Catalytic Static Mixers for the Continuous Flow Hydrogenation of a Key Intermediate of Linezolid (Zyvox)

Article abstract of DOI:10.1021/acs.oprd.8b00153

Catalytic static mixers (CSMs) were used for the efficient preparation of a key intermediate of the antimicrobial drug linezolid (Zyvox). The approach combines 3D printing and additive manufacturing techniques with continuous flow processing to produce a

Full text of DOI:10.1021/acs.oprd.8b00153

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Communication
Catalytic Static Mixers for the Continuous Flow
Hydrogenation of a Key Intermediate of Linezolid (Zyvox).
James Gardiner, Xuan Nguyen, Charlotte Genet, Mike
Horne, Christian Harald Hornung, and John Tsanaktsidis
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00153 • Publication Date (Web): 14 Sep 2018
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Catalytic Static Mixers for the Continuous Flow Hydrogenation of a Key
Intermediate of Linezolid (Zyvox).
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,†
†
†
‡
†
James Gardiner* , Xuan Nguyen, Charlotte Genet, Mike D. Horne, Christian H. Hornung, John
Tsanaktsidis
†
†
CSIRO Manufacturing, Bayview Avenue, Clayton, VIC 3169, Australia
‡
CSIRO Mineral Resources, Bayview Avenue, Clayton, VIC 3169, Australia
Supporting Information Placeholder
Table of Contents Graphic
ABSTRACT: Catalytic static mixers (CSMs) were used for the efficient preparation of a key intermediate of the antimicrobial drug
Linezolid (Zyvox). The approach combines 3D printing and additive manufacturing techniques with continuous flow processing to
produce a general method for catalytic hydrogenations and the rapid production of the target molecule, without the need for catalyst
removal or recovery.
Keywords: Catalytic static mixer, continuous flow, hydrogenation, heterogeneous catalysis, Linezolid.
Linezolid (Zyvox)(Figure 1), developed by Pfizer and ap-
proved in 2000, is the first of a new class of antibiotics, the
oxazolidinones, to be introduced to the market in over 35
Linezolid, and other next generation oxazolidinone-based
antimicrobial drugs such as Radezolid and Torezolid (Figure
1), can be prepared in several ways. Most reported methods
2
1
years. It is highly effective in the treatment of severe Gram-
involve installing the oxazolidinone moiety via an isocyanate
or carbamate intermediate, both of which are derived from the
corresponding aromatic amine. Rivaroxaban (Xarelto, Bayer
positive infections including those caused by Streptococcus
pneumoniae, the challenging methicillin-resistant Staphylo-
coccus aureus (MRSA), and vancomycin resistant Enterococ-
cus faecium (VRE) organisms, for which it is often used as a
last line of defence. Linezolid is the only FDA approved med-
icine for the treatment of multi-drug resistant pneumonia and
MRSA skin infections and in 2013-2014 had annual sales of
US $1.35 billion.
2
AG). (Figure 1), an anticoagulant blood thinner with annual
3
sales of US$3.65B, is also prepared by similar means. Pfizer’s
second generation process for the manufacture of Linezolid is
4
shown in Scheme 1.
O
O
O
O
N
F
N
F
H
N
N
H
2
, Pd/C
CbzCl
N
O
NO
2
NH
2
O
2
3
F
catalytic hydrogenation in batch
1
Linezolid (Zyvox)
N
O
N
N
O
O
N
O
N
Cl
HN
N
F
OH
O
O
O
N
F
H
Cl
N
O
N
HCl
N
O
N
HN
2-
1
N
OBn
N
LiOtBu
Cl
OPO
3
O
H
N
F
F
5
N
4
N
N
Na+
2
Torezolid
Radezolid
O
N
O
O
Scheme 1. Pfizer’s second generation process for the synthesis
of Linezolid (1).
H
Cl
4
N
S
N
O
O
Rivaroxaban (Xarelto)
A key transformation in this process is the early stage palladi-
um-catalyzed hydrogenation of the substituted nitrobenzene 2
to the corresponding aniline 3 prior to its conversion to carba-
Figure 1. The oxazolidinone antimicrobial drugs Linezolid
Zyvox), Torezolid and Radezolid, and the anticoagulant
blood thinner Rivaroxaban (Xarelto).
