Comparison of a Batch and Flow Approach for the Lipase-Catalyzed Resolution of a Cyclopropanecarboxylate Ester, A Key Building Block for the Synthesis of Ticagrelor

Abstract

In this study a batch reactor process is compared to a flow chemistry approach for lipase catalysed resolution of the cyclopropyl ester (±)-3. (1R, 2R)-3 is a precursor of the amine (1R, 2S)-2 which is a key building block of the API ticagrelor. For both flow and batch operation, the biocatalyst could be recycled several times, whereas in the case of the flow process the reaction time was significantly reduced.2

Hydroxynitrile lyases covalently immobilized in continuous flow microreactors

“…[15][16][17][18][19][20][21][22] Flow systems are advantageous compared to batch operation as no catalyst separation step is required, the catalyst can easily be reused, higher productivities can be achieved and catalyst instability problems due to high shear forces are precluded. [23][24][25] Additionally, the microreactor technology provides a handle to tune reaction conditions, facile scale-out by parallelizing multiple units and process intensification or even automation. On top of that, process safety is improved by reduced reactor volumes and possibilities for in situ generation of hazardous substances.…”

Continuous flow biocatalysis

“…The use of enzymes wrapped in inert gauze “tea bags” allowed direct comparison of enzyme-based kinetic resolution in batch vs. continuous flow. 224 In this example, Turner and co-workers demonstrated a significant reduction in reaction times for the continuous flow lipase-catalyzed resolution of a cyclopropanecarboxylate ester. A 5.5 min residence time in a packed bed reactor housing Thermomyces lanuginosus lipase compared favourably to the batch reaction after 23 h. The authors cite a 64-fold improvement in space-time yield from 0.4 mmol /(L. h) in batch to 28.2 mmol /(L. h) in continuous flow.…”

“…Continuous flow lipase resolution of a cyclopropane carboxylate ester in a packed bed reactor for a total residence time of 40 min. 224 …”

Flow Biocatalysis: A Challenging Alternative for the Synthesis of APIs and Natural Compounds

“…While, to the best of our knowledge, no scale-up for the biosynthesis of pharmaceutically relevant terpenes has been reported yet, immobilized enzymes have already found several applications in the synthesis of different APIs and API precursors, even on a large scale. For instance, Turner et al employed this approach for the synthesis of a ticagrelor building block [132]. Ticagrelor ( 9) is one of the world's leading medicaments for the treatment of acute coronary symptoms, which presents (1R,2S)cyclopropylamine (8) as its main core (Scheme 7).…”