Glaxosmithkline

Jason Tierney and colleagues in the synthesis, automation, and chemical technologies department at GlaxoSmithKline's (GSK) Harlow, England, R&D facility are part of the firm's lead generation effort. Syntheses are approached in arrays. The chemists do not just make large numbers of compounds; they do chemistry around a family of targets to generate novel compounds. The family concept is intended to maximize opportunities of finding hits.

The scientists look at microwave chemistry to "scale up the synthesis of novel templates for array synthesis," Tierney says. And they are utilizing chemistries that are often difficult to perform under conventional conditions.

Microwave chemistry, Tierney says, must be integrated into the drug discovery process without creating new bottlenecks but rather with consideration for other processes in the workflow. The possible bottlenecks with microwave chemistry include reagent management, crimping the vials, and problems in postreaction workup steps.

The GSK lab has a Personal Chemistry/Biotage synthesizer that can do 120 reactions in one run followed by an automated workup. Quality control results from, for example, mass and NMR spectrometry, are generated in batches as work progresses, so "this is a good workflow for the processing of larger arrays," Tierney says.

As his group looked around for optimized ways of getting reagents in and contents out of vials in the context of microwave chemistry, they chose a Genesis robot from equipment maker Tecan to add chemical building blocks or reagents to vials. In collaboration with an in-house automation group, the scientists developed racks--leaning to minimize reagent wastage--that allow them to add up to 96 reagents from 4- or 20-mL vials to the microwave vials.

"You can tell the robot quite easily which microwave vials to add the solutions to," Tierney says. There's no need to decap the vials, because the Tecan needles perforate the septum of the vial and remove the reagent contents via aspiration. The needles then dispense the contents, and the vials are returned to the racks.

Within the past year, Tierney's group has also been working to integrate microwave chemistry into the automated postreaction workup for solid-phase extraction. The researchers developed microwave vial racks for the Zinsser Redi robot to enable the addition of solid supported polymer reagents or silica reagents directly to microwave vials.

Another aspect in the integration of microwave chemistry is the degree of method development it necessitates. Tierney says the Biotage scale-up synthesizer, the Advancer, offers an attractive degree of "direct scalability" for both solution- and solid-phase chemistry.