(
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mate 4. Nitro reductions of this type are a common transfor-
CSMs coated with palladium were selected to perform the
transformation of 2 to 3. The CSMs consist of 3-D printed
metal inserts (150mm x 6mm), designed for optimal mixing
under continuous flow conditions, onto which the metallic
catalyst is deposited using an axial flow cell and standard elec-
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mation in many synthetic processes with a vast array of condi-
5
tions having been developed for this purpose. Flow processes
for this transformation have also been developed using hydro-
gen gas or transfer hydrogenation, utilizing catalyst plugs,
fixed beds, and microbeads however issues of pressure, uni-
form flow, heat transfer and optimal mixing still present chal-
12
troplating techniques. The tubular flow reactor itself is ap-
proximately the size of a loaf of bread and contains a set of 12
CSMs which are simply and easily inserted into the tubular
reactor and operated in series inside the temperature controlled
housing (Figure 2). The reactor volume is 39 mL and a hydro-
gen gas line is attached at the front end of the reactor to facili-
tate gas liquid/mixing with the substrate. A detailed descrip-
6
,7
lenges particularly on larger scale. Fixed bed reactors for
example result in large pressure drops over the course of the
reactor resulting in low flow rates. In the synthesis of Linezol-
id, preparation of 3 is typically carried out in a batch reactor
using Pd/C as the catalyst and a hydrogen atmosphere. Batch
reactions of this type often take between 8-24 hrs depending
on scale and require rigorous mixing of the gas and liquid
phases under increased pressure or temperature as well as sub-
0
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1b
tion of the reactor and its use has recently been reported.
The set of 12 CSMs used herein contain a total of 2.357g
Pd(0) with approximately 0.2g per insert. Figure 3 shows SEM
images of the Pd(0)-coated CSM surface highlighting high
surface area clumps of palladium particles arrayed over the
metal surface. The use of CSMs for catalytic reactions of this
type allows for a free flowing homogeneous solvent stream
throughout the reactor while removing the need for post reac-
tion workup or filtration of the catalyst from the product.
sequent removal/recovery of the Pd catalyst by filtration
8
(
Celite) during work up. Recently Vapourtec Ltd demonstrat-
ed that palladium on charcoal slurries can be used effectively
under continuous flow conditions for the catalytic transfer
hydrogenation of 2 to 3. An effective product yield of approx-
imately 6g/h of 3 was demonstrated with the preparation of 2
9
also having been achieved via continuous flow. However this
approach still requires the continuous pumping of a 30mg/ml
Pd-C slurry through the reactor, filtration of the catalyst, and
post reaction workup. Risk of blockage using slurries and re-
covery and reuse of the catalyst still present a challenge in this
regard.
As part of a wider aim, we have sought to develop strategies
for the more efficient and cost-effective preparations of key
life-saving and life-improving therapeutic compounds such as
Linezolid. A key aspect of this approach is the use of continu-
ous flow chemistry which has found value in research and
industry in recent years for improving methodology and effi-
10
ciency of industrial manufacturing processes. Recently we
have introduced a new approach to heterogeneous catalyst in
11
flow in the form of catalytic statics mixers (CSMs). CSMs
are designed to promote increased flow rate through the reac-
tor and offer significant advantages with respect to cost, de-
sign and processability compared with other current technolo-
gies. Herein we present the use of CSMs for the continuous
flow preparation of the key intermediate 3 in the synthesis of
Linezolid that is not only efficient and scalable, but produces
the product catalyst free without the need for post process
work up.
We apply the use of CSMs to carry out the efficient hetero-
geneous catalysis of 2 to 3 using an immobilised catalyst sys-
tem which also acts as the flow guide and mixer inside the
tubular reactor unit. This novel continuous flow hydrogenation
reactor contains a series of 3D printed catalytic static mixers
Figure 2. A schematic and image of the CSM reactor and the
individual CSMs housed within.
(
Figure 2) which can be coated with a variety of different het-
erogeneous catalysts. The CSMs were designed and printed in
house, and the catalyst was deposited via electroplating. Pre-
vious work from our group has shown the versatility of this
approach for liquid/gas hydrogenations of other nitro contain-
ing molecules and we envisage this as a general approach to
1
1
transformations of this type. Screening parameters such as
catalyst, temperature, gas and liquid feed rates, pressure and
concentration are all able to be simply varied using the reactor
allowing starting parameters to be easily devised. In addition
Figure 3. SEM images of the surface of a Pd(0)-coated cata-
lytic static mixer.
3
D printing allows for mixers of any size and design to be
tailored and fabricated rapidly at low cost.
