Riding the Microwave

Kaboom! explosions are rarely reassuring sounds. It is, however, the loud truth that the development of equipment for microwave-assisted organic synthesis has been propelled by pioneering chemists who have exploded, and occasionally continue to explode, reaction vials or who have blown the doors off the domestic microwave ovens on their benchtops.

For example, in one of the first papers on the subject of microwave synthesis [Tetrahedron Lett., 27, 279 (1986)], chemist Richard Gedye and his colleagues at Laurentian University documented a "violent explosion." Michael J. Collins, chief executive officer of microwave equipment manufacturer CEM Corp., says that in the early days, those mishaps happened in his development labs, too. "That is how you learn," he says. Nicholas Leadbeater, an organic chemist at the University of Connecticut who does much microwave chemistry, makes no secret of such experiences in his lab.

To explore microwave-assisted syntheses in the 1980s and a good part of the '90s, chemists bought their benchtop instrument, the domestic microwave, in their local appliance stores. These devices lacked both precise temperature and pressure control, but they did help scientists advance the proof of principle, which in turn spawned an equipment market served today by four companies: Biotage, CEM, Milestone, and Anton Paar.

Pharmaceutical companies and biotech firms are increasingly taking up this technology and applying it for library synthesis and medicinal chemistry, for lead discovery and optimization, and even for scale-up. As the popularity of microwave-assisted synthesis grows and as the markets develop, instrument makers continue to engineer their equipment to position themselves in the most dynamic market updraft.

Scott E. Wolkenberg, a chemist in the technology-enabled synthesis group at Merck Research Labs, encountered microwave technology in graduate school, but he admits he did not use it much before he started working in industry in 2003. "Now I go there before I go to the hot plate," he says. Jason Tierney, who has been in the high-throughput chemistry division of GlaxoSmithKline (GSK) since 2002, also first tried microwave chemistry in graduate school. His department, he says, was "one of the pioneers in using microwaves," with equipment in place since 2000. He and his colleagues approach microwave chemistry as "a first port of call, because it is easy to perform and one obtains a quick answer."

The need for speed at drug companies is intensified by the sharp drop in new chemical entities filed with the Food & Drug Administration since the mid-1990s. At Bristol-Myers Squibb (BMS), the idea is to see how microwave chemistry can assist drug discovery chemists in pushing back that trend, says John Dodd, the firm's director of chemistry. Accelerating reactions is one attractive facet.

"Microwave chemistry allows you to access reactions that normally would not have not been attempted because of the long reaction times," Dodd says. BMS set up its first microwave equipment in 2001. Within six months, chemists started to demand the instruments, and BMS has bought more of them from both Biotage and CEM. "The chemists are driving this now," he says. "This is not a question of management saying this is a great way for you to be more productive."

Tierney confirms this experience. "We are able to do new chemistries that we haven't thought possible." Microwave chemistry makes heated chemistries--for example, Buchwald-like chemistry--more controllable for syntheses. In some cases of aromatic substitution, a palladium catalyst is not needed at higher temperatures, he says.

William Lennox, who is a chemist at biotech company PTC Therapeutics in South Plainfield, N.J., is currently readying a compound for preclinical trials. With conventional heating, the compound takes anywhere from 20 to 48 hours to make. "It takes 10 minutes in the microwave," Lennox says. C. Oliver Kappe, an organic chemist at Karl-Franzens University of Graz, in Austria, says that hearing chemist Rajender Varma speak in 1998 was his "eye opener" on the subject of microwave chemistry. Kappe began working with Varma, experimenting with reactions in domestic microwave units. After obtaining good, even "spectacular," results, he became a self-proclaimed fan, and his work now focuses on microwave synthesis. He has equipment from all four instrument manufacturers and puts together workshops, such as an American Chemical Society short course, as well as special sessions in companies.

IN SOME life sciences firms, microwave synthesis has caught on in a big way, Kappe observes; in others, it is practiced only by a select few. "Some say [microwave synthesis] is merely shifting the bottleneck," he explains. If more compounds are made, more of them need to be purified and characterized.

