Scale-up and Optimization of a Continuous Flow Synthesis of an α-Thio-β-chloroacrylamide

Article abstract of DOI:10.1021/acs.oprd.0c00079

Use of continuous flow processing to undertake a multistep chlorination cascade has been achieved with effective inline workup and end-of-line crystallization in batch, leading to isolation of α-thio-β-chloroacrylamide Z-3 in pure form from a complex reac

Full text of DOI:10.1021/acs.oprd.0c00079

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Full Paper
Scale-up and Optimization of a Continuous
Flow Synthesis of an #-Thio-#-chloroacrylamide
Olga C Dennehy, Denis Lynch, Stuart G. Collins, Anita R. Maguire, and Humphrey A. Moynihan
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00079 • Publication Date (Web): 19 May 2020
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Scale-up and Optimization of a Continuous Flow Synthesis of
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an α-Thio-β-chloroacrylamide
Olga C. Dennehy,† Denis Lynch,† Stuart G. Collins,*,† Anita R. Maguire,*,‡
and Humphrey A. Moynihan*,†
†School of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and
Solid State Pharmaceutical Centre, University College Cork, Cork T12 K8AF, Ireland.
‡School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research
Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork T12
K8AF, Ireland
E-mail: Anita R. Maguire - a.maguire@ucc.ie
Stuart G. Collins - stuart.collins@ucc.ie
Humphrey A. Moynihan - H.Moynihan@ucc.ie
* Corresponding author
KEYWORDS: Continuous processing, flow chemistry, process impurities, α-thio-β-
chloroacrylamides
ABSTRACT:
Use of continuous flow processing to undertake a multistep chlorination cascade has been
achieved with effective inline work-up and end-of-line crystallization in batch leading to isolation
of α-thio-β-chloroacrylamide Z-3 in pure form from a complex reaction mixture, exploiting the
advantage of efficient heat transfer in flow. During the development of a continuous flow strategy
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for the production of appreciable quantities of the α-thio-β-chloroacrylamides, difficulties
surrounding a labour and resource intensive work-up followed by final product isolation were
addressed. A greener solvent choice was applied to the chemical synthesis which enabled inline
purification and separation, resulting in the crystallization of pure product directly from the
reaction mixture. This process was readily scalable and demonstrated control over impurity
formation and removal, which is key in an industrial setting.
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INTRODUCTION
α-Thio-β-chloroacrylamides are valuable compounds for organic synthesis due to their diverse
functionality which enables a wide array of useful transformations,1-2 including nucleophilic
substitution,3-4 1,3-dipolar cycloadditions,5-6 oxidation of the sulfide group7-8 and Diels–Alder
reactions9 (Figure 1). Preparation of the prototypical α-thio-β-chloroacrylamide Z-3 consists of a
three step synthesis (Scheme 1), including a cascade reaction as the final step (Scheme 2). Control
over the cascade temperature and efficient heat transfer are crucial parameters in directing the
reaction to the desired α-thio-β-chloroacrylamide product. Therefore, when conducted in batch, a
previously optimised ‘hot plunge’ method is necessary to achieve this, whereby a solution of α-
thioamide 2 and N-chlorosuccinimide (NCS) in toluene is immersed into a preheated oil bath at 90
°C; slower heating was found to noticeably compromise product yield and purity.3
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O
R3S
Nu
R2
N
R1
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Nu-
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X
O
O
C
Y
Y
Z
R3S
X
R3S
R2
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R2
Z
SR3
O
N
N
R1
R1
C
Cl
Cl
Cl
1 N
R
R2
[O]
O
R3S(O)n
Cl
R2
N
R1
n = 1,2
Figure 1. Synthetic transformations of α-thio-β-chloroacrylamides.1-9
Scheme 1. Three-step small scale batch preparation of α-thio-β-chloroacrylamides1
Cl
Cl
SPh
O
SPh
O
HNHTol, Et3N
CH2Cl2, rt, 4 h
HSPh, NaOEt
EtOH, rt, 20 h
1.95 eq. NCS
NHTol
Cl
NHTol
Cl
NHTol
Toluene, 3 h
90 °C hot plunge
O
O
-thioamide
2
80-90% yield
-thio--chloroacrylamide
-3
-chloroamide
1
94% yield
Z
91% (ca.5 g)
Recent work has assessed the challenges associated with scaling-up this three-step process,
successfully enabling samples of up to 25 g of the α-thioamide 2 to be prepared (Scheme 3).10, 11
However, scale-up of the final cascade step has posed more serious practical considerations with
regard to achieving the 'hot-plunge' effect in batch. Heat transfer through larger volumes results in
a delay reaching the desired temperature in the bulk of the reaction medium.
