Volume 9
Number 1
January 2024
Pages 1–212
Reaction Chemistry
& Engineering
Linking fundamental chemistry and engineering to create scalable, efficient processes
rsc.li/reaction-engineering
ISSN 2058-9883
PAPER
Darren L. Riley et al.
The synthesis of bupropion hydrochloride under greener and
safer conditions utilizing flow technologies
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PAPER
Cite this: React. Chem. Eng., 2024,
9, 45
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The synthesis of bupropion hydrochloride under
greener and safer conditions utilizing flow
technologies†
Lorinda T. van Wyk,a Nicole C. Neyt,ab Jaimee Jugmohan,b
Jenny-Lee Panayides b and Darren L. Riley *a
Globally, major depressive disorders are a leading cause of disconsolateness affecting more than 300
million individuals. Bupropion is a unique dopamine-norepinephrine reuptake inhibitor (DNRI) commonly
utilized in the treatment of depression, smoking cessation, ADHD and other addictions. Herein, we report
our attempts to develop a greener, safer and more sustainable process for the preparation of bupropion
hydrochloride employing flow chemistry. The use of obnoxious and corrosive liquid bromine was evaded
Received 18th August 2023,
Accepted 14th November 2023
DOI: 10.1039/d3re00443k
through the employment of polymer-bound pyridinium tribromide and environmentally questionable
solvents NMP and DMF were substituted with greener co-solvent systems with appreciable success. The
final telescoped flow process afforded bupropion hydrochloride in a 69% overall yield, with improved
process mass intensity, productivity and purity, as well as a reduction in reagents/solvents designated as
rsc.li/reaction-engineering
red or amber in terms of H-codes.
Introduction
Major depressive disorder (MDD); also known as clinical
depression; is a prevalent chronic, recurring, and enfeebling
mood disorder characterised by persistent feelings of sadness
and morbidity affecting up to 20% of the population.1–4
According to the World Health Organization, unipolar
depressive disorders may become a major leading disease
burden by 2030, a quandary which has been intensified in a
post-COVID-19 pandemic world where job-losses and
economic/emotional hardships continue to be felt in many
countries.5–8 Even though depression is amongst one of the
most treatable mental disorders, 34–46% of MDD patients are
said to have treatment-resistant depression, responding
inadequately
to
the
standard
antidepressant
monotherapies.1,2 Bupropion hydrochloride 1a, was developed
and marketed by the Burroughs Wellcome fund in 1985 under
trade names, Wellbutrin and Zyban.9,11 It is a unique
unicyclic aminoketone drug with an atypical norepinephrine
dopamine disinhibitor mode of action which makes it useful
for the treatment of depression and as a smoking cessation
supplement.12,13 Though effective as an anti-depressant on its
a
Department Chemistry, University of Pretoria, Pretoria, 0028, South Africa.
E-mail: Darren.riley@up.ac.za; Tel: +2712 420 3097
b
Pharmaceutical Technologies, Chemicals cluster, CSIR, Pretoria campus, Pretoria,
0001, South Africa
† Electronic supplementary information (ESI) available. See DOI: https://doi.org/
10.1039/d3re00443k
This journal is © The Royal Society of Chemistry 2024
own, the drug is commonly prescribed conjointly with
Selected Serotonin Reuptake Inhibitors in cases where
incomplete response to the first-line antidepressant is seen.3
Additionally, bupropion analogues have recently been found
to act as indirect dopamine agonists in the treatment of
cocaine and methamphetamine addictions.12
In the last decade, the use of flow- and microreactors for
the synthesis of organic substrates has increased
considerably presenting a means of carrying out reactions in
a safer, faster, and more efficient manner. This process
technology has gained popularity for its ability to deal with
hazardous or noxious materials in a more controllable
fashion, and when coupled with solvent recycling, the use of
greener solvents, the reuse of reagents and in-line waste
treatments it affords a more sustainable means of
synthesizing molecules.14,15 The technology is often directly
scalable and depending on the process at hand can allow one
to
telescope
multistep
processes
as
continuous,
uninterrupted sequences with in-line downstream processing
and purification.16
The first total synthesis of bupropion hydrochloride 1a
was patented by the Burroughs Wellcome Co. (now
GlaxoSmithKline) in 1974 (Scheme 1).9 Since then, several
variations have been reported almost exclusively employing
the same basic synthetic strategy with variations to the
reagents and/or solvents.11,17–19 The general approach
involves three stages commencing with an α-bromination of
3′-chloropropiophenone 2 using molecular bromine in
dichloromethane (DCM) to afford α-bromoketone 3 which is
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Reaction Chemistry & Engineering
Scheme 1 Synthetic route for the preparation of bupropion hydrochloride 1a.
subsequently treated with excess tert-butylamine in
acetonitrile in a nucleophilic displacement reaction to afford
the free base 1b. Thereafter, treatment with concentrated
hydrogen chloride in diethyl ether affords the commercial
salt form of the molecule 1a.9
Bromination reactions are pivotal in generating useful
intermediary organobromide building blocks, but a notable
drawback to their use is that they are almost exclusively
prepared using molecular bromine either directly, or
indirectly. Molecular bromine poses a significant safety risk
as it is toxic, highly corrosive and sublimes at ambient
temperature. Furthermore, and of relevance to the synthesis
of bupropion hydrochloride 1a, α-brominated species are
generally lachrymatory in nature presenting additional safety
challenges. A variety of bromination reactions utilizing flow
conditions have been reported, often making use of
molecular bromine.20–24 Several greener, more sustainable
alternatives including photochemical brominations with
N-bromosuccinimide, in situ generated metal bromide (FeBr3)
and ionic salt bromination sources such as KOBr and NaBr
have been reported with enhanced safety while affording
comparable yields.21–30 Critically speaking, if reagent
lifecycles are considered, the use of molecular bromine,
despite its associated hazards, has a cost and sustainability
advantage over most “greener” alternatives as they inevitably
have their genesis with molecular bromine itself.
