Multigram-scale flow synthesis of the chiral key intermediate of (-)-paroxetine enabled by solvent-free heterogeneous organocatalysis

Article abstract of DOI:10.1039/c9sc04752b

The catalytic enantioselective synthesis of the chiral key intermediate of the antidepressant (-)-paroxetine is demonstrated as a continuous flow process on multi-gram scale. The critical step is a solvent-free organocatalytic conjugate addition followed

Full text of DOI:10.1039/c9sc04752b

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Multigram-scale flow synthesis of the chiral key
intermediate of (ꢀ)-paroxetine enabled by solvent-
free heterogeneous organocatalysis†
Cite this: Chem. Sci., 2019, 10, 11141
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
bc
ad
*
*
Sandor B. O¨ tvos,
Miquel A. Pericas
and C. Oliver Kappe
´
¨
`
The catalytic enantioselective synthesis of the chiral key intermediate of the antidepressant (ꢀ)-paroxetine
is demonstrated as a continuous flow process on multi-gram scale. The critical step is a solvent-free
organocatalytic conjugate addition followed by a telescoped reductive amination–lactamization–amide/
ester reduction sequence. Due to the efficient heterogeneous catalysts and the solvent-free or highly
concentrated conditions applied, the flow method offers key advances in terms of productivity and
sustainability compared to earlier batch approaches.
Received 20th September 2019
Accepted 18th October 2019
DOI: 10.1039/c9sc04752b
rsc.li/chemical-science
(ꢀ)-Paroxetine is a selective serotonin reuptake inhibitor mar- appealing.6 Accordingly, there is an increasing number of
keted as Paxil/Seroxat which is widely used for the treatment of reports on multistep ow syntheses of APIs and pharmaceuti-
depression, anxiety and panic disorder.1 The published proce- cally relevant intermediates.6,7 However, these studies rarely
dures for its synthesis involve 10–15 reaction steps and typically involve catalytic enantioselective transformations.8 The over-
utilize chiral auxiliaries, classical resolution methods, enzy- whelming majority of the examples reported to date cover
matic asymmetrizations or naturally occurring homochiral achiral products, or, in the case of chiral targets, asymmetry is
starting materials to introduce asymmetry.2 In most of these typically derived from commercially available chiral building
synthetic routes, the corresponding ((3S,4R)-4-(4-uorophenyl) blocks without exploiting enantioselective transformations.6,7
piperidin-3-yl)methanol (1) is obtained as key chiral interme-
Inspired by the above ndings and limitations, we aimed for
diate which can readily be converted into the active pharma- a continuous ow strategy for the catalytic enantioselective
ceutical ingredient (API) upon etherication with sesamol and synthesis of the chiral key intermediate of (ꢀ)-paroxetine. We
removal of the protecting group on nitrogen (Fig. 1).2 Catalytic intended to use only inexpensive achiral starting materials in
enantioselective transformations have also been exploited for combination with a highly efficient organocatalytic approach.
the synthesis of (ꢀ)-paroxetine or its advanced intermediates.3 The synthetic strategy relies on the enantioselective asymmetric
These methods require less synthetic steps and provide more conjugate addition between 4-uorocinnamaldehyde and
direct access to the target API, but their applicability for dimethyl malonate to yield chiral aldehyde 2 which can subse-
manufacturing is limited by the low productivity of the catalytic quently be converted into phenylpiperidinone 3 via a three-step
asymmetric key step.
cascade involving imine formation, reduction and lactamiza-
Continuous ow processing offers numerous benets over tion, to nally provide key intermediate 1 by means of reduction
conventional batch syntheses.4 From the viewpoint of pharma- of the amide and ester moieties (Scheme 1).
ceutical manufacturing, the safe and scalable access to
While most of the published target-oriented organocatalytic
hazardous chemistries5 and the ability to combine multistep asymmetric syntheses involve homogeneous catalysts under
reactions into telescoped ow sequences is particularly batch conditions,9 we aimed to utilize a resin-bound organo-
catalyst under ow conditions.10 This not only enables facile
product isolation, but, if catalyst deactivation can be
aInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010
Graz, Austria. E-mail: sandor.oetvoes@uni-graz.at
bInstitute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science
¨
and Technology (BIST), Av. Paısos Catalans 16, E-43007 Tarragona, Spain
c
´
`
`
Departament de Quımica Inorganica i Organica, Universitat de Barcelona (UB), E-
08028 Barcelona, Spain
dCenter for Continuous Synthesis and Processing (CCFLOW), Research Center
Pharmaceutical Engineering (RCPE), Inffeldgasse 13, A-8010 Graz, Austria. E-mail:
oliver.kappe@uni-graz.at
† Electronic supplementary information (ESI) available: Synthetic procedures,
additional batch and ow reaction data, characterization data, copies of NMR
spectra and HPLC chromatograms. See DOI: 10.1039/c9sc04752b
Fig. 1 Antidepressant (ꢀ)-paroxetine and its chiral key intermediate.
