Reducing the Complexity of Commercial-Scale Amide Formation

It is well known that amide-formation chemistry can be inefficient and warrants further investigation. This issue has been addressed in the chemical literature, most recently in a study by the American Chemical Society Green Chemistry Institute Roundtable that is particularly relevant to pharmaceutical synthesis (1). The study found that, out of a random selection of drug candidates, amide-bond formation was used in the synthesis of 84% percent of drug candidates.

Partnering for commercial development
The only theoretical by-product of amide formation is water, but examples of this type of reaction are incredibly rare, according to Barrie Rhodes, director of technology development for the CMO Aesica. “Frequently,” he says, “commercial-scale amide syntheses for pharmaceutical manufacture require overly complex stoichiometric coupling agents or reagents.”

Aesica has set as goals the reduction of this complexity in conventional amide syntheses and the development of more sustainable (green) chemical transformations that are practical on a commercial scale. In the pursuit of those goals, the company has partnered with the University of Nottingham for the commercial development of alternative methods in amide-bond synthesis. The partnership’s aim is to revolutionize traditional amide-formation techniques by generating alternative methods for amide-bond formation that will be more eco-friendly and chemically versatile, according to Rhodes.

The new approach should be commercially available to Aesica customers later in 2013. The company is actively seeking commercial opportunities to work with potential compounds that could benefit from the novel technology. “We envisage this new development helping pharmaceutical companies that encounter problems with amide synthesis, and due to the utilization of more sustainable reagents, production costs will be lowered while chemical yields will be increased,” Rhodes notes.

The benefits of DABAL

The initial chemistry was developed in 2005 by Simon Woodward, professor of synthetic organic chemistry at the University of Nottingham in the United Kingdom. The coupling reagent of interest is DABAL-Me3, which is an adduct of trimethylaluminum and DABCO (1,4-diazabicyclo[2.2.2]octane). Unlike trimethylaluminum which is very pyrophoric, DABAL-Me3 is a free-flowing solid that can be handled in air (2). In addition to its use in amide-bond formation (3), DABAL-Me3 has been used for the methylation of aldehydes and imines (4, 5), the methylation of aryl and vinyl halides (6), and conjugate additions to enones (7).

With respect to amide bond-formation, DABAL-Me3 can be used to generate amides from unactivated esters and amines that, with conventional routes, require the use of trimethylaluminum or diisobutylaluminum hydride (3). In addition, reactions with DABAL-Me3 tolerate various functional groups, including acetals, alcohols, alkenes, alkynes, ethers, nitriles, hindered esters, and BOC groups. Stereocenters in non-peptidic species are not racemized. Importantly, the preparation of aromatic and aliphatic amides can generally be carried out in an air atmosphere. It should be noted that the rate of the reaction can be accelerated with the use of microwave irradiation, and products can be isolated in 51–99% yield in 8–16 minutes (8).

Preliminary studies on DABAL-Me3 at the university were undertaken using funds awarded by the Engineering and Physical Sciences Research Council (EPSRC) under the Research Development (Pathways to Impact) Funding Scheme. “Since realizing the initial development of our coupling agent in 2005, one of our goals has been to see this novel technology used in larger-scale industrial environments,” remarks Woodward. “We look forward to collaborating with Aesica and seeing the full commercial potential of this novel technology in API manufacture,” he adds.

The chemistry that Aesica is commercializing is more atom-efficient than some other types of amide-formation chemistry and offers a novel synthetic route to make amides from both esters and carboxylic acids, according to Rhodes. Some of the technology is in the very early stages of development and will likely be patentable, so Rhodes is unable to disclose any additional details. He does note that the chemistry is generally applicable and flexible in terms of its ability to prepare amides, and, therefore, any API that either contains amide bonds or goes through an amide intermediate during its synthesis could benefit from this technology. In addition, Rhodes believes that the new amide production technology will enable cheaper and simpler routes to market for many compounds.

Open innovation opportunities
This partnership with the University of Nottingham is the Aesica Innovation Board’s (AIB) fourth with an academic institution in less than six months, according to Rhodes. The AIB was established to help bridge the growing R&D gap by identifying early-stage technologies for development into commercial applications.

“The University of Nottingham is renowned for its excellence in chemistry research and has a strong background in green and sustainable chemistry. That, coupled with its interest in open innovation (in that risk and reward are shared) as a model, has been very beneficial. Effectively, the university has the expertise in terms of the technology while Aesica brings its expertise in terms of commercialization and a global network in the pharmaceutical industry,” Rhodes explains.

The start of something good
The partnership for the development of amide bond-formation chemistry is just the start of a hopefully long-term collaboration between Aesica and the university, according to Rhodes. The collaboration builds upon announced plans by the University of Nottingham to establish a Center of Excellence for Sustainable Chemistry, which will be partly funded by an investment from the Higher Education Funding Council for England (HEFCE) UK Research Partnership Investment Fund. The Center aims to form creative partnerships with innovative companies to develop new chemical-based technologies that minimize environmental impact and are both energy and resource efficient, according to a university press release.
“As Aesica further enhances its innovation program, we will seek to develop new technologies, not only with the University of Nottingham, but with other academic institutions as well, in the fields of both API and formulated products manufacture,” concludes Rhodes.

References
1. D. J. C Constable et al., Green Chem. 9 (5), 411-420 (2007).
2. S. Woodward, Synlett. 10, 1490-1500 (2007).
3. A. Novak et al., Tetrahedron Lett. 47 (32), 5767-5769 (2006).
4. B. Kallolmay et al., Angew. Chem. Int. Ed. 44 (15), 2232-2234 (2005).
5. Y. Mata, J. Org. Chem. 71 ( 21), 8159-8165 (2006).
6. T. Cooper et al., Adv. Synth. Catal. 348 (6), 686-690 (2006).
7. A. Alexakis et al., Chem. Commun. 22, 2843-2845 (2005).
8. D. Glynn et al., Tetrahedron Lett. 49 (39), 5687-5688 (2008).