Over the past two decades, continuous processing has been employed with increasing frequency
within the pharmaceutical and fine chemical industries for synthesis of active pharmaceutical
ingredients (APIs) and natural products.12–14 The process advantages inherent to flow chemistry
include improved mass transfer and efficient heat transfer, facilitated by use of high surface-area-
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to-volume ratios of tubular reactors, safer access to extreme temperature and pressure conditions,
enhanced reproducibility, inline workups and automated operation.15–20 Use of flow chemistry has
been shown to enable additional possibilities for introducing process control via feedback loops,
where suitable inline or online spectroscopic analysis allows the product profile of the reactor
output to be managed in real-time.21 Ease of scale-up is a further positive attribute of continuous
processing; while traditional scale-up, with its associated challenges, is required for batch
processes, additional, alternative, options to achieve increased production are available through
flow chemistry, whereby the process can either be run for longer (scale-out) or whereby multi-
reactors can be run in parallel (numbering up).12,22,23
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Continuous flow processing has been successfully applied to this step as a scalable ‘hot plunge’
equivalent and to overcome these heat transfer issues. This enabled the production of more material
than would be possible in batch through scaling-out the process, therefore removing the any
potential problems associated with heat and mass transfer in scale-up. Significant difficulties still
remained in achieving a complete process operable on the desired scale, including management of
the various impurities generated in the cascade process, removal of the poorly soluble succinimide
by-product and isolation of batches of solid Z-3 in acceptable yield and purity.10,11
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Scheme 2. α-Thio-β-chloroacrylamide cascade mechanism.24
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Cl
PhS
O
O
Cl
PhS
O
O
O
NCS
-HCl
-H+
PhS
PhS
Cl-
PhS
Cl
NHTol
NHTol
NHTol
NHTol
NHTol
NHTol
Cl-
H
Cl
O
2
9
N
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O
Cl
O
O
O
PhS
PhS
PhS
Cl
-HCl
NCS
NHTol
NHTol
4
Cl-
Cl
O
H
O
H
O
H
O
O
Cl
O
Cl
-H+
PhS
Cl
PhS
PhS
Cl
NCS
PhS
Cl
PhS
Cl
PhS
NHTol
NHTol
NHTol
NHTol
NHTol
NHTol
Cl
Cl
Cl
Cl
Cl
Cl-
6
Z-3
Cl
O
Cl
O
H
PhS
Cl
O
-HCl
NHTol
PhS
Cl
-HCl
PhS
Cl
NHTol
Cl
NHTol
5
Cl
Cl
7
In the batch process, toluene was used as the reaction solvent for the final step (Scheme 1). The
succinimide by-product is only soluble in toluene at higher temperatures, allowing it to be
effectively removed by precipitation and filtration on cooling the reaction mixture.3 However, in
a continuous flow process precipitation of succinimide causes blockages in the system. This
difficulty had been addressed by replacing toluene with acetonitrile as the reaction solvent, as
succinimide is highly soluble in acetonitrile, enabling the reaction implementation in a
continuous flow process (Scheme 3).10 Removal of the succinimide by-product subsequently
required employment of a static batch-type work-up, in which acetonitrile was evaporated under
vacuum, the residue was then dissolved in toluene and cooled on ice, enabling separation of the
precipitated succinimide by filtration. Toluene was then removed from the filtrate and the
product mixture was purified by recrystallization from an ethyl acetate/heptane mixture (Scheme
3).10 A fully operational flow process would require that the succinimide by-product removal
also be carried out in flow. Herein, we describe the development of a fully operational flow
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process for this step, including reaction and inline work-up before product isolation as a batch
crystallization process.
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Scheme 3. Overview of previously reported modified continuous and batch process
approach for the 3 step synthesis and isolation of Z-3 (including implentation of the cascade
reaction as continuous using acetonitrile as the solvent)10
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Step 2
HSPh, aq NaOH
Step 1
NH2Tol, DIPEA
Cl
Cl
SPh
O
NHTol
Cl
NHTol
EtOH, reflux, 1 h
EtOAc, 25°C,
2.5 min res. time
continuous
O
O
batch
-chloroamide
1
-thioamide
2
92% yield
94% yield
SPh
NHTol
O
2
Step 3
SPh
550 mL
(0.2M in MeCN)
2.5 mL/min
Cl
NHTol
8 bar
O
-thio--chloroacrylamide
10 mL
Z-3
57% (19.3 g)
130 o
C
NCS
550 mL
2 min
(0.4M in MeCN)
2.5 mL/min
continuous
Solvent
swap
Solvent
swap
Cool &
Filter
Toluene
Toluene
EtOAc/Heptane
MeCN
Z-3
Z-3
Z-3
Recrystallisation
Product &
succinimide
byproduct
Product
Z-3
Product &
succinimide
byproduct
Succinimide
Byproduct
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RESULTS AND DISCUSSION
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The requirement for multiple solvent swaps for effective implementation of the α-thio-β-
chloroacrylamide cascade step in a continuous system was identified as a key process challenge.