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was placed in an Omnit® glass column (10 or 6.6 mm ID,
adjustable height) and the reaction was investigated under
continuous ow conditions. Initially, CH2Cl2 was employed as
solvent as it provided the best results in terms of ee and
conversion during the batch experiments, and at the same time
it ensured good swelling of the polystyrene-based catalyst
carrier. It was found that the rate of reaction was signicantly
enhanced without loss of ee upon heating the catalyst bed to
50 ꢁC (Table S5†). It was also observed that an increase in
reactant concentration resulted in a signicant improvement in
conversion (Table S6†). This important nding inspired us to
investigate the reaction further under solvent-free conditions.
Eliminating the solvent from a synthetic transformation
offers signicant advantages in terms of process costs,
sustainability and productivity.14 Notably, there are only very
few examples for solvent-free reactions using solid-supported
organocatalysts,15 and, to the best of our knowledge, not
involving continuous ow techniques. Gratifyingly, catalyst 4
performed well under neat conditions, despite the lower
swelling of the carrier resin and thus the smaller bed volume in
the more polar medium (Fig. S1†). During systematic optimi-
zation of the reaction conditions, we managed to reduce the
malonate excess to 2 equiv. byꢁusing a residence time of 20 min
(70 mL minꢀ1 ow rate) at 60 C, and reached 93% conversion
with complete chemoselectivity and 97% ee (Tables 1 and S7–
S9†). In this optimum reaction mixture, the concentration of 4-
uorocinnamaldehyde was 2.48 M as determined experimen-
tally. To evaluate the preparative capabilities per one lab day,
the above conditions were directly utilized for scale-out in a 7 h
long continuous ow experiment (Fig. 2). 17.26 g of chiral
aldehyde 2 were isolated aer simply removing unreacted
components by evaporation (84% isolated yield, 97% ee). The
large-scale synthesis offered a productivity of 2.47 g hꢀ1 of pure
product, which is outstanding among continuous ow organo-
catalytic processes reported to date.10 The scale-out study was
completed using only 1 g (0.464 mmol) of catalyst 4. Despite the
neat conditions, this proved highly robust with practically
constant selectivity (95–98% ee and 100% chemoselectivity) and
only a small decrease in catalytic activity (93–85% conversion;
see Fig. S2† for details). The above data result in an effective
catalyst loading of 0.6 mol% and an accumulated TON of 132
for the experiment. The space-time yield (STY) for this reaction
was calculated as 1.76 kg Lꢀ1 hꢀ1. Notably, the process involved
low amount of waste formation as indicated by an E-factor of
only 0.7. Notably, aer the rst 7 h long experiment, the same
batch of organocatalyst was reused in two more preparative-
scale runs to accumulate 2 for the optimization of the next
step. (See details in the ESI†).
Scheme 1 Synthetic strategy toward 1.
minimized, readily facilitates scale-out of the ow synthesis by
increasing processing time.11
We selected
a
polystyrene-supported cis-4-hydrox-
ydiphenylprolinol TBS ether (4, Table 1) as catalyst, which was
recently developed as a modied version of classical trans
analogues,12 and was employed for additions of hydroxylamine
derivatives to enals.13 This catalyst has not yet been investigated
in conjugate additions of malonates, however, becouse of the cis
arrangement and the TBS protecting group, we anticipated
higher activity and improved robustness than in earlier cases.12b
Initial trials with catalyst 4 (f ¼ 0.464 mmol gꢀ1) in the 4-
uorocinnamaldehyde-dimethyl malonate conjugate addition
were carried out as small-scale batch reactions. To our delight,
aldehyde 2 (cf. Scheme 1) was formed with up to 98% ee under
an array of reaction conditions (Tables S1–S3†). It was
conrmed that the reaction tolerated different solvents and
conversion was improved in the presence of AcOH as additive.
Aer the successful preliminary experiments, 1 g of catalyst 4
Table 1 Optimization of the organocatalytic conjugate addition under
solvent-free flow conditionsa
Malonate
(equiv.)
