Smarter Synthesis

Green thinking sometimes seems a long way off for those of us in medicinal chemistry, whose primary aim is to find drug candidates by utilizing chemical optimization. It can be hard to gauge an appropriate effort-to-benefit ratio from an environmental point of view. But in fact, there is much that we can do to promote greener working practices in our labs, particularly in terms of waste.

To bring green thinking to our medicinal chemistry labs, in 2014 we carried out an assessment of our activities and held a series of workshops on improving sustainability. Annual in-house data on waste and solvents were collected; for example, from electronic laboratory notebooks. The solvents used were checked against the solvent guide developed by the CHEM21 consortium to assess their environmental impact. Data collected on waste were compared to the number of test compounds synthesized and the scale of repeated batches. We found we were producing roughly 12 kg of waste per gram of test compound, and that 10 percent of that waste contained halogen, which is particularly damaging to the environment.

Having identified where we could do better, several workshops were run for all our personnel. The goal was to stimulate discussion on how much waste we produce and get everyone committed to contributing to increased sustainability. Principles for categorizing solvents, reagents and reaction conditions according to environmental impact were presented in the workshops. Then smaller sub-teams looked at how to apply green thinking in our daily work and a dedicated action group was formed to ensure execution of practicable suggestions and keep us on-track with our long-term sustainability commitment. To widen the impact of the measures, we also shared these with all our contract research organizations (CROs) in regular face-to-face meetings.

In general, many of our efforts targeted the planning phase of the optimization cycle in discovery. Good planning is critical if you want to achieve better compounds and synthesis routes. In the past, a medicinal chemist’s productivity was measured by the number of compounds generated; however, future measures will focus on efficiency in structure design. The focus will be on how many compounds were synthesized before the next level of target profile could be reached (hit, lead, pre-candidate) and how long it took. Quality rather than quantity in structure design reduces waste!

We have also agreed to update our internal process for smooth and efficient initial early scaling up from milligrams to grams or tens of grams based on green thinking. The revised process description will provide guidance for scientists on what is important to consider at each scale, or each repeated batch. Practical suggestions included avoiding unnecessary purifications, higher concentration of the reaction conditions, greener solvents and reagents, bringing back ‘old fashioned’ crystallization in purification, filtering literature searches by greener reagents, and many more.

Many good suggestions from the workshops have been implemented and people across the department have been motivated to bring green thinking into their daily work. It’s not just scientists, either – in fact, technical staff were some of the most interested in green chemistry. CROs were also interested to hear about our efforts, although it remains to be seen how far they will adopt green thinking into their activities and how we can monitor that development. Interaction with our local academic institutions will be important if we are to stay at the forefront of green chemistry. In the meantime, we will continue to measure waste produced and efficiency of structure design on an annual basis, with a view to setting specific targets once we have a clearer understanding of the trends.

Most encouragingly from what we have seen so far, we are confident that green thinking can not only help the environment but also accelerate the discovery process.