Use of ω-Transaminase Enzyme Chemistry in the Synthesis of a JAK2 Kinase Inhibitor

Frodsham, Lianne; Golden, Michael; Hard, Susan; Kenworthy, Martin N.; Klauber, David J.; Leslie, Kevin; MacLeod, Claire S.; Meadows, Rebecca E.; Mulholland, Keith R.; Reilly, Julie; Squire, C.J.; Tomasi, Simone; Watt, Denise; Wells, Andrew S.

doi:10.1021/op400133d

Cited by 50 publications

(36 citation statements)

References 8 publications

(16 reference statements)

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“…A TA has also been used in the manufacture of an inhibitor of JAK2 kinase, which could be used for the treatment of idiopathic myelofibrosis and polycythaemia rubra vera (Frodsham et al 2013). The bottleneck in the scale-up of the known chemical synthesis route was unwanted epimerisation of the key chiral amine coupling partner, which required chiral chromatography, an undesirable process from the industrial point of view.…”

Section: Pilot and Large-scale Processesmentioning

confidence: 99%

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Recent developments in biocatalysis beyond the laboratory

et al. 2015

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Recent developments in biocatalysis, where implementation beyond the laboratory has been demonstrated, are explored: the use of transglutaminases to modify foods, reduce allergenicity and produce advanced materials, lipases for biodiesel production, and transaminases for biochemical production. The availability and application of enzymes at pilot and larger scale opens up possibilities for further improvements of biocatalyst-based processes and the development of new processes. Enzyme production, stability, activity, re-use, and product retrieval are common challenges for biocatalytic processes. We explore recent advances in biocatalysis within the process chain, such as protein engineering, enzyme expression, and biocatalyst immobilization, in the context of these challenges.

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Section: Pilot and Large-scale Processesmentioning

confidence: 99%

“…The application of V. fluvialis TA in the manufacture of a JAK2 kinase inhibitor of (Frodsham et al 2013,)was followed by demonstration of the activity of whole-cell biocatalyst with high substrate load and a yield of 66 % and [99 % e.e. .…”

Section: Ta-based Process Designmentioning

confidence: 99%

Recent developments in biocatalysis beyond the laboratory

et al. 2015

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“…This means that at first glance such a process is not only economically infeasible, but indeed far away from the targets which would be required for economic industrial exploitation [3]. Interestingly, in common with many other biocatalytic reactions, via a combination of protein engineering and clever use of reaction, reactor and process engineering, a cost effective process can be established (see Figure 3), and excellent precedent has already been set with the synthesis of sitagliptin by Merck and Co (USA) [42,43], and other examples by Cellgene/Cambrex (USA and Sweden) [44] and Astra Zeneca (UK and Sweden) [45].…”

Section: Transaminasesmentioning

confidence: 99%

Biocatalytic process development using microfluidic miniaturized systems

Krühne

Heintz

Ringborg

et al. 2014

Green Processing and Synthesis

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Abstract:The increasing interest in biocatalytic processes means there is a clear need for a new systematic development paradigm which encompasses both protein engineering and process engineering. This paper argues that through the use of a new microfluidic platform, data can be collected more rapidly and integrated with process modeling, can provide the basis for validating a reduced number of potential processes. The miniaturized platform should use a smaller reagent inventory and make better use of precious biocatalysts. The EC funded BIOINTENSE project will use ω-transaminase based synthesis of chiral amines as a test-bed for assessing the viability of such a high throughput biocatalytic process development, and in this paper, such a vision for the future is presented.

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“…These molecules are valuable building blocks for the preparation of APIs including antiarrhythmics (e. g. vernakalant), antibiotics (e. g. moxifloxacin), anti-epilepsy agents (e. g. levetiracetam and pregabalin), and antidiabetics (e. g. sitagliptin). [6] Among the examples of ATAs application on an industrial scale, [7][8][9][10][11][12] a milestone was placed by Merck and Codexis 10 years ago with the synthesis by transamination of sitagliptin (Januvia®), the first marketed oral antihyperglycemic drug belonging to the gliptin family. This bioprocess allowed the replacement of a high-pressure rhodium-catalyzed asymmetric enamine hydrogenation step by applying a highly engineered ATA variant.…”

Section: Introductionmentioning

confidence: 99%

Use of Immobilized Amine Transaminase from Vibrio fluvialis under Flow Conditions for the Synthesis of (S)‐1‐(5‐Fluoropyrimidin‐2‐yl)‐ethanamine

et al. 2020

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We report on the covalent immobilization of the (S)‐selective amine transaminase from Vibrio fluvialis (Vf‐ATA) and its use in the synthesis of (S)‐1‐(5‐fluoropyrimidin‐2‐yl)‐ethanamine, a key intermediate of the JAK2 kinase inhibitor AZD1480. Immobilized Vf‐ATA on glyoxyl‐agarose (activity recovery: 30 %) was used in a packed‐bed reactor to set‐up a continuous flow biotransformation coupled with a straightforward in‐line purification to circumvent the 2‐step process described in literature for the batch reaction. The newly developed biotransformation was run in a homogeneous system including dimethyl carbonate as a green co‐solvent. Optically pure (S)‐1‐(5‐fluoropyrimidin‐2‐yl)‐ethanamine (ee >99 %) was isolated in 35 % yield.

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Use of ω-Transaminase Enzyme Chemistry in the Synthesis of a JAK2 Kinase Inhibitor

Abstract: ω-Transaminase enzyme chemistry provides an excellent methodology to build synthetically useful chiral amines from their corresponding ketones. An application of this methodology, providing a long-term commercial manufacturing route to a JAK2 kinase inhibitor, is reported herein.

Cited by 50 publications

References 8 publications

Recent developments in biocatalysis beyond the laboratory

Recent developments in biocatalysis beyond the laboratory

Biocatalytic process development using microfluidic miniaturized systems

Use of Immobilized Amine Transaminase from Vibrio fluvialis under Flow Conditions for the Synthesis of (S)‐1‐(5‐Fluoropyrimidin‐2‐yl)‐ethanamine

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