Pharmaceutical Technology, Pharmaceutical Technology, October 2022, Volume 46, Issue 10
Pages: 24–28
Numerous benefits will eventually lead to large-scale applications in pharmaceutical manufacturing.
Electrochemistry offers many strategic advantages for increasing the sustainability and efficiency of small-molecule synthesis. It also has the potential to enable the creation of molecules not accessible using more traditional chemistry. As a consequence, interest in this technology is increasing in both academia and industry. Three researchers having a strong impact in this area through their independent work and collaborations with industry include Phil Baran of The Scripps Research Institute (1), Siegfried Waldvogel of Johannes Gutenberg University in Mainz, Germany (2), and Song Lin at Cornell University (vide infra).While its use in medicinal chemistry and drug discovery has been increasing, implementing these reactions at large scale under good manufacturing practice (GMP) conditions has been challenging.
The potential benefits are driving companies to develop chemical and engineering solutions that allow the use of electroorganic chemistry for the production of complex pharmaceutical intermediates at the kilogram scale (3).
Electrochemistry research in the Lin Laboratory
Song Lin, associate professor in the Department of Chemistry and Chemical Biology at Cornell University, has been focused for several years on developing new electrochemical processes that address important needs in organic synthesis. “Harnessing electrochemistry to solve the challenging transformations in organic synthesis is one of the most important research interests in our group,” he observes.
One of those areas relates to cross-electrophile coupling (XEC) of organic halides for C–C bond formation. Despite great advances in this area, Lin notes that the selective XEC of two alkyl halides for C(sp3)–C(sp3) bond formation remains elusive using traditional chemical approaches.
Inspired by the generation of C(sp3)–C(sp3) bonds via SN2 displacement, his research group, in collaboration with scientists at Caltech and Merck, envisioned a new approach to cross-coupling of two (one tertiary and one primary) alkyl halides by exploiting the disparate electronic and steric properties (1).
“This electrochemical approach enables XEC of a diverse range of unactivated and functionalized alkyl halides, including α-haloboronic esters, α-halosilanes, benzylic chlorides, and allylic/propargylic halides, under transition-metal-free conditions with excellent selectivity,” Lin states. It also operates by a mechanism different from that previously reported for cross-coupling reactions catalyzed by nickel complexes. “This new strategy circumvents the generation of Ni-alkyl intermediates that could often lead to unselective electrophile activation and various side reactions,” he explains.
As a result, the e-XEC reaction shows improved selectivity compared to known methods for C(sp3)–C(sp3) XEC. “This new reaction provides a robust and selective method for constructing C(sp3)-C(sp3) bonds, which remains a critical problem in modern organic chemistry. It will be particularly beneficial for drug discovery given that recent research in medicinal chemistry has demonstrated a correlation between higher fractions of sp3 carbons in drug candidates with improved success rates in clinical trials,” Lin says.
To date, the reaction has been scaled up to 20 mmol, providing multigram quantities of desired products in excellent yield. Lin hopes to further scale up the method to create a wide range of molecules for drug discovery. He does caution, however, that a wide gap remains between the current optimal laboratory conditions and GMP requirements for commercial pharmaceutical manufacturing. “We need to overcome several issues before further scale up the reaction, including using less of a safer electrolyte than the currently used tetrabutylammonium perchlorate and avoiding the use of a sacrificial magnesium anode.”
In addition to the e-XEC reaction, the Lin group has used an electrocatalysis strategy for the oxidative difunctionalization of alkenes (2). He and his colleagues are also working to further scale up the electrochemical diazidation of alkenes, another transformation developed by his group (3). This reaction provides an efficient and robust approach to the synthesis of precursors of vicinal diamines, a functional moiety that is widely prevalent in many natural products and a large number of bioactive compounds.
References
S. Lin et al., “Electrochemically Driven Cross-Electrophile Coupling of Alkyl Halides,” ChenRxiv, Dec. 13, 2021. DOI: 10.26434/chemrxiv-2021-c2hd6-v2.
Juno C. Siu, Niankai Fu, and Song Lin, Acc. Chem. Res., 53, 547-560 (2020). DOI: 10.1021/acs.accounts.9b00529 .
N. Fu, et al., Science, 357, 575-579 (2017). DOI: 10.1126/science.aan6206.
A more sustainable, safer, and less expensive alternative
“Electrons,” says Markus Furegati, a senior principal scientist at Novartis, “are ‘reagents’ that can be regarded as green, safe, and cheap. One mole of electrons costs less than one US dollar, and there is significantly less waste generated during manufacturing.” In some cases, he adds, an electrochemical approach offers better selectivity compared to classical procedures.