Ethyl acetate was proposed as a potentially suitable alternative solvent for the reaction due to its
success as a crystallization solvent.10 Successful implementation and optimization of ethyl acetate
as solvent for the process could make an inline aqueous work-up feasible, which is not possible in
acetonitrile, due to its miscibility. Ethyl acetate was tested as the reaction solvent on a small scale
using the batch ‘hot plunge’ method, which established that the cascade reaction would proceed
successfully in that solvent, and displayed a similar performance to using acetonitrile or toluene in
batch. Full consumption of α-thioamide 2 was observed, with a crude product consisting of 87.7%
for the desired Z-3, 8.8% of the isomer E-3 and 3.5% of the acrylamide 4 (by 1H NMR analysis).
Once the reaction was complete, a water wash was effective at removing the succinimide by-
product. In advance of transferring this process to a continuous flow system (Scheme 4), the
practical solubility limitation of NCS in ethyl acetate at room temperature was examined and a
0.25M solution established as the maximum working process concentration (a 0.3M solution was
found to be saturated at room temperature and contained precipitated material). Our previously
reported flow method (using acetonitrile),10 was initially attempted with 0.1M solution of α-
thioamide 2 and 0.2M solution of NCS, but using ethyl acetate as an alternative solvent. The
parameters chosen for investigation on a 10 mL scale were a 2 min residence time, 2.5 mL/min
flow rate at each pump, and reaction temperatures of both 130 °C and 120 °C. Analysis of these
experiments indicated that they had not gone to completion, with large quantities of dichloride 5
and acrylamide 4 remaining in the crude reaction mixture. Further conditions were therefore
investigated to optimize the reaction in ethyl acetate on a continuous flow platform (Tables 1–4),
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with the work-up consisting of taking the reaction solution into an offline separating funnel and
washing with water and brine to remove the succinimide by-product. As evident from Table 1,
longer residence times were needed to produce Z-3 as the major product compared to the
conditions optimized for acetonitrile.
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Scheme 4. Proposed continuous synthesis of Z-3 in ethyl acetate
SPh
NHTol
O
SPh
O
2
Cl
NHTol
in EtOAc
8 bar
Z-3
10 mL
NCS
in EtOAc
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Table 1. Optimization of residence time for synthesis of α-thio-β-chloroacrylamide Z-3 in a
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6
continuous process using EtOAc as solventa
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9
O
O
Cl
PhS
Cl
PhS
NHTol
NHTol
NHTol
SPh
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NHTol
5
4
O
2
10 mL
(0.1 M in EtOAc)
SPh
O
SPh
O
NHTol
8 bar
Cl
Cl
130 °C
10 mL
NCS
10 mL
(0.2 M in EtOAc)
E-3
Z-3
O
O
Cl
PhS
Cl
PhS
Cl
NHTol
NHTol
Cl
Cl
6
7
entry
residence
time
flow rate
(mL/min)
product ratio
Z-3
E-3
4
5
7
6
(min)
(%b)
50.3
76.3
77.9
83.3
85.8
(%b)
11.0
10.4
11.4
11.5
10.6
(%b)
6.0
4.8
3.6
3.2
2.0
(%b)
(%b)
0.0
0.0
3.2
0.5
0.3
(%b)
0.3
0.5
0.8
1.1
1.2
1
2
3
4
5
2
3
4
5
6
2.5
1.667
1.25
1
32.4
8.0
3.1
0.4
0.1
0.833
a1 equivalent of 2 (10 mL of 0.1 M solution in EtOAc) was reacted with 2 equivalents of NCS (10 mL of 0.2 M in
EtOAc). bMolar ratio (%) determined by HPLC analysis using relative response factors to compare the peak area of
each component (see Supporting Information); samples were prepared following aqueous work-up and concentration
of EtOAc solution, for dissolution in MeCN for HPLC analysis.
To improve the overall process intensity, the system volume was increased by adding another
reactor coil (see SI, Table S3); this change resulted in a higher throughput while maintaining the
residence time and therefore increased the reaction output per unit of time. The reaction
temperature was further increased to 140 °C, with a view to increasing the rate of reaction and to
confirm that an 8 bar back-pressure regulator was sufficient to keep ethyl acetate as a liquid.25 To
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enhance the process output further, the flow rates (rather than the solution concentration) were
used to control the reaction stoichiometry. This enabled an increased concentration of α-thioamide
2 to be used as a feedstock while working within the solubility limitations of NCS in ethyl acetate.
Therefore, a 1:1 ratio of reagent concentration was used, with a 1:2 ratio of flow rates. These
concentrations were then increased from 0.1M to 0.15M and then to 0.2M solutions with residence
times being optimized once again (Table 2 and SI, Table S4). Excellent conversion to Z-3 was
observed at 0.15M concentration using a 7 min residence time (Table 2, entry 2), with this possibly
attributable to the increased concentration of HCl in solution. When assessed beside a higher
concentration of 0.2M for a 5 min residence time (Table 2, entry 3), there was a slight decrease in
the relative quantity of product obtained. However, considering the increase in reaction output per
unit of time (due to the higher concentration and shorter residence time), this still represented an
improvement in process intensity for scale-up.
