Heating under high-frequency inductive conditions: Application to the continuous synthesis of the neurolepticum olanzapine (Zyprexa)

Article abstract of DOI:10.1002/anie.201302239

Hot chemistry! High-frequency inductive heating and flow chemistry are an ideal match for high-temperature synthesis. This is demonstrated in the multistep flow synthesis of the neurolepticum olanzapine (Zyprexa) that included three reactions with inductive heating and two purification steps conducted as continuous processes. Copyright

Full text of DOI:10.1002/anie.201302239

Angewandte
Chemie
Communications
Flow Synthesis
J. Hartwig, S. Ceylan, L. Kupracz,
L. Coutable,
A. Kirschning*
&&&& — &&&&
Heating under High-Frequency Inductive
Conditions: Application to the
Continuous Synthesis of the
Neurolepticum Olanzapine (Zyprexa)
Hot chemistry! High-frequency inductive
heating and flow chemistry are an ideal
match for high-temperature synthesis.
This is demonstrated in the multistep
flow synthesis of the neurolepticum
olanzapine (Zyprexa) that included three
reactions with inductive heating and two
purification steps conducted as continu-
ous processes.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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DOI: 10.1002/anie.201302239
Flow Synthesis
Heating under High-Frequency Inductive Conditions: Application to
the Continuous Synthesis of the Neurolepticum Olanzapine
(Zyprexa)**
Jan Hartwig, Sascha Ceylan, Lukas Kupracz, Ludovic Coutable, and Andreas Kirschning*
The use of micro- or mesofluidic reactors has become a key
enabling technology[1] in academia and industry.[2] The rapid
heating of reactants inside the flow device is an important
issue when syntheses are conducted in mesofluidic reactors at
high flow rates. Ideally, heating should be combined with high
pressure to achieve sufficiently high reaction rates.[3] Conven-
tional heating relies on convective heat transfer which is often
too slow to serve the purposes of flow chemistry. Alternative
techniques are: a) heating with microwave irradiation, which
can be utilized when reactor materials are microwave trans-
parent[4] and b) the direct electric heating of tubular reac-
tors.[5]
Recently, we applied inductive heating (IH) to mesoflui-
dic reactors by using ferromagnetic materials like steel beads,
copper metal, and superparamagnetic nanostructured parti-
cles in fixed beds.[6,7] Magnetic and conductive materials
normally heat up in an oscillating magnetic field due to
Jouleꢀs heating and hysteresis; however, superparamagnetic
particles heat up due to Brown and Nꢁel relaxation.[6]
Depending on the external inductor, an oscillating field with
medium (15–25 KHz) or high frequency (780–850 KHz) can
Figure 1. a) HF inductor with inductor coil; b) MAGSILICA 300[12]
be generated (Figure 1). We found that this technique allows
for very rapid heating of a large number of diverse reactions
(top), steel beads 0.4 mm (bottom, left), steel beads 0.8 mm[13]
(bottom, right).
under flow conditions, thereby avoiding hazardous radia-
tion.[7] Commonly, a stronger magnetic field (H) and higher
frequency (f) increase the amount of induced heat for most
materials. The frequency also correlates with the skin depth,
which is the distance at which most of the induced energy is
absorbed within the material. Because of this phenomenon,
medium frequencies are preferentially employed when larger
objects are heated, whereas high frequencies are ideally
suited for smaller objects and superparamagnetic nanomate-
rials.[8,9]
that this new heating technique can be utilized in a complex
application. The continuous multistep flow synthesis of the
atypical neurolepticum olanzapine (Zyprexa)[10] could only be
accomplished with an advanced heating method. In this study
we employed a custom-made high-frequency inductor (Fig-
ure 1a)[11] which can accommodate a cartridge-type flow
reactor made of glass, PEEK (polyether ether ketone),
ceramic, and a coil reactor made of Hastelloy C-steel.
To compare the two types of inductors (mf, hf) we first
placed several magnetic and/or conducting materials of the
same volume in microwave vials and then positioned them in
medium-frequency (15–25 kHz) and a high-frequency (300
and 780–800 kHz, respectively) oscillating fields. For compar-
ison, all experiments were run at maximum power and the
temperature on the surface was measured with an IR
pyrometer (see the Supporting Information (SI)).
Herein we disclose the first applications of high-frequency
(hf) inductors to organic synthesis. We further demonstrate
[*] J. Hartwig, Dr. S. Ceylan, L. Kupracz, Dr. L. Coutable,
Prof. Dr. A. Kirschning
Institut fꢀr Organische Chemie
Leibniz Universitꢁt Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
E-mail: andreas.kirschning@oci.uni-hannover.de
[**] This work was supported in part by the Fonds der Chemischen
Industrie (PhD scholarship for J.H.) and by Henkel AG & Co. KGaA
(Dꢀsseldorf (Germany)). We thank H. Herzog and Prof. S. Katusic
(EVONIK Industries AG, Essen (Germany)) for technical support
and Dr. D. Candito for helpful discussions.