Electrochemistry offers a mild and efficient alternative to conventional chemical approaches specifically for redox transformations, according to Song Lin, associate professor in the Department of Chemistry and Chemical Biology at Cornell University. “Upon the application of an appropriate potential, organic molecules can lose or gain an electron at the electrode surface and generate highly reactive intermediates, such as radicals, carbocations, and carbanions. In the process, the potentially expensive, hazardous, and toxic oxidizing and reducing reagents employed in canonical redox reactions may be replaced by greener, less toxic, and milder electron donors and acceptors,” he explains. Lin also observes that many studies have demonstrated the potential of electrochemistry to achieve transformations that are challenging to realize using chemical redox reagents.
One of the keys to success for electrochemical reactions is for the functional group of interest to have an appropriate redox potential compared to the rest of the molecule, according to Claudio Bomio, principal scientists II with Novartis. Precise control of the applied potential can, Lin notes, provide the ability to selectively activate complex molecules and generate highly reactive intermediates in a controlled fashion. “The selectivity of electro-oxidations can be tuned using a set of parameters not usually used in organic chemistry, such as choice of voltage, electrode material, the use of redox mediators, etc., which expands the scope and utility of electrochemistry for organic synthesis,” adds Bomio.
In addition to the low cost due to the waste-free and sustainable nature of electrons, Frederic Buono, senior associate director of chemical development in the United States at Boehringer Ingelheim, points out that electrochemistry technology is also easy to manipulate and fast to assess. “Using process analytical technologies, it is possible to monitor the generation of specific impurities and the overall reaction conversion and selectivity in real time and adjust the power and/or voltage units as needed,” he explains.
With respect to chemical reactivity, Buono also comments that electrochemical methods often exhibit a high functional group tolerance as well as higher reactivity. The latter allows reduction of the quantities of some reagents needed and thus the production of less waste and toxic by-products. Electrochemical reactions are also typically performed under milder conditions (temperature and pressure) than those necessary with traditional approaches, according to Buono. Furthermore, to halt electrochemical reactions simply requires switching off the power, whereas with traditional organic chemistry an extra reagent must often be added.
Growing synthetic applications
Because of the many benefits that electrochemistry possesses over traditional approaches in organic synthesis, it could play a major role in chemical/intermediate production, Buono contends. Bomio agrees: “Electrochemistry is an area of tremendous growth in academic research, with new methods and reactions emerging every day.”
Based on published literature, Jeff Song in Boehringer Ingelheim’s chemical development group in the US notes that there is a large variety of transformations for which electrochemistry is an attractive synthetic method, such as oxidations (e.g., oxidative intermolecular/intramolecular coupling, Pinnick/Anelli oxidation, Shono oxidation, etc.), reductions (e.g., Birch reduction, reductive cross-electrophile coupling), C=N formation (azines and oximes), methoxylation, and amination. “The benefits of electrochemistry for these transformations are relative to the functional tolerance of the complex molecular structures,” he adds.
The rising interest is driven in part by the fact that oxidation and reduction reactions are among the most important and frequently executed processes in organic synthesis, according to Lin. “In the pharmaceutical industry, the ability to replace oxidation and reduction reactions that involve hazardous or waste-generating reagents used for the synthesis of APIs or their intermediates with electrochemical processes is very attractive. Synthetic electrochemistry can realize similar transformations through electron transfer between organic molecules and electrodes, avoiding the use of hazardous or toxic stoichiometric redox reagents. Moreover, the controllable applied potential results in the potential ability of electrochemistry towards selective functionalization of complex molecules,” he says.
From small to large scale
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Electrochemistry is definitely not limited to small scale, and there are, according to Laurin Wimmer, senior expert, science and technology with Novartis, quite a few established processes in industry. He points to production of the fragrance compound lysmeral by BASF at more than 10 kilotonnes per year as one of the largest and most well-known industrial electro-organic processes. Lin adds that there are also many other chemicals, such as adiponitrile (a key intermediate in the manufacture of Nylon 6, 6 polymers) (4) and azobenzene (5), produced at industrial scale using electrochemical processes.
In the pharmaceutical industry, electrochemistry is widely used in medicinal chemistry labs and also in early development for the synthesis of intermediates on a gram scale, says Song. At Boehringer, electrochemistry is also applied for the synthesis of impurities.
Electrochemistry at large scale: continuous development
Inspiration from academic leaders in the field of electrochemistry and their achievements in organic synthesis is leading to the exploration of electro-organic technologies for process development and commercial manufacturing, Wimmer contends. While for small-scale laboratory applications stirred electrochemical cells are most common, industrial processes typically rely on a flow-chemistry approach (6).
In recent years, Jeff Song remarks that it has become more common to use electrochemistry in day-to-day operations as commercial laboratory reactors became more available in batch and flow mode. The throughput of these reactors is still very limited, however.
Indeed, Buono emphasizes that a key limitation to further scale-up and commercial manufacturing is the lack of both standard manufacturing equipment and the technical knowledge for scale-up, including understanding of the impact of electrode materials on reaction output, reaction parameters, and other aspects that can change with scale. In most cases, he notes that companies have been using in-house-built reactors to perform electrochemistry at the kilogram scale.
There are other challenges to implementing electrochemical processes for organic synthesis at large scale beyond the lack of knowledge and experience in scaling up electrochemical processes and the need for suitable equipment. Buono highlights the lack of specific regulations regarding the use of electrochemical technology in pharmaceutical manufacturing.
Lin, meanwhile, points to safety concerns related to the application of a high current in the presence of flammable organic solvents; the price, concentration, and safety of the electrolyte; the price, availability, and potential passivation of electrode; the generation of hazardous gases such as H2 or O2; and the current density and ratio between the electrode surface area and reactor volume.
Despite these issues, based on the evidence accorded by the numerous papers generated by academic/pharmaceutical collaborations, most major pharmaceutical companies are actively exploring potential applications of electrochemistry, according to Wimmer. For instance, Lin notes that companies including Merck, Bristol-Myers Squibb, and Genentech are interested in the development of electrochemical methods to synthesize APIs. Researchers at Merck, in fact, published an article describing the successful scale-up of an organic electrosynthetic method from milligram to kilogram scale (7).
“In general,” Lin states, “the widely accepted means to industrialize an electrochemical process is the combination of continuous flow technique with electrochemistry. The short distance between two electrodes results in a significant decrease in the ohmic drop of the system, enabling electrolysis with very low concentration of electrolyte. Moreover, the large ratio between electrode area and reaction volume compared to batch cells is beneficial for the electrolysis efficiency,” he explains.
There are efforts underway to establish the needed large-scale equipment that will enable commercial electrochemical processes. One example of note, according to Buono, is the Enabling Technology Consortium, which is working to design and build both laboratory- and manufacturing-scale electrochemical reactors that meet the safety, robustness, and productivity requirements for each scale.
Witnessing the renaissance of synthetic organic electrochemistry
The trajectory for electrochemistry in the pharmaceutical industry appears to be an exciting one. Furegati anticipates progress to occur along a pathway similar to that observed for modern photochemistry. “The availability of easy-to-use equipment and broader literature coverage will facilitate the use of electrochemistry for niche applications. Success in these areas will then stimulate the development of commercial solutions,” He adds that if contract research and contract manufacturing organizations actively pursed and implemented electrochemical processes, the barrier to adoption could be potentially lowered.
There is already, says Lin, a renaissance in synthetic organic electrochemistry underway. “Breakthroughs and advances in this area have led synthetic organic chemists to gradually realize the powerful potential of electrochemistry as a robust technique in organic synthesis, stimulating a tremendous surge of research interest in this field amongst the organic chemistry community. In this context, we believe more practical and efficient electrochemical reactions will be reported in the future,” he explains.
If certain steps are taken, the influence of electrochemistry in organic synthesis can be further strengthened, according to Lin. One would be the development of electrochemical methods for late-stage functionalization of complex bioactive molecules and biomacromolecules such as peptides, nucleotides, and sugars. Another would be the fabrication of novel electrodes to explore new reactivities and tune the selectivity of electrochemical methods. A more long-term goal would be the development of enantioselective electrochemical transformations.
A further area of interest for both Lin and Buono is the extension of electrochemical applications through the combination of electrochemistry with other promising synthetic techniques. Electrophotocatalysis (8) and bioelectrocatalysis (9), for instance, may provide avenues for the discovery of new reactivities and enable wider use of electrochemical solutions by process chemists. Buono also envisions the combination of artificial intelligence, automation, and electrochemistry enabling the rapid optimization of electrochemical reactions (10).
Lin firmly believes that all of these developments and the adoption of electrochemical processes in general by the pharmaceutical industry will be expedited through the establishment of intimate collaborations between academia and industry. “In academia, we are more interested in the discovery of new reactivities and typically overlook the cost and safety issues related to reagents. We also in general lack the experience needed to efficiently scale up electrochemical reactions. By collaborating with industry partners, we gain greater knowledge of practical requirements for synthetic methods used in both drug discovery and commercial manufacturing.”
The end result, Lin concludes, will be industrializable electrochemical processes that are more sustainable and scalable. Fortunately, many such collaborations are already in place and actively engaged in exploring electrochemical processes.
References
M. Yan, Y. Jawamata, and P. S. Baran, Chem. Rev., 117, 21, 13230–13319 (2017).
S. R. Waldvogel et al., Angewandte Chemie Int. Ed. 57(20), 5594-5619 (May 14, 2018).
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