Microwave-Driven
Compound Synthesis: Turning Up the Heat on Med Chem
By Vicki
Glaser
February 14,
2007
Microwave-based
chemical synthesis for small-molecule drug discovery
offers several advantages. Medicinal chemists are
finding that they can use microwave energy to catalyze
a broad range of chemistries, and that by putting a
moderate amount of energy into a reaction to drive
chemical transformations, they can achieve higher
yields and greater purity and can realize significant
improvements in efficiency and productivity. The
impact of this technology on the pharma and biotech
industries will expand as new, lower-cost, personal
microwave systems designed for chemistry development
and lead optimization come to market, and as larger
units capable of reproducible and cost-effective scale
up of the technology make large-scale,
microwave-driven compound synthesis a reality.
Mark
Bradley, professor of high-throughput chemical biology
at the University of Edinburgh (U.K.), identifies
three key benefits of using microwave energy to
catalyze the synthesis of organic small molecules:
convenience, faster reaction speeds, and enhanced
reaction control. Microwave energy can heat reactions
to higher temperatures in a much shorter time than
conventional heat sources, substantially reducing
reaction times. The degradation of reaction products
and undesired side reactions that can occur with
conventional heating are typically due to the length
of heating required to drive the reaction to
completion. By putting in the same amount of energy,
or even more energy faster, microwave synthesizers can
yield more, purer product.
This
may be particularly advantageous as biopharma
companies increasingly focus on the synthesis of more
natural compounds — such as compounds derived from
bacteria — that may be more sensitive to the
degradative effects of prolonged heating.
Still
Early Days
Michael
Collins, president and CEO of CEM Corp., describes
microwave synthesis as being “at a relatively early
stage in adoption in the medicinal chemistry
marketplace, with its major impact yet to be
realized.” Initial applications of the technology
focused on driving high-temperature reactions, such as
transition metal-mediated coupling chemistries that
require temperatures in the range of 120o–200oC and are typically run under pressurized
conditions.
However,
these reactions represent only about 10%–15%
of the chemistries used by medicinal chemists,
according to Collins. Broader market penetration will
depend on greater recognition of the potential for
using microwave energy to improve the speed and
productivity of the bulk of reactions that are now run
at ambient to moderate temperatures. These reactions
would proceed more efficiently at slightly elevated
temperatures, in the range of 50o–60oC,
under reflux conditions using microwave energy.
Microwave
synthesis “is not a passing fad,” says Farah
Mavandandi, marketing product manager at Biotage, but
its obstacles to broader adoption remain. “People
are more aware and accepting of it today, but they
still tend to categorize reactions that will work in a
microwave synthesizer and those that will not.” In a
few cases this distinction is a valid one, but many of
these chemistries are compatible with microwave
synthesis, and, in fact, could run faster and better
at higher temperatures in short periods of time.
Widespread adoption of the technology will simply take
time and education.
Eventually,
in Bradley’s view, with “greater understanding of
the effects of microwave energy on catalysis,”
microwave systems will replace current chemical
synthesis methods that rely on conventional heat
sources.
Evolving
the Technology
Microwave
energy can shorten reaction times 10-fold across a
broad range of chemistries, Collins asserts. Chemical
transformations such as hydrogenation, for example,
which are routinely done at room temperature and may
take 12–24hours
can be completed in five minutes, according to Grace
Vanier, senior scientist in the synthesis group at CEM.
Streamlining the synthesis and optimization of novel
chemical scaffolds and using microwave energy for the
rapid creation of analogue libraries would make it
easier for medicinal chemists to explore new
chemistries, revisit promising synthesis protocols,
and resurrect attractive, yet troublesome lead
compounds that were previously sidelined because they
were too complex, too cumbersome, or too recalcitrant
to optimization efforts.
Since
their introduction into the biopharma market in the
early 2000s, when commercial microwave instruments
were designed to apply focused energy to catalyze
chemical reactions in a sealed reaction tube, the
systems have primarily evolved with a focus on
reducing the cost of the technology, maximizing
control and reproducibility, and making the technology
more accessible at the level of the individual
medicinal chemist.
When
Biotage (then called Personal Chemistry) brought the
first commercial microwave synthesizer to the market,
it was intended for high-throughput chemistry and
included microwave and liquid-handling technology in
one instrument. Current systems are easier to use,
require less training, and allow “chemists to think
like chemists,” says Mavandadi. Chemists only need
to think about their chemistry and select a
temperature and time — based on the rule of thumb
that for every 10-degree increase in reaction
temperature the reaction time is halved.
Next-Generation
Systems
Lower-cost,
moderate-throughput systems are now coming to market
to meet the current emphasis in medicinal chemistry on
synthesizing fewer compounds more rapidly. A typical
medicinal chemist might run only three or four
reactions in a day, one after the other, to experiment
with and optimize various reaction parameters or to
synthesize analogue libraries containing a couple
dozen compounds.
“Microwave
synthesis provides a powerful tool in combination with
flash chromatography setups,” allowing chemists to
evaluate one sample at a time, says Collins. Compared
to larger, automated units, the next-generation,
personal microwave synthesizers that fit in a hood
bring this capability to the individual chemist. CEM
will introduce Discover 1 in the spring, a microwave
synthesizer from the Discover line of modular systems
based on single-mode, Focused technology, designed as
a personal unit for chemistry development and small
library synthesis applications. Discover 1 systems do
not require pressurized vessels, can accommodate
standard laboratory glassware, and can be used like a
high-tech hotplate. The recently introduced Discover
S-Class offers an optional digital camera, allowing
visual monitoring of the reaction as it takes place.
Explorer modules combine with the Discover platform
for automated vessel handling, allowing for unattended
operation of up to 96 reactions.
Future
advances in microwave synthesis technology will
address the issue of scale up, predicts Mavandadi, as
compounds discovered using microwave synthesis in
medicinal chemistry groups are moving into the
process, and scale-up labs and larger quantities are
needed for iterative screening, lead optimization, and
preclinical studies. Currently available microwave
systems can produce up to kilogram quantities of
material. To keep the scale up of microwave synthesis
linear and the chemistry itself unchanged is a
challenging process that requires modifying the
instrument design and transitioning from single-mode
to multi-mode heating.
Also
on the horizon is the realization of ongoing efforts
to combine microwave synthesis technology with the
rapidly advancing field of microfluidics to leverage
the dual advantages of accelerated reaction times with
smaller reaction volumes and faster mixing and sample
preparation.
Copyright
2007, Cambridge Healthtech Institute. All Rights
Reserved.
|