In the case of MAGSILICA 300,[12] high-frequency induc-
tion provided temperatures close to 3008C in less than 1 min,
while the medium-frequency inductor was inefficient in
heating these nanostructured particles. Steel beads with
a diameter of 0.4 mm demonstrated more extreme behavior:
only hf induction provided temperatures around 4008C. In
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302239.
2
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addition, we investigated the use of a Hastelloy C-steel coil
reactor (inner diameter= 0.75 mm; length = 70 cm; V=
0.3 mL); toluene was pumped through the coil reactor at
a flow rate of 4 mLminÀ1 at a power input of 10%. In the
pressurized system temperatures up to 3608C could be
achieved at this high flow rate. It must be noted that it is
not possible to determine the temperature precisely yet,
because the temperature of the reactor surface is measured,
not that of the heating material. These simple experiments
showed us that extremely rapid heating to high temperatures
can be achieved when magnetic/conductive materials are used
in combination with hf induction. Such high and rapid heating
is ideally suited to flow chemistry applications where resi-
dence time is short. The reaction vessel was heated by
embedding the whole reactor in the homogeneous electro-
magnetic field of either a U-shaped [IH(mf)] or a coil-shaped
[IH(hf)] electromagnetic inductor. This guarantees homoge-
neous heating of the whole vessel. After a short warmup
period the temperature of the vessel is only influenced by the
cold solvent that enters the reactor which results in a small
temperature drop of 5–108C at the reactor inlet. We went on
to demonstrate the utility of this heating method in the
difficult Claisen rearrangement of allyl aryl ether 1 under
batch conditions (Table 1). We had shown that this test
reaction can be conducted at around 2008C, but under
conventional conditions we never achieved full conversion.[6b]
When a capped vial was heated in an oil bath, the
rearranged product 2 was isolated in only 17% yield after 2 h,
while microwave heating and inductive heating under similar
conditions provided 2 in yields of 38% and 39%, respectively.
It is noteworthy that under high-frequency conditions almost
complete conversion was achieved at 2058C in a much shorter
time, while at 2258C a substantial degree of decomposition
was observed. High-frequency inductive heating seems to
resultsin a much hotter surface, which leads to higher reaction
rates in close proximity to the nanostructured particles. We
extended our studies to flow experiments using a ceramic
reactor filled with MAGSILICA (Scheme 1). At a flow rate of
Scheme 1. Claisen rearrangement of allyl aryl ether 1 under flow
conditions by IH(hf) with MAGSILICA. [a] Temperature determined on
the reactor surface using an IR pyrometer. bpr= back pressure
regulator.
0.5 mLminÀ1 and a temperature of 2408C complete conver-
sion was achieved along with a high yield of isolated product
(91%). This example clearly shows the advantages of high
rapid heating in organic synthesis. Reactions that are difficult
to achieve under standard convection heating may now be
possible.
We then went on to increase the complexity of the
application by demonstrating that it can be used in a multistep
flow sequence. We chose olanzapine (3), one of the best-
selling drugs worldwide. It exerts antagonistic activity towards
the dopamine receptor type 4 (D4 receptor) and the
serotonine receptor type 2 (5HT2 receptor).[10,14]
Our synthesis is related to a previously published
sequence.[15] However, while the patent describes a nucleo-
philic aromatic substitution between 2-fluoronitrobenzene
and aminothiazole 5, which proceeds in only modest yield, we
employed the Buchwald–Hartwig amination[16] of aryl iodide
4 and aminothiazole 5 as the initial step (Scheme 2). We
tested many reaction conditions and found that the Xantphos
ligand in combination with tetra-n-butylammonium acetate
promoted amination of aryl iodide 4 in excellent yield
(> 90%) in THF and in ethyl acetate (Table 2). Ethyl acetate
Table 1: Comparison between conventional heating (external oil bath),
microwave irradiation, and medium- and high-frequency inductive
heating (IH) under batch conditions.
Heating
mode
Conditions[a]
Yield
[%][b]
oil bath
2008C, toluene, 120 min
Si/C, 2008C, toluene, 120 min
17
38
microwave
heating[c]
IH(mf)
25 kHz, 2008C, MAGSILICA, toluene,
39
120 min
IH(hf)
IH(hf)
800 kHz, 2058C,[d] MAGSILICA, toluene,
89
Scheme 2. Olanzapine (3) and building blocks 4–6.