However, in recounting the advantages of microwaves, Kappe points out that microwave heating dramatically accelerates reaction times when compared to heating in an oil bath. In addition, side reactions are reduced, yields often increase, and microwaves also help optimize reactions rapidly, permitting efficient synthesis of new chemical entities and probing of new chemical reactivity.

In a review paper just published [Angew. Chem. Int. Ed., 43, 6250 (2004)], Kappe outlines the wide spectrum of microwave-assisted chemistries currently being explored: Suzuki, Heck, and Stille reactions; various types of transition-metal-catalyzed reactions; heterocycle synthesis; various solution-phase organic transformations; and solid-phase organic syntheses. He believes that in time, microwave equipment will push fire, the hotplate, and the oil bath out of the lab to become the "Bunsen burners of the 21st century."

At a Biotage user-group meeting in October in Princeton, N. J., a lunch table of chemists from pharmaceutical and chemical companies exchanged informational tidbits about various microwave instruments. Some were still shopping for an instrument. A chemist at a large drug company mentioned that his bench holds two synthesizers, one from Biotage and the other from CEM. He and his colleagues use both more or less interchangeably, he said.

The chemists plunged into shoptalk about what they see as differences between their instruments, from reaction vessel size and vial options to temperature and reaction monitoring to experiences with technical servicing. Picking a system, it appears, depends as much on lab needs as personal preferences.

Early adopters of microwave technology have been in high-throughput chemistry, says Kelvin Hammond, vice president of business development of the discovery chemistry group at Biotage. Medicinal chemists are taking it on board for difficult reactions, he says, but not as a replacement for conventional heating. A higher percentage of researchers are using microwave technology in high-throughput chemistry than are using it in medicinal chemistry, Hammond says. "Even with all the excitement about microwave technology, it is not being used by more than 10% of medicinal chemists in the U.S.," CEM's Collins adds.

Some of the current market hurdles have a historical underpinning. Chemistry performed in kitchen microwaves produced results that were published in journals, but these syntheses turned out to be difficult to reproduce, Tierney says. Besides the safety issues, hot and cold spot problems were caused by the appliance's variable field strengths. Wolkenberg says that in those days, "it was very easy to be a skeptic" and that there was a "black-box feeling about microwaves."

A number of pharmaceutical company researchers say the skepticism began to abate when professional microwave equipment emerged with consistent geometries that permitted reaction parameters to be controlled and measured more precisely.

As Kappe explains, these changes in equipment design and the greater controllability and reproducibility have helped microwave synthesis gain greater acceptance since the late 1990s. Domestic ovens are so-called multimode instruments, in which the microwaves are reflected by the walls of the cavity. Multimode equipment can irradiate multiple vessels in a cavity, whereas a single-mode design involves irradiating one vessel at a fixed distance from the radiation source. Both Biotage and CEM have chosen the single-mode concept for the reactors in their low-volume synthesis systems. Milestone proceeded with a multimode design.

CONSIDERABLE COMPETITION for market share exists between these companies, as does pressure to lower prices. Collins believes the "critical price point to get onto every chemist's bench is in the $10,000 range." Roy Mirchandani, president of Milestone North America, agrees that the "price points will be driven down" while still allowing for a support structure from the manufacturers. "If we can get it down to the price of a UV or an IR-- the $15,000 range--we are in good shape," he says. "We are not that far from that now."

Collins, who founded CEM in 1978, has long sold microwave equipment for the process and quality-control market for functions like measuring fat and moisture content in foods. Collins holds his company privately in order to be able, he says, to take a longer term view than a public company can. In the past year--CEM's fiscal year ended Sept. 30--he says 80% of his $49 million in revenue was generated in the process and analytical areas, which are "successful but maturing markets." The life sciences segment, which involves equipment for organic synthesis, has grown from nothing three years ago to 15–20% of his revenue. "It is obviously going to be our high-growth area over the next five years," Collins says.