Flow rate
b
#
(mL min‒1
)
T (ꢁC)
Conv.c (%)
eed (%)
1
2
3
4
5
6
7
9
3
3
3
2
2
2
100e
100e
100e
100e
70f
50
50
60
70
60
60
60
91
81
89
94
93
94
99
98
98
97
95
97
97
95
Aer having established a reliable ow process for the
synthesis of chiral aldehyde 2, we next turned our attention to
the subsequent tandem reductive amination–lactamization to
yield lactam 3 (cf. Scheme 1), which was previously achieved
exclusively in batch, typically in the presence of NaBH(OAc)3.3
50g
20h
a
1 equiv. 4-uorocinnamaldehyde, 0.6 equiv. AcOH as additive, 1 g
b
catalyst
4 in Omnit® column, solvent-free. No side product Taking environmental aspects into consideration, we exploited
c
formation, chemoselectivity was 100% in all reactions. Determined
instead a heterogeneous catalytic approach using 5% Pt/C as
catalyst and H2 gas.16 A stainless steel column (4.6 mm ID,
100 mm height) was used as catalyst bed and was charged with
by 1H-NMR analysis of the crude product. Determined by chiral
d
HPLC. e tr¼ 14 min. f tr¼ 20 min. g tr¼ 28 min. h tr¼ 70 min.
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cis) at 100 ꢁC (Tables 2 and S11†). In order to maximize
productivity, the effects of the reactant concentration were also
explored (Tables 2 and S13†). We were delighted to nd that the
reaction proceeded smoothly close to the solubility limit at
concentrations as high as 2.0 M in 2-MeTHF, which was chosen
as a greener alternative to traditional solvents.17 Utilizing the
optimum conditions as shown in Table 2, entry 7, the system
proved stable during multiple preparative-scale runs, and
resulted in ca. 4 g hꢀ1 of pure product, with isolated yields of
$96% and ee of 96%. Importantly, the catalytic process was very
clean: according to ICP MS measurements, practically no metal
leaching occurred from the catalyst bed, and inorganic
byproducts were not formed.
Fig. 2 Multigram-scale continuous flow organocatalytic synthesis of
chiral aldehyde 2.
Because of the need for extreme conditions and/or
specialist catalysts,18 a heterogeneous catalytic hydrogenation
approach would not have been feasible for the subsequent
amide/ester reduction at lactam 3. In search for an appropriate
method to yield key intermediate 1, we did not consider typical
LiAlH4 reductions due to the formation of large amounts of
metallic waste and the possible incompatibility with larger-
scale ow operations (e.g. precipitation).2 Instead, we focused
on borane reductions, a well-established technology frequently
implemented in the pharmaceutical industry on scale.19 As
a result of the risks associated (thermal decomposition or
formation of B2H6 and H2 in the presence of moisture), borane
a mixture of 200 mg of 5% Pt/C and 400 mg of activated char-
coal. H2 gas was introduced into the system from a gas cylinder
using a mass ow controller (MFC). It was observed that the
reductive amination readily took place with benzylamine as
reaction partner, but in the case of lower temperatures or an
excess of 2, signicant amount of double alkylation occurred,
indicating incomplete lactamization (Tables 2, S11 and S13;
Fig. S4†). This could easily be remedied by pumping the starting
materials in a 1 : 1 ratio and heating the reactor to 100 ꢁC.
Gratifyingly, the ee was around 96% in all the experiments, and
the desired trans lactam 3 was formed as the major product.
Interestingly, the diasteromeric ratio was strongly dependent on
the temperature applied: it reached a maximum of 93 : 7 (trans/
Table 3 Completing the flow synthesis of 1: Optimization of the
BH3$DMS-mediated amide/ester reduction
Table 2 Synthesis of lactam 3: effects of reaction conditions on the
tandem reductive amination–lactamization sequence
Flow rate
c (M)
(mL minꢀ1
)
3/
T
Conv.c
(%)
Chemosel.c
(%)
trans/
BH3$DMS
ratio
Chemosel.b,c
(%)
a
a
#
2
BAb
(ꢁC)
cisc
#
P1
P2
Conv.b (%)
1d
2d
3d
4d
5d
6e
7e
0.2
0.2
0.2
0.2
0.26
1.0
2.0
0.2
0.2
0.2
0.2
0.2
1.0
2.0
25
50
80
100
100
100
100
95
98
42f
56 : 44
78 : 22
89 : 11
93 : 7
91 : 9
93 : 7
93 : 7
1d
2
3
4
5
200
100
130
140
150
260
390
200e
100f
70f
1 : 10
1 : 10
1 : 5.4
1 : 4.3
1 : 3.3
1 : 5.4
1 : 5.4
96
74
94g
100
100
70h
100
100
100
100
100
99
100
100
100
100
95
76
100
93
100
100
100
100
100
60f
50f
6
7
140e
210g
a
a
95–96% ee was measured in all reactions (by using chiral HPLC). b BA
95‒96% ee was measured in all reactions (by using chiral HPLC).
stands for benzylamine. c Determined by 1H-NMR analysis of the crude
Determined by 1H-NMR analysis of the crude product. 1a formed
b
c
product. d Toluene as solvent. e 2-MeTHF as solvent. f 58% dialkylation. as minor product in entries 1, 4, 5 and 7. At 50 ꢁC. tr¼ 30 min.
d
e
g
f
6% dialkylation. h 30% dialkylation.
tr¼ 60 min. g tr¼ 20 min.
