Angewandte
Chemie
DOI: 10.1002/anie.200903055
Synthesis Design
The Continuous-Flow Synthesis of Ibuprofen**
Andrew R. Bogdan, Sarah L. Poe, Daniel C. Kubis, Steven J. Broadwater, and
D. Tyler McQuade*
Organic synthesis is a powerful enterprise that continues to
develop more selective and efficient chemical methods and
synthetic routes. To synthesize complex molecules, whether in
academic laboratories or industrial manufacturing, reactions
are often performed iteratively in batch reactors. Although
these stepwise methods are effective, they are also very
wasteful. The pharmaceutical industry, for example, produces
reactor that eliminates the need for purification and isolation
steps.
To achieve this continuous-flow synthesis, a careful
retrosynthetic analysis of ibuprofen was performed, consid-
ering the synthesis of ibuprofen as an entity, as opposed to a
series of independent reactions steps. Reactions therefore had
to be designed such that byproducts and excess reagents from
one reaction were compatible with downstream reactions. In
this way, reactions could be performed in sequence without
any breaks in the synthesis. The general three-step synthesis
2
5–100 kg of waste for every kilogram of a complex molecule
[
1]
synthesized. Though chemists are constantly striving to
devise more efficient syntheses, recent reminders of a
resource-limited world underscore the need for more sustain-
able methods and technologies to synthesize molecules of
importance. The application of new technologies, such as
microreactors, to organic synthesis can be used to achieve this
[37]
of ibuprofen we investigated is outlined in Scheme 1.
[2]
[
3–13]
goal.
Microreactors are a developing technology used to
perform safer, more efficient, and more selective chemical
[3–19]
transformations in microchannels or narrow-bore tubing.
The many advantages associated with conducting reactions in
[5]
flow are attributed to large surface-area-to-volume ratios
that allow precise reaction control through rapid heat transfer
[
20–23]
and mixing.
single reactor for extended periods of time
addition of more identical flow reactors in parallel, a process
The syntheses can be scaled up by running a
[
24]
or by the
Scheme 1. Proposed synthetic route to ibuprofen. “iodine”=I or PhI-
2
(OAc) , TMOF=trimethylorthoformate.
2
[
25–27]
known as numbering up.
Although most applications of microreactors in organic
synthesis have focused on single-step reactions,
[3–19]
recent
We surveyed multiple catalysts for the Friedel–Crafts
examples have demonstrated multistep reaction sequences in
acylation. Of these, AlCl provided the highest yield, but
3
[
20,28–32]
flow.
Our group has a long-standing interest in the
byproducts from this reaction proved to be incompatible with
downstream steps. Mixing isobutylbenzene (IBB, 1) and
propionic acid with triflic acid (TfOH) proved to also be an
development of new methodologies that enable the rapid and
[
33–36]
efficient synthesis of important small molecules.
Specif-
[
38–40]
ically, we have aimed to run multistep reaction sequences in
effective method to synthesize 2 (Figure 1).
This TfOH/
[
35,36]
one pot (i.e. in batch reactors)
microreactors).
or in series (i.e. in
propionic acid system was not only effective with the first step
but was also compatible with the second step.
[33,34]
We report herein a three-step, continu-
ous-flow synthesis of ibuprofen, a high-volume, nonsteroidal
anti-inflammatory drug (NSAID), using a simplified micro-
To run acylation experiments under continuous-flow
conditions, a solution of IBB and propionic acid was mixed
with a stream of TfOH at a tee junction, resulting in plug
flow (see the Supporting Information). When the reactor was
heated to 508C with a five-minute residence time, only a 15%
[
41]
[*] D. T. McQuade
Department of Chemistry and Biochemistry
Florida State University, Chemical Sciences Laboratory
Tallahasee, FL 32306 (USA)
Fax: (+1)850-644-8281
E-mail: mcquade@chem.fsu.edu
A. R. Bogdan, S. L. Poe, D. C. Kubis, S. J. Broadwater
Department of Chemistry and Chemical Biology
Cornell University, Baker Laboratory, Ithaca, NY 14853 (USA)
[**] D.T.M. acknowledges NSF SGER, ARO (grant no. W911NF-06-1-
0315), NSF (CHE-0809261), and Florida State University for
financial support.
Figure 1. Setup of the Friedel–Crafts acylation in a flow reactor.
Angew. Chem. Int. Ed. 2009, 48, 8547 –8550
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8547