Nucleophilic substitution reactions are salient solvent and
base dependent transformations. These displacement reactions
have been demonstrated under flow conditions with multiple
electrophiles, often outperforming their related batch
counterparts.31 In a more modernized approach, nucleophilic
substitutions have also been performed in ionic-liquids under
flow conditions.32 Unfortunately, these reactions are often
carried out in unfavourable solvents such as N-methyl-2pyrrolidone (NMP), N,N-dimethylformamide (DMF) and
dimethylsulfoxide (DMSO) which are employed to aid in the
solubilization of the reaction matrix but which have associated
safety and environmental concerns (NMP and DMF) and are
challenging to remove during downstream processing.
Ley and co-workers have previously reported a flow
synthesis of the free base form of bupropion 1b while
showcasing the use of novel automation technologies. In this
instance, the approach outlined in Scheme 1 was adopted
and the first two stages were optimized and telescoped under
flow conditions to afford the free base 1b. The first stage
bromination was performed with molecular bromine
affording 3 in 95% yield. The subsequent nucleophilic
displacement step was performed in NMP affording the free
46 | React. Chem. Eng., 2024, 9, 45–57
base 1b in 80% yield. Telescoping of the process; which
consisted of four-unit operations; culminated in the
production of the free base of bupropion 1b in an overall
yield of 80% and production rate of 2.88 g h−1. Although this
flow process proved to be efficient in terms of both yield and
productivity, we envisioned improving the process further in
terms of overall greenness and safety.19
In this paper, we describe our attempts to develop a
telescoped synthesis of bupropion hydrochloride 1a under
flow conditions with a focus on increasing safety, reducing
waste generation, employing the use of greener reagents/
solvents, and improving energy efficiency. Critically,
hazardous molecular bromine (Stage 1) and N-methyl-2pyrrolidone (Stage 2) were identified as two key players which
required replacement with greener/safer alternatives.
Results and discussion
1st generation – batch processes
Stage 1. Initially, we elected to validate the originally
reported approach9 for the synthesis of bupropion
hydrochloride 1a (Scheme 1) to obtain a performance
benchmark in terms of efficiency, greenness and safety. In
addition to the validation, we also investigated several
modifications to previously reported approaches with the aim
of identifying more sustainable conditions which would also
facilitate subsequent flow translation and telescoping.
The bromination of 3′-chloropropiophenone 2 (Scheme 2)
was investigated under batch conditions using several
brominating reagents including, molecular bromine,
N-bromosuccinimide (NBS), ammonium bromide/oxone and
polymer supported pyridinium tribromide (Table 1).
Molecular bromine proved to be most favourable when
performed in dichloromethane with a short reaction time (40
min) at ambient temperature when employing a modest
excess of bromine. Downstream processing only required
quenching with aqueous potassium carbonate; followed by
extraction to afford 3 in an 87% isolated yield (Table 1, entry
1). Notably, the same approach at reflux with a prolonged
Scheme 2 Bromination of 3′-chloropropiophenone 2.
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Table 1 Batch bromination reactions utilising different bromine sources
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Entry
b
1
2
3
4
5
6
7
8
9
Brominating agent
Equivalents
Reaction time
Temperature (°C)
Solvent
Conc. (M)
2
3
4
Bromine
Bromine
Bromine
Bromine
NBS/p-TsOH
NH4Br and oxonec
PyBr3 polymer bound
PyBr3 polymer bound
PyBr3 polymer bound
1.1
2.0
1.1
1.1
1.5
1.5
1.5
1.5
1.5
40 min
12 h
40 min
40 min
12 h
48 h
12 h
12 h
12 h
rt
40 (1 h) → rt (11 h)
rt
rt
Reflux
60
60
60
60
DCM
DCM
ACN
EtOAc
ACN
MeOH
ACN
EtOAc
DCM
0.5
0.5
0.5
0.5
0.5
0.2
0.5
0.5
0.5
0
0
0
0
25
64
0
0
0
100 (87)
2
76
93
75
36
88
100
91
0
98
24
7
0
0
12
0
9
a
Conversions estimated by comparison of integral areas of 2, 3 and 4 in 1H NMR spectra, isolated yields provided in brackets.
Wellcome Co. method.9 c Precipitation noted.
reaction time and in the presence of excess bromine resulted
in unwanted dibromination affording 4 as a by-product which
proved challenging to remove (entry 2). As dichloromethane
was undesirable from a sustainability point of view, we
elected to screen the process in acetonitrile as a greener
alternative. The selection of acetonitrile was driven by the fact
that it readily solubilised 2, and concurrent development of
the second stage suggested that acetonitrile (in conjunction
with a co-solvent) could be utilised for both stages 1 and 2 of
the process. Unfortunately, brominating with molecular
bromine in acetonitrile under comparable conditions was
characterised by the formation of appreciable amounts of the
unwanted dibrominated product 4 (entry 3). The employment
of a p-TsOH catalysed NBS or ammonium bromide/oxone
mediated brominations showed poor conversions and
required longer reaction times (entries 5 and 6) and the latter
was characterised by significant precipitation which made the
translation thereof to flow unappealing. Finally, the use of
polymer bound pyridinium tribromide afforded comparable
conversions and yields to that achieved with molecular
bromine and only required simple extractive downstream
processing, albeit at a significantly longer reaction time (12 h
vs. 40 min) (entries 7–9).