As equipment makers innovate, they realize that they must tune in to their customers' needs. At Milestone's R&D labs in Germany and Switzerland, pharma partnerships lead to information that flows back into the engineering of a product, Mirchandani says.

Farah Mavandadi, a chemist and product manager at Biotage, explains that the firm's field chemists run workshops with users as a way to spread the word about both their instruments and the possibilities of microwave chemistry. The feedback from these collaborations enters the R&D process. One example is power-level settings. "We used to have no settings, initially, and all reactions were heated the same way," she says. The challenge for the reaction is that it can heat too quickly and overshoot a temperature setting, ruining the synthesis of a desired product. Currently, the instrument's software offers three power settings.

Collins says his company is about to release the Investigator, which is a microwave synthesizer with a built-in, specially developed, low-cost Raman spectrometer. Unlike infrared technology, Raman can "see through the reaction vessel and monitor the chemistry," he says. Real-time monitoring of a reaction is "sort of a chemist's dream" and of particular interest in microwave chemistry, in which reactions proceed so quickly.

Another recent CEM development is the addition of cooling technology, with which microwave syntheses are simultaneously cooled with compressed gas. The firm also offers a synthesizer that uses a fluid-cooling medium to lower the vessel temperature down to –50 C. As Collins explains, the first wave of microwave synthesis has involved chemistry at –200 C, which he calls high-temperature chemistry. For medicinal chemists, however, perhaps only a third of the work involves reactions at these temperatures.

"This opens the other 70% of the chemistry," Collins says, listing as application examples stereospecific reactions, asymmetric chemistry, and carbohydrate chemistry. The combination of microwave synthesis and cooling has now yielded a new market: peptide synthesis. "People told me three to four years ago there is no way you can do peptide synthesis with a microwave because it is normally done at room temperature," he says. And yet, "we are now able to make small proteins."

SOME CHEMISTS believe one barrier to widespread adoption of microwave synthesis is a lack of understanding of the nature of dielectric heating with microwaves and how to adapt chemistries. One aspect of microwave-generated heat is dipolar polarization, in which a dipole tries but does not quite succeed in aligning itself with the electric field. Ionic conduction is a second aspect of microwave heating; heat is generated as ions follow the electric field. These heating aspects are crucial when making solvent choices for microwave synthesis, and they can also present new opportunities. What's really interesting, Tierney says, is that "by using microwave chemistry, we are able to look at new properties of solvents."

Researchers are seeking to use ionic liquids to heat nonpolar solvents in microwaves. A slightly underrated solvent is water. "At higher temperatures, water becomes more like an organic solvent in terms of its dielectric properties," says Tierney, who is intrigued by some supercritical water chemistry. A microwave synthesizer by Austrian equipment maker Anton Paar has caught his eye. "They have a system by which they can run near-critical water chemistry at 290 C," he says.

A POTENTIALLY LARGE market for equipment manufacturers is scale-up for process-scale, microwave-assisted syntheses. Biotage and CEM have returned to multimode design for these syntheses, which are performed in batches.

One such scale-up model is the Biotage Advancer, which can handle volumes from 50 to 300 mL. Only a handful of these instruments have been placed in labs. One of them is at Merck Research Labs, where scale-up chemist Joseph M. Pawluczyk and colleagues have put it to work. "The greatest amount we have had so far is 50 g per run, all the way down to 2 g," he says. They have processed a total of 400 g since May.

As microwave chemistry becomes increasingly integrated into chemists' work, Pawluczyk expects more colleagues to come knocking on his door. "The sooner we can give the medicinal chemists their intermediates, the sooner they can get to making new analogs," he says. Usually he follows "the medchem procedure" with few alterations, unless a reagent is too expensive at the larger scale or too dangerous to work with.

"The reason we looked at the Advancer instrument was to give us the capability to scale up a microwave reaction," he says. Some reactions have been done only in a microwave environment, and if that has led to a key intermediate, microwave chemistry will be needed to reproduce the reaction, he says.

