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Manufacture Small Molecules

Battery Powered Inspiration

Electric cars are feats of engineering and technology that ultimately provide cheaper and cleaner transport options. And their batteries have recently become a source of inspiration for scientists at Scripp Research, who have developed a system to help with small molecule drug manufacturing (1).  

The team, led by Phil Baran, a professor at Scripps Research and a member of The Medicine Maker 2019 Power List, developed the system in response to a challenge set by Pfizer to synthesize a compound at the commercial scale using a Birch reduction. The reaction has been a staple for organic chemists since the 1940s; reactive metals, like lithium, are dissolved in liquid ammonia to manipulate molecules with ring-shaped structures. “Although the Birch reaction is commonly used, the use of lithium and ammonia make it highly unsafe and malodorous,” explains Phil Baran, Professor at Scripps Research. Birch reactions on the kilogram-scale are often avoided by chemists due to the risks that they present. Ammonia, is known to be highly corrosive and irritating to the eyes and the skin, while lithium is highly flammable and even explosive when exposed to air or water.

While large scale Birch reactions are few and far between, the Scripps team were spurred on by a story of a successful attempt. “Our motivation to accomplish our goal peaked when we discovered Pfizer’s kilogram-scale synthesis of the anti-Parkinson’s F1 drug candidate sumanirole, which employed a Birch reduction. What they had achieved was a rare and remarkable achievement in chemical manufacturing! Despite the risks, we weren’t prepared to shy away from the challenge,” adds Byron Peters, postdoctoral associate in the Baran Lab at Scripps Research. Pfizer used customized equipment to administer lithium metal and enough ammonia to fill three Boeing 747 airliners in the gas phase. 2300 liters of flammable hydrogen gas was liberated on quenching the reaction.

The Scripps scientists celebrating the publication of their research. Left to right, Kevin R, Yu K, Byron P, and Solomon R.

Baran’s team, however, have developed a method that avoids the dangers commonly associated with the process. During their early experimentation, they noticed the build up of solids on the electrodes used in their reactions. When they consulted their collaborators, Shelley Minteer, a professor at the University of Utah, and Matt Neurock, Shell Professor of Chemical Engineering and Materials Science at the University of Minnesota, they realized that they were observing the formation of solid electrolyte interfaces (SEIs). SEIs protect the lithium within electrodes from overcharging or being consumed by surrounding media and are used in batteries, including those used for electric cars, smartphones and laptops.

Using their newfound understanding of SEIs to their advantage, the team began to investigate a range of additives designed to manipulate the SEI layer’s thickness and protect the integrity of the electrochemical cell. “With a more intuitive sense of how to improve the reaction, we identified two cheap non-toxic reagents which enabled us to carry out the Birch reaction at room temperature,” explains Solomon Reisberg, Graduate Research Fellow and co-author of the paper detailing the group’s research. Most excitingly for the team was the fact that they were able to scale-up the reaction to a 100-gram scale for less than $250 with the help of Asymchem, a CDMO based in China.

The team is looking forward to using their electrochemical discovery in other avenues of synthesis and as a draw to entice more chemists to use electrochemistry as a synthetic tool. However, they are still firmly focused on developing scalable methodologies.

“Reaction scalability was our goal from the outset. We’re glad that we were able to achieve it in a safe, cost-efficient way,” Kevin Rodriguez, NIH Diversity Research Fellow at the Baran Lab says. “This adventure really shows off the power of collaboration between industry and academia, especially in identifying and solving real problems that require a realm of interdisciplinary knowledge that spans beyond one’s own field.”

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  1. P Baran, “Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry”, Science, 838-845. (2019) PMID: 30792297

About the Author

Maryam Mahdi

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After finishing my degree, I envisioned a career in science communications. However, life took an unexpected turn and I ended up teaching abroad. Though the experience was amazing and I learned a great deal from it, I jumped at the opportunity to work for Texere. I'm excited to see where this new journey takes me!

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