Making API Synthesis Greener

The authors explain chemical transformations that are achievable through certain biocatalytic routes.
Sep 01, 2012
Volume 2012 Supplement, Issue 5

The pharmaceutical industry is under severe pressure to make its API processes greener, lower costs, minimize waste, and shorten existing syntheses. The need for economical, robust, scalable, and reliable processes for the synthesis of chiral APIs and intermediates has resulted in process chemists tuning their skills at the interface of chemistry and biology and embracing biocatalysts and biocatalytic processes in organic synthesis. This shift has resulted in biocatalysis becoming the workhorse of the chemists' toolbox for chiral chemistry.

FIgure 1: Possible transformations using biocatalysis (selectAZyme platform, Almac).
Why has there been a surge in the application of this green technology? The key difference in using biocatalysis today compared with 10 years ago is that now all the supporting technologies that can make a difference in enzyme development, such as bioinformatics, enzyme evolution, and high-throughput screening, allow for an efficient turnaround in process development and enzyme evolution. Libraries of enzymes in the form of screening panels that contain all the materials required to screen against a given substrate can be used as an efficient way to identify and use biocatalysts for a given process. For example, the biocatalysis group at Almac has developed the selectAZyme platform, a proprietary platform that consists of a range of enzyme types, including hydrolases, carbonyl reductases, transaminases, P450 monooxygenases, nitrile hydratases, and nitrilases, to provide access to a broad range of chiral compounds, such as acids, esters, alcohols, amines, and amides. Figure 1 illustrates typical transformations performed by the selectAZyme platform.

Figure 2: Example of a timeline for implementation of an enzyme platform (selectAZyme, Almac) involving enzyme selection, scale-up, and commercial manufacture.
The timeline for selection of a given biocatalyst, scale-up, and manufacture of a given product is similar to that of the timelines for conventional chemistry optimization and scale-up. Typical timelines are shown in Figure 2.

Biocatalysis at work

To illustrate the improvements in a synthesis that can be made using biocatalysis, take the example of Phase IIb compound in which nine steps of chemistry resulted in the formation of three chiral centers of a registered starting material with a global yield of 7.4%. The project was initiated with certain key objectives:

  • Increase productivity of the process > 50% kg/L/day
  • Achieve a > 20% reduction in waste
  • Remove expensive and toxic solvents
  • Remove heavy metals and subsequent contamination
  • Remove the necessity for specialized equipment (e.g., original synthesis used high-pressure hydrogenation)
  • Develop a process with consistent quality of product
  • Lower the cost per kilogram of product.

The original chemistry involved a myriad of steps, including a late-stage classical resolution using an expensive amine resolving agent and high-pressure hydrogenation using metal catalysis. The late-stage resolution resulted in large volumes having to be processed to step seven in the original synthesis. Almac's challenge was to make a scalable lower-volume route that had green and cost incentives for changing the process. Almac completed route invention, proof-of-concept demonstration, scale-up of hundreds of kilograms, and final commercial production of metric tons. The revised route consisted of five steps using three different selectAZyme enzymes with a global yield of 23.4%.

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