The Application of a Continuous Grignard Reaction in the Preparation of Fluconazole

Article abstract of DOI:10.1002/ejoc.201701002

The application of continuous methods in the synthesis of active pharmaceutical ingredients continues to receive significant attention in the academic as well as the industrial research communities. One of the major advantages of continuous methods is the ability to safely access kinetic synthons as well as highly reactive reagents that are typically unavailable through traditional batch methods. In this work, we report the high-yielding, clean formation of an aryl-turbo Grignard and its selective addition to a highly-enolizable 1,3-dichloroacetone, for the continuous synthesis of a key intermediate for fluconazole, a widely-prescribed anti-fungal agent. In addition, process optimization of the final API was also carried out to arrive at a semi-continuous method to this essential medicine.

Full text of DOI:10.1002/ejoc.201701002

A Journal of
Accepted Article
Title: The Application of a Continuous Grignard Reaction in the
Preparation of Fluconazole
Authors: Frank B. Gupton, Sudha Korwar, Somi Amir, Perrer N. Tosso,
Caleb J. Kong, Swara Fadnis, Bimbisar K. Desai, Saeed
Ahmad, Nakul S. Telang, and Thomas D. Roper
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701002
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701002
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European Journal of Organic Chemistry
10.1002/ejoc.201701002
COMMUNICATION
The Application of a Continuous Grignard Reaction in the
Preparation of Fluconazole
Sudha Korwar, Somi Amir, Perrer N. Tosso, Bimbisar K. Desai, Caleb J. Kong, Swara Fadnis, Nakul S.
Telang, Saeed Ahmad, Thomas D. Roper, B. Frank Gupton*[a]
[
5]
Abstract: The application of continuous methods in the synthesis of
active pharmaceutical ingredients continues to receive significant
attention in the academic as well as the industrial research
communities. One of the major advantages of continuous methods is
the ability to safely access kinetic synthons as well as highly reactive
reagents that are typically unavailable through traditional batch
methods. In this work, we report the high-yielding, clean formation of
an aryl-turbo Grignard and its selective addition to a highly-enolizable
Since its commercialization , the process for the preparation of
fluconazole has suffered from low overall yields (<35%). Although
the synthesis has been re-visited[ more recently, these efforts
have been restricted to conventional batch conditions.
Furthermore, these approaches have been confined to the use of
expensive organolanthanoid-based reagents.
6]
In this work, we report the development of a continuous process
for the formation of a highly reactive turbo-Grignard reagent and
its use in the synthesis of fluconazole. Grignard reagents have
been widely used on both laboratory and commercial scale and is
one of the most common organometallic reagents used for the
formation of carbon-carbon bonds. However, its application with
highly-enolizable compounds such as 1,3-chloroacetone (3) has
been previously avoided due to unfavourable side reactions[6a]. In
1,3-dichloroacetone, for the continuous synthesis of a key
intermediate for fluconazole, a widely-prescribed anti-fungal agent. In
addition, process optimization of the final API was also carried out to
arrive at a semi-continuous method to this essential medicine.
Introduction
In recent years, flow chemistry has emerged as a vital tool, not
only for conducting laboratory scale organic synthesis, but also in
the manufacture of active pharmaceutical intermediates (APIs)
this application, the use of i-PrMgCl.LiCl and
increased yields for both the formation of the corresponding turbo-
Grignard reagent and allowed the clean addition to the pivotal
4 provided
[
1]
and molecules of medicinal value . Continuous processes often
achieve heightened efficiencies and selectivity as a direct result
of the control of critical reaction parameters and enhanced heat
and mass transfer properties. Continuous methods can also
provide increased access to alternative reaction pathways and/or
high energy intermediates that would be inaccessible in batch
intermediate 2.
A significant benefit of this approach for
continuous processing was recognized in the ability to carry out
both reactions in a single solvent in the absence of solid reactants
or by-products
operations [2]. Furthermore, continuous flow techniques can be Results and Discussion
exploited to improve the safety profile of chemical processes,
making flow chemistry an enabling technology for reactions that
In the evaluation of alternative approaches to streamlining the
[
3]
would otherwise be too hazardous to be performed on scale .
