At TAPI, we are dedicated to advancing sustainable pharmaceutical manufacturing by harnessing the power of cutting-edge science—particularly biocatalysis. One of our recent successes exemplifies this commitment: the development of a scalable, environmentally responsible biocatalytic process for the production of a complex chiral intermediate used in the synthesis of Avacopan. This achievement not only overcomes long-standing challenges in stereoselective synthesis; it also demonstrates the broader potential of enzyme-based technologies to streamline pharmaceutical production.
By integrating biocatalysis into our development workflows, we offer innovative, greener alternatives to traditional chemical routes—delivering benefits in efficiency, selectivity, and sustainability. These capabilities are now a core part of our value proposition, both for our internal portfolio and for partners through our CDMO services. Whether optimizing existing processes or designing new synthetic pathways, we are helping to redefine what’s possible in pharmaceutical manufacturing through biocatalytic innovation.
The Challenge: Double Stereocontrol with High Yield and Low Waste
The synthesis of 2,3-disubstituted cyclic amines — especially with full control over two adjacent stereocenters — has historically been a significant challenge in API development. Traditional chemical synthesis routes for Avacopan’s (2R,3S)-2-arylpiperidine-3-carboxylate intermediate rely on diastereomeric crystallization, a process that discards nearly half of the material and yields only 42%.
We saw an opportunity to develop a cleaner, more efficient alternative. Inspired by the principles of green chemistry, our team sought a stereoselective, biocatalytic solution that could reduce waste and improve scalability.
The Solution: Enzyme-Catalyzed Amine-Imine Transformations
Through extensive enzyme screening, we developed two innovative routes using imine reductases (IREDs):
- Oxidative kinetic resolution of the racemic amine, followed by catalytic hydrogenation for enantiomer recovery — successfully scaled up to kg scale.
- Dynamic kinetic reduction using enantiocomplementary IREDs — demonstrated at lab scale, showing strong potential for further development.
These pathways hinge on the reversible imine-enamine tautomeric equilibrium, which allows for efficient recycling of undesired stereoisomers and high selectivity toward the desired (2R,3S)-configured intermediate.
Key Innovations
- Enzyme Selection and Cofactor Regeneration
We identified four commercial IREDs capable of enantioselective oxidation and two others for dynamic kinetic reduction. However, to make the process robust and scalable, we also needed an efficient system for cofactor regeneration.
Traditionally, NADPH oxidases (NOx) were used for this role but posed challenges due to their sensitivity to solvents. Our breakthrough came with the application of alcohol dehydrogenase (ADH) enzymes — specifically from Lactobacillus brevis — as a more stable and scalable alternative for cofactor regeneration. This was the first reported use of ADHs in IRED-catalyzed oxidations, marking a significant step forward in biocatalysis.
- High Selectivity and Improved Yields
Our enzymatic process achieved exceptional selectivity:
- Oxidative route: >99.5% ee and >99.9% de
- Reductive route: 98.3% ee and >99.9% de
The oxidative route also significantly improved overall yield. By coupling it with a catalytic hydrogenation recovery step, we reached 72% yield across cycles — a dramatic improvement over the 42% achieved by conventional crystallization.
- Scalable, Safe, and Sustainable
Safety and scalability were paramount. Unlike earlier methods using monoamine oxidases and hazardous reducing agents (like boranes), our enzymatic routes avoid incompatible chemicals. The oxidation process was safely scaled to kg levels, with a high space-time yield of 37.2 g/L/day — a strong metric for industrial viability.
In terms of sustainability, the use of biodegradable enzymes, mild conditions, and minimized waste supports our commitment to environmentally responsible API production.
A Model for Future Development
Our biocatalytic model provides a practical framework for innovation in pharmaceutical manufacturing, tackling issues that rise from a standard chemical synthesis approach:
- It illustrates how the stereo controlled synthesis of complex amines can be achieved efficiently using green chemistry, addressing a long-standing synthetic challenge.
- It expands the perceived role of ADHs by demonstrating their effectiveness in oxidation reactions, opening new avenues within biocatalysis.
- It highlights how enzyme-driven processes can achieve both economic scalability and environmental responsibility—two critical priorities for the industry.
Partnering for Innovation: CDMO Services at TAPI
This breakthrough in the synthesis of Avacopan API exemplifies how targeted innovation, grounded in green chemistry principles, can transform pharmaceutical manufacturing. With better yields, reduced environmental impact, and strong scalability, this process is not just a milestone for TAPI — it’s a glimpse into the future of sustainable use of biocatalysis in pharmaceutical manufacturing.
This achievement reflects more than scientific innovation—it demonstrates what’s possible when advanced technologies meet end-to-end CDMO support. At TAPI, we offer integrated CDMO services across every stage of development, from route scouting and process design to scale-up, GMP production, and commercial supply.
Our global network spans 13 manufacturing sites and 5 R&D centers, supported by ~450 scientists and a deep toolbox of enabling technologies—from biocatalysis and flow chemistry to particle engineering and ultrafiltration. Whether your program involves small molecules, peptides, oligonucleotides, fermentation products, or HPAPIs, we’re ready to tailor solutions that accelerate your success.