Although the use of molecular bromine utilising flow
technology has been well documented,22–24 the employment
of polymer bound pyridinium tribromide caught our interest
as its use would largely mitigate the toxicity and corrosion
risks associated with molecular bromine, thereby improving
the safety profile of the process. Critically speaking though,
its use would require the employment of packed-bed reactor
(PBR) technologies which present engineering challenges,
particularly as the reagent is consumed stoichiometrically,
b
Burroughs
and polymer bound reagents also generally have significantly
higher costs than analogous non-supported reagents. In this
case, however, the polymer can be regenerated; but this then
requires treatment with molecular bromine.
Alternatively, the use of an activated alcohol at the alpha
position would circumvent the issues of using bromine as
previously demonstrated by Coelho and co-workers.33
Unfortunately, in the context of this work the approach was
deemed unattractive as it required two additional steps (5 vs.
3) and the triflate group utilised represented twice the atom
economy burden of bromine.
Stage 2. The displacement of the bromine group with
tert-butylamine (Scheme 3) was investigated in various solvents
with the primary goal of transitioning away from NMP (see
Table 2 for selected examples, for additional examples see
section 1.4.4 of the ESI†). Mechanistically, the reaction requires
the use of excess tert-butylamine as the displaced bromide
anion rapidly converts any unreacted amine to the analogous
bromide salt which commonly precipitates as an unreactive byproduct. The screens were performed in pressure tubes to
maintain a temperature of 95 °C across all solvent systems
investigated and to prevent potential loss of the volatile
tert-butylamine starting material. Notably, in all instances
timeous analysis and determination of the yield of the free base
1b is necessary as it decomposes rapidly (see section 1.4.4 of
the ESI† for decomposition study).
When performed in acetonitrile as described by Burroughs
Wellcome Co. using 3.0 equivalents of tert-butylamine at 95
°C for 4 hours an isolated yield of 86% of the free base form
1b was achieved, but the approach was characterised by the
formation of a thick precipitate of tert-butylammonium
bromide and was not amenable to flow translation (Table 2,
Scheme 3 Nucleophilic substitution of 3 with tert-butylamine.
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Table 2 Nucleophilic substitution of 3 with tert-butylaminea
Entry
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b
1
2
3
4
5
6
Solvent
tert-BuNH4+Br− ppt
Unreacted 3 present
Decomposition observed
Yield% 1b
ACN
50% ACN:DCM
75% ACN:DCM
90% ACN:DCM
85% ACN:DMSO
90% ACN:DMSO
Yes
No
Yes (minimal)
Yes
No
Yes (minimal)
No
Yes
No
No
No
No
No
No
No
No
No
No
86
24
76
78
75
77
General reaction conditions: 95 °C, 4-hour reaction time, 0.5 M concentration, 3.0 equivalents of tert-butylamine.
method.9
a
entry 1). The addition of a solubilising co-solvent in the form
of DCM or DMSO significantly reduced the amount of
precipitate observed. In the case of DCM, the yield decreased
sharply as the ratio of DCM was increased (entries 2–4).
Alternatively, the use of 10–15% DMSO in acetonitrile (entries
5 and 6) largely solubilised the precipitate while affording
yields in the range of 75–77%.
Stage 3. Finally, the conversion of 1b to bupropion HCl 1a
proved to be most favourable in the presence of ethereal
solvent mixes (Table 3, entries 1–6). The use of ethanolic or
aqueous HCl led to disappointingly low yields of 30% and
32% respectively (entries 7 & 8), however, this was not
unexpected as the salt 1a has an appreciable solubility in
polar protic solvents (see section 1.4.6 of the ESI† for
solubility study). Finally, hydrogen chloride gas, which is
more sustainable and amenable to scale-up afforded good
yields of 89% and 94% respectively when performed in
cyclohexane and ethyl acetate (entries 9 & 10).
2nd generation – flow translation and optimisation
Stage 1. Following our initial batch investigations, we next
set out to translate each step in the process to flow while
keeping the conditions amenable for eventual telescoping.
Several bromination approaches were screened (see Table 4
for examples and section 1.5.1 of ESI† for more information)
and polymer supported pyridinium tribromide again proved
Table 3 Preparation of 1a utilising different HCl sources and solvent
combinationsa
Entry
HCl source
HCl conc. (M)
Solvent
Yield%c 1a
1d
2
3
4
5
6
7
8b
9
10
Et2O*HCl
Et2O*HCl
Et2O*HCl
Et2O*HCl
MeOH*HCl
EtOH*HCl
EtOH*HCl
HCl (32%)
HCl gas
HCl gas
2
2
2
2
3
1.25
1.25
8.8
—
—
Et2O
Hexane
Cyclohexane
EtOAc
Et2O
Et2O
EtOAc
Neat
EtOAc
Cyclohexane
95
91
89
94
86
82
30
32
94
89
General reaction conditions: 0 °C, 2.0 equivalents of HCl, 1.2 gram
free base 1b in 100 mL solvent (0.05 M). b 8.0 equivalents of HCl,
solvent free. c Isolated yield. d Adaptation of the Burroughs Wellcome
Co. method.9
a
48 | React. Chem. Eng., 2024, 9, 45–57
b
Burroughs Wellcome Co.
to be attractive affording near quantitative conversion with
an isolated yield of 81% and a productivity rate of 2.66 g h−1
when performed in acetonitrile (Table 4, entry 3, Scheme 4).
