Chemical synthesis can be summarized as the manipulation of chemical bonds. The process is essential to many manufacturing processes, but can present tough challenges. Catalyzed reactions offer one potential solution and broadly fall into two categories: heterogeneous and homogeneous. They differ in the phase of the catalyst and the reaction medium; heterogeneous corresponds to different phases, homogenous corresponds to the same phase. Each type of catalysis has its own inherent advantages, and both can be used depending on the chemistry. To an organic chemist, it comes as no surprise that catalysis is important, offering the ability to shorten reaction times, often under more economically viable reaction conditions, while ensuring the formation of appropriate geometries. Typically, any non-catalyzed synthetic process is achieved by carrying out a reaction, followed by purification and isolation steps. The process is then repeated until the desired product is obtained. Catalysis has the potential to streamline the process by opening alternative reaction pathways or overcoming additional purification or isolation steps.
Because of its proven history in fine chemical applications, catalysis is being increasingly adopted in the pharma industry for the production of APIs. In my view, there are two notable reactions that have revolutionized the synthesis of small molecule pharmaceuticals. First, and perhaps the most significant, is the cross-coupling reaction, which allows new carbon-carbon bonds to be precisely forged. The most commonly used cross-coupling reactions are carried out with palladium-based transition metal complexes as catalysts, using the Nobel Prize winning Suzuki and Heck reaction cycles. These two catalyzed reaction cycles are similar in concept: a catalyst mediates the joining of two organic reagents to make new carbon-carbon bonds – typically a difficult but essential step in any synthetic process. Though there are several alternatives, the key differentiator of using cross-coupling reactions is the precise nature of carbon bond formation available. Although cross coupling is used for a variety of reactions today, its scope was limited when it was first introduced. In the Suzuki reaction, for example, only aryl groups could be tolerated initially, which fundamentally limited the scope of potential pharmaceutical products. However, over the years, metallurgical research has resulted in the extension of tolerated functional groups through the broadening of our chemical understanding. Nowadays, the Suzuki reaction can be readily applied to aryl, alkenyl and alkynyl compounds (1) – a significant advance, as pharmaceutical synthesis involves many diverse functional groups. The second example of where catalysis has revolutionized synthesis is ester hydrogenation – another essential chemical conversion process that splits an ester molecule into two alcohol products. Alcohol functional groups are common components of API materials, so ester hydrogenation is a viable route for drug component synthesis. However, prior conversions relied on metal hydride catalysts, which generate significant material waste and require time-consuming workup procedures, making them unfavorable for industrial applications.
To increase atom efficiency and achieve a more selective method of ester hydrogenation, Gusev catalysts are a good option. The Gusev catalyst, devised by Dmitry Gusev in 2013 (2), is a simple ruthenium metal complex (referred to as Ru-SNS) that is capable of selective conversion of esters into useful alcohol chemicals. The Gusev catalyst offers increased chemoselectivity (the selectivity for reacting at certain chemical sites), and is capable of achieving conversion rates of 90 percent for certain benchmarked esters (3). Recent years have seen unprecedented levels of challenge and competition in the pharma marketplace. The industry must seek out ways to reduce the costs of R&D and manufacture. Currently, there is much focus on biologics and emerging cell therapies as the future of medicine. But small molecule drugs will always have a significant role to play, and the introduction of catalysts can help reduce manufacturing costs (4). Catalysis has the potential to streamline any chemical process and, when applied to the pharma industry, can help avoid the production of waste, while facilitating faster API synthesis.
Newsletters
Receive the latest analytical science news, personalities, education, and career development – weekly to your inbox.
References
- AJ Lennox and GC Lloyd-Jones, “Selection of boron reagents for Suzuki-Miyaura coupling,” Chem Soc Rev, 43, 412-413 (2014). PMID: 24091429. D Spasyuk, S Smith and DG Gusev, “Replacing Phosphorus with Sulfur for the Efficient Hydrogenation of Esters,” Angew Chem Int Ed Eng., 52, 253-2542 (2013). PMID: 23355424. J Pritchard et al., “Heterogeneous and homogeneous catalysis for the hydrogenation of carboxylic acid derivatives: history, advances and future directions,” Chem Soc Rev, 44, 3808-3833 (2015). PMID: 25941799. C Bernard, “Challenges in catalysis for pharmaceuticals and fine chemicals”, Platinum Metals Rev, 52, 110-113 (2008).