The results for the conversion of 2 to 3 using Pd-coated
CSMs in a continuous flow process are shown in Table 1. Eth-
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c
anol was initially selected as a solvent for consistency with
batch procedures. Other solvents were examined for increased
spectroscopic monitoring if desired. Increasing the liquid
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flow rate to 3 ml min also gave 100% conversion under the
solubility with ethyl acetate and THF proving superior, alt-
hough the maximum concentration achieved was 0.62M. As a
first attempt, a 0.1M solution of the substituted nitrobenzene 2
same conditions. Due to the limited solubility of 2 in ethanol
we searched for a more suitable solvent. Common organic
solvents such as acetonitrile and dichloromethane also gave
limited solubility however ethyl acetate and THF proved more
suitable. At 0.25M (entry 3) and at 0.42M (entry 4) in ethyl
-
1
in ethanol was passed through the reactor at 1 mL min with a
-
1
-1
hydrogen flow rate of 4 ml min (0.0024 mol min ), at a tem-
perature of 120 °C and a pressure of 20 bar. Pleasingly, this
resulted in 100% conversion to the corresponding amine 2
-
1
acetate, at a flow rate of 2.5 mL min , 100% conversion of 2
to 3 was successfully achieved. Mass balance analysis was
carried out indicating a 96% mass recovery of the product
after collection. At a concentration of 0.42M in ethyl acetate
this corresponds to a normalised space time yield (STY), of
(entry 1). The reaction can also be followed visually as the
solution of nitrobenzene 2 is a bright yellow colour which
turns colourless upon reduction to 3. Incomplete conversion
could be easily detected by observing the degree of yellow
colour present in the output stream and is amenable to in-line
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
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-
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317 g L h .
Table 1. Solvents, concentrations, reaction conditions, conversion and throughput data for the hydrogenation of 2 to 3 using CSMs.
All reactions were carried out at 120 °C.
Entry
Solvent
Conc.
M]
P
L
G
G/L
Conv.
[%]
Flow rate prod
TOF
STY
Yieldprod
-
-
-1
-1
-1 -1
-1
[
[bar]
[ml min
[ml min
[mol/mol]
[mol h ]
[mol/mol*h ]
[g L h ]
[g h ]
1
1
]
]
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOAc
EtOAc
EtOAc
EtOAc
THF
0.1
0.1
20
20
20
20
20
24
24
24
24
1
3
4
4
24
8
>99
>99
>99
>99
60
0.006
0.018
0.038
0.063
0.076
0.075
0.118
0.084
0.09
0.27
0.82
1.71
2.86
3.44
3.41
5.35
3.82
4.09
30
1.2
3.6
91
0.25
0.42
0.42
0.25
0.62
0.62
0.5
2.5
2.5
5
4
3.8
2.3
1.1
11.6
2.3
3.9
4.8
191
317
382
377
594
423
453
7.5
4
12.4
14.9
14.7
23.2
16.5
17.7
4
5
10
10
10
10
>99
63
5
THF
3
75
THF
3
>99
-
1
Reactor volume = 0.039 L; Mass of catalyst = 2.357 g ; ncat = 0.022 moles; Flow rate prod (mol h ) = Flow rate Subs x (conv. % / 100); Flow rate Subs (mol
-1
-1
-1 -1
h ) = (L /1000) x conc. x 60 min x conc.); TOF (molprod/molcat h ) = Flow rate prod / ncat; moles; STY (g L h ) = Flow rate prod / reactor volume x 1000 x
MWprod; Yieldprod = Flow rate prod x MWprod. Typical reaction runs were carried out using 20 mL of substrate solution giving a residence time of ~7 mins
-1
at a liquid flow rate of 3 mL min . Maximum volume of substrate used per run was 50 mL. Collected product streams includes an additional 1 reactor
volume of solvent for washing.
In an effort to increase throughput the liquid flow rate was
Under these conditions the effective STY was increased to 453
-
1
-1 -1
next increased to 5 mL min , however under these conditions
the conversion dropped to 60%. To address this and up the
g L h , giving our prototype laboratory scale flow reactor the
potential of multikilogram/litre/day, and the effective product
-
-1
conversion we increased the hydrogen flow rate to 10 mL min
yield was increased to 17.7g h corresponding to 425g of 3
1
-1
(
0.0073 mol min ) and the pressure to 24 bar, in line with
per day given the current reactor volume.