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Table 2. Optimization of residence times for synthesis of α-thio-β-chloroacrylamide Z-3 in a
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continuous process using 1:1 reagent concentrations and 1:2 flow ratesa
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O
O
Cl
PhS
Cl
PhS
NHTol
NHTol
NHTol
SPh
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NHTol
5
4
O
2
10 mL
in EtOAc
SPh
O
SPh
O
NHTol
8 bar
Cl
Cl
140 °C
10 mL
140 °C
10 mL
E-3
Z-3
NCS
20 mL
in EtOAc
O
O
Cl
PhS
Cl
PhS
Cl
NHTol
NHTol
Cl
Cl
6
7
entry conc.
flow rate flow rate residence
time
product ratio
(M)
2
NCS
Z-3
E-3
4
5
7
6
(min)
(%b) (%b) (%b) (%b) (%b) (%b)
(mL/min) (mL/min)
1
2
3
4
5
0.15
0.15
0.2
1.333
0.952
1.333
1.111
0.741
2.667
1.905
2.667
2.222
1.48
5
7
5
6
9
85.6 10.7 1.7
0.4
0.0
0.0
0.0
0.0
0.4 1.2
0.5 0.6
0.5 0.7
0.5 0.7
0.6 0.3
91.8
86.5
87.6
89.9
5.9
9.1
8.1
6.2
1.2
3.2
3.1
3.0
0.2
0.2
a1 equivalent of 2 (in EtOAc) was reacted with 2 equivalents of NCS (in EtOAc) by using a 1:2 ratio of flow rates
(rather than solution concentration) at 140 °C. bMolar ratio (%) determined by HPLC analysis using relative response
factors to compare the peak area of each component (see Supporting Information); samples were prepared following
aqueous work-up and concentration of EtOAc solution, for dissolution in MeCN for HPLC analysis. Additional entries
to this table are available in Table S4, SI
As success for this transformation is dependent on reaction stoichiometry, data on the impact of
adjusting the equivalents of NCS using various flow rates was also gathered. The results obtained
(Table 3) were comparable to Table 2, entry 3 at a 5 min residence time and using 0.2 M reagent
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solutions. The reaction was run with a 1:2 ratio of α-thioamide 2 to NCS and the corresponding
reaction mixture contained 87% of the desired Z-α-thio-β-chloroacrylamide Z-3. 1.95 equivalents
of NCS are typically employed in the batch process, this ratio of NCS to starting material being
found to optimize the yield of the required product Z-3 versus impurities. The experiments in Table
3 highlight the sensitivity of the reaction to stoichiometry as this is a critical parameter of the
process. The results obtained demonstrate the enhanced control over the cascade reaction by
exploiting a key advantage of a continuous approach in that the flow rate of a reagent stream can
be adjusted to predictably alter the product profile.
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55
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59
60
In this case, by adjusting the flow rate of NCS to a 1:1 ratio of α-thioamide 2 to the NCS (Table 3,
entry 1), the major product of the reaction was observed to be acrylamide 4, at approximately 79%
of the crude reaction mixture. It was also seen that 2.1 equivalents (Table 3, entry 5) gave the
highest percentage of the Z-α-thio-β-chloroacrylamide Z-3, although there was also an increase
seen for the E-isomer E-3 and over-chlorination products, which can be more difficult to remove
in higher quantities.
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Table 3. Optimization of equivalents of NCS for synthesis of α-thio-β-chloroacrylamide Z-3
5
6
in a continuous process using 5 min residence timea
7
8
9
O
O
Cl
PhS
Cl
PhS
NHTol
NHTol
NHTol
SPh
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NHTol
5
4
O
2
(0.2 M in EtOAc)
SPh
O
SPh
O
NHTol
8 bar
Cl
Cl
140 °C
10 mL
140 °C
10 mL
E-3
Z-3
NCS
(0.2 M in EtOAc)
O
O
Cl
PhS
Cl
PhS
Cl
NHTol
NHTol
Cl
Cl
6
7
entry equiv
flow rate
flow rate
NCS
product ratio
of
NCS
2
Z-3
E-3
2
4
5
7
6
(%b) (%b) (%b)
(%b) (%b) (%b) (%b)
(mL/min) (mL/min)
1
2
3
4
5
6
1
2
2
9.1
1.2
8.0
8.0
7.7
8.9
7.1
10.7
0.0
0.1
0.0
0.0
0.0
79.0
19.7
11.1
7.2
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.1
0.2
0.2
0.7
3.2
0.0
0.5
0.4
0.4
1.5
5.4
1.8
1.9
1.95
2.1
2.2
1.429
1.379
1.356
1.290
1.25
2.571
2.621
2.644
2.710
2.75
71.7
80.2
84.5
88.5
83.4
0.4
0.9
a1 equivalent of 2 (10 mL of 0.2M solution in EtOAc) was reacted with various equivalents of NCS (0.2M in EtOAc)
at 140 °C for a 5 min residence time. bMolar ratio % determined by HPLC analysis using relative response factors to
compare the peak area of each component (see Supporting Information); samples were prepared following aqueous
work-up and concentration of EtOAc solution, for dissolution in MeCN for HPLC analysis.