In this instance, a 1.0 M stock solution of 2 in acetonitrile
was pumped through PBR's housing a total of 1.5 equivalents
of the polymer supported pyridinium tribromide (TR = 25
min, Temp = 60 °C). Thereafter, the resultant mixture was
pumped through a PBR housing excess ground potassium
carbonate (employed to scavenge residual bromine and/or
hydrogen bromide) followed by a back pressure regulator (8
bar). The approach was also investigated using ethyl acetate
as the reaction solvent, unfortunately, the use thereof was
characterised by the formation of the dibrominated product
4 in varying quantities with a best result affording 91%
conversion to 3 with 9% dibrominated 4 present (entry 4).
The spent polymer supported pyridinium tribromide was
regenerated by treatment with molecular bromine with a
limited loss in activity (regeneration unoptimized). When
using the regenerated polymer at the optimised conditions
(Table 4, entry 3), 3 was afforded with a conversion of 93%
(vs. 98% with new polymer). Comparable yields could be
realised by increasing the residence time to 30 minutes and
increasing the stoichiometric excess of the supported
pyridinium tribromide to 2.0 equivalents.
Stage 2. The nucleophilic displacement step was screened
in acetonitrile in combination with either DCM or DMSO (see
section 1.5.2 of ESI† for screens employing DCM as a cosolvent). The use of DCM was characterised by the formation
of a fine precipitate which required the use of in-line
sonication to prevent reactor blockages and fouling.
Alternatively, the use of DMSO, which was also more
attractive from a greenness and sustainability point of view,
afforded complete homogeneity. Unfortunately, its use was
not without challenges as its removal during downstream
processing proved to be cumbersome from both a time and
energy usage point of view. Notably, the increased time
required to remove the DMSO has the potential to negatively
impact the isolated yield of the free base 1b which
decomposes rapidly (see section 1.4.4 of the ESI† for
decomposition study).
We were able to demonstrate the displacement under flow
conditions (Scheme 5) employing a 95% ACN:DMSO solvent
mix without any deleterious effects on the solubility or the
yield. Under these conditions, a 1.0 M stock solution of 3
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Table 4 Bromination of 2 under flow conditions
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Entry
1
2
3
4
Brominating agent
b
Bromine liquid
NH4Br and oxonec
PyBr3 polymer boundd
PyBr3 polymer boundd
TR (min)
Temp (°C)
Solvent
Conc. (M)
2
3
4
10
50
25
90
44
130
60
40
DCM
MeOH
ACN
EtOAc
0.25
0.2
1.0
1.0
0
50
0
0
96 (84)
50
98 (81)
91
4
0
2
9
a
Conversions estimated by comparing the integral areas of 2, 3 and 4 in 1H NMR spectra, isolated yields given in brackets. b General reaction
conditions: 0.5 M stock solution of 2, 0.5 M stock solution of elemental bromine. c General reaction conditions: 0.2 M stock solution of 2,
crushed ammonium bromide and oxone in a PBR. d General reaction conditions: 1 M stock solution of 2, 1.5 equivalents of pyridinium
tribromide polymer housed in a PBR.
Scheme 4 α-Bromination of 3′-chloropropiophenone 2 under flow conditions.
Scheme 5 Nucleophilic substitution reaction for the formation of bupropion 1a under flow conditions.
(prepared under batch conditions and purified via column
chromatography) in ACN was combined with a 3.0 M stock
solution of the tert-butylamine (90% ACN:DMSO) at a T-piece
mixer prior to passage through a 25 mL PTFE coil reactor (TR
= 20 min, Temp = 90 °C). The resulting solution was then
quenched at a second T-piece mixer with water prior to
passage through a BPR and collection. The free base
bupropion 1b was isolated in a yield of 98% with a
production rate of 5.06 g h−1. In a subsequent offline salt
formation step the free base 1b was converted into the
desired product 1a utilising ethereal hydrogen chloride in
cyclohexane in 87% yield.
3rd generation – telescoped flow process
We next focused our attention on linking the first two stages
to afford a single uninterrupted process. Unfortunately, direct
linking of the two stages was characterised by the unexpected
in-line precipitation of tert-butylammonium bromide. We
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suspected that this was arising as bromine and/or hydrogen
bromide was leaching into stage 2 and was not being
completely neutralised by the potassium carbonate scavenger.
To circumvent this issue, we reverted to the use of 85% ACN:
DMSO and employed the use of a sonicator at the T-piece
mixers to help solubilise the salt. Concurrently we also
investigated the use of alternative scavengers including:
Amberlite IRA-400, Dowex anion exchange resin and sodium
thiosulfate (Table 5).