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Fig. 3 Flow synthesis of phenylpiperidin 1 via telescoped reductive amination–lactamization–amide/ester reduction sequence.
complexes are typically employed as 1–2 M solutions either in 1.58 mm ID) at 90 ꢁC. The telescoped system proved stable, and
batch or in ow.19,20 Aer promising preliminary experiments the eluting product solution was collected continuously for
with BH3$THF and BH3$dimethylsulde (DMS) complex solu- 100 min aer reaching steady state. Aer work-up and chro-
tions (Tables S14 and S15†), we attempted the amide/ester matographic purication, 4.95 g of analytically pure phenyl-
reduction by using neat BH3$DMS (10 M) as reducing agent piperidine 1 was isolated (83% yield) with an excellent ee of
with the aim to maximize productivity. To this end, a 1.0 M 96%. The STY of the process was calculated as 0.31 kg Lꢀ1 hꢀ1
solution of 3 in dry 2-MeTHF and the reducing agent were and productivity was 2.97 g hꢀ1 of pure product, which is
pumped as separate feeds, and the combined mixture was a signicant improvement compared to previously described
directed through a reaction coil (PFA tubing, 1/800 OD, 1.58 mm approaches towards this class of target molecules.3
ꢁ
ID) heated to 90 C. The effects of individual ow rates were
carefully examined (Table 3) to nd out that a residence time of
30 min in combination with a substrate/reducing agent ratio of
Conclusions
around 1 : 5 is optimal to quantitatively and selectively reduce For the rst time, a continuous ow process was developed for
both ester and amide moieties. Importantly, the direct appli- the asymmetric synthesis of phenylpiperidine 1, the chiral key
cation of the neat complex was safe under the strictly
intermediate of (ꢀ)-paroxetine. The critical step of the process
controlled ow conditions, and it ensured a productivity of
3.94 g hꢀ1 of pure product, which is unprecedented among
continuous borane reductions using solutions of the reducing
agent.20 The enantiomeric purity was not affected by the reac-
tion (96% ee).
was a solvent-free enantioselective conjugate addition in the
presence
of
a
polystyrene-supported
cis-4-hydrox-
ydiphenylprolinol as heterogeneous organocatalyst. The chiral
adduct was processed further via a telescoped reductive ami-
nation–lactamization–amide/ester reduction sequence, which
Aer successful step-by-step optimization, we nally wanted took advantage of a heterogeneous catalytic hydrogenation
to combine the catalytic reductive amination–lactamization and approach and the application of neat BH3$DMS as reducing
the subsequent amide/ester reduction into an uninterrupted
ow sequence (Fig. 3, S5 and S6†).21 Both individual steps were
achieved in 2-MeTHF, therefore no solvent switch was necessary
in the telescoped synthesis. Similar to the stepwise process,
2.0 M solutions of aldehyde 2 and benzylamine were pumped as
agent unprecedented in earlier ow reactions. The solvent-free
(or highly concentrated) conditions in combination with the
remarkably robust catalysts enabled a signicant chemical
intensication, leading to a productivity of 1 on multigram per
hour scale. In addition, the process offered high chemo- and
separate feeds (P1 and P2, each at 100 mL minꢀ1) and were stereoselectivity generating minimal amounts of waste,
combined with H2 gas before passing through a catalyst bed demonstrated by a cumulative E-factor of 6.22 The only solvent
packed with a mixture of 200 mg of 5% Pt/C and 400 mg of used in the synthesis is 2-MeTHF, a bio-derived solvent.
activated charcoal. During reductive amination, one equivalent
of water is released which must be removed in order to prevent
decomposition of BH3$DMS downstream. The gas–liquid
Conflicts of interest
mixture exiting the Pt/C column was therefore directed through
There are no conicts to declare.
˚
a cartridge packed with 5 g of freshly activated 4 A MS. Excess H2
was separated continuously from the liquid mixture through
a buffer ask. The dried and degassed feed containing a ca. 1 M
solution of lactam 3 was re-incorporated through a 3-port valve
at 200 mL minꢀ1 (P3) and was combined with a stream of neat
BH3$DMS (P4, at 110 mL minꢀ1) for amide/ester reduction
during passage through a reaction coil (PFA tubing, 1/800 OD,
Acknowledgements
¨
SBO acknowledges the Austrian Science Fund (FWF) for nan-
cial support through project M 2413-B21. We are grateful to
Prof. Wolfgang Kroutil, Dr Michael Fuchs, Dr Carles Rodrıguez-
Escrich and Dr Patricia Llanes for their support.
´
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11146 | Chem. Sci., 2019, 10, 11141–11146
This journal is © The Royal Society of Chemistry 2019