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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 120^o–200^oC 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 50^o–60^oC, 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.

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