20 min
800 kHz, 2258C,[d] MAGSILICA, toluene,
decomp.
20 min
was the solvent of choice because of its full compatibility in
the subsequent steps.
A 1:1 mixture of iodobenzene 4 and aminothiazole 5 was
pumped into a reactor that was filled with steel beads and
encased in an inductor. Mixing the starting materials with the
base Bu4NAc right at the start resulted in the formation of 7 in
[a] The experiments were conducted at 2008C in a closed vial, well above
the boiling point of toluene. [b] Yield of isolated product. [c] Microwave
heating was conducted in the presence of SiC as toluene does not absorb
microwave irradiation efficiently; temperature measurement: experi-
ments with microwave and oil bath heating: temperature sensor; IH
experiments: IR pyrometer. [d] Adjusted by inductor power.
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Table 2: Optimization of the Buchwald–Hartwig reaction under flow
conditions; reactor filled with steel beads (0.8 mm) and placed in an
inductor [IH(mf)]; test scale: 0.05 mmol.
Scheme 4. Acid-promoted cyclization of aniline 8 under flow condi-
tions using a coil reactor in inductive high-frequency field (test scale:
0.05 mmol); temperature measured on surface by IR pyrometer: 808C,
solution temperature measured after the reactor with K-element:
1408C.
leads to rapid heating to higher temperatures inside the
tubular reactor so that exposure of the reaction mixture to
high temperatures can be better controlled by reactor length
and flow rate alone. We found that mf conditions always
provided an impure product, while hf inductive heating of 8
dissolved in a 0.2m HCl solution in EtOAc/MeOH (4:1) at
808C quantitatively provided benzodiazepine 9. Lower flow
rates led to decomposition; higher flow rates did not give full
conversion. Also, the HCl concentration (< 0.4m) was crucial,
otherwise substantial decomposition and polymerization
occurred. In pure ethyl acetate no conversion to benzodiaze-
pine 9 was observed, while the reaction in pure methanol gave
low yields. Solvent mixtures consisting of ethyl acetate and
dichloromethane also gave good overall yields of crystalline
benzodiazepine 9 at 808C, but the reaction time had to be
extended by a factor of 3.
Next, we investigated the preparation of olanzapine (3)
from benzodiazepine 9 and piperazine 6 under thermal
conditions (ꢀ 1508C). Both batch and flow conditions led to
substantial decomposition. When lower temperatures (110–
1408C) were employed, yields for 3 were below 35%. Lewis
acids dramatically improved the yields (Table 3). We pre-
pared a new silica-supported titanium catalyst (10; see the
Supporting Information) which provided 3 in over 90% yield
at 1208C. Under batch and flow conditions the best results
were obtained with BF3·Et2O (Table 3, entries 1 and 2).
However, the silica-based titanium Lewis acid 10 can be
applied as a fixed-bed material. In this case MAGSILICAwas
the material of choice, because when it was mixed with the
Lewis acid 10, rapid and “homogeneous” catalyst heating was
achieved which furnished a cleaner product (Table 3, entry 4).
Conventional heating of the same reactor with a steel block
gave lower yields and more byproducts (Table 3, entry 3).
Remarkably, olanzapine (3) could still be isolated in 87%
yield after the reaction had been repeated seven times (each
0.075 mmol scale). ICP-MS analysis revealed that Ti leaching
is negligible with only 0.0135% loss after a period of 6 h in
methanol at 1208C (see the Supporting Information). Under
the typical reaction conditions, titanium leaching of d =
0.136 ppm during the first 6 h and d = 0.261 ppm for the
following 20 h in solution were observed, resulting in d =
19.9 ppm titanium in the final product. Thus most of the
titanium (> 99%) remains immobilized, which guarantees the
durability of the catalyst for long-term application as well as
low contamination of the drug.
T
Flow rate
[mLminÀ1
Base
In-line extraction[c]
Yield
[%][d]
[8C][a]
]
addition[b]
50
50
50
50
0.06
0.08
0.06
0.06
1st stream
2nd stream
2nd stream
2nd stream
À
À
À
+
73
81
91
90
[a] Temperature measured on surface with IR pyrometer. [b] Mode of
base addition; the term 2nd stream refers to a solution of base that is
added to the 1st stream composed of reactants and catalyst. [c] Vertically
placed reactor (5 mL), equipped with cotton wool on bottom and filled
with distilled water. [d] Yield of isolated product.
comparably low yield (73%). When the base was added to the
first stream directly before the reactor inlet, undesired
reactions in the storage flask were prevented. The coupling
product 7 was isolated in 91% yield, comparable to the yield
under batch conditions (608C, 2 h, 89%; RT, 18 h, 92%).