Measures to reduce the overall reaction times were also examined by expanding the system volume
through addition of a third reaction coil. The maximum combined flow rate in the PFA coils when
working above 100 °C is 6 mL/min, therefore 5 min was the lowest residence time possible
(comparable to Table 2, entry 3). Shorter times were checked using two coils but no improvement
in efficiency was evident (Table S5). Following this series of optimization experiments, a trial
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scale-up experiment was carried out using approximately 13 g of the α-thioamide 2, which took
ca. 2 h 15 min to complete (Scheme 5). The work-up was completed offline (washing with water,
brine and drying over MgSO4). The crude product ratio for this experiment, analysed by HPLC,
showed 80% of Z-3 relative to the other reaction impurities. The isolated product required two
recrystallizations (ethyl acetate/heptane) to obtain 7.97 g (56% yield) of 98% pure material by
HPLC.
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50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Scaled-up preparation of Z-3 at 140 °C, with a residence time of 5 min and using
2.0 equiv NCS
SPh
NHTol
2 mL/min
O
2
SPh
O
235 mL
0.2M in EtOAc
Cl
NHTol
8 bar
Z-3
7.97 g
98% purity
56% Yield
10 mL
140 
10 mL
140 
10 mL
140 
NCS
470 mL
0.2M in EtOAc
C
C
C
4 mL/min
To improve on this result, the reaction temperature was increased to 145 °C while keeping ethyl
acetate from vaporizing, allowing a number of different sets of conditions to be run using 3 coil
reactors. The optimum conditions were found to be 2.05 equivalents of NCS at 145 °C (Table 4,
entry 2) and these conditions were brought forward to optimize an inline work-up.
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Table 4. Optimization of residence time and stoichiometry at 145 °C for synthesis of α-thio-
β-chloroacrylamide Z-3 in a continuous processa
7
8
9
entry
residence
time
temp equiv
product ratio
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19
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46
47
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50
51
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53
54
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57
58
59
60
(°C)
of
Z-3
(%b)
79.8
82.2
79.0
79.6
E-3
(%b)
8.6
4
5
7
6
(min)
(%b)
10.8
8.8
(%b)
0.0
0.0
0.0
0.0
(%b)
0.3
0.3
0.3
0.2
(%b)
0.5
0.5
0.5
0.5
NCS
1
2
3
4
5
145
145
145
140
2
2.05
2
5
8.2
5.5
5.5
8.1
12.1
11.7
2
8.0
a1 equivalent of 2 (0.2M solution in EtOAc) was reacted with a solution of NCS (0.2M in EtOAc). Molar ratio %
determined by HPLC analysis using relative response factors to compare the peak area of each component (see
Supporting Information); samples were prepared following aqueous work-up and concentration of EtOAc solution,
for dissolution in MeCN for HPLC analysis.
b
Inline work-up development. After the synthetic parameters for the final step were optimized,
the next goal was to develop a product isolation protocol that could be carried out in a continuous
manner. This work involved using a membrane separator to remove the succinimide by-product
via extraction into an aqueous wash, while keeping the product in an organic phase. Initial
development involved pumping water to join the product stream via a T-piece (Scheme 6), as
extraction into water had been found to work well for a conventional batch work-up and product
isolation.
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Scheme 6. Continuous synthesis of Z-3 in ethyl acetate with inline separation of succinimide
5
6
using an aqueous wash
7
8
SPh
H2O
NHTol
1.967 mL/min
9
10
11
12
13
14
15
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52
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57
58
59
60
O
2
Liq. Phase
Separator
SPh
O
in EtOAc
Cl
NHTol
8 bar
Z-3
10 mL
145 oC
10 mL
145 oC
10 mL
145 oC
NCS
in EtOAc
H
N
Aqueous
Phase
O
O
4.033 mL/min
The reaction employs 2.05 equivalents of NCS and, as such, the aim of the work-up would be to
entirely remove the succinimide by-product that is generated. In this case, 1H NMR spectroscopic
analysis was used to monitor succinimide removal, as its characteristic resonance can be clearly
seen as a 4H signal at 2.76 ppm in CDCl3, and could be compared to the β-hydrogen singlet of Z-
3 at 8.05 ppm to afford a product ratio. HPLC was not a suitable analytical technique for this work
as small quantities of the succinimide were not readily detected by this method. When the aqueous
stream was added at a 2 mL/min flow rate (relative to a combined organic stream at 6 mL/min),
the ratio of product to succinimide in the crude material recovered was observed to be 1:1.06
(Table 5, entry 1) and when increased to a 5 mL/min stream of water, a product to succinimide
ratio of 1:0.63 was determined by 1H NMR integration (Table 4, entry 4). The minor difference in
efficiency of removal of succinimide between entries 5 and 6 is not believed to be experimentally
significant.