The telescoping was performed using a 1.0 M 3′chloropropiophenone 2 stock solution in acetonitrile which
was pumped (0.16 mL min−1) through a PBR housing 1.5
equivalents of polymer-bound pyridinium tribromide (TR = 25
min, Temp = 60 °C) followed by a second PBR housing the
investigated scavenger (Scheme 6 – black). The resulting
mixture was then combined with a 3.0 M stock solution of
tert-butylamine in 70% ACN:DMSO (0.16 mL min−1) at a
T-piece mixer (sonicated, Temp = 60 °C). The resultant
stream was passed through a 25 mL PTFE coil (TR = 78.1
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Table 5 Initial telescoping with different scavenger agentsa
Scavenger
Total flow
rate (mL Min−1)
Temperature (°C)
Entry
Column
Coil
Column
Coil
Yield%b
1b
1
2
3
4
5
6
Amberlite IRA-400
Sodium thiosulfate
Dowex
Potassium carbonate
Sodium thiosulfatec
Potassium carbonatec
0.32
0.32
0.32
0.32
1.25
1.25
60
60
60
60
60
60
90
90
90
90
90
90
25
25
25
25
25
25
78.1
78.1
78.1
78.1
20
20
51
51
55
53
63
77
a
Residence time (min)
Reactions were performed on a 0.5-gram scale based on 2. b Isolated yield. c Recycling (Scheme 7 – red).
min, Temp = 90 °C) prior to being quenched with water (0.16
mL min−1) at a second T-piece mixer which was submerged
in a sonicated bath (Temp = 60 °C) followed by a 5 mL
“dissolution” loop and 8 bar BPR. In all instances the
scavengers screened performed comparably, but yields were
only modest in the range of 51–55% (Table 5, entries 1–4).
At this stage it was suspected that the drop-off in yield
was a result of partial decomposition of the free base product
1b, as a brown discolouration of the reaction matrix was
observed. In the set-up employed, the flow rate required for
the full conversion of the first stage resulted in a longer than
optimal residence time (78.1 minutes) for the second stage in
the direct linking. A smaller coil reactor of suitable internal
diameter was not accessible at the time of testing, as a result
we opted to employ a recycling system for the first stage,
affording an optimal flow rate of 1.26 mL min−1 for the
second stage (Scheme 6 – red), leading to an improved yield
of 77% for the free base 1b when using potassium carbonate
as the scavenger (entry 6).
Our ultimate aim was to deliver a fully automated
continuous flow process which integrated downstream
processing of both the free base 1b and bupropion HCl 1a
while minimizing chemical exposure/handling. As such we
next shaped our investigation to include a downstream
solvent swap to afford the free base 1b in a solvent system
that was compatible with the final salt formation step. An inline solvent swap from acetonitrile to a more appropriate
water immiscible extracting solvent was required. The solvent
swop also served to i) remove excess tert-butylamine, ii)
remove unwanted bromide salts and iii) remove DMSO as
part of the aqueous waste fraction. Thereafter, the organic
fraction could be triturated with an appropriate hydrogen
chloride source to afford the desired salt 1a.
To facilitate the downstream solvent swap and subsequent
extraction, the post reactor setup was modified to include an
integrated rotary evaporator (Scheme 7, Fig. 1). The rotatory
evaporator bleed valve was replaced with a customized
screwcap fitted with three 1/16″ diameter holes through which
PTFE tubing could be fed allowing the reaction mixture to
collect in the rotatory's evaporation flask. A second line from a
peristaltic pump was inserted via the customized cap to
facilitate the delivery of extraction solvents and finally, a third
line connected to an HPLC pump was inserted to facilitate the
removal of material from the evaporation flask.
Operationally, upon exiting the back-pressure regulator of
the main flow reactor, the reaction mixture entered the rotary
evaporator. The acetonitrile solvent fraction and unreacted
tert-butylamine were evaporated and the rotary was primed
with cyclohexane followed by a saturated solution of sodium
chloride and/or potassium carbonate (to aid in the removal
of the DMSO and ensure complete neutralization) using the
second line. Extraction was facilitated by allowing the
evaporation flask to rotate, and thereafter the biphasic
mixture was allowed to separate, and the organic layer was
pumped out of the rotary evaporator using the third line. The
resultant mixture was then fed into a Biotage® phase
Scheme 6 Initial 3rd generation flow synthesis of free base bupropion 1b.
50 | React. Chem. Eng., 2024, 9, 45–57
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Scheme 7 Final 3rd generation staggered flow synthesis of bupropion hydrochloride 1a.
Fig. 1 Final 3rd generation staggered flow synthesis of target bupropion 1a.
separator allowing the removal of remaining traces of the
aqueous phase and subsequent collection of the organic
layer. A second extraction was performed in a similar fashion
and the organic fractions were combined and pumped
directly into a cooled (0 °C) in-line triturator,34 pre-primed
with ethereal hydrogen chloride to obtain the desired
hydrochloride salt 1a.
The reaction conditions remained constant as described
previously utilizing a 1.0 M 3′-chloropropiophenone 2 stock
solution which was pumped through PBR's connected in
series housing a combined 1.5 equivalents of pyridinium
tribromide (TR = 34.3 min, Temp = 60 °C) which was followed
by several PBR's again connected in series housing 14.5
equivalents of ground potassium carbonate. A manual
selector valve was included between the final PBR housing
the polymer reagent and the first PBR housing the scavenger
to divert any front-running leached brominated species (first
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20 minutes of reaction) to waste instead of going through
and compromising the potassium carbonate scavenger. Upon
exiting the final PBR, the reaction mixture was combined
with a 3.0 M stock solution of tert-butylamine in 70% ACN:
DMSO (17.2 eq.) at a T-piece submerged in a sonicating bath
(Temp = 60 °C). The use of excess tert-butylamine was
employed to counter the dispersion of 3 as it was pumped
through the PBR's. The resulting mixture was subsequently
passed through a 25 mL PTFE coil (TR = 20 min, Temp = 90
°C) prior to being quenched with distilled water at a second
T-piece mixer (submerged in an ultrasound bath, Temp = 60
°C). The resultant mixture was passed through a 5 mL PTFE
“dissolution” loop and ultimately fed through a BPR into the
evaporation flask mounted on the rotary evaporator. Upon
complete collection, the in-line work-up procedure described
previously was performed. The combined organic fractions
were subjected to an in-line salt formation affording
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bupropion hydrochloride 1a in a 62% isolated yield across
three stages equating to ∼85% per stage (Scheme 7, Fig. 1,
ESI† section 1.6.2). Under these conditions a productivity rate
of 1.55 g h−1 for the free base 1b was realised, but
disappointingly, the overall purity of the final product 1a
decreased significantly from 96.6% (generation 1) and 99.9%
(generation 2) to only 86.5%.