Safety considerations are most important when scaling up reactions, Pawluczyk says. "It is a different story if a small 5-mL vial explodes in your reactor than when you have 10 times the quantity." For now, Merck is still testing the instrument, but Pawluczyk likes what he has seen thus far.

Current work at Merck with the Advancer involves a compound called L-870812 that is needed in large quantity. This compound, an inhibitor of an enzyme that helps the HIV virus replicate, has potential for patients who develop resistance to other antiviral drugs. Pawluczyk's supervisor, James P. Guare, has been asked to prepare 700 g to support ongoing studies, and the chemists are exploring using the Advancer, particularly in the context of amide coupling. "It will be a true test of the Advancer," Pawluczyk says.

Tierney, too, has experienced and likes this "direct scalability" for both solution- and solid-phase chemistry. "One can take exactly the same conditions you run in a 20-mL vial; scale it up to 100 mL or beyond with exactly the same concentration of reagents, same temperature, and same time; and obtain exactly the same result as for the 20-mL vial," he says.

Scale-up is an important market for his company, Biotage's Hammond says. At the moment, the ceiling in terms of product output is about 500 g. What will undoubtedly happen, in his view, is that larger outputs in microwave chemistry will be processed in flow-through devices. That could bring a just-in-time manufacturing process to pharma, he says. For example, a manufacturer may need to make three batches of a hay fever medication in expectation of a spring with high pollen counts. If the spring turns out wetter than forecast, the manufacturer is stuck with too much product. Instead, Hammond says, the product could be made as needed.

CEM is just as interested in scale-up for clinical trials and also sees the future in continuous-flow systems. Collins says his company has added a flow-through capability to its basic reactor and reports that a customer has made 1 kg of product. The next step, he says, will be pilot-scale systems handling 10 to 100 kg. Collins predicts that such reactors are the "next logical step" and will become available in the next year or two. "There is no reason why microwave technology cannot make production-scale product," he says.

SCALE-UP IS "the substantial future for us and for the technology," Mirchandani says. Milestone just unveiled its latest synthesizer, a continuous-flow reactor in which reagents enter the reactor from the bottom and flow out the top through a heat exchanger.

This first instrument for kilogram-scale microwave-assisted synthesis has been an "enormous challenge," Mirchandani says, because it involves dealing with a gradient that must be kept homogenous, along with all the other parameters, such as temperature, pressure, and safety. He sees a pent-up demand for such flow-through systems. "If it rolls out well, it will make a substantial impact on our company's revenue," he says. "We hope to have ownership of that market for some time."

BMS's Dodd is not convinced that microwave technology is a must at the large scale. "At that level, a two-day reaction is not that big a deal--unlike the situation in research, when you need feedback loops with biology constantly," he says. Dodd also asks if providing the safety for possible exothermic releases of pressure may be too costly a proposition for large-scale microwave chemistry reactors.

Pawluczyk wonders if, down the road, process chemists will consider using microwave chemistry, or if they will always need to re-design the synthesis. "We haven't crossed that bridge yet," he says.

Lennox, on the other hand, is ready to cross it. The challenge is that there is not much of a bridge yet. Lennox used to work at Wyeth, where he had a Personal Chemistry/Biotage system. Now, CEM instruments inhabit his lab at PTC. As a medicinal chemist at a large pharmaceutical company, "you really just think about making your compound," he says. Once the compound becomes a candidate, "you hand it off," and someone else takes care of large-scale synthesis.

"At a smaller company," Lennox says. "you do medicinal chemistry, and you do scale-up chemistry and process development work--there is nobody to hand it to." As he thinks about the broad tasks he wants to take on, he scours the marketplace for equipment that will help make the 20 kg of product he needs for preclinical work. Lennox believes such scale-up work is a large potential market for microwave synthesis. He has yet to find the right equipment, but no doubt it is coming.