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Table 5. Impact of flow rate of water on the level of succinimide by-product present in the
crude product mixture from continuous synthesis of Z-3 in ethyl acetate (Scheme 6)a
7
8
9
entry flow rate of H2O
(mL/min)
ratio of Z-3 vs. succinimideb
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1
2
3
4
5
2
3
4
5
6
1 : 1.06
1 : 0.94
1 : 0.82
1: 0.63
1: 0.75
aCombined organic product stream at a flow rate of 6 mL/min, as in Scheme 6, for all entries. bRatio determined by 1H NMR using
the 4H succinimide signal at 2.76 ppm, which was compared to the β-hydrogen singlet of Z-3 at 8.05 ppm.
Aqueous saturated sodium bicarbonate solutions were investigated as an alternative to water but
very similar results were observed. A second aqueous addition was also examined; this was
connected and the tubing used was extended, where various combinations of two water additions,
two aqueous saturated sodium bicarbonate additions and a combination of water and aqueous
saturated sodium bicarbonate additions were assessed, with improved performance noted when
adding water first, followed by NaHCO3 solution. The best result for the process was where
combined organic streams at a flow rate of 6 mL/min met successive aqueous streams, both work-
up streams, each also at a flow rate of 6 mL/min, which afforded a product to succinimide ratio of
1:0.19, as observed by 1H NMR analysis (Table S6, entry 16 in SI).
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Scheme 7. Reaction setup using an aqueous NaHCO3 work-up stream (see, Table S7 entry
16 in SI)
7
8
9
aq NaHCO3
6 mL/min
H2O
6 mL/min
SPh
10
11
12
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16
17
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19
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49
50
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58
59
60
NHTol
1.967 mL/min
O
2
Liq. Phase
Separator
SPh
O
in EtOAc
Cl
NHTol
1 m
2.57 m
8 bar
Z-3
10 mL
145 o
10 mL
145 o
10 mL
145 o
NCS
in EtOAc
C
C
C
H
N
O
Aqueous
Phase
O
4.033 mL/min
In using a combination of water and sodium bicarbonate mixtures with various lengths of tubing
and a chip mixer to maximise contact and mixing between the immiscible phases, it proved
difficult to reduce the succinimide level below 1:0.19. Consequently, sodium hydroxide solutions
were examined as an alternative to sodium bicarbonate, to investigate if any improved performance
could be seen without degrading the product (Table 5). Substantial improvement was observed
when 1M NaOH was used, especially when this was employed as the first aqueous addition,
followed by water as the second aqueous addition (Table 5, entry 6).
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Table 6. Optimization of continuous work-up using aqueous NaOH and water for removal
of succinimide by-producta
7
8
9
SPh
Pump 1
Pump 2
NHTol
1.967 mL/min
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11
12
13
14
15
16
17
18
19
20
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60
O
2
Liq. Phase
Separator
SPh
O
in EtOAc
a
b
Cl
NHTol
8 bar
Z-3
10 mL
145 o
10 mL
145 o
10 mL
145 o
NCS
in EtOAc
C
C
C
H
N
Aqueous
Phase
O
O
4.033 mL/min
entry
work-up pump 1
reagent
work-up pump 2
reagent
tube length
a + b
ratio of Z-3
vs.
succimimideb
[flow rate (mL/min)]
H2O [5]
[flow rate (mL/min)]
0.5 M NaOH [3]
0.5 M NaOH [5]
1 M NaOH [5]
1 M NaOH [6]
1 M NaOH [6]
H2O [6]
(m)
1
2
1 + 1.57
1 + 1.57
1 + 1.57
1 + 1.57
1 + 2.57
1 + 2.57
1 + 1.57
1 + 1.57
1 + 1.57
1 + 1.57
1 + 1.57
1 : 0.42
1 : 0.39
H2O [5]
3
H2O [5]
1 : 0.03
4
H2O [6]
1 : 0.03
5
H2O [6]
1 : 0.01
6
1M NaOH [6]
0.5M NaOH [5]
0.5M NaOH [6]
1M NaOH [5]
1 M NaOH [4]
1 M NaOH [3]
1 M NaOH [3]
1 : 0.002
1 : 0.024
1 : 0.017
1 : 0.011
1 : 0.014
1 : 0.016
1 : 0.017
7
H2O [5]
8
H2O [6]
9
H2O [5]
10
11
12
H2O [4]
H2O [3]
H2O [5]
1 + 1.57
aCombined organic stream at a flow rate of 6 mL/min for all entries. Ratio determined by H NMR using the 4H succinimide
b
1
signal at 2.76 ppm, which was compared to the β-hydrogen singlet of Z-3 at 8.05 ppm.