4th generation staggered flow process
We revisited the process to determine whether the loss in
yield and purity noted was arising as a result of one or more
of the downstream processing operations (see section 1.7.1.
of ESI† for additional information). It was determined that i)
the absence of an extractive work-up after stage 1 resulted in
decreased yields and could be linked to the formation of the
Reaction Chemistry & Engineering
thick tert-butylammonium bromide precipitate observed in
generation 3 and ii) the use of excess tert-butylamine resulted
in a sharp drop-off in yields isolated even when using 3
which had been subjected to an extractive work-up.
Practically, both of these issues were overcome through
introducing an inline extraction between stages 1 and 2
which allowed us to remove the PBR housing potassium
carbonate and replace it with a rotary evaporator and
Zaiput™ membrane separator. The flow stream could then
be neutralized with 50% aqueous potassium carbonate in the
rotary evaporator, at the same time this then allowed us to
reduce the tert-butylamine equivalents required for stage 2
from 17.2 to 4.0 equivalents. During this time, we also
elected to perform the salt formation step using HCl gas
generated in situ to eliminate the use of non-green and
hazardous diethyl ether and additional focus was also placed
Scheme 8 4th generation flow synthesis of bupropion hydrochloride 1a.
52 | React. Chem. Eng., 2024, 9, 45–57
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across three stages equating to ∼88% per stage at a
production rate of 1.78 g h−1 for the free base 1b.
The 4th generation staggered telescoped approach
outperformed the 3rd generation telescoped flow process in
terms of final yield of 1a isolated (69% vs. 62%) and offered
several additional advantages such as the reduced need for
the off-line distillation to recover unreacted amine due to a
4.3-fold decrease in the amount of tert-butylamine used.
Furthermore, the addition of the work-up step in between
the two stages mitigated precipitate formation in the flow
system making further scale-up more attractive, it also led to
an appreciably increase in the product purity from 86.5 to
97.8% for the final salt 1a while still ensuring a staggered
continual process with minimal handling and exposure to
chemicals throughout. Lastly, the elimination of the ethereal
hydrogen chloride and use of reduced quantities of extraction
solvents led to a reduction in associated process costs and
the volume of waste produced.
on the minimization of the extraction solvents quantities to
reduce waste generation and improve overall greenness
(Scheme 8, see ESI† section 1.7.2).
The staggered telescoped process was performed as
follows: a 1.0 M 3′-chloropropiophenone 2 stock solution was
pumped through a series of PBR's housing a total of 1.5
equivalents of pyridinium tribromide (TR = 25 min, Temp =
60 °C). Thereafter, the reaction mixture was passed through a
BPR and into the rotatory's evaporation flask which was preprimed with a 50% potassium carbonate solution. After
collection was completed, the acetonitrile solvent was
removed in vacuo and ethyl acetate was introduced into the
rotary evaporator through a second line. After sufficient
rotation, the biphasic mixture was pumped through a
Zaiput™ membrane separator (OB-900). The extraction was
repeated after which time the combined organic fractions
were pumped back into the rotary evaporator fitted with a
new evaporation flask. The ethyl acetate solvent (the distillate
could be collected and redistilled off-line to recover the ethyl
acetate, see ESI† section 1.9.2) was removed in vacuo and the
flask was re-primed with acetonitrile to afford a 1.0 M stock
solution of 3. The brominated material 3 was then combined
with a 4.0 M stock solution of tert-butylamine in 70% ACN:
DMSO at a T-piece mixer and the resultant stream passed
through a 25 mL PTFE coil reactor (TR = 20 min, Temp = 90
°C). The mixture was then combined with a water quench
line at a second T-piece mixer and subsequently passed
through a 5 mL “dissolution” loop and BPR prior to
collection in the rotary evaporator. The mixture was subjected
to a solvent swap and extraction, utilizing ethyl acetate, as
described previously. The acetonitrile solvent and unreacted
tert-butylamine fraction could be recovered directly from the
rotary evaporator's solvent trap if desired (>80% percentage
recovery) but not unexpectedly this was contaminated with
water (<10%) and unreacted tert-butylamine (∼2%) and
complete recycling of the solvent would require additional
off-line operations (see ESI† section 1.9.2). The biphasic
solution was pumped through the Zaiput™ membrane
separator (OB-900) and finally into a pre-cooled flask fitted
with a PTFE gas delivery tube. The resultant mixture was
treated with HCl gas generated from sulfuric acid and
sodium chloride. The final isolation of bupropion
hydrochloride 1a was achieved in an overall yield of 69%
Analysis and comparison of generations 1 to 4
In an effort to better understand and quantify the process
improvements in terms of greenness, safety and sustainability
we analysed each generation using the CHEM21 toolkit.35 The
toolkit was selected as it provides standard quantitative green
metrics, and it also holistically assesses non-numerical
variables qualitatively through the use of an easy to interpret
red, amber and green flag system. In addition, we also
performed an analysis of how the mass distribution of
reagents and solvents changed over the four generations.