Because the overall quantity of these species is limited in a flow
reactor as compared to a bulk solution preparation, the build-up
of potentially dangerous or explosive compounds is greatly
minimized.
fluconazole synthesis, the focus of our effort turned to
intermediate 2 (Figure 1). We considered an approach that would
access 2 by employing a Grignard reaction to install the
fluorinated aromatic component rather than an alternative
organolanthanoid-based reagent (Figure 1). There exists
significant precedence for the application of Grignard chemistry in
continuous operations[ and the dihaloketone 3 is a readily
available starting material in the chlorinated form.
7]
One of the major objectives of our group is to improve the process
efficiencies of active pharmaceutical ingredients (APIs) by
applying the principals of process intensification which include the
[4]
integration of continuous flow reactor platforms . In this body of
work, we report our efforts to develop a streamlined process for
the preparation of fluconazole, a widely prescribed anti-fungal
®
agent. Fluconazole (trade name Diflucan ) was launched in
1
988[5] and rapidly became a primary treatment for patients
suffering from serious fungal infections. More recently, its use has
risen among cancer and HIV-infected patients as well as in
support of organ transplants. The drug can be administered either
orally or by injection.
Figure 1. retrosynthesis to fluconazole.
Initially, we explored the formation of the Grignard reagent (table
1) under sub-ambient condition (Table 1, Entry 1) which resulted
in a moderate conversion. Further attempts to increase the
conversion by increasing the temperature and using diglyme as a
solvent did not result in any noticeable improvement. There are
several indications that turbo Grignard reagents (i-PrMgCl.LiCl)
accelerate the halogen magnesium insertion . Hence, we applied
this reagent to this system, which provided excellent conversion
[
[
a]
b]
Department of Chemistry and Department of Chemical and Life
Science Engineering, Virginia Commonwealth University, 601 W.
Main St. Richmond, VA 23220, USA. Email: bfgupton@vcu.edu
Supporting information for this article is given via a link at the end of
the document.
[8]
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European Journal of Organic Chemistry
10.1002/ejoc.201701002
COMMUNICATION
to the desired product (6) within 15 min (Table 1, entry 4). The
observed accelerated reaction rate provided evidence that the
reaction could be transferred to a continuous platform.
Table 3. Optimization of preparation of 2 in flow.
Table 1: Optimization of activation and reaction conditions in batch
Solvent
reaction)
Conv[c]
(%)
o
Entry
Temp. ( C)
[Mg]
(
Equiv. of
Equiv. of
t
R
=min
Lewis acid
Conv. to 2
Entry
(%)[
a]
6
3
1
2
3
4
0
60
80
0
Mg
Mg
THF
56[d]
63[d]
27[d]
97[e]
1
2
3
4
5
1.1
2
1
1
1
1
1
1
2
-
-
-
-
65[a]
71[a]
84[b]
Diglyme
Diglyme
THF
Mg
2
0.7
1
i-PrMgCl.LiCl
2
90[b]
[
a] Mg turnings or i-PrMgCl.LiCl, [b] 4 (1 equiv.), 1.3M i-PrMgCl.LiCl (1.1
o
equiv.), 0 C, 15 min. [c] conversion determined by HPLC; product quenched
73[a]
2
1
3 2
BF OEt
by MeOH, [d] refers to 5, [e] refers to 6.
[
a] conversion determined by HPLC. [b] isolated yield.
Given the success with the batch Grignard reactions, we inspired
from the previous studies[7] to optimize the chemistry in flow
With the preparation of organomagnesium reagent optimized, the
solution of the Grignard reagent collected was further streamed
in-line with the 1,3-dichloroacetone 3 to obtain the intermediate 2.
Our initial results were modest (Table 3, Entry 1), however, by
attenuating residence time and increasing the relative input of our
Grignard, we were able to maximize conversion and obtain an
isolated yield of 90% for this transformation (Table 3, Entries 2-4).
We also evaluated BF -OEt as a Lewis acid catalyst, but with no
3 2
measurable increase in conversion or rate enhancement. (Table
3, Entry 5).
(
Table 2). At room temperature, the reaction progressed with
moderate conversion at a residence time of 1 min (Table 2, Entry
). Increasing the residence time to 2.5 min led to an increase in
1
the Grignard formation (Table 2, Entry 2). Finally, the best
conversion was realized when using 1.8 equiv. of the turbo
Grignard (Table 2, Entry 4) to deliver a conversion of 96%.
Increasing the temperature did not provide any measurable
advantage. This result demonstrated that under continuous flow
conditions, this chemistry could be carried out with significant
reduction in the reaction time.