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9
Following this work-up optimization, where each of these reactions were carried out on an 8 mL
scale, a mid-scale trial was performed including an inline work-up (Scheme 8), flowing 118 mL
(containing 6.4 g) of α-thioamide 2 solution through the system and using a 5 mL/min flow rate of
0.5M aqueous NaOH followed by 5 mL/min of water. This experiment was also carried out to look
out for possible degradation of the desired product on contact with aqueous NaOH, potentially
with a resulting decrease in yield. The yield obtained after recrystallization from an ethyl acetate,
heptane mixture was 70%, producing 5 g of α-thio-β-chloroacrylamide Z-3, with a Z-3 to
succinimide ratio of 1:0.021.
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60
Scheme 8. Continuous α-thio-β-chloroacrylamide synthesis performed at a mid-scale
including an inline work-up
0.5 M NaOH
5 mL/min 5 mL/min
H2O
SPh
NHTol
1.967 mL/min
O
2
Liq. Phase
Separator
SPh
O
in EtOAc
0.2 M
Cl
NHTol
1.57 m
1 m
8 bar
Z-3
10 mL
145 o
10 mL
145 o
10 mL
145 o
NCS
in EtOAc
0.2 M
C
C
C
H
N
Aqueous
Phase
O
O
4.033 mL/min
However, when using a NaOH work-up on a larger scale, it was noticed that liquid–liquid
membrane separation did not perform as well as at test scale, requiring some manual separation of
the organic layer from the aqueous layer. There was further investigation into reducing the volumes
of the aqueous additions (Table S7 in SI); however, no improvement in separation was observed.
Going forward, a gravity-based continuous separator was used for the final optimized work-up
(Table S8 in SI). In the scale-up development, impurities 4 and E-3 remained in the crystallized
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Z-3 product; to overcome this the number of equivalents of NCS used was increased to 2.1 (Table
5
6
S8 in SI).
7
8
9
The corresponding experiment was performed with the first aqueous addition of 0.5 M NaOH
pumping at 5 mL/min, followed by the second addition of water at 3 mL/min through a 200 µL
chip mixer (in place of the T-piece) to improve the mixing at the final aqueous addition (Scheme
9). No succinimide was observed in the Z-3 product by 1H NMR spectroscopy when run at a 5 g
scale. These final conditions were subsequently scaled-up (scaled-out) to a process using 30 g of
α-thioamide 2 over approximately 5 hours, with the Z-3 product being crystallized from the
reaction solution by reducing the volume of ethyl acetate in vacuo and carrying out a solvent/anti-
solvent batch crystallization with heptane, and cooling on ice. 20.2 g (60.5 % yield) of the product
Z-3 was obtained which was >99 % pure by HPLC analysis and did not contain any evidence for
the presence of succinimide by 1H NMR spectroscopic analysis. The recovery of over 60% yield
of Z-3 (>3 times the scale possible in batch) in analytically pure form from this streamlined
continuous process without chromatography is particularly notable as the composition of the crude
reaction mixture prior to the inline washings and crystallization (based on the optimization work)
contains a complex mixture including 2.1 equivalents of succinimide, approx. 85-88% of Z-3, 8-
9% of E-3, with minor amounts of the other by-products 4, 6 and 7.
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Scheme 9. Optimized scale-up of continuous α-thio-β-chloroacrylamide synthesis using 2.1
5
6
equiv. of NCS and an inline work-up
7
8
9
SPh
NHTol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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58
59
60
O
2
H2O
3 mL/min
0.5 M NaOH
5 mL/min
(0.2 M in EtOAc)
1.935 mL/min
Liq. Phase
Separator
8 bar
1 m
1.57 m
Reduce volume
Add heptane
Cool
200 µL
Chip Mixer
10 mL
145 °C
10 mL
145 °C
10 mL
145 °C
Filter
H
Aqueous
Phase
N
O
O
NCS
(0.2M in EtOAc)
4.065 mL/min
SPh
Cl
NHTol
O
Z-3
>99% Purity
20.2 g
60.5 % Yield
CONCLUSION
A continuous flow process has been optimized for a cascade chlorination process to include an
inline work-up and an end-of-line batch crystallization, and has been successfully scaled-up to
processing 30 g in approximately 5 hours. This process optimization achieved the complete
removal of 2.1 equivalents of the succinimide by-product, as well as isolation by crystallization to
effectively remove all cascade impurities. This strategy demonstrates a broader approach to
reaction process optimization, proactively addressing issues commonly posed in industrial process
development—including impurity management, heat transfer, inline work-up and removal of
stoichiometric by-products—through use of continuous processing technology to facilitate
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streamlining of the required unit operations into sequential directly telescoped steps. Scalability
issues are overcome by means of ‘scale-out’, while incorporating a greener approach by using
reduced solvent volume and a greener solvent. It demonstrates an improved safety profile by
reducing product handling due to end-of-line isolation only. There is an increase in time economy
and simplicity by conveniently streamlining the process in continuous flow and removing tedious
work-up and purification steps. Effective management of impurity formation is achieved by
enhanced control of the reaction, and this could potentially be developed further through the
inclusion of inline spectroscopic analysis to provide live feedback of the reaction progress for
immediate parameter adjustment. Achieving this level of control in a complex multistep reaction
cascade (Scheme 2) which proceeds through a series of intermediates is particularly notable. The
continuous flow process enables the chlorination cascade to be undertaken at scale; under batch
conditions the scale is limited (typically 1–10 g) by the efficiency of heat transfer in a ‘hot plunge’.3
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60
EXPERIMENTAL
General Experimental
Solvents were distilled prior to use as follows: ethyl acetate was distilled from potassium
carbonate. All commercial reagents were used without further purification unless otherwise stated.