Comparison of green metrics
Several sustainability metrics and productivity rates calculated
for generations 1–4 are highlighted in Table 6. Following our
CHEM21 analysis several observations were noted.
i) The calculated reaction mass efficiencies RME (and
related operational efficiencies OE) suggest that the batch
approach and standalone flow approach (generations 1 and
2) are superior, affording more product per unit mass of
starting reactants. This was not unexpected, as when moving
to generation 3 the excess of tert-butylamine employed was
increased from 3.0 to 17.2 equivalents before being reduced
back to 4.0 equivalents in generation 4.
Table 6 Sustainability metrics for generations 1–5a
Generation
Yield%
AE%
RME%
OE%
Total PMI
Productivity rate 1b (g h−1)
Space time yield 1b (g h−1 L)
% Purityb
1d
2e
3f
4c,g
71.1
69.2
62.1
69.4
63.1
63.1
63.1
63.1
32.9
29.7
9.9
24.5
52.1
47.0
15.7
38.9
135.3
155.1
203.0
114.7
1.1
1.5
1.6
1.8
10.1
24.6
18.3
29.6
96.6
99.9
86.5
97.8
a
Calculations were performed with the aid of the CHEM21 green metrics toolkit, see ESI† section 1.9 for description of metrics and summary
of Green Metrics analysis. b Determined by ECIC qNMR method.10 c The HCl (g) was generated chemically and we were unable to quantify the
amount introduced into the reactor, as such we assumed the use of 2.0 equivalents HCl which proved to be sufficient in generations 2 and 3
when calculating the green metrics. d H&S: Br2 (red: H330, H400), tert-butylamine (amber: H331), Et2O*HCl (amber: H331, H224), Et2O (H224)
& DCM (H351). e H&S: tert-butylamine (amber: H331), Et2O*HCl (amber: H331, H224) & cyclohexane (red: H400, H410). f H&S: tert-butylamine
(amber: H331), Et2O*HCl (amber: H331, H224) & cyclohexane (red: H400, H410). g H&S: tert-butylamine (amber: H331).
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ii) The atom economy is modest, but the shortfall is solely
resultant from the need to install and subsequently displace
a bromine at the alpha-position of 2. Unfortunately, few
viable alternative synthetic approaches exist to install the
required tert-butylamine.
iii) The process mass intensity (PMI), which is arguably
the more important green metric, suggests that generation 4
is more attractive. The initial flow translation and telescoping
(generations 2 and 3) performed worse than generation 1,
this was also not unexpected as larger unoptimized work-up
solvent volumes were utilised; these were subsequently
reduced during the optimisation of generation 4.
iv) The productivity of the flow-based approaches was
superior with generation 4 affording a 2.6-fold increase in
space–time yield over that of generation 1.
v) Finally, in terms of safety we reduced the number of
reagents, reactants, and solvents with red or amber health
and safety (H&S) codes. The final generation only has an
amber flag for the use of tert-butylamine (H331) which
cannot be avoided as it is structurally required in the final
molecule.
Comparison of raw materials mass distribution
An analysis of the mass of raw materials distribution for the
reaction was performed, revealing in the case of both
generations 1 and 2 that the organic solvents contributed
between 70 and 77% of the total reaction mass suggesting a
high waste and cost burden (Fig. 2, see ESI† section 1.8 for
detailed breakdown). Translation to generation 3 resulted in
a substantial improvement with the organic solvent
Fig. 2 Mass distribution of reagent vs. solvents.
54 | React. Chem. Eng., 2024, 9, 45–57
Reaction Chemistry & Engineering
contribution reducing to 42% of the total mass. This change
arose as the extractive work up after stage 1 was avoided, but
as noted previously, the overall yield and purity for
generation 3 was inferior to that of generations 1 and 2. To
circumvent these shortfalls we elected to include an
extractive work-up between the first two stages in generation
4. Fortunately, the resulting mass penalty was largely negated
through i) the reduction of the work-up solvent masses and
ii) by swopping to the use of gaseous hydrogen chloride for
the final salt formation.
Overall, we believe that generation 4 represents an
efficient synthetic process with tangible improvements linked
to safety and greenness which are well aligned with eight of
the twelve principles of green chemistry (Fig. 3).
Comparison of generation 4 with previously reported
processes
Finally, the CHEM21 toolkit35 was employed to benchmark
generation 4 against several previously reported syntheses of
bupropion 1b and bupropion hydrochloride 1a (Table 7, see
section 1.9.1 of ESI† for a detailed comparison of the
previously reported approaches).
In contrast to the approaches by Burrough's Welcome Co.,
Perrine and Ley the use of molecular bromine and
problematic dichloromethane, NMP and diethyl ether were
avoided through replacement with more appropriate solvents:
acetonitrile (amber), DMSO (green) and ethyl acetate (green).
Fig. 3 Alignment of generation 4 with eight of the twelve principles of
green chemistry.