Higher flow rates or lower temperatures resulted in reduced
yields, while higher temperatures led to decomposition. We
found that the base had to be removed from the crude product
to achieve good yields in the next step. An in-line extractor,
consisting of a vertically oriented cylinder, equipped with
a frit or cotton wool at the bottom and filled with distilled
water, turned out to be a practical solution.
For the subsequent reduction of the nitro group we chose
the metal-free reducing agent triethylsilane and a Pd-doped
fixed-bed reactor.[17] Gratifyingly, the reduction proceeded
smoothly in ethyl acetate under flow conditions (97%; batch
94%) using Pd/C (Scheme 3). Here, heating was achieved
externally by encasing the reactor in a metal block. Remark-
ably, the catalyst could be used for more than 250 h without
loss of activity (corresponds to a loading of less than
0.3 mol%).
The development of a flow protocol for the acid-promoted
cyclization of aniline 8 and formation of thieno[1,5]-benzo-
diazepine 9 demonstrated the advantages of hf over mf
inductive heating (Scheme 4). High-frequency induction
With the results from the individual reactions in hand, we
commenced with the continuous three-step synthesis of
Scheme 3. Reduction of nitroarene 7 under flow conditions. Test scale:
0.058 mmol, Pd/C 30 mg (10 mol%), reactor volume 3 mL.
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Scheme 5. Continuous synthesis of olanzapine (3): 4 and 5 each 0.027m; Et3SiH in EtOAc [2 vol% H2O] 0.6m; HCl in MeOH 0.6m;
benzodiazepine 9 0.019m; MeOH/NMP (3:1); temperature measured on surface with IR pyrometer for inductively heated reactors; temperature
measured by K-Element for steel-block reactors and for reaction mixtures leaving reactors after hf induction.
Table 3: Lewis acid promoted introduction of the piperazine moiety
under flow conditions; temperature measured on surface by IR
pyrometer; test scale: 0.075 mmol.
was achieved with an additional reactor (3 mL volume)
providing 293 mg in 83% yield. In this test study we chose
relatively dilute conditions compared to what industrial
processes ideally require. Still, the productivity is high, in
terms of time and overall reaction volume. The patent
describes a productivity of 1.88 mmolLRÀ1 hÀ1 (LR = reaction
volume in liters) in a discontinuous batch system. The method
reported here, not optimized with respect to productivity,
already has a productivity of 3.97 mmolLRÀ1 hÀ1 (Scheme 5).
In conclusion, we have disclosed the first applications of
high-frequency inductive heating [IH(hf)] in synthetic
organic chemistry. High reaction temperatures can be gen-
erated rapidly in pressure-resistant flow devices in a simple
setup. This heating technology was implemented in a multi-
step continuous process for the preparation of the neuro-
lepticum olanzapine.[19] It was possible to substantially reduce
the required time and amount of materials. This showcase
synthesis demonstrates the power of inductive heating in
combination with different reactor designs and heating
materials.
Entry
Mode
Lewis
acid
T
[8C]
Time or
flow rate
Yield
[%][a]
1
2
3
4
batch
flow[b]
flow
BF3OEt2
BF3OEt2
10
120
18 h
91
92
75[c]
120[d]
85[c]
0.06 mLminÀ1
0.066 mLminÀ1
0.066 mLminÀ1
80
flow[e]
10
87[f]
[a] Yield of isolated product. [b] Steel beads. [c] Surface temperature
generally lower than internal temperature. [d] MAGSILICA conventionally
heated by external steel block. [e] MAGSILICA. [f] Yield of isolated
product after 7th run; packed bed.
Received: March 16, 2013
Published online: && &&, &&&&
Keywords: Buchwald–Hartwig reaction · flow chemistry ·
.
inductive heating · medicinal chemistry · microreactors
thieno[1,5]-benzodiazepine 9 starting from aryl iodide 4 and
thiophene 5 (Scheme 4). Besides the in-line extraction, the
process was further improved by including a cartridge filled
with silica after the in-line extractor in order to remove traces
of Pd.[18] Furthermore, the reaction mixture that left the
second reactor after reduction of the nitro group was
collected in a glass vessel where remaining hydrogen gas
was liberated allowing for more constant flow rates. At this
point a stream of HCl in MeOH (0.6m) was added and the
solution was injected into the tubular reactor. It was possible
to conduct the three steps continuously for 30 h without
chromatographic purification to obtain 313 mg (88% yield) of
thieno[1,5]-benzodiazepine 9. It is noteworthy that the overall
reactor volume is about 8 mL for all three steps and no
solvent switch is necessary. The formation of olanzapine (3)
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