Table 4. Telescope of 4 to the intermediate 2.
Table 2. Optimization of the flow process for 6 using turbo Grignard reagent.
i-PrMgCl.LiCl
Conv[a] (%)
o
Entry
Temp ( C)
t
R
= min
[
equiv.]
t
R
= min
Reactor 2
Entry
Yield (%)
1
2
3
4
5
1.1
r.t.
r.t.
r.t.
r.t.
50
1
55
80
85
96
96
Reactor 1
1.1
2.5
2.5
2.5
2.5
1[a]
2[a]
3[a]
1
1
1
72
70
74
87
1.4
2.5
2.5
2.5
1.8
2.5
1
1.8
4
[
a] conversion determined by HPLC; product quenched by MeOH
[a] reactions were streamlined without the continuous stirring tank reactor.
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European Journal of Organic Chemistry
10.1002/ejoc.201701002
COMMUNICATION
We then attempted to consolidate the process by telescoping 4 to
Conclusion
2
over two reactors (table 4). When the reaction was streamlined,
a moderate yield of 74 % yield was realized (entry 3). The yield
was further improved to 87% yield when introducing a continuous
stirred tank reactor (entry 4). We are currently investigating the
benefits of this dual reactor system in similar applications. In order
to quantify the efficiency of this system, we calculated the volume-
time output (VTO), the throughput of a reaction relative to its
reactor space. For the addition of the turbo-Grignard into 1,3-
chloroacetone the VTO for the continuous reaction was 8.962 x
This work reports the formation and application of a turbo-
Grignard reagent to cleanly access a key intermediate towards
fluconazole, with high-throughput using continuous flow
technology. Not only were the efficiency gains realized by the
process quantified with a remarkably low VTO of 8.962 x 10 m3
-
7
-1
h kg , but the safety concerns involved with organometallic
reagents were addressed through a continuous flow approach. In
doing so, it should be noted that the optimized process conditions
that were established clearly demonstrates the enhanced window
of operability provided by continuous method development that
would have been otherwise unattainable in batch mode. The
elaboration of this intermediate was further optimized using low-
cost starting materials to deliver fluconazole. Future work will
include closing the gap in this final process to find conditions
amenable to a fully-continuous process as well as applying these
principles and technologies to other active pharmaceutical
ingredients.
0-7 m h kg . For reference, process chemists aim for a VTO <1
3
-1
1
[
9]
for a chemical step
With the flow optimization of the key intermediate 2 at hand, we
sought to investigate the last synthetic step towards fluconazole.
We recognize that prior efforts to carry out this step required
significantly long reaction times (up to 16h)[6a], which precludes
the application of flow chemistry in this instance. For this reason
we elected to confine our research effort towards developing
optimum batch conditions for the conversion from 2 to 1. Process
optimization began with screening organic or inorganic bases, Acknowledgments
taking into account the pKa value of the 1,2,4-triazole, in particular, This work was supported by The Defense Advanced Research
to circumvent the possibility of having isomers derived by reaction
of N-4 atoms of the 1,2,4-triazole. Initially, MeOH was chosen as
the reaction solvent screen across organic bases under batch
conditions. Although this helped with the solubility of the reactants,
it gave very poor conversion to fluconazole (table 5, entries 1-2).
Subsequently, we attempted inorganic bases (entries 3-7), which
converted moderately to the desired product. In the case of DMF
as the solvent, increasing temperature did not provide any
significant improvement (entry 6). Interestingly, when using
Projects Agency (DARPA) (W911NF-16-2-0023).
Keywords: Fluconazole • flow • continuous • turbo Grignard
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European Journal of Organic Chemistry
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COMMUNICATION
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European Journal of Organic Chemistry
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COMMUNICATION
Continuous flow chemistry
Sudha Korwar, Somi Amir, Perrer N.
Tosso, Bimbisar K. Desai, Caleb J.
Kong, Swara Fadnis, Nakul S. Telang,
Thomas D. Roper, B. Frank Gupton*,
Corresponding Author(s)*
Text for Table of Contents
Page No. – Page No.
The Application of a Continuous
Grignard Reaction in the Preparation
of Fluconazole
This work describes the semi-continuous synthesis of the anti-fungal agent fluconazole via high-yielding and clean formation of an
aryl-turbo Grignard followed by its selective addition to a highly-enolizable 1,3-dichloroacetone in a continuous operation to form the
precursor to the API.
*
Fluconazole
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