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Table 7 Comparison of previously reported processesa
Metric
Burroughs Wellcome9,b
Perrine11
Ley19,c
Z. A. J. Pharmad
Hurst and Sherwood36
Rileye, f
Yield
Purity
AE%
PMITotal
PMISolv
PMIRRC
RME
Reaction time
Solvents – stage 1
71
96.6
63.1
135.3
132.1
3.2
32.9
>4 h
80
98
63.1
174.2
170.0
4.2
24.1
>20 min
80g
NR
59.7
566.1g
563.3g
2.9
35.0
29.7 minh
78 (21)
≥99.9 (ND)
63.1
17.4 (72.6)
13.8 (50.9)
3.6 (21.8)
28.9 (4.7)
>8.5 h
68
NR
60.5
167.7
160.6
7.1
14.2
90 min
69
97.8
63.1
114.7 (72.9)
110.3 (68.5)
4.1
24.5
45 minh
Solvents – stage 2
Solvents – stage 3
N/A
Solvents – work-up
Stoichiometric excess
Critical elements
Energy
Batch/flow
Work up
Health and safety
a
Calculations were performed with the aid of the Chem21 green metrics toolkit, in the case of qualitative variables red = undesirable, amber =
acceptable and green = desirable. b Based on in-house validation of the Burroughs Wellcome Co. approach (generation 1), original patent does
not have sufficient information for full analysis. c Analysis for the preparation of the free base 1b, preparation of the salt form 1a not reported.
d
Values in brackets represent those obtained during in-house validation of the process. e Analysis of generation 4, values in brackets represent
a scenario including an 80% recovery of ethyl acetate and acetonitrile and use of 2.0 equivalents of HCl (g). f Analysis performed using Br2 as
an input for Polymer bound PyBr3 as the spent polymer is not consumed in the reaction and is readily regenerated with Br2. g Offline work-up
solvents used as reported for the single flow reactions in the supplementary information of the manuscript. h Combined residence time.
The process still required the use of excess tert-butylamine
(an issue experienced in all previously reported approaches),
but we were able to restrict this to 4.0 equivalents without
any deleterious effects. We also avoided the use of sulphur
containing reagents commonly employed to quench
brominations (e.g. sodium thiosulfate and sodium
metabisulfite) as sulphur is amber flagged in terms of critical
elements with an estimate global supply of 50–500 years
remaining. The overall PMI of 114.7 is lower than previously
reported approaches with the exception of that patented by Z.
A.J. Pharma. The value is approaching the desirable value of
100 which is often targeted for pharmaceutical preparations,
and if recycling of solvents (acetonitrile and ethyl acetate) is
considered this could readily be reduced to a value close to
70. In the case of Z.A.J. Pharma a solvent free approach with
a total PMI value of only 17.4 is claimed, however, the
approach employs extensive heating for prolonged periods
(>8.5 h). This heating was at odds with our observations
linked to unwanted dibromination in stage 1 and free base
decomposition in stage 2. We elected to validate the
approach in-house and were only able to isolate 1a in an
overall yield of 21%, notably the first stage showed ∼20%
dibromination (see sections 1.4.6 and 1.9.1 of ESI† for
additional information).
In terms of safety the staggered continuous flow approach
reduced chemical exposure, limited the volume of material
reacting at a given time and allowed on-the-fly processing of
the lachrymatory intermediate 3. Finally, from an energy
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perspective the translation to flow is predicted to reduce the
overall energy burden relative to the analogous batch
processes, and the design also allowed us to utilise the
energy required during the solvent swops to recover partially
purified ethyl acetate and acetonitrile for recycling.
Conclusion
The synthesis of bupropion hydrochloride 1a has been
reimagined and revised in an effort to improve greenness,
sustainability and safety. The approach adopted avoided the
use of toxic and corrosive molecular bromine and
undesirable solvents like dichloromethane, NMP and diethyl
ether commonly utilised in previously reported approaches.
In summary, the process is comprised of a three-stage
staggered flow synthesis affording bupropion hydrochloride
1a in an overall yield of 69% (97.8% purity). The approach
afforded an appreciable decrease in process mass intensity
relative to previous reports. The approach is well suited for
solvent recycling (acetonitrile and ethyl acetate) and the use
of integrated downstream processing limits chemical
exposure to the preparation of stock solutions and recovery
of the final salt 1a.
Critically speaking, it is important to consider that i) the
offline regeneration of the polymer supported pyridinium
tribromide requires the use of molecular bromine, despite
this we feel its use is warranted as it reduces the risk in the
primary process as well as the additional waste burden
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associated with the use of other unsupported alternatives to
molecular bromine, and ii) the use of excess tert-butylamine
is not desirable from a health and safety point-of-view but
due to the mechanistic limitations of the reaction it cannot
be reduced significantly while maintaining adequate process
performance.
Author contributions
The manuscript was compiled with contributions from all
authors. This final version of the manuscript was approved
by all authors.
Conflicts of interest
The authors declare no competing conflicts.
Acknowledgements
This work was supported by the National Research
Foundation
of
South
Africa
(grant
number
SRUG190329425006), the University of Pretoria and the
Council for Scientific and Industrial Research (CSIR).
Opinions expressed in this publication and the conclusions
arrived at are those of the authors, and are not necessarily
attributed to the NRF or CSIR. The authors would like to
gratefully acknowledge Mamoalosi Selepe for NMR
spectroscopy services, Madelien Wooding for mass
spectroscopy services, Frikkie Malan for SC-XRD services,
Solly Motaung for PXRD services, Ncholu Manyala and Vusani
Maphiri for raman spectroscopy, Erna van Wilpe for SEM
assistance at the University of Pretoria's microscopy
laboratory, Uniqsis Ltd. and Vapourtec Ltd. for flow
equipment.
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