11a
previous optimisation processes. We also found that THF
gave increased solubility of 2 up to 0.62M, and subsequently
adopted this solvent system for applying the new reaction
conditions. At this higher concentration in THF, and at a liquid
During these experiments high catalytic activity was ob-
served with quantitative conversion observed in most cases.
-1
Turn-over frequencies (TOF) ranged from <1 h for lower
-1
substrate concentrations (0.1M) to 7.5 h for higher concentra-
-
1
flow rate of 5 ml min , a conversion of 63% was achieved
although this was still not ideal. Dropping the liquid flow rate
tions (0.5M). While we have previously demonstrated higher
throughputs with our reactor using higher concentrations of
more soluble substrates, the low solubility of 2 has been a
limiting factor in this case. For example, our previous studies
on the reduction of cinnamaldehyde gave TOF’s of >20 and
-
1
to 3 mL min led to a slight increase to 75% conversion and
after a little optimisation and a lowering of the substrate con-
centration to 0.5M, >99% conversion of 2 to 3 was achieved
-
1
-1 11b
(
entry 9). Subsequent evaporation of the solvent gave the
amine 3 as a white solid. For a 20 mL sample of substrate at
.5 M this gave 1.88g of 3 at 96% mass recovery. NMR and
LC-MS analysis showed that the product 3 was obtained in
99% purity. Examination of the gas stoichiometry shows that
the molar ratio of hydrogen to substrate was 4.8:1 (Table 1).
STY values of 0.7 Kg L h ,
values superior to other re-
7b,c
ported flow methods. In addition nitro reductions are also
known to be exothermic, however under all conditions de-
scribed here it is notable that no exotherm was observed via
0
>
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the thermocouple closest to the reactor inlet (one of 3 monitor-
ing temperature along the reactor path).
The Supporting Information is available free of charge on the
ACS Publications website.
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Typical side products of nitro reductions such as condensa-
tion products were not observed, nor were any desfluorinated
products, however a minute trace (<0.1%) of the hydroxyla-
mine byproduct was observed by LC-MS. Hydroxylamines are
genotoxic and potentially explosive if concentrated, however
Pt(V)/C catalysts have been especially developed to avoid the
Characterization data, reactor design and operation (PDF).
AUTHOR INFORMATION
Corresponding Author
* Email: james.gardiner@csiro.au
13
formation of such byproducts. CSMs with such doped cata-
lyst coatings are currently under development. ICP-OES anal-
ysis also showed that leaching of the Pd catalyst is very low
with values detected < 1ppb, indicating that the Pd catalyst is
exceptionally well bound to the surface of the static mixer.
Pleasingly we found that the CSMs are also catalytically ro-
ORCID
James Gardiner: 0000-0003-0298-5790
Christian H. Hornung: 0000-000203678-6565
0
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Notes
1
1
The authors declare no competing financial interest.
bust observing that with regular activation, a single set of 12
Pd-coated CSM inserts were able to be used almost continu-
ously for hydrogenation reactions for over a year without sig-
nificant loss of catalytic activity. Further CSM design and
catalyst optimisation of this and related processes are ongoing.
ACKNOWLEDGMENT
The authors thank Oliver Hutt, Dayalan Gunasegaram, Andrew
Urban and Darren Fraser for helpful discussions.
This general approach of using CSMs in continuous flow
offers several advantages, namely (a) tubular reactor technolo-
gy is simple and well understood offering excellent control
over liquid and liquid/gas reactions conditions (b) 3D printing
allows for rapid design and manufacture of tailored mixer
solutions for many different liquid and gas flow applications;
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(
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In summary, we have used palladium-coated 3D printed
catalytic static mixers (CSMs) to demonstrate a versatile and
efficient method for the continuous flow hydrogenation of the
key intermediate 3 in the synthesis of the antimicrobial drug
Linezolid (Zyvox). A simple reactor housing the CSMs was
successfully applied to carry out the reduction of the substitut-
ed nitrobenzene 2 to its corresponding amine 3 with potential
for a half-kilogram per day output. This is 3 times the output
of current continuous flow methods for the preparation of this
intermediate. Our continuous process makes use of 3D print-
ing and additive manufacturing techniques to produce static
mixers capable of both highly efficient mixing and heteroge-
neous catalysis, and crucially eliminates the need for catalysis
removal or recovery post processing. We present this as a
general, low-cost and efficient method for this type of trans-
formation for the production of 3 and similar pharmaceutical
and industrially relevant intermediates and products. The de-
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(
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