1H (300 MHz) NMR spectra were recorded on a Bruker Avance 300 MHz NMR spectrometer. All
spectra were recorded at 300 K in deuterated chloroform (CDCl3) unless otherwise stated, using
tetramethylsilane (TMS) as internal standard. Chemical shifts (δH and δC) are reported in parts per
million (ppm) relative to TMS and coupling constants are expressed in hertz (Hz). Splitting
patterns in 1H spectra are designated as s (singlet), d (doublet), dd (doublet of doublets), t (triplet),
q (quartet) and m (multiplet). Low resolution mass spectra (LRMS) were recorded on a Waters
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Quattro Micro triple quadrupole instrument in electrospray ionization (ESI) mode using 50%
acetonitrile-water containing 0.1% formic acid as eluent; samples were prepared employing
acetonitrile as solvent.
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HPLC was performed on an Agilent Technologies 1290 Infinity II LC system (Agilent
Technologies, Santa Clara, CA, USA) on Agilent Chemstation (Rev. C.01.07 SR2 [255]) software
for data acquisition. Chromatography was carried out using an Agilent Eclipse XDB-C18 reverse
phase column (150 mm x 4.6 mm, 5 μm) with a flow rate of 0.7 mL/min. Samples were injected
(2 µL) by the autosampler and were detected by the Diode Array Detector at 250 nm.
All continuous processes were carried out using a Vapourtec R-series flow reactor. This consists
of four piston pumps and has the potential to connect four temperature controlled tubular reactors.
Before using the system, the pumps and all reaction tubing, coils and connections are purged with
the solvent to be used in the reaction in preparation. The tubular reactor coils contained PFA tubing
of 1 mm internal diameter and had an internal volume of 10 mL. The reactor coils used for this
work had a temperature range of −70 °C to 150 °C and, when used above 100 °C, the maximum
flow rate was 6 mL/min, to accommodate an operating pressure limit of 15 bar for the process.
The temperature control was via a contact thermometer, measuring the external temperature of the
reactor coil. The gravity liquid–liquid separator involved the aqueous–organic stream flowing into
approximately 100 mL of water and the organic layer was continuously removed once it reached
in excess of approximately 20 mL.
Optimized Flow Process with Inline Workup
A solution of α-thioamide (30.0 g, 0.11 mol) in EtOAc (553 mL) and a solution of N-
chlorosuccinimide (31.0 g, 0.23 mol) in EtOAc (1,161 mL) were prepared. The α-thioamide
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solution was pumped (1.935 mL/min) into a T-piece where it met the solution of NCS (4.065
mL/min). The combined stream passed through three 10 mL reactor coils at 145 °C (5.0 min
residence time). To the reaction stream, 0.5 M aqueous NaOH was pumped (5 mL/min) through 1
m of tubing before water was pumped (3 mL/min) to join the stream in a 200 µL chip mixer and
was pumped through 1.57 m of tubing before entering the continuous liquid phase separator. The
reactor output was collected and most of the solvent was removed under reduced pressure, with
heptane added as an antisolvent to crystallize the product from solution. The desired Z-3 product
was isolated as an off-white solid (20.2 g, 60.5 %); δH (300 MHz, CDCl3) 2.29 (3H, s, ArCH3),
7.09 (2H, d, J 8.4, ArH), 7.20-7.31 (7H, m, ArH), 8.04 (1H, s, CHCl), 8.61 (1H, br s, NH); MS
(ESI+): m/z 304 ([M+H]+).
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications website at DOI:
Experimental procedures, optimization tables for additional work supporting development of the
continuous process in ethyl acetate (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: stuart.collins@ucc.ie (S.G.C.).
*E-mail: a.maguire@ucc.ie (A.R.M.).
*E-mail: H.Moynihan@ucc.ie (H.A.M.).
ORCID
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Stuart G. Collins 0000-0002-3110-1037
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Anita R. Maguire 0000-0001-8306-1893
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Humphrey A. Moynihan 0000-0003-2700-2746
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was undertaken as part of the Synthesis and Solid State Pharmaceutical Centre
supported by Science Foundation Ireland and co-funded under the European Regional
Development Fund (grant: SFI SSPC2 12/RC/2275 and SFI SSPC3 Pharm5 12/RC/2275_2) and
with use of equipment provided by Science Foundation Ireland though a research infrastructure
award for process flow spectroscopy (ProSpect) (grant: SFI 15/RI/3221).
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