01: Introduction
02: Solvents
03: Carbon
04: Catalysis
05: Waste
06: Progress
01: Introduction
02: Solvents
03: Carbon
04: Catalysis
05: Waste
06: Progress
Greening Global Health
Catalysis
Palladium-catalyzed cross couplings are among the most widely used catalytic reactions in the pharmaceutical industry, but how can chemists reconcile these reactions’ powerful bond-forming abilities with their sustainability drawbacks?
05: Waste
Go to next section
05: Waste
Go to next section
As one of the 12 pillars of green chemistry, catalysis is touted as a strategy that provides shorter synthetic routes, improves the efficiency of chemical processes, and reduces chemical waste. In the pharmaceutical industry, there’s a “huge pressure” to deliver materials in short time frames and at low cost, says Yongda Zhang, Distinguished Research Fellow at Boehringer Ingelheim. The sustainability benefits of catalysis, therefore, often align directly with the pharmaceutical industry’s financial and time priorities, such as when a catalyst system enables a shorter overall route to a desired active pharmaceutical ingredient (API) or gives higher selectivity for a desired product.
But for all the benefits catalysts can offer, they also have limitations. Authors of a 2018 review on transition metal catalysis in the pharmaceutical industry note that “it would be a fallacy to think all catalysis is green.”
For example, precious metal catalysts, such as platinum, rhodium, iridium, and palladium, have come under fire in recent years. Their high, volatile costs, low abundance, and associated greenhouse gas emissions are held in tension with the sustainable promises of catalysis.
For the pharmaceutical industry, that tension is exemplified most acutely in its reliance on palladium-catalyzed cross-coupling reactions. An analysis of Organic Process Research & Development papers published between 2017 and 2021 found that among those describing the synthesis of APIs, 43% involved reactions using transition metal catalysts. Of these, over 80% used a palladium catalyst, and most of the palladium-catalyzed reactions were cross-coupling reactions.
As the pharmaceutical industry pushes toward increasingly ambitious sustainability targets, its reliance on palladium-catalyzed cross couplings underscores a tension between sustainability and the indispensable chemistry that enables modern drug synthesis.
Palladium catalysts reliably enable essential bond-forming steps yet also introduce concerning environmental and resource costs. More earth-abundant transition metals such as nickel, cobalt, copper, or iron, can also catalyze cross-coupling reactions and could offer a more sustainable alternative to palladium. While these systems have been used in API syntheses, examples are limited. Improving the sustainability of the pharmaceutical industry’s most widely used catalytic reactions depends on making informed trade-offs and advancing continuous improvements through process optimization and deeper mechanistic understanding.
Cross-coupling reactions use palladium to join an electrophilic and a nucleophilic partner to forge new carbon-carbon or carbon-heteroatom bonds. Named cross-coupling reactions are defined by the identities of the coupling partners and, in some cases, by the specific catalyst. For example, a Suzuki reaction forms a carbon-carbon bond by coupling an organic halide with an organoboron species. A Buchwald-Hartwig reaction forms a carbon-nitrogen bond by coupling an organic halide with an amine.
Since the first reported palladium-catalyzed cross-coupling reactions in the 1970s, these reactions have proven to tolerate a range of functional groups, follow well-defined mechanisms, and provide many options for customizing performance (for example, the identity of coupling partners, bases, ligands, or solvents). Their reliability and tunability make them ideal for the pharmaceutical industry, where synthetic efficiency and short timelines are top priorities.
The Power of Palladium
For all the potential efficiencies palladium-catalyzed cross-couplings offer, these reactions do carry sustainability drawbacks.
The Problem of Palladium
03: Carbon
Go to previous section
03: Carbon
Go to previous section
If you just look at the Suzuki reaction... a whole chemical infrastructure is built for that reaction in a way. It’s such a convenient, easy tool. It’s always going to work.
David Leahy,
Vice President of Drug Substance Development at Biohaven
“
When Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki received the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed cross-coupling reactions, the Nobel Committee specifically praised these reactions’ sophistication and ability to enable more-efficient drug syntheses. “This is how med chemists are putting molecules together,” says Leahy. And for process chemists, palladium catalysis offers reliability: “We understand it.”
An early example of the power of palladium-catalyzed cross-coupling reactions is the synthesis of losartan. Losartan is a drug used to treat high blood pressure and is one of the most prescribed medications in the US. In 1994, researchers at Merck & Co. and DuPont Merck Pharmaceutical reported a convergent synthesis of losartan that required three linear steps and was enabled by a Suzuki coupling. The previously published route required five steps and used an organotin reagent, a free radical bromination step, and a Grignard reaction. By using a palladium-catalyzed cross-coupling reaction, the researchers accessed losartan in fewer steps with fewer harmful stoichiometric reagents.
“A catalytic reaction in isolation may not look like the most sustainable reaction of all time. But if it’s cutting out three or four different steps from the synthesis, now that may be a more sustainable approach,” says Leahy.
First, there’s the problem of palladium itself. Its abundance in the Earth’s crust is estimated to be roughly 1/100th of nickel’s and 1/100,000th of iron’s. Because palladium typically occurs only in small amounts within much larger ore deposits, extracting it requires energy- and resource-intensive processes. Producing 1 kg of palladium has an estimated global warming potential (GWP) of 3,800 kg of carbon dioxide equivalent. In contrast, nickel has an estimated GWP of 6.5 kg of CO2 equivalent, and iron has an estimated GWP of only 1.5 kg of CO2 equivalent.
These metrics have a real impact on the GWP of a palladium-catalyzed cross-coupling reaction. For example, during a life cycle assessment of Buchwald-Hartwig aminations to form a pharmaceutically relevant substrate, AstraZeneca scientists found that palladium catalysts accounted for approximately 30% of the overall process’s GWP.
Environmental Footprint of Palladium
Cross-coupling reactions also typically require bond activation, hence the use of organohalide and organoboron species in the Suzuki reaction. Forming these species adds synthetic steps and introduces a source of stoichiometric waste.
For the improved synthesis of losartan, for example, one of the three overall steps is the formation of an arylboronic acid. Halide salt and boric acid are stoichiometric by-products of the coupling reaction. The need to preactivate the carbon centers for coupling reactions diminishes these reactions’ atom economy. This trade-off is inherent to most cross-coupling reactions.
Stoichiometric Waste from Coupling Partners
Palladium removal is a unique challenge for the pharmaceutical industry and is another factor that can negatively impact the sustainability of palladium-catalyzed reactions. The amount of palladium residue that can be present in a final drug product is tightly regulated. Process chemists in the pharmaceutical industry, therefore, try to avoid including palladium in the late steps of an API synthesis, since doing so avoids more stringent removal processes. But the alternative—placing palladium-catalyzed reactions at the beginning of a synthetic route—often means that more palladium is required because of the larger scale of those reactions.
Scavengers that preferentially bind palladium are often used to sequester palladium during API syntheses. For example, Zhang and his coworkers at Boehringer Ingelheim developed a palladium-catalyzed allylic alkylation reaction that uses a cysteine-based scavenger system to remove residual palladium. This reaction is the first step of an overall chemical process that was awarded the 2024 Peter J. Dunn Award by the American Society Green Chemistry Institute Pharmaceutical Roundtable.
However, using scavengers generates waste, which must be considered when evaluating a process’s cost and sustainability. Some scavengers, like activated charcoal, can also capture a fraction of the API, reducing the efficiency of an overall synthetic route.
Removing palladium from these reactions creates an opportunity to recover the metal. But with homogenous catalyst systems, the ligands used to stabilize the palladium during the cross-coupling reaction are not recovered. The whole catalyst system, therefore, is not reused, which is at odds with one of the reasons catalysts are considered “green.”
Removing Palladium from APIs
If it’s possible... we will try to avoid palladium catalysts.
Yongda Zhang,
Distinguished Research Fellow at Boehringer Ingelheim
“
The efficiency and reliability of palladium-catalyzed cross-coupling reactions make them a mainstay of the pharmaceutical industry, despite their flaws. Chemists in the pharmaceutical industry are actively looking for ways to improve the sustainability of these reactions, and, by the same measure, reduce costs.
Reducing the amount of palladium required for a given reaction is a top priority for process chemists. Palladium often accounts for a significant portion of a process’s cost and carbon footprint, so reducing the amount of catalyst provides a clear way to lower expenses while improving sustainability.
“We’re actually very fortunate that sustainability and cost typically go hand in hand,” says Leahy. Other strategies reported in the literature from chemists working in the pharmaceutical industry include using more-accessible ligands, greener solvents, and heterogenous palladium catalysts.
In a recent example, researchers at Amgen reported an improved commercial synthesis of sotorasib, a drug used to treat non-small-cell lung and colorectal cancers. One of the improvements included optimizing a Suzuki coupling by lowering the palladium catalyst’s loading from a molar percentage of 2.5% to 0.6%, swapping dioxane for a more sustainable solvent, and using a less corrosive arylboroxine coupling partner. The overall yield was increased from 38% to 65% and more than 20-unit operations were removed. The improved process was recognized with a 2022 US Environmental Protection Agency Green Chemistry Challenge Award.
Improving the sustainability of cross-coupling reactions by swapping palladium for more-Earth-abundant alternatives is a significant challenge. Though some of the first reported cross-coupling reactions used nickel or copper catalysts instead of palladium ones, for several reasons palladium became (and remains) the catalyst system of choice.
Whereas palladium catalysts are typically restricted to well-understood mechanisms that cycle between Pd0 and PdII oxidation states, first-row transition metals can access a wider range of oxidation states. As a result, they undergo complex one- and two-electron mechanisms that are not as well understood as those of palladium, introducing extra variables that make scaling reactions using these catalysts risky. Palladium catalysts also typically tolerate a wider range of functional groups in the coupling partners. The predictability of palladium catalysis plays into the pharmaceutical industry’s aversion to risk, especially when scaling chemistry to batch scales, and supports the industry’s cost, efficiency, and time priorities.
But there is growing interest within the pharmaceutical industry in exploring alternatives to palladium, particularly nickel. “You’re probably going to look at both palladium and nickel,” says Michael Haibach, a Principal Research Scientist at AbbVie. “There may be cases where the palladium and nickel catalysts with relatively inexpensive ligands end up at similar catalyst loading, then nickel will have a significant advantage in terms of the cost and resource flexibility.”
Catalyzing Change
Companies are actively collaborating with researchers at academic laboratories to improve these systems—and build the chemical research infrastructure necessary—through mechanism studies, catalyst precursor development, substrate scope, ligand design, and method optimization. (Multiple recent examples of cross-coupling reactions can be found in American Chemical Society journals.)
In 2013, Genentech reported a nickel-catalyzed Suzuki reaction for the synthesis of pictilisib with a catalyst-loading molar percentage of only 0.03%. The nickel system provided higher yields than a corresponding palladium catalyst system, used readily available ligands, and allowed the removal of the metal catalyst with a simple aqueous wash and crystallization.
For now, it’s clear that palladium catalysis for cross-coupling reactions will remain one of the pharmaceutical industry’s go-to reactions for building new drugs. In isolation, these catalytic systems may not appear to be sustainable. But, when considering the entire process of preparing an API, no better alternative may be available.
Sustainability must be considered within a wider context—and in the pharmaceutical industry, that context is that chemists are synthesizing medicines that benefit patients’ lives. “We have to make a drug,” Leahy says. “What matters is this: Is the approach I have to making my drug better than the last approach?”
The Next Cycle
01: Introduction
01: Introduction
02: Solvents
02: Solvents
03: Carbon
03: Carbon
04: Catalysis
04: Catalysis
05: Waste
05: Waste
06: Progress
06: Progress
measures the mass of raw materials, reactants, and solvents used in a synthetic process—essentially the total mass of the chemical system. Higher PMI means more materials are used per unit of final product.
Process mass intensity (PMI)
Since the first reported palladium-catalyzed cross-coupling reactions in the 1970s, these reactions have proven to tolerate a range of functional groups, follow well-defined mechanisms, and provide many options for customizing performance (for example, the identity of coupling partners, bases, ligands, or solvents). Their reliability and tunability make them ideal for the pharmaceutical industry, where synthetic efficiency and short timelines are top priorities.
When Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki received the 2010 Nobel Prize in Chemistry
The Power and the
Problem of Palladium
The elements of a green catalyst (C&EN, 2024)
Read More
Read More
Diversification of Pharmaceutical Manufacturing Processes: Taking the Plunge into the Non-PGM Catalyst Pool (ACS Catalysis, 2024)
Read More
Read More
Palladium Extraction Following Metal-Catalyzed Reactions: Recent Advances and Applications in the Pharmaceutical Industry (OPR&D, 2023)
Read More
Read More
Learn more
The levels of palladium permitted in drug products is lower than nickel, copper, and iron. Removing Pd from APIs often involves processing steps that use additional chemical reagents and solvents.
Reference: International Council For Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline For Elemental Impurities Q3D(R2), April 2022 https://database.ich.org/sites/default/files/Q3D-R2_Guideline_Step4_2022_0308.pdf
Extracting palladium produces an estimated 3,800 kg CO2 equivalents per kg palladium, more than 500 times larger than cobalt, nickel, copper, and iron.
Reference: Philip Nuss and Matthew J. Eckelman “Life Cycle Assessment of Metals: A Scientific Synthesis,” PLoS ONE, 9 (2014): e101298 https://doi.org/10.1371/journal.pone.0101298
Pd
Co
Ni
Cu
Fe
Elements
4,000
3,500
3,000
2,500
2,000
1,500
1,000
500
0
Global Warming Potential (kg CO2 -eq/kg)
Co
Ni
Cu
Fe
10
8
6
4
2
0
Co
Ni
Cu
Fe
Though Pd-catalyzed cross coupling offers a relatively efficient route to forming new C—C and C—N bonds, palladium catalysis has several drawbacks related to its sustainability.
Palladium-catalyzed cross-coupling reactions help chemists form key bonds in active pharmaceutical ingredients (APIs).
Click on the structures to learn more
Venetoclax
Abemaciclib
Losartan
Losartan is an angiotensin II receptor blocker used to treat high blood pressure. It is one of the most prescribed medications in the world and its reported syntheses from Merck and Dow use a Pd-catalyzed Suzki Miyaura reaction
Reference: Robert D. Larson et al., “Efficient Synthesis of Losartan, A Nonpeptide Angiotensin II Receptor Antagonist,” J. Org. Chem. 59 (1994): 6391–6394 https://doi.org/10.1021/jo00100a048.
Losartan
Abemaciclib is a CDK inhibitor used to treat advanced or metastatic breast cancers. Reported syntheses from its originator, Eli Lilly and Company, include three palladium-catalyzed cross coupling reactions
Reference: Michael P. Carroll et al., “Development of an Improved Route for the Synthesis of an Abemaciclib Intermediate,” Org. Proc. Res. Dev. 23 (2019): 2549–2555 https://doi.org/10.1021/acs.oprd.9b00347; Michael P. Carroll et al., “Optimized Synthesis of an Abemaciclib Intermediate: Improved Conditions for a Miyaura Borylation/Suzuki Coupling Process,” Org. Process Res. Dev. 28 (2024): 4127–4136 https://doi.org/10.1021/acs.oprd.4c00381.
Abemaciclib
Venetoclax is used to treat leukemias and lymphomas in adults and is the first protein-protein interaction inhibitor approved for cancer treatment. Its reported process-scale synthesis from AbbVie includes two palladium-catalyzed cross coupling reactions
Reference: Yi-Yin Ku and Michael D. Wendt “Synthetic Routes for Venetoclax at Different Stages of Development,” in Complete Accounts of Integrated Drug Discovery and Development: Recent Examples from the Pharmaceutical Industry Volume 2, 1–25: ACS Symposium Series, 2019; Yi-Yin Ku and Michael D. Wendt “Development of a Convergent Large-Scale Synthesis for Venetoclax, a First-in-Class BCL-2 Selective Inhibitor,” J. Org. Chem. 84 (2019): 4814–4829 https://doi.org/10.1021/acs.joc.8b02750.
Venetoclax
Palladium-catalyzed cross-coupling reactions are vital to the pharmaceutical industry.
Pd (81.2%)
Ru (6.9%)
Cu (5.3%)
Ir (3.8%)
Rh (2.1%)
Mn (0.7%)
Frequency of catalytic metals and reaction types in API syntheses reported in OPR&D from 2017–2021.
81.2%
6.9%
5.3%
3.8%
2.1%
0.7%
Explore Pd in detail
Explore Pd in detail
Suzuki couplings and Miyaura borylations are some of the most common Pd-catalyzed cross-coupling reactions in API synthesis.
Frequency of catalytic metals and reaction types in API syntheses reported in OPR&D from 2017–2021.
Reference: Vittorio Farina, “How to Develop Organometallic Catalytic Reactions in the Pharmaceutical Industry,” Org. Proc. Res. Dev. 27 (2023): 831–846, https://doi.org/10.1021/acs.oprd.3c00086.
Suzuki coupling (28.6%)
Miyaura borylation (17.3%)
C—N coupling (9.8%)
Negishi coupling (5.3%)
C—H activation (3.7%)
Alkoxycarbonylation (3.7%)
Heck reaction (3.7%)
Sonogashira coupling (3%)
Others (6.1%)
17.3%
3.7%
3.7%
3.7%
3%
6.1%
5.3%
9.8%
28.6%
Back
Back
Reference: Vittorio Farina, “How to Develop Organometallic Catalytic Reactions in the Pharmaceutical Industry,” Org. Proc. Res. Dev. 27 (2023): 831–846, https://doi.org/10.1021/acs.oprd.3c00086.
Electrocatalysis
Electrocatalysis
Electrochemistry offers a promising route to make reduction and oxidation (“redox”) reactions more sustainable. Instead of relying on undesirable stoichiometric chemical redox reagents—which generate significant waste—electrochemical methods use electricity and reusable electrodes to transfer electrons.
Electrochemical mediators and catalysts help overcome challenges with electron transfer for many organic molecules. While examples of electrochemical transformations at API scale remain rare, improved reactor design and process optimization could lead to broader adoption.
LEARN MORE ABOUT Electrocatalysis
^
LEARN MORE ABOUT Electrocatalysis
^
Scaling Organic Electrosynthesis: The Crucial Interplay between Mechanism and Mass Transport
Synthetic Organic Electrochemistry: An Enabling and Innately Sustainable Method
Organic Electrosynthesis: From Laboratorial Practice to Industrial Applications
Photocatalysis
Photocatalysis
Photocatalysis uses light energy to access excited state reactivity. Photocatalysts have been used in a range of challenging reactions relevant to the pharmaceutical industry, including late-stage functionalization and [2+2] cycloadditions.
Though many photocatalysts use precious transition metals like Ir and Ru, organic photocatalysts and photocatalysts using more abundant metals like tungsten are available. Developing reactions with specialized flow reactors can improve their efficiency.
LEARN MORE ABOUT Photocatalysis
^
LEARN MORE ABOUT PHOTOCATALYSIS
^
Visible Light Photocatalysis: Applications and New Disconnections in the Synthesis of Pharmaceutical Agents
Photoredox Catalysis in Organic Chemistry
Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry
Biocatalysis
Biocatalysis
Biocatalysis is one of the most exciting opportunities for sustainable catalysis in the pharmaceutical industry.
Enzyme-based catalysts are made from inexpensive, renewable reagents, operate in green solvents, and—through engineering and directed evolution—can have exquisite selectivity. There are several exciting examples of biocatalysis used at scale for API synthesis.
However, developing biocatalysts can be time-consuming, making it challenging to use these catalysts in the fast-paced pharmaceutical industry.
LEARN MORE ABOUT BIOCATALYSIS
^
LEARN MORE ABOUT BIOCATALYSIS
^
Biocatalysis in the Pharmaceutical Industry: The Need for Speed The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development
The Evolving Landscape of Industrial Biocatalysis in Perspective from the ACS Green Chemistry Institute Pharmaceutical Roundtable
Other Green
Catalysis Strategies
Though palladium and other transition metals are among the most common catalysts used within the pharmaceutical industry, other classes are finding increased use and offer unique sustainability advantages.
Example of a palladium catalyzed cross-coupling reaction.
01: Introduction
01: Introduction
02: Solvents
02: Solvents
03: Carbon
03: Carbon
04: Catalysis
04: Catalysis
05: Waste
05: Waste
06: Progress
06: Progress