Enhancing the reproducibility of synthetic chemistry reactions

The Respiratory Synthetic Chemistry Team, part of the Drug Discovery Organisation at GlaxoSmithKline (Stevenage, UK) has, using a Radleys Lara™ Controlled Laboratory Reactor (CLR), been able to achieve improved control of a Grignard Alkylation such that the reaction can now be repeated with a higher degree of reproducibility.

The preparation & and scale-up of intermediates and target compounds using a wide range of synthetic chemistry methodologies and techniques is an integral part of the Drug Discovery process. With long standing experience in the use of controlled laboratory reactors the Synthetic Chemistry Group selected the Lara CLR as an 'off-the-shelf' system with flexibility and potential for improved control and reproducibility of reactions up to the 5 litres scale.

Traditionally the control of Grignard alkylation reactions in the laboratory is managed by manual control of stirring, reaction temperatures and reagent addition. However this methodology did not always give reliable reaction control nor generate a reproducible procedure. Using their new Lara CLR a new methodology was developed where the reactor and contents were pre-cooled and the Grignard reagent added using automated pump control with a maximum set temperature at which point the pump would stop. With a combination of system cooling and pump control, the reagent addition proceeded very smoothly with excellent temperature control. Feedback of a rise in reactor temperature, results automatically in cooling the jacket and limiting the addition rate so that near isothermal reaction conditions are maintained. The Lara CLR system has enabled the Stevenage team to repeat the Grignard Alkylation reaction with a high degree of reproducibility.

The Radleys Lara CLR was selected by the team at GSK as it delivered a compact integrated solution with the ease-of-use, enhanced reaction reproducibility and time savings (through automation and data collection) sought by the Synthetic Chemistry Group.

Looking to the future, the Stevenage team is now investigating how the Lara CLR can be used to fully automate additions to reactions through provision of simultaneous control of system cooling, addition pump and a weighing balance.