Biocatalysis for Industrial Process Development

Meadows, Rebecca E.; Mulholland, Keith R.; Schürmann, Martin; Golden, Michael; Kierkels, Hans; Meulenbroeks, Elise; Mink, Daniel; May, Oliver; Squire, C.J.; Straatman, Harrie; Wells, Andrew S.

doi:10.1002/9781118697856.ch09

Cited by 5 publications

(10 citation statements)

References 16 publications

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“…The enzymatic synthesis of ( S )‐1‐(5‐fluoropyrimidin‐2‐yl)‐ethanamine ( 3 ) was performed by using Vf ‐ATA immobilized on glyoxyl‐agarose in view of transferring the bioconversion from batch to a flow system. As a preliminary approach, the amination of the non‐fluorinated ketone was carried out with the aim of exploring the reaction conditions, testing the feasibility of the bioconversion with the newly immobilized enzyme, and setting‐up a downstream process that might be more straightforward than that described in literature . ( S )‐MBA ( 2 ) was selected as the amino donor because it was also used in the activity assay and it is commonly used as benchmark substrate with ( S )‐selective transaminases (both in batch and in flow systems) .…”

Section: Resultsmentioning

confidence: 99%

“…( S )‐MBA ( 2 ) was selected as the amino donor because it was also used in the activity assay and it is commonly used as benchmark substrate with ( S )‐selective transaminases (both in batch and in flow systems) . Moreover, ( S )‐MBA is the amino donor used in the synthesis of ( S )‐1‐(5‐fluoropyrimidin‐2‐yl)‐ethanamine reported by Meadows et al . The reaction was performed at pH 8, according to the enzymatic assay conditions (see also Figure S2).…”

Section: Resultsmentioning

confidence: 99%

“…Another example of a pre‐industrial ATA‐catalyzed process was developed by AstraZeneca for the production of ( S )‐1‐(5‐fluoropyrimidin‐2‐yl)‐ethanamine ( 3 , Scheme A), a key intermediate in the synthesis of the JAK2 kinase inhibitor AZD1480, a molecule targeting idiopathic myelofibrosis and polycythaemia rubra vera . The well‐known ATA from Vibrio fluvialis ( Vf ‐ATA) was selected among 60 transaminases; process conditions were optimized on a gram scale starting from the fluorinated ketone ( 1 ) and using ( S )‐α‐methylbenzylamine ( 2 , ( S )‐MBA) as the amino donor.…”

Section: Introductionmentioning

confidence: 99%

“…The reaction was performed in a biphasic system by using toluene to pull out the co‐product acetophenone ( 4 ). The continuous extraction was necessary to shift reaction equilibrium and to avoid product inhibition effects . Since the synthesized amine is water soluble, the purification protocol relies on the conversion of the amine to the corresponding Boc‐derivative followed by extraction and precipitation of the amine hydrochloride with HCl in iso ‐propanol.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“… Comparison of predicted and measured conversions with a 1:1 donor/acceptor reaction. Data were extracted from i) Gundersen et al.,13 ii) Gundersen et al.,11 iii) Tufvesson et al.,12 iv) Fesko et al.,14 and v) Meadows et al 15. The line represents a match between experimental and predicted quantum mechanics (QM) values.…”

Section: Validation Of the Methodsmentioning

confidence: 99%

A Practical and Fast Method To Predict the Thermodynamic Preference of ω‐Transaminase‐Based Transformations

et al. 2015

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As imple, easy-to-use, and fast approach method is proposed and validated that can predict whether atransaminase reaction is thermodynamically unfavourable. This allowed us to deselect, in the present case, at least 50% of the reactions because they werethermodynamically unfavourable as confirmed by experiment. Once al arger data base is established, in silico screening of severaln ew reactions (new target molecules) can easily be performed each day.w-Transaminases (EC 2.6.1.18)h ave overt he last decade gained significant interest as biocatalysts to produce enantiopure chirala mines owing to their highs electivity and broad substrate repertoire. If ap rochiral amino acceptor undergoes an aminotransferase reaction with an aminod onor,t he reaction then yields an amine product and ak eto co-product. wTransaminases can either be applied in thes ynthetic direction, the main focus of this communication, or in kinetic resolution.[1] This provides au seful way to produce chiral amines for pharmaceuticals or fine chemicals, as demonstrated by several commercial applications. [2,3] However,i np ractices everal challenges are often encountered during process development such as enzyme inhibition, poor substrate binding,a nd/or unfavorable thermodynamics. To shift the equilibrium towards product formation, one hast o, in practice, often add an excess amount of the amino donor and/or remove the co-product.Ac ommon solution is to add an excess amount of the amine donor; [4] however,t he isolation of an amine product from ar eaction mixture still containing al arge excess amount of ac hemically very similara mino donor represents am ajor downstream processing challenge. Another possible solution is to remove the co-product, either physically or chemically.A simple strategy used if the co-product is volatile is to evaporate it, [5] which thus physically removesi tf rom the reaction. Using isopropylamine as the aminodonori na ne xcess amount under reduced pressure, for instance, usually resultsi nh igh conversionst owards the target product, [3,5] but it can also lead to the formation of aS chiff base of the amino donor with the acceptork etone and low atom efficiency on the amino donor side or the requirement of large amino donor recycling streams. Chemical strategies such as enzymatic cascades [6] and the use of amine donors, which produce ac o-product that undergoes aspontaneous reaction, [7,8] both efficientlyc onvert the co-product into another compound. The successfully applied strategyt or emove pyruvic acid as ac o-producto riginating from the amino-donor alanine( using enzymatic cascades by employing lactate dehydrogenasec oupled to glucosed ehydrogenase) generally works well [6] but comesw itht he disadvantage of having to produce or purchase at least three enzymes insteado fo nly one transaminase.Whereas such protocols may be successful, they are not always applicable on large scale and they always incura dditional time in process development and additional costs for the process itself. An alternative strategy could ...

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Asymmetric Synthesis of Chiral Halogenated Amines using Amine Transaminases

2018

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Amine transaminases (ATAs) are versatile and industrially relevant biocatalysts that catalyze the transfer of an amine group from a donor to an acceptor molecule. Asymmetric synthesis from a prochiral ketone is the most preferred route to the desired amine product, as it is obtainable in a theoretical yield of 100 %. In addition to the requirement of active and enantioselective ATAs, the choice of a suitable amine donor is also important to save costs and to avoid additional enzymes to shift the equilibrium and/or to recycle the cofactors. In this work, we identified suitable (R)‐ and (S)‐ATAs from Aspergillus fumigatus and Silicibacter pomeroyi, respectively, to afford a set of halogen‐substituted derivatives of brominated or chlorinated 1‐phenyl‐2‐propanamine, 4‐phenylbutan‐2‐amine, and 1‐(3‐pyridinyl)ethanamine. Optimization of the donor–acceptor ratio enabled application of isopropylamine as an amine donor, which resulted in high conversions and amines with 73–99 % ee.

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Biocatalysis for Industrial Process Development

Cited by 5 publications

References 16 publications

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

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

A Practical and Fast Method To Predict the Thermodynamic Preference of ω‐Transaminase‐Based Transformations

Asymmetric Synthesis of Chiral Halogenated Amines using Amine Transaminases

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