgiculerOen4lin)e.
and 5 to the acid 3. Thus, the reaction is very sensitive to After separating the gas from the liquid DstOreI:a10m.1,0t3h9e/Dl0iqGuCi0d22w2a5Js
changes in the water content at low base loadings. Full fed using a HPLC pump through an inline flow cell (0.8 mL
conversion and more than 90% yield of 2 could be achieved by internal volume, max. pressure 10 bar) for monitoring by a
increasing the base loading to 0.2 equivalents and the pressure
to 30 bar (entry 3). More importantly, the reaction displayed
good reproducibility at these conditions. The use of anhydrous
MeOH and fresh NaOMe solution provided an increase in
desired alcohol 2 (entry 4), whilst decreasing the formation of
the acid side product 3. The throughput could be increased by
operating at a higher concentration (1.5 M), without a drop in
conversion or yield observed (entry 5). The pressure could also
be decreased whilst maintaining full conversion and high yield
benchtop low field NMR spectrometer (Spinsolve Ultra 43 MHz,
Magritek).33 This enabled the online monitoring of the reaction
progress for all the main reaction species by 19F NMR
spectroscopy, with a spectrum acquired approximately every 20
s and >800 measurements taken in total. Figure 5 shows the
percentage of starting material 1, alcohol 2 and side product 3
over operation time as determined by integration of the peaks
1
9
for the spectra generated by the inline F NMR measurements.
The system performed consistently for the duration of the run.
Moreover, the data points for the inline measurements very
closely corresponded to the values for the data points of the
(
entry 6a). The reaction was also performed at a shorter
residence time within the reactor setup, corresponding to 0.33
mL/min for each liquid pump and 50 mL /min H to provide 35
n
2
collected fractions that were measured manually offline by 19
NMR, thus validating the inline method. The residence time was
longer for the long run due to the consumption of H gas. For
the optimization experiments, the feeds were injected via a
F
min residence time. These conditions resulted in >99%
conversion of 1 and 87% alcohol 2, with the remaining present
as the acid 3 side product (entry 7). This result indicates that
some formation of the side product 3 from remaining substrate
2
1
could also be occurring after the reactor within the collection sample loop (6 mL each) over 30 min. For the long run, feeds
vessel. We conducted control experiments using acid 3 as were introduced continuously through the pumps. Therefore H
2
starting material instead of ester 1. In these experiments only is not consumed throughout the entire reactor for the
recovered acid 3 and some transesterification to the methyl optimization experiments, thus accounting for the difference in
ester 5 (5-7%) was observed (Table S3). The reaction provided
the observed residence time between the optimization
experiments and long run (entry 6b). Overall, the process was
operated at “steady-state” conditions for approximately 220
minutes. A >99% conversion of 1 and 98% selectivity towards 2
was observed. After combining the fractions from the operation
at “steady-state” conditions (corresponding to the 220
minutes). After removal of MeOH, a simple extraction protocol
was performed using ethyl acetate (EtOAc) as solvent to obtain
alcohol 2 in 98% isolated yield based on “steady-state”
operation. A throughput of 3.7 g/h was obtained, corresponding
9
1% yield of alcohol 2 even when using 2.2 equiv of H and 25
2
min residence time (entry 8). A reaction with Gusev’s Ru-SNS
catalyst (B) was performed as a comparison (entry 9). Under
similar conditions, the use of Ru-SNS resulted in low conversion
of 1, trace amount of desired product, and high selectivity to
hemiacetal 4. A lower activity of Ru-SNS, with higher selectivity
towards the hemiacetal intermediate 4 when compared to
using Ru-MACHO as catalyst, has been reported by Dub and co-
workers.32
Table 2. Results from the optimization experiments in continuous flow.a
.
to a space-time yield of 1.0 g/(L min). One could envisage how
the throughput could be increased by transfer to a larger scale
coil reactor without a drop in performance as described
elsewhere.17a
p
C
1,0
Base
[eq]
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
t
res
Conv. 1
[%]
Yield 2
[%]
73/0
26/40
91/93
95
Entry
ab/1bb
(
bar)
20
20
30
30
30
20
20
20
20
20
[M]
1.0
1.0
1.0
1.0
1.5
1.0
1.0
1.0
1.0
1.0
[min]
50
50
55
55
55
55
70
30
25
55
1
80/9
34/50
>99
>99
>99
>99
>99
>99
>99
23
2
a/2b
a/3b
4c
3
5c
96
6
ac
96
6
b (long run)c
98
7c,d
8 c,e
9f
87
91
1
a0.4 mL/min total liquid flow rate, both liquid feeds were pumped at equal flow
rates, 30 mL
n
/min H
2
flow rate, 0.065 mol% catalyst loading, 60 °C temperature.
b
Reagents were introduced for 30 min then switched to carrier solvent. Pre-stirring
of base and catalyst for 15 min. Anhydrous MeOH and fresh NaOMe solution
c
d
stored under Ar used. 0.66 mL/min total liquid flow rate, 50 mL
n
/min H
2
flow rate.
d
f
1
mL/min total liquid flow rate, 50 mL
n
/min H
2
flow rate. Ru-SNS used as catalyst.
Figure 5: Results of the inline 19F NMR measurements for the long run. Values are
calculated by using 19 F NMR integrals of the peaks. Ester 1 and 5 (•), alcohol 2 (•), and
A long run experiment was performed over a total operation
time of nearly 6 hours to demonstrate the stability of the side product 3 (•). Alcohol 2 (♦) measured offline for validation. Conditions used are
given in Table 2, entry 6.
process (entry 8b). A gas-liquid separator was incorporated into
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J. Name., 2013, 00, 1-3 | 5
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Article
Journal Name
The flow protocol provides benefits in terms of scalability, solvent necessary for the work-up compared to a Ru-MACHO
View Article Online
DOI: 10.1039/D0GC02225J
safety and product quality over a batch autoclave protocol. The hydrogenation (13).
addition of reagents can be carefully manipulated to provide
Table 4 shows a comparison for the qualitative green
the desired stoichiometry. The exotherm associated with base metrics between the LAH and Ru-MACHO reductions. In the
addition can be minimized, because heat generated can be green metrics toolkit, colored flags (green, amber, red) are
removed quickly. Typical commercial batch reactors can given to each reaction to assess how green they are regarding
operate between 2 and 6 bar, therefore higher pressures each criterion. A green flag means “preferred”, amber “is
require more specialized and expensive equipment. There is no acceptable-some issues” and red is “undesirable”. The Ru-
headspace filled with gas within a flow reactor and a flow MACHO hydrogenation receives green flags because it is
reactor facilitates improved safety due to the small volumes of catalytic and performed in flow. On the other hand, the LAH and
4
pressurized equipment needed. Furthermore, a flow protocol NaBH reductions require stoichiometric reagent and are
operates at steady-state, therefore providing consistent currently performed in batch, which results in amber flags for
product output as shown by Figure 5. The in-line NMR also these criteria. All reactions are operated within an energy
enables improved understanding the performance of the efficient temperature window (0-70 °C) which results in green
continuous process, thus aiding in waste prevention through an flags. The LAH reduction uses THF at reflux conditions and is
increase in process understanding.
thus less energy efficient than the Ru-MACHO reaction, which is
performed below its reflux temperature. Running the LAH
reaction at reflux results in an approximately 6-fold increase in
energy consumption as opposed to performing the reaction at
Table 3. Comparison of quantitative green metrics for the Ru-MACHO hydrogenation
flow protocol and the batch protocols for the LAH and NaBH reduction.
4
3
4,36
Metric
Conv. [%]
Yield [%]
AE
Ru-MACHO
LAH
>99
93
NaBH
>99
91
4
5 °C below reflux.
Due to the high amount of energy used
>99
98
78
75
96
6
when heating to reflux, this results in a red flag for the LAH
reduction. The simple extraction for the Ru-MACHO protocol
results in a green flag, whereas the LAH and NaBH reactions
4
require a number of extractions and an exothermic aqueous
quench (amber flag).
66
66
RME
61
54
OE
91
81
PMI reaction
PMI work-up
PMI total
E factor
10
23
8
41
110
133
132
Table 4. Comparison of qualitative green measures for reductions using LAH, NaBH and
4
14
13
52
Ru-MACHO.
51
Criterion
Type of
Ru-MACHO
Catalytic
LAH
NaBH
4
aCalculations based on LAH and NaBH
ref. 27 respectively.
reduction protocols reported in ref. 26 and
4
Stoichiometric
Stoichiometric
reaction
Reactor
Flow
60
Batch
Batch
Table 3 shows the results from the green metrics
assessment for the Ru-MACHO hydrogenation, the LAH
T [°C]
66
Yes
0
No
Reflux
No
reduction, and the NaBH
environmental impact, a green metrics toolkit developed by
4
reduction. For the comparison of the
Workup
Extraction
MeOH/EtOAc
Ru
Quench/Extraction
Quench/Extraction
Solvent
THF/H
2
O/MTBE
MeOH/H
2
O/EtOAc
B
3
4
Clark and co-workers in 2015 was used. The values used for
the calculations are shown in Tables S5-S7. All the reactions
reach full conversion and provide good selectivity and yield,
however; the Ru-MACHO hydrogenation reaches a higher value
for yield. In addition, the Ru-MACHO protocol performs better
for atom economy (AE) and reaction mass efficiency (RME),
therefore has a higher optimum efficiency (OE). The Green
Chemistry Institute Pharmaceutical Roundtable selected
process mass intensity (PMI) as their preferred mass-based
green metric.35 PMI corresponds to the total mass used in a
process divided by the mass of the product. The reaction PMI
accounts for the all the chemicals in the reaction, whereas the
total PMI accounts for the chemicals used in the reaction and
the work-up procedure. The total PMI is over 3-fold lower for
the Ru-MACHO hydrogenation (14) when compared to the LAH
reduction (52), and over 6-fold lower when compared to the
Critical element
Li, Al
Na
The Ru-MACHO reaction only uses green solvents (methanol
and ethyl acetate), and also the NaBH reduction (methanol and
4
ethyl acetate), while the LAH reduction uses THF and MTBE
which are considered of medium concern (amber flag). The
main drawback of the Ru-MACHO protocol is that ruthenium is
considered a critical element, for which the supply could run out
in the following 5-50 years (red flag). Although, the ruthenium
catalyst is employed at a very low loading (0.065 mol%). An
additional amber flag is added because the catalyst is not
currently recovered. The supply of sodium is considered to be
sustainable into the future, but boron supply is expected for
00-500 years so results in an amber flag. The supply for lithium
and aluminum are predicted to be sufficient for 100-500 more
years, which results in an amber flag. However, the demand
of lithium is rising rapidly due to its use in Li-ion batteries.
Currently, Ru-MACHO is not recycled as part of the
continuous flow protocol, therefore we also evaluated the
green metrics associated with its batch synthesis (Table 5 and
Table S8). Ru-MACHO (A) can be prepared from the
1
37
NaBH
MACHO flow protocol is substantially more sustainable than the
LAH and NaBH reductions. The E-factor shows the same trend,
whereby a higher E factor is observed for the LAH (51) and
NaBH (132) reductions, largely due to the high amount of
4
protocol (110). These results demonstrate that the Ru-
4
4
6
| J. Name., 2012, 00, 1-3
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Journal Name
Article
commercially
phino)ethyl]ammoniumchloride
carbonylchlorohydridotris(triphenylphosphine)ruthenium(II)
available
bis[(2-diphenylphos- completed within 1 h residence time. The flow process operates
View Article Online
DOI: 10.1039/D0GC02225J
(D)
and at 60 °C and 20 bar with a much smaller excess (3.3ꢀequivalents
of H
These metrics are very favorable, especially when loading (0.065 mol%) afforded the desired alcohol product in
considering that only 0.065 mol% of Ru-MACHO are used for the 98% isolated yield. In particular, the continuous flow protocol
2
) of gas than required for batch processes. A low catalyst
1
3, 38
(E).
hydrogenation.
was operated for nearly 6ꢀh run time (total duration) to produce
1
9
1
3.7 g of the API precursor. F NMR was successfully
Table 5. Quantitative green metrics for the synthesis of Ru-MACHO (A) from bis[(2-
diphenylphos-phino)ethyl]ammoniumchloride (D) and
carbonylchlorohydridotris(triphenylphosphine)ruthenium(II) (E)
incorporated inline for real-time process monitoring of the long
run. The environmental impact of the hydrogenation was
assessed and compared to an existing stoichiometric lithium
aluminum hydride reduction (LAH). The process mass intensity
of the hydrogenation represents over a 3-fold reduction when
compared to the LAH reduction, and over a six-fold reduction
H
H
N
PPh2
Ph P
2
PPh2 1. aq. NaOH, PhMe
. RuHCl(CO)(PPh3)3
N
H
Ru
P
2
(
E)
CO
when compared to the NaBH reduction. The flow protocol
Ph
4
HCl
D
2
PhMe, reflux
H
Cl
represents an improvement in terms of atom economy, safety
and scalability, and also reduces energy consumption and
solvent usage.
A
Ph P
3
PPh3
Ru
Ph P
3
CO
Cl
E
Acknowledgements
Metric
Conv. [%]
Yield [%]
Value
The CCFLOW Project (Austrian Research Promotion Agency FFG
No. 862766) is funded through the Austrian COMET Program by
the Austrian Federal Ministry of Transport, Innovation and
Technology (BMVIT), the Austrian Federal Ministry for Digital
and Economic Affairs (BMDW), and by the State of Styria
>99
85
11
8
PMI reaction
PMI work-up
PMI total
19
18
(
(
Styrian Funding Agency SFG). The INFRA FLOW project
Zukunftsfonds Steiermark No. 9003) is funded by the State of
E factor
aCalculations based on the batch protocol reported in ref. 13.
Styria (Styrian Funding Agency SFG). J. G. thanks the Banco
Santander-Fundación San Pablo-CEU for a mobility fellowship
The hydrogenation is applied to the synthesis of a precursor
for a drug candidate, therefore the contamination by Ru metal Conflicts of interest
should be considered. Furthermore, for executing this
chemistry on industrial scale, strategies should be considered
for the recovery of Ru because it is a critical element. A
maximum contamination of 10 ppm is the regulatory limit for
There are no conflicts to declare.
Notes and references